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Female Hormone Replacement Therapy
Updated: 08/26/2004


[Effectiveness of interferon, glycyrrhizin combination therapy in patients with chronic hepatitis C].

Abe Y, Ueda T, Kato T, et al.

Nippon Rinsho. 1994 Jul; 52(7):1817-22.

SNMC (stronger Neominophagen C), whose active component is glycyrrhizin (a saponin extracted from licorice) has been utilized to improve the liver function in Japan. To assess the effectiveness of interferon (IFN), SNMC combination therapy in patients, who did not respond to IFN therapy alone, we investigate 28 patients with histology of CAH 2B at 12 weeks after IFN administration. 15 patients received IFN alone continuously (group A), and 13 patients received IFN with SNMC (group B) for 12 weeks thereafter. Normalization of serum ALT level was observed in 33.3% of group A and in 64.3% of group B. Disappearance of serum HVC RNA was 13.3% in group A and 38.5% in group B. But these data were not significant statistically. Histological improvement was not significant, between group A and B by Knodel's HAI score, but reversal of histological grade (Europe classification) was noted more frequently in group B. A case of posttransfusion hepatitis type C, exacerbated by IFN therapy is reported. HLA class I antigen was strongly expressed in the liver tissue after administration of IFN. In this case, potentiation of cellular immunity was thought to be the cause of the exacerbation and IFN, SNMC combination therapy was useful in improving liver function

Nutritional factors in the etiology of the premenstrual tension syndromes.

Abraham GE.

J Reprod Med. 1983 Jul; 28(7):446-64.

The premenstrual symptom complex many women experience in a moderate to severe form can be divided into four subgroups. Because there is more than one syndrome and nervous tension is one of the most common symptoms, the term premenstrual tension syndromes (PMTS) is used. The most common subgroup, PMT-A, consists of premenstrual anxiety, irritability and nervous tension, sometimes expressed in behavior patterns detrimental to self, family and society. Elevated blood estrogen and low progesterone have been observed in this subgroup. Administration of vitamin B6 at doses of 200-800 mg/day reduces blood estrogen, increases progesterone and results in improved symptoms under double-blind conditions. Women in this subgroup consume an excessive amount of dairy products and refined sugar, and progesterone may be of value in them. The second-most-common subgroup, PMT-H, is associated with symptoms of water and salt retention, abdominal bloating, mastalgia and weight gain. The severe form of PMT-H is associated with elevated serum aldosterone. Vitamin B6 at high dosage suppresses aldosterone and results in diuresis and clinical improvement. Vitamin E helps the breast symptoms. Methylxanthines and nicotine should be curtailed and sodium limited to 3 gm/day. PMT-C is characterized by premenstrual craving for sweets, increased appetite and indulgence in eating refined sugar followed by palpitation, fatigue, fainting spells, headache and sometimes the shakes. PMT-C patients have increased carbohydrate tolerance and low red-cell magnesium. Adequate magnesium replacement results in improved glucose tolerance tests and decreased PMT-C symptoms. Deficiency of the prostaglandin PGE1 may also be involved in PMT-C. PMT-D is the least common but most dangerous because suicide is most frequent in this subgroup. The symptoms are depression, withdrawal, insomnia, forgetfulness and confusion. In ten PMT-D patients the mean blood estrogen was lower and the mean blood progesterone higher than normal during the midluteal phase. Elevated adrenal androgens are observed in some hirsute PMT-D patients. Two PMT-D patients with normal blood progesterone and estrogens had high lead levels in hair tissue and chronic lead intoxication. This subgroups needs careful medical attention when the symptoms are severe. Therapy should be individualized according to the results of the evaluation

Efficacy of ipriflavone in established osteoporosis and long-term safety.

Agnusdei D, Bufalino L.

Calcif Tissue Int. 1997; 61 Suppl 1:S23-S27.

Ipriflavone (i.p.), an isoflavone derivative, is currently used in several countries for prevention and treatment of osteoporosis. Recently, 149 elderly, osteoporotic women (65-79 years) with prevalent vertebral fractures were enrolled in two Italian, multicenter, double-blind, 2-year studies. Women were randomly allocated to receive either oral i.p. (200 mg T.I.D. at meals) or matching placebo, plus 1 g oral calcium daily. One hundred eleven subjects completed the 2-year treatment period. A significant increase in forearm bone mineral density (BMD), measured by dual photon absorptiometry (DPA), was obtained after i.p. treatment. Women receiving the placebo showed only a limited bone loss during the treatment period, probably due to calcium supplement; however, a significant between-treatment difference was obtained in both studies. Urinary hydroxyproline was significantly decreased in i.p.-treated patients, suggesting a reduction in bone turnover rate. A reduction of incident vertebral fractures was observed in i.p.-treated women compared with control subjects. A significant improvement of bone pain and mobility has also been pointed out in one of the studies. To date, 2769 patients have been treated with i.p., for a total of 3132 patient/years, in 60 clinical studies performed in Italy, Japan, and Hungary and reviewed for long-term safety assessment. The incidence of adverse reactions in ipriflavone-treated patients (14.5%) was similar to that observed in subjects receiving the placebo (16.1%). Side effects were mainly gastrointestinal. Few patients presented reversible modifications of laboratory parameters. The data from the above studies show that long-term treatment with i.p. may be considered safe, and may increase bone density and possibly prevent fractures in elderly patients with established osteoporosis

A double blind, placebo-controlled trial of ipriflavone for prevention of postmenopausal spinal bone loss.

Agnusdei D, Crepaldi G, Isaia G, et al.

Calcif Tissue Int. 1997 Aug; 61(2):142-7.

One hundred ninety-eight postmenopausal women (aged 50-65 years) with vertebral bone density (VBD) 1 SD below the mean value for normal, age-matched, postmenopausal subjects were enrolled in six Italian centers and 134 completed 2 years of treatment. All subjects were randomly allocated to a 2-year treatment with oral ipriflavone (200 mg t.i.d.) or a matching placebo, according to a double-blind, parallel group design. All patients also received an oral daily calcium supplement of 1 g as calcium carbonate. VBD and markers of bone turnover were measured at baseline, and every 6 months. A complete routine analysis of liver and kidney functions along with hematological parameters were measured before and at the end of treatment period. The valid completers analysis showed a significant increase of VBD in ipriflavone-treated women with average percent changes of +1.4 after 1 year, and +1% at the end of treatment period (P < 0.05). The placebo group presented a significant decrease of VBD after 2 years of treatment (P < 0.05). The difference between treatments was significant (P < 0.01). The intention to treat analysis confirmed the significant decrease of VBD in the placebo group, with no changes in ipriflavone-treated women. Skeletal ALP significantly decreased in ipriflavone-treated women (P < 0.05). Serum BGP and urine HOP/Cr showed a significant decrease only in ipriflavone-treated women, suggesting an inhibitory effect on bone turnover rate. Adverse reactions, mainly gastrointestinal, occurred to a similar extent in the two treatment groups. The evaluation of patients' compliance, assessed by residual tablets count, revealed a drug intake of more than 80% after 2 years in 92.5% and 92.8% of patients treated with ipriflavone or placebo, respectively. This study demonstrates that ipriflavone can prevent bone loss in postmenopausal women with low bone mass

Ipriflavone in the treatment of postmenopausal osteoporosis: a randomized controlled trial.

Alexandersen P, Toussaint A, Christiansen C, et al.

JAMA. 2001 Mar 21; 285(11):1482-8.

CONTEXT: Data on the efficacy and safety of ipriflavone for prevention of postmenopausal bone loss are conflicting. OBJECTIVES: To investigate the effect of oral ipriflavone on prevention of postmenopausal bone loss and to assess the safety profile of long-term treatment with ipriflavone in postmenopausal osteoporotic women. DESIGN AND SETTING: Prospective, randomized, double-blind, placebo-controlled, 4-year study conducted in 4 centers in Belgium, Denmark, and Italy from August 1994 to July 1998. PARTICIPANTS: Four hundred seventy-four postmenopausal white women, aged 45 to 75 years, with bone mineral densities (BMDs) of less than 0.86 g/cm(2). INTERVENTIONS: Patients were randomly assigned to receive ipriflavone, 200 mg 3 times per day (n = 234), or placebo (n = 240); all received 500 mg/d of calcium. MAIN OUTCOME MEASURES: Efficacy measures included spine, hip, and forearm BMD and biochemical markers of bone resorption (urinary hydroxyproline corrected for creatinine and urinary CrossLaps [Osteometer Biotech, Herlev, Denmark] corrected for creatinine), assessed every 6 months. Laboratory safety measures and adverse events were recorded every 3 months. RESULTS: Based on intent-to-treat analysis, after 36 months of treatment, the annual percentage change from baseline in BMD of the lumbar spine for ipriflavone vs placebo (0.1% [95% confidence interval (CI), -7.9% to 8.1%] vs 0.8% [95% CI, -9.1% to 10.7%]; P =.14), or in any of the other sites measured, did not differ significantly between groups. The response in biochemical markers was also similar between groups (eg, for hydroxyproline corrected for creatinine, 20.13 mg/g [95% CI, 18.85-21.41 mg/g] vs 20.67 mg/g [95% CI, 19.41-21.92 mg/g]; P =.96); urinary CrossLaps corrected for creatinine, 268 mg/mol (95% CI, 249-288 mg/mol) vs 268 mg/mol (95% CI, 254-282 mg/mol); P =.81. The number of women with new vertebral fracture was identical or nearly so in the 2 groups at all time points. Lymphocyte concentrations decreased significantly (500/microL (0.5 x 10(9)/L]) in women treated with ipriflavone. Thirty-one women (13.2%) in the ipriflavone group developed subclinical lymphocytopenia, of whom 29 developed it during ipriflavone treatment. Of these, 15 (52%) of 29 had recovered spontaneously by 1 year and 22 (81%) of 29 by 2 years. CONCLUSIONS: Our data indicate that ipriflavone does not prevent bone loss or affect biochemical markers of bone metabolism. Additionally, ipriflavone induces lymphocytopenia in a significant number of women

Topical progesterone cream has antiproliferative effect on estrogen-stimulated endometrium.


Obstet Gynecol. 2001;(97(4, Suppl. 1)):S10.

The influence of dietary protein and carbohydrate on the principal oxidative biotransformations of estradiol in normal subjects.

Anderson KE, Kappas A, Conney AH, et al.

J Clin Endocrinol Metab. 1984 Jul; 59(1):103-7.

Dietary protein, when substituted for carbohydrate or fat, can increase cytochrome P-450-dependent drug oxidation rates in humans. Endogenous estrogens, as well as drugs, are also metabolized by cytochrome P-450 and other enzymes in the hepatic endoplasmic reticulum. Therefore, it was of interest to determine whether variations in diet can alter the major metabolic pathways for estrogens, as assessed by radiometric methods. Eight normal men were fed a high protein diet (44% of calories as protein, and 35% as carbohydrate for 2 weeks), followed by a high carbohydrate diet (70% of calories as carbohydrate and 10% as protein) for an additional 2 weeks. The fat and total energy contents of the two diets were equal. The percent oxidation of [2-3H]estradiol, measured as 3H2O released, which is an in vivo measure of 2-hydroxylation of endogenous estrogen, was greater in all eight men during the high protein dietary period than during the high carbohydrate dietary period (44 +/- 3% and 33 +/- 3%, respectively, means +/- SE, P less than 0.005). In contrast, 16 alpha-hydroxylation of estrogen, as measured using [16 alpha-3H]estradiol, did not change significantly. Our findings demonstrate that dietary components can alter estradiol oxidation in humans and that the 2- and 16 alpha-hydroxylases for estrogen are under separate regulatory control. The influences of specific nutrients on estrogen metabolism may have potential significance for diseases in which these hormones may play a role in clinical expression

Effects of soy isoflavones on atherosclerosis: potential mechanisms.

Anthony MS, Clarkson TB, Williams JK.

Am J Clin Nutr. 1998 Dec; 68(6 Suppl):1390S-3S.

It has long been recognized that coronary heart disease rates are lower in Japan, where soy consumption is common, than in Western countries. In experimental studies, atherosclerosis was reduced in animals fed diets containing soy protein compared with those fed diets with animal protein. Recently, several lines of evidence have suggested that the components of soy protein that lower lipid concentrations are extractable by alcohol (eg, the isoflavones genistein and daidzein). We recently evaluated the relative effect of the soy protein versus the alcohol-extractable components of soy on cardiovascular disease and its risk factors. Young male and female cynomolgus monkeys were fed diets that contained either 1) casein-lactalbumin as the source of protein (casein), 2) soy protein isolate from which the isoflavones were alcohol extracted (SPI-), or 3) isoflavone-intact soy protein (SPI+). The SPI+ group had significant improvements in LDL cholesterol and HDL cholesterol. Only HDL cholesterol was significantly improved in the SPI- group males compared with the casein group. The casein group had the most atherosclerosis, the SPI+ group had the least, and the SPI- group was intermediate but did not differ significantly from the casein group. Potential mechanisms by which soy isoflavones might prevent atherosclerosis include a beneficial effect on plasma lipid concentrations, antioxidant effects, antiproliferative and antimigratory effects on smooth muscle cells, effects on thrombus formation, and maintenance of normal vascular reactivity

In vitro synthesis of 16 alpha-hydroxyestrone by female rat liver microsomes: its possible role in the etiology of breast cancer.

Arts CJ, Wilmer JW, de Bie AT, et al.

J Steroid Biochem. 1990 Aug 28; 36(6):527-31.

Liver homogenates from female rat strains (Sprague-Dawley, Wistar and Fisher) were incubated in a NADPH regenerating medium in the presence of labelled and unlabelled estrone. Liver microsomes isolated from male rats and female mice were used as positive controls. Using HPLC and paper chromatography, under the experimental conditions used it was found that liver homogenates from female rats were able to convert estrone to various metabolites such as 16 alpha-hydroxyestrone. In a mutagenicity assay (Ames test), with 16 alpha-hydroxyesterone as test substance, two strains (TA98 and TA1538) of the five strains tested showed a 2-3-fold increase in the number of his+ revertants relative to the control values. Estrone did not cause any mutagens in the test used. It is concluded that female rats are able to synthesize 16 alpha-hydroxyestron in vitro. Whether this compound is risk factor for breast cancer remains unclear

Estrogen metabolism and laryngeal papillomatosis: a pilot study on dietary prevention.

Auborn K, Abramson A, Bradlow HL, et al.

Anticancer Res. 1998 Nov; 18(6B):4569-73.

Evidence exists that estrogen metabolism has a role in the pathogenesis of recurrent respiratory papillomatosis (RRP). This disease has a papillomavirus etiology and is characterized by recurrent benign tumors with a significant propensity to become malignant. We have measured the systemic transformation of estrogen using an enzyme-linked-immunoassay to measure estrogen metabolites in the urine of patients with RRP and compared these ratios to the severity of RRP, a measure of the average growth rate of papillomas. Our results show an inverse relationship between the ratio of C-2 to C-16 alpha-hydroxylated estrogens and the severity of RRP. In a pilot study, patients consumed cruciferous vegetables to induce C-2-hydroxylation. In this group of patients, an increase in the ratio correlated with an improvement in RRP. The ratio did not change in a subset of these patients, and their RRP did not improve. Regardless, the ratio correlated with severity of their RRP

Physiologic aspects of natural and surgical menopause.

Bachmann G.

J Reprod Med. 2001 Mar; 46(3 Suppl):307-15.

With oophorectomy, the physiologic changes associated with menopause occur quickly and with a significant impact on a woman's quality of life. In naturally menopausal women, ovarian hormone biosynthesis provides low circulating levels of estrogen and androgen. In the surgically menopausal woman, estrogen and androgen levels are significantly reduced. In surgically menopausal women for whom supplemental estrogen is prescribed, sex hormone binding globulin levels increase dramatically, resulting in reduced bioavailability of the remaining estrogens and androgens that result from peripheral conversion. This paper reviews the physiologic changes associated with natural and surgical menopause and the effects of estrogens and androgens at the cellular level. It describes the effects of hormone replacement on endogenous hormones and on the symptoms of menopause that result from physiologic changes, including vasomotor instability, sexual dysfunction and urinary complications. It also addresses the effects of estrogen/androgen therapy on physiologic symptoms

Androgen cotherapy in menopause: evolving benefits and challenges.

Bachmann GA.

Am J Obstet Gynecol. 1999 Mar; 180(3 Pt 2):S308-S311.

The hormonal effects of estrogen and androgen were first investigated at the beginning of the twentieth century. Estrogen, which was first synthesized in the 1920s, has been shown to improve menopausal symptoms, decrease the incidence of osteoporosis, have a beneficial impact on plasma lipid profiles, probably reduce ischemic cardiovascular disease, and possibly improve cognition. In addition, retrospective studies have found a decreased incidence of Alzheimer's disease among women receiving estrogen replacement therapy compared with those not receiving this form of postmenopausal therapy. Androgen has been written about in the medical literature since 1936, when Mocquot and Moricard described its use to relieve vasomotor symptoms in postmenopausal women. During the 1940s and 1950s numerous reports appeared in the literature describing the effectiveness of estrogen-androgen combination therapy for improving the overall feeling of well-being, energy level, libido, and quality of life for postmenopausal women. Recent studies have also shown estrogen-androgen therapy to contribute to the prevention of osteoporosis and reduce serum levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. Both historical data and evolving data support further evaluation of the use of estrogen-androgen replacement therapy in postmenopausal women

Timing of surgery during the menstrual cycle and prognosis of breast cancer.

Badwe RA, Mittra I, Havaldar R.

J Biosci. 2000 Mar; 25(1):113-20.

There are conflicting reports on the differential effect of surgery performed during the two phases of the menstrual cycle, namely, follicular and luteal, and prognosis of operable breast cancer. A statistical meta-analysis of the published evidence suggests a modest survival benefit of 15+/-4% when the operation is performed during the luteal phase. Further research in this area might provide a novel avenue to understand the natural history of breast cancer. A spin off from these studies might be the understanding of the importance of events that occur at the time of surgery in determining long term prognosis

Intramuscular depot medroxyprogesterone versus oral megestrol for the control of postmenopausal hot flashes in breast cancer patients: a randomized study.

Bertelli G, Venturini M, Del Mastro L, et al.

Ann Oncol. 2002 Jun; 13(6):883-8.

BACKGROUND: Hot flashes are frequent in postmenopausal breast cancer patients, especially when treated with tamoxifen. Estrogen replacement therapy is the most effective treatment for hot flashes, but its use is controversial in breast cancer survivors. Progestins may offer a good alternative for the control of hot flashes in this setting; in particular, oral megestrol acetate has been proven effective in a randomized, placebo-controlled clinical trial. With the aim of further improving these results, we have designed a randomized study comparing oral megestrol acetate with depot intramuscular (i.m.) medroxyprogesterone acetate (MPA) for the control of hot flashes in postmenopausal patients with a history of breast cancer. PATIENTS AND METHODS: Seventy-one postmenopausal patients were randomized to receive an i.m. injection of depot MPA 500 mg on days 1, 14 and 28, or oral megestrol acetate 40 mg daily for 6 weeks. Patients recorded daily the number and severity of their hot flashes; response was defined as a > or =50% decrease in the number and severity of hot flashes. RESULTS: At week 6, hot flashes were reduced by 86% on average in the whole group of patients, without significant differences between the two progestins. Response was obtained by 75 and 67% of patients receiving MPA or megestrol, respectively (P = 0.5). Responders were followed to assess maintenance of response (without further treatment), which was significantly better with i.m. MPA: in this group, 89% of responders still showed a benefit at week 24, compared with 45% in the megestrol group (P = 0.03). CONCLUSIONS: Our study shows that a short cycle of i.m. depot MPA injections provides significant and long-lasting relief from postmenopausal hot flashes in patients with a history of breast cancer, offering an alternative to estrogen replacement therapy or prolonged administration of oral megestrol

Estradiol 16 alpha-hydroxylation in the mouse correlates with mammary tumor incidence and presence of murine mammary tumor virus: a possible model for the hormonal etiology of breast cancer in humans.

Bradlow HL, Hershcopf RJ, Martucci CP, et al.

Proc Natl Acad Sci U S A. 1985 Sep; 82(18):6295-9.

In this report, we describe our findings on the relationship between estradiol 16 alpha-hydroxylation and mammary tumor incidence. A close correlation between the two has been demonstrated with 16-hydroxylation being elevated in strains with a high incidence of tumors, such as RIII and C3H, and low in strains with a low incidence of cancer, such as C57BL. The extent of reaction is highly reproducible and unaffected by age or presence of overt mammary tumors. Studies on the inheritance of estradiol 16 alpha-hydroxylase showed that it is inherited as an autosomal dominant and is not correlated with estradiol 2-hydroxylase or androgen and progestin 16 alpha-hydroxylases. In addition, the reaction was shown to be markedly enhanced by the presence of murine mammary tumor virus and diminished in the absence of the virus. These studies establish a relationship between genetics, hormonal factors, and murine mammary tumor virus, the three key factors in mammary tumorigenesis

Effects of pesticides on the ratio of 16 alpha/2-hydroxyestrone: a biologic marker of breast cancer risk.

Bradlow HL, Davis DL, Lin G, et al.

Environ Health Perspect. 1995 Oct; 103 Suppl 7:147-50.

Xenobiotic estrogens are external compounds with estrogenic activity that may thereby affect the risk of breast cancer. This paper describes a mechanism by which xeno-estrogens may affect the development of breast cancer. Estradiol metabolism proceeds by hydroxylation at one of two mutually exclusive sites at C-2 and C-16 alpha. The catechol pathway yields the weakly estrogenic 2-hydroxyestrone (2-OHE1), which inhibits breast cell proliferation. In contrast, the alternative pathway yields the genotoxic 16 alpha-hydroxyestrone (16 alpha-OHE1), which enhances breast cell growth, increases unscheduled DNA synthesis, and oncogene and virus expression, and increases anchorage-independent growth. Using a radiometric assay that measures the relative formation of 16 alpha-OHE1 versus 2-OHE1 from specifically tritiated estradiol in (ER+) MCF-7 cells, we compared the ratio of 16 alpha-OHE1/2-OHE1 observed after treatment with the known rodent carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) with the ratios after treatment with DDT, atrazine, gamma-benzene hexachloride, kepone, coplanar PCBs, endosulfans I and II, linoleic and eicosapentenoic acids, and indole-3-carbinol (I3C). These pesticides significantly increase the ratio of 16 alpha-OHE1/2-OHE1 metabolites to values comparable to or greater than those observed after DMBA. In contrast, the antitumor agent I3C increased 2-OHE1 formation and yielded ratios that are 1/3 of those found in unexposed control cells and 1/10th of those found in DMBA-treated cells. Thus the ratio of 16 alpha-OHE1/2-OHE1 may provide a marker for the risk of breast cancer. Assays of this ratio, which can be measured in spot urines, may prove useful for a variety of in vitro and in vivo studies bearing on breast cancer risk

Indole-3-carbinol. A novel approach to breast cancer prevention.

Bradlow HL, Sepkovic DW, Telang NT, et al.

Ann N Y Acad Sci. 1995 Sep 30; 768:180-200.

The results show that all of the carcinogens, oncogenes, and tumor-associated viruses that we have studied profoundly affect the extent of 2- and 16 alpha-hydroxylation in a prorisk direction. All of the dietary and biological responses associated with increased cancer risk decrease 2-hydroxylation and increase 16 alpha-hydroxylation. Remarkably, although PAHs are reported to induce P450-1A1, we have found them to decrease 2-hydroxylation. Finally, using indole-3-carbinol to induce 2-hydroxylation results in the chemoprevention of mammary tumors in rodents and recurrences of laryngeal papillomas in humans. Also correlating with these studies in HPV is the decrease in the C-2/C-16 alpha metabolite ratio observed in women with CIN relative to control subjects. The greatest decrease was observed in women with the most severe form, CIN3 (Figure 23). These findings are under further investigation

2-hydroxyestrone: the 'good' estrogen.

Bradlow HL, Telang NT, Sepkovic DW, et al.

J Endocrinol. 1996 Sep; 150 Suppl:S259-S265.

The issue of the role of 2-hydroxyestrone (2-OHE1) in breast cancer has been the subject of considerable controversy as to whether it is carcinogenic or anticarcinogenic. The expanding data base outlined below is most consistent with the conclusion that 2-OHE1 is anticarcinogenic. In every experimental model in which 2-hydroxylation was increased, protection against tumors was achieved. Correspondingly, when 2-hydroxylation was decreased, an increase in cancer risk was observed. Even more dramatically, in the case of laryngeal papillomas induction of 2-hydroxylation with indole-3-carbinol (I3C) has resulted in inhibition of tumor growth during the time that the patients continue to take 13C or vegetables rich in this compound

Reuters Health News Release: Testosterone Patch Helps Female Sexual Dysfunction.

Braunstein G, (Cedars-Sinai Medical Center UoCLA.

Reuters Health News Release. 1999;1999 Jun 16.

Biological effects of a diet of soy protein rich in isoflavones on the menstrual cycle of premenopausal women.

Cassidy A, Bingham S, Setchell KD.

Am J Clin Nutr. 1994 Sep; 60(3):333-40.

The influence of a diet containing soy protein on the hormonal status and regulation of the menstrual cycle was examined in six premenopausal women with regular ovulatory cycles. Soy protein (60 g containing 45 mg isoflavones) given daily for 1 mo significantly (P < 0.01) increased follicular phase length and/or delayed menstruation. Midcycle surges of luteinizing hormone and follicle-stimulating hormone were significantly suppressed during dietary intervention with soy protein. Plasma estradiol concentrations increased in the follicular phase and cholesterol concentrations decreased 9.6%. Similar responses occur with tamoxifen, an antiestrogen undergoing clinical trial as a prophylactic agent in women at high risk for breast cancer. These effects are presumed to be due to nonsteroidal estrogens of the isoflavone class, which behave as partial estrogen agonists/antagonists. The responses to soy protein are potentially beneficial with respect to risk factors for breast cancer and may in part explain the low incidence of breast cancer and its correlation with a high soy intake in Japanese and Chinese women

Replacement of dehydroepiandrosterone enhances T-lymphocyte insulin binding in postmenopausal women.

Casson PR, Faquin LC, Stentz FB, et al.

Fertil Steril. 1995 May; 63(5):1027-31.

OBJECTIVE: To demonstrate bioavailability of 3 weeks of oral micronized DHEA and to delineate changes induced on insulin sensitivity, morphometric indexes, and lipoprotein profiles. DESIGN: Oral micronized DHEa (50 mg/d) was administered in 3-week treatments to 11 postmenopausal women in a prospective, placebo-controlled, randomized, blinded, crossover trial with an interarm washout. After dose (23 hour) serum DHEA, DHEAS, T, and cortisol levels were measured, as were fasting lipoproteins, oral glucose tolerance tests (OGTT), T-lymphocyte insulin binding and degradation, and urine collagen cross-links. Morphometric changes were determined by hydrostatic weighing. RESULTS: Dehydroepiandrosterone sulfate, DHEA, T, and free T increased up to two times premenopausal levels with treatment. Fasting triglycerides declined; no change in collagen cross-links or morphometric indexes was noted. Oral glucose tolerance test parameters did not change, but both T-lymphocyte insulin binding and degradation increased with DHEA. CONCLUSION: Fifty milligrams per day of oral DHEA gives suprahysiologic androgen levels; 25 mg/d may be more appropriate. Dehydroepiandrosterone enhanced tissue insulin sensitivity and lowered serum triglycerides. Rationale is provided for postmenopausal replacement therapy with this androgen

Facial wrinkling in postmenopausal women. Effects of smoking status and hormone replacement therapy.

Castelo-Branco C, Figueras F, Martinez de Osaba MJ, et al.

Maturitas. 1998 May 20; 29(1):75-86.

BACKGROUND: There is some evidence that hormone replacement therapy may produce significant improvements in fine wrinkling, while aging skin is more frequently found in smokers. However, studies of the combined effect of a protective factor, such as HRT, and a damaging factor, such as smoking, are rare. OBJECTIVES: To determine in postmenopausal women the relationship between smoking status and the average number of packets of cigarettes since the subject took up smoking (packs-years) on the one hand, and facial wrinkling on the other, and to evaluate the role of hormone replacement therapy in the prevention of wrinkles in smokers and non-smokers. METHODS: All subjects were recruited from our menopause clinic at Hospital Clinic i Provincial in Barcelona and were placed into one of three groups according to their smoking status: 215 life-long non-smokers, 306 former smokers and 209 current smokers. Smoking status, pack-years and hormone replacement were assessed by direct questioning. Facial wrinkle scores were estimated by standardized visual assessment. RESULTS: The relative risk of moderate-severe wrinkling for current smokers compared to that for life-long non-smokers was 2.57 (confidence interval: 1.83-3.06; P < 0.0005). Pack-years was positively related to facial wrinkles. Life-long non-smokers receiving HRT had lower facial wrinkle scores than Life-long non-smokers who had never received HRT. HRT did not, in general, modify the facial wrinkle score in current smokers. CONCLUSION: Our results suggest that the risk of facial wrinkles is greater in smokers and that HRT does not diminish this risk

Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo.

Chang KJ, Lee TT, Linares-Cruz G, et al.

Fertil Steril. 1995 Apr; 63(4):785-91.

OBJECTIVE: To study the effect of E2 and P on the epithelial cell cycle of normal human breast in vivo. DESIGN: Double-blind, randomized study. Topical application to the breast of a gel containing either a placebo, E2, P, or a combination of E2 and P, daily, during the 10 to 13 days preceding breast surgery. PATIENTS: Forty premenopausal women undergoing breast surgery for the removal of a lump. MAIN OUTCOME MEASURES. Plasma and breast tissue concentrations of E2 and P. Epithelial cell cycle evaluated in normal breast tissue areas by counting mitoses and proliferating cell nuclear antigen immunostaining quantitative analyses. RESULTS: Increased E2 concentration increases the number of cycling epithelial cells. Increased P concentration significantly decreases the number of cycling epithelial cells. CONCLUSION: Exposure to P for 10 to 13 days reduces E2-induced proliferation of normal breast epithelial cells in vivo

Within-person variability of the ratios of urinary 2-hydroxyestrone to 16alpha-hydroxyestrone in Caucasian women.

Chen Z, Zheng W, Dunning LM, et al.

Steroids. 1999 Dec; 64(12):856-9.

The ratio of urinary 2-hydroxyestrone (2-OHE1) to 16alpha-hydroxyestrone (16alpha-OHE1) has been suggested as a potential biomarker for breast cancer risk. We evaluated within-person variability of this biomarker in ten healthy Caucasian women aged 23-58 years. Each study participant was asked to provide an overnight fasting morning urine sample once a week for an average of 8 weeks. These urine samples were assayed for 2-OHE1 and 16alpha-OHE1 by using competitive enzyme immunoassay kits purchased from the ImmunaCare Corporation. The coefficients of variation for urinary 2-OHE1/16alpha-OHE1 over the study period ranged from 13.7 to 59.6% (mean, 33.3%) in our study participants. There was a good correlation between the level of the urinary 2-OHE1/16alpha-OHE1 ratio in any single urine sample and the average ratio over the 8-week study period from the same woman, with the mean correlation coefficient of 0.85. These results indicated that the within-person variation of the 2-OHE1 to 16alpha-OHE1 ratio for most women was moderate and the level of this ratio in a single urine sample, in general, reflects reasonably well the level of this biomarker over a 2-month period

Prospective double-blind study of CEE3 in peri- and postmenopausal women: effects on bone loss and lipoprotein lipids.

Cheng GJ, Liu JL, Zhang Q, et al.

Chin Med J (Engl ). 1992 Nov; 105(11):929-33.

A prospective double-blind study was carried out in 136 women 0.5 to 21 years since menopause (YSM) in order to demonstrate the effects of a long-acting estriol derivative-Nylestriol (CEE3) on bone loss and lipoprotein lipids. They were orally administered at 2 mg of CEE3 or placebo every 2 weeks. Among 90 subjects who finished 1 year of medication, 49 received CEE3 and 41 placebo. The results were: 1. Serum ALP, Ca/Cr and Hop/Cr in fasting urine decreased in 3 months (P < 0.05); 2. Menopause-related reduction of forearm bone density was restrained; 3. LDL-C decreased in 3 months and HDL-C increased in 6 months (P < 0.05), with no significant changes in TC and TG; 4. Side effects were mild. 1/3 of those with intact uterus had spotting and another 1/3 had moderate withdrawal bleeding after the addition of medroxyprogesterone acetate at the end of 12 months of CEE3 therapy. This study demonstrates that CEE3 is effective and acceptable for preventing osteoporosis and lipoprotein lipids disorder in postmenopausal women. Long-term application awaits further studies

Phytochemicals for the prevention of breast and endometrial cancer.

Cline JM, Hughes CL, Jr.

Cancer Treat Res. 1998; 94:107-34.

Although there is evidence that phytochemicals decrease the incidence of breast and endometrial cancer, many observations are only phenomenologic, and much work needs to be done to explore basic mechanisms and the strategic exploitation of their interactions. The multiplicity of phytochemical actions at different sites in the process of tumorigenesis may eventually lead to the development of a multiagent strategy designed to maximize the complementary effects of different agents. A number of effects with possible relevance to cancer chemoprevention have been excluded from this review, including effects of phytochemicals on the immune response; the question of dietary restriction, which has a profound effect on tumorigenesis; the relatively low methionine levels in some phytochemicals such as soy, which may limit the synthesis of polyamines necessary for tumor growth [151]; and the fact that diets higher in plant products are usually lower in fat and result in leaner individuals with less potential for the synthesis of estradiol in adipose tissue. Also, many studies dealing solely with in vitro mutagenesis were excluded

Re: Ethnic differences in estrogen metabolism in healthy women.

Coker AL, Crane MM, Sticca RP, et al.

J Natl Cancer Inst. 1997 Jan 1; 89(1):89-90.

The use of estrogens and progestins and the risk of breast cancer in postmenopausal women.

Colditz GA, Hankinson SE, Hunter DJ, et al.

N Engl J Med. 1995 Jun 15; 332(24):1589-93.

BACKGROUND. The effect of adding progestins to estrogen therapy on the risk of breast cancer in postmenopausal women is controversial. METHODS. To quantify the relation between the use of hormones and the risk of breast cancer in postmenopausal women, we extended our follow-up of the participants in the Nurses' Health Study to 1992. The women were asked to complete questionnaires every two years to update information on their menopausal status, use of estrogen and progestin preparations, and any diagnosis of breast cancer. During 725,550 person-years of follow-up, we documented 1935 cases of newly diagnosed invasive breast cancer. RESULTS. The risk of breast cancer was significantly increased among women who were currently using estrogen alone (relative risk, 1.32; 95 percent confidence interval, 1.14 to 1.54) or estrogen plus progestin (relative risk, 1.41; 95 percent confidence interval, 1.15 to 1.74), as compared with postmenopausal women who had never used hormones. Women currently taking hormones who had used such therapy for 5 to 9 years had an adjusted relative risk of breast cancer of 1.46 (95 percent confidence interval, 1.22 to 1.74), as did those currently using hormones who had done so for a total of 10 or more years (relative risk, 1.46; 95 percent confidence interval, 1.20 to 1.76). The increased risk of breast cancer associated with five or more years of postmenopausal hormone therapy was greater among older women (relative risk for women 60 to 64 years old, 1.71; 95 percent confidence interval, 1.34 to 2.18). The relative risk of death due to breast cancer was 1.45 (95 percent confidence interval, 1.01 to 2.09) among women who had taken estrogen for five or more years. CONCLUSIONS. The addition of progestins to estrogen therapy does not reduce the risk of breast cancer among postmenopausal women. The substantial increase in the risk of breast cancer among older women who take hormones suggests that the trade-offs between risks and benefits should be carefully assessed

Survival of premenopausal breast carcinoma patients in relation to menstrual cycle timing of surgery and estrogen receptor/progesterone receptor status of the primary tumor.

Cooper LS, Gillett CE, Patel NK, et al.

Cancer. 1999 Nov 15; 86(10):2053-8.

BACKGROUND: Premenopausal breast carcinoma patients who undergo tumor excision during the follicular phase of their menstrual cycle may have a significantly worse prognosis than those whose tumors are excised in other phases of the menstrual cycle. METHODS: Outcome was determined in a series of 112 premenopausal women with operable breast carcinoma in relation to the timing of surgery within the menstrual cycle and the estrogen receptor (ER) and progesterone receptor (PR) status of their primary tumors as determined by immunohistochemistry. RESULTS: Those patients with ER positive tumors who underwent surgery in the early and luteal phase of the cycle had a significantly better survival than women with ER negative tumors (chi-square test = 15.56; P < 0.001). This also was true for PR status (chi-square test = "18.21;" P < 0.001). After follicular phase surgery, tumor receptor status had no effect on overall survival. Patients with the best prognosis had ER/PR positive tumors excised on Days 0-2 and 13-32 but even those women with ER or PR negative tumors removed during the luteal phase of their menstrual cycle fared better than patients whose tumors were removed during the follicular phase. CONCLUSIONS: There was a better survival rate for patients with both ER/PR positive and negative tumors treated during the luteal phase of the menstrual cycle. This could be the result of progesterone acting on the surrounding peritumoral normal tissue, thereby exerting a straitjacket effect and improving cohesion of the primary carcinoma. Unopposed estrogen in the follicular phase of the cycle may enable more tumor emboli to escape and successfully establish micrometastases

Breast cancer incidence in women with a history of progesterone deficiency.

Cowan LD, Gordis L, Tonascia JA, et al.

Am J Epidemiol. 1981 Aug; 114(2):209-17.

In order to investigate the nature of the association of involuntarily delayed first birth and risk of breast cancer, 1083 white women who had been evaluated and treated for infertility from 1945-1965 were followed prospectively through April 1978 to ascertain their breast cancer incidence. These women were categorized as to the cause of infertility into two groups, those with endogenous progesterone deficiency (PD) and those with nonhormonal causes (NH). Women in the PD group had 5.4 times the risk of premenopausal breast cancer compared to women in the NH group. This excess risk could not be explained by differences between the two groups in ages at menarche or menopause, history of oral contraceptive use, history of benign breast disease or age at first birth. Women in the PD group also experienced a 10-fold increase in deaths from all malignant neoplasms compared to the NH group. The incidence of postmenopausal breast cancer did not differ significantly between the two groups

The clinical use of androgens in female sexual disorders.

Davis SR.

J Sex Marital Ther. 1998 Jul; 24(3):153-63.

Sexual health is an important component of overall health and well being. Multiple factors clearly influence an individual's sexuality; however, there is a general trend in Western societies to blame psychosocial factors for diminished sexuality in women. Sex steroid hormones are important determinants of sexual function in women and men, and there is increasing agreement that androgens play a key role in female sexuality. Androgen levels in women decline substantially during the reproductive years, with little change subsequent to spontaneous menopause. The most common complaint of women experiencing androgen deficiency is loss of sexual desire, and several studies have now shown improvements in a number of parameters of sexuality in postmenopausal women treated with exogenous testosterone

Hormone replacement therapy and breast cancer: revisiting the issues.

DeGregorio MW, Taras TL.

J Am Pharm Assoc (Wash ). 1998 Nov; 38(6):738-44.

OBJECTIVE: To assess current ideas about the benefits and risks of estrogen and hormone replacement therapy (ERT/HRT) in postmenopausal women. DATA SOURCES: MEDLINE searches, supplemented by various texts, of the literature on HRT, ERT, and selective estrogen receptor modulators (SERMs): tamoxifen, toremifene, and raloxifene. DATA SYNTHESIS: HRT is primarily used for improving quality of life in women suffering from vasomotor symptoms associated with menopause. HRT is beneficial in postmenopausal women for preventing cardiovascular disease, osteoporosis, and Alzheimer's disease. Review of meta-analyses of clinical trials showed that ERT/HRT ever-users (patients who have ever used ERT/HRT) did not have an increased risk of breast cancer, but current users did have an increased risk, with some studies reporting increasing risk with duration of ERT. No relationship was found between dose or the addition of progestin to ERT and increased breast cancer risk. Overall breast cancer mortality rates associated with HRT were decreased in current users. In general, HRT does not increase the risk of breast cancer in women with a family history of the disease, compared with those without a family history. New HRT strategies that could potentially prevent breast cancer are now being developed. The SERMs tamoxifen and toremifene appear to have positive clinical effects on bone and serum lipids; they are currently being investigated for use as breast cancer chemopreventive agents. Raloxifene, a new SERM used for the prevention of osteoporosis, is an alternative for women who cannot tolerate HRT. Unfortunately, these SERMS have anti-estrogenic effects and thus cause vasomotor adverse effects such as hot flashes and vaginal dryness. In addition, SERMs do not protect against heart disease or prevent osteoporosis as well as does HRT. CONCLUSION: Presently, SERMs will not become first-line HRT, as the positive effects of ERT/HRT may outweigh any potentially increased risk of breast cancer. The development of new agents with pharmacodynamic profiles similar to that of ERT/HRT but lacking its adverse effects would be greatly beneficial for postmenopausal women

Effects of extracts from Cimicifuga racemosa on gonadotropin release in menopausal women and ovariectomized rats.

Duker EM, Kopanski L, Jarry H, et al.

Planta Med. 1991 Oct; 57(5):420-4.

Remifemin is an ethanolic extract of the rhizome of Cimicifuga racemosa (C.r.) and is used to relieve climacteric hot flushes. In the present study the effects of this preparation on LH and FSH secretion of menopausal women were investigated. After an 8 weeks treatment, LH but not FSH levels were significantly reduced in patients receiving the Cimicifuga extract. To further characterize the endocrinologically active principles of this plant extract, a lipophilic extract of C.r. was prepared and subjected to Sephadex chromatography. Fractions obtained were tested for their ability to reduce LH secretion in ovariectomized (ovx) rats and to compete in vitro with 17 beta-estradiol for estrogen receptor binding sites. Three types of endocrinologically active compounds were obtained: (1) Constituents which were not ligands for the estrogen receptor but suppress LH release after chronic treatment, (2) constituents binding to the estrogen receptor and also suppressing LH release, and (3) compounds which are ligands for the estrogen receptor but without an effect of LH release. It is concluded that the LH suppressive effect of C.r. extracts observed in menopausal women and ovx rats is caused by at least three different synergistically acting compounds

The prognostic value of altered estrogen metabolism in breast cancer (Ann. Surg. Oncol. Suppl. Abstr.). Presented at 53rd Annual Cancer Symposium, Society of Surgical Oncology, New Orleans, Louisiana, March 16-19, 2000.


2000;March 16-19, 2000

The phytoestrogen genistein reduces bone loss in short-term ovariectomized rats.

Fanti P, Monier-Faugere MC, Geng Z, et al.

Osteoporos Int. 1998; 8(3):274-81.

The incidence of fractures and of osteoporosis differs between Oriental and Western Caucasian women. This may depend, at least in part, on nutritional factors, including dissimilarities in dietary intake of phytoestrogens. To investigate this possibility, 2-month-old female rats were ovariectomized (OVX) or sham-operated (SHAM), fed a casein-based diet, injected daily with subcutaneous genistein (GEN), the most abundant and best characterized phytoestrogen, or vehicle (Veh) and killed 21 days after surgery. As expected, ovariectomy resulted in loss of bone mineral density (BMD) and in uterine atrophy. However, administration of 5 micrograms GEN per gram body weight (b.w.) ameliorated the ovariectomy-induced loss of BMD (189 +/- 2 mg/cm2 in OVX and 192 +/- 2 in OVX with 5 micrograms GEN/g b.w. per day; p < 0.05). One microgram GEN per gram body weight did not affect the BMD loss and the effect of the 5 micrograms and 25 micrograms GEN per gram body weight were statistically not different. A trend toward reduced uterine atrophy (21% reduction) was noted with the 25 micrograms GEN dose, but not with the 1 microgram and 5 micrograms doses. A separate experiment with 2 x 2 factorial design was conducted to elucidate the mechanism by which GEN ameliorates ovariectomy-induced bone loss. In this experiment, histomorphometry demonstrated a dramatic reduction in trabecular bone volume after ovariectomy (7.6 +/- 0.7% of total bone volume in SHAM-Veh vs 3.3 +/- 0.2% in OVX-Veh; p < 0.01) and less bone loss in OVX rats injected with 5 micrograms GEN per gram per day (3.3 +/- 0.2% of total bone volume in OVX-Veh vs 5.2 +/- 0.4% in OVX-GEN; p < 0.01). Administration of GEN was associated with higher bone formation rate per tissue volume and with a trend toward a higher number of osteoblasts per bone perimeter. The parameters of bone resorption were not affected by GEN. The concentration of serum osteocalcin and the urinary excretion of deoxypyridinoline provided corroborating results. Since production of proinflammatory cytokines is intimately involved in the pathogenesis of postmenopausal osteoporosis, the effect of GEN on lipopolysaccharide-induced in vitro production of Tumor necrosis factor-alpha (TNF alpha) was tested in monocytic cells from the same four rat groups. Production of TNF alpha was markedly elevated in OVX-Veh as compared with the SHAM-Veh rats, but this was blocked by GEN in the OVX rats. This study shows that GEN reduces both trabecular and compact bone loss after ovariectomy and that this protective effect differs from that of estrogen, since it depends on stimulation of bone formation rather than on suppression of bone resorption. Lack of action of GEN on uterine atrophy supports the possibility that this GEN dose affects target tissues via non-estrogenic mechanisms. Modulation of cytokine production may be involved in the effect of GEN on bone

Biological properties of 16 alpha-hydroxyestrone: implications in estrogen physiology and pathophysiology.

Fishman J, Martucci C.

J Clin Endocrinol Metab. 1980 Sep; 51(3):611-5.

Metabolism of estradiol in men with cirrhosis and subjects with systemic lupus erythematosus results in an excessive formation of 16 alpha-hydroxyestrone. Examination of the biological activity of this metabolite showed that it is a potent uterotropic agent and that it exhibits minimal affinity for the human sex hormone-binding globulin. These biological characteristics are consistent with a hyperestrongenic response to the substance, which may be reflected in the pathology and etiology of these diseases

Estrogen metabolite ratios as biomarkers of hormonally related breast cancer risk (conference abstract).

Fleisher MSDBHL.

Clin Chem. 1996;(42:):S261.

Estradiol and progesterone regulate the proliferation of human breast epithelial cells.

Foidart JM, Colin C, Denoo X, et al.

Fertil Steril. 1998 May; 69(5):963-9.

OBJECTIVE: To study the effects of estradiol and progesterone on the proliferation of normal human breast epithelial cells in vivo. DESIGN: Double-blind randomized study. SETTING: Departments of gynecology and of cell biology at a university hospital. PATIENT(S): Forty postmenopausal women with untreated menopause and documented plasma FSH levels of >30 mIU/mL and estradiol levels of

[Transdermal replacement hormone therapy: a trend or an advantage?].

Foidart JM, Desreux J, Pintiaux A, et al.

Rev Med Liege. 1998 Apr; 53(4):208-11.

This review describes the clinical usefulness of transdermal hormone replacement therapy. This route of administration is particularly important in women with hypertriglyceridemia, in hypertensive postmenopausal women, in women who smoke or have an increased risk of biliary or liver disorder, for those who display a reduced glucose tolerance or in women who are at risk of thrombotic disorders. The avoidance of the "first passage effect" is ensured by the transdermal application of estrogen and probably explains the superiority of this route of steroid administration

Progesterone inhibits growth and induces apoptosis in breast cancer cells: inverse effects on Bcl-2 and p53.

Formby B, Wiley TS.

Ann Clin Lab Sci. 1998 Nov; 28(6):360-9.

Progesterone inhibits the proliferation of normal breast epithelial cells in vivo, as well as breast cancer cells in vitro. But the biologic mechanism of this inhibition remains to be determined. We explored the possibility that an antiproliferative activity of progesterone in breast cancer cell lines is due to its ability to induce apoptosis. Since p53 and bcl-2 genetically control the apoptotic process, we investigated whether or not these genes could be involved in the progesterone-induced apoptosis. We found a maximal 90 percent inhibition of cell proliferation with T47-D breast cancer cells after exposure to 10 microM progesterone for 72 hours. Control progesterone receptor negative MDA-231 cancer cells were unresponsive to these two concentrations of progesterone. After 24 hours of exposure to 10 microM progesterone, cytofluorometric analysis of T47-D breast cancer cells demonstrated 43 percent had undergone apoptosis without signs of necrosis. After 72 hours of exposure to 10 microM progesterone, 48 percent of the cells had undergone apoptosis and 40 percent demonstrated "leaky" membranes. Untreated cancer cells did not undergo apoptosis. Evidence proving apoptosis was also demonstrated by fragmentation of nuclear DNA into multiples of oligonucleosomal fragments. After 24 hours of exposure to either 1 microM or 10 microM progesterone, the expression by T47-D cancer cells of bcl-2 was down-regulated, and that of p53 was up-regulated as detected by semiquantitative RT-PCR analysis. These results demonstrate that progesterone at a concentration similar to that seen during the third trimester of pregnancy exhibited a strong antiproliferative effect on at least two breast cancer cell lines. Apoptosis was induced in the progesterone receptor expressing T47-D breast cancer cells

Identification of glycyrrhizin as a thrombin inhibitor.

Francischetti IM, Monteiro RQ, Guimaraes JA, et al.

Biochem Biophys Res Commun. 1997 Jun 9; 235(1):259-63.

Glycyrrhizin (GL), an anti-inflammatory compound isolated from Glycyrrhiza glabra, was identified as a new thrombin inhibitor: (a) It prolonged plasma recalcification and thrombin and fibrinogen clotting times, and (b) it inhibited thrombin-induced, but not collagen-, PAF- or convulxin-induced platelet aggregation. On the other hand, GL did not block thrombin's amidolytic activity upon S-2238. Furthermore, the fluorescence emission intensity of dansyl-thrombin was increased upon GL binding. Moreover, GL displaced hirudin as an inhibitor of thrombin-catalyzed hydrolysis of S-2238. Our data provide evidence that GL is a selective inhibitor of thrombin (the first one isolated from plants) that is able to exert its anti-thrombin action by interacting with the enzyme's anion binding exosite 1. A pharmacophoric search identified GL as a sialyl Lewis X (SLe[X]) mimetic compound able to inhibit selectin binding to SLe(X). However, SLe(X) did not affect thrombin clotting activities, which indicates a lack of its interaction with thrombin and distinguishes both molecules. It is suggested that the anti-inflammatory effect of GL may be due to its effective anti-thrombin action

Magnetic resonance imaging of overall and regional body fat, estrogen metabolism, and ovulation of athletes compared to controls.

Frisch RE, Snow RC, Johnson LA, et al.

J Clin Endocrinol Metab. 1993 Aug; 77(2):471-7.

The association of menstrual dysfunction of athletes with changes in body composition has been controversial, because most estimations of body fatness have been indirect. Using magnetic resonance imaging, we quantified the sc and internal fat over a specific volume from the fifth thoracic vertebra to femoral fat in the upper thigh and at 4 other anatomical landmarks of 17 athletes (13 oarswomen and 4 runners) compared to that in 11 nonathletic controls. The magnetic resonance imaging data were also analyzed for the athletes and controls in relation to ovulatory status, which was determined by assay of urinary pregnanediol glucuronide, and in relation to the extent of 2-hydroxylation of estradiol to a nonpotent metabolite, 2-hydroxyestrone, which was evaluated by radiometric analysis. We found that 1) the relative and absolute body fat values of the athletes were significantly less (P < 0.05) than those of the controls overall and at each of the six regional sites, although the body weights of the rowers were significantly heavier than those of the controls, and the runners did not differ from the controls; 2) the ratio of sc fat to internal fat was 80%:20% among both athletes and controls, even though the athletes had significantly less fat; 3) the extent of estradiol 2-hydroxylation was significantly (P = "0.005)" inversely related to total fat as a percentage of the total volume and to sc fat as a percentage of the total volume (P = "0.004)" overall and at each of the regional fat depots; 4) athletes with menstrual disorders had significantly decreased sc and internal fat overall and at all regional sites compared to controls; and 5) a subgroup of ovulatory rowers had an apparent increase or lack of decrease in internal fat at the level of vertebrae lumbar 4, sacral 1, and sacral 4, compared to controls, whereas their sc fat was decreased at these sites compared to that in controls. Changes in regional fat deposits of both sc and internal fat may be involved in the menstrual dysfunction of the athletes in addition to their decreased overall fatness. The body weight and body mass index of well trained athletes can be a misleading index of body composition

Role of androgens in surgical menopause.

Gelfand MM.

Am J Obstet Gynecol. 1999 Mar; 180(3 Pt 2):S325-S327.

For the patient who has had her ovaries and uterus removed, the acute onset of surgical menopause is of primary concern during the immediate postoperative period. The initiation of hormone replacement therapy at this time eliminates most symptoms that result from the abrupt onset of menopause. Thus the patient can deal with the side effects from her operation without the added burden caused by the physiologic changes from the loss of her gonadal hormones. Most patients who undergo surgical menopause (total abdominal hysterectomy with bilateral salpingo-oophorectomy) at the McGill University Menopause Clinic receive estrogen-androgen replacement therapy in the recovery room. This occurs provided that the diagnosis is not cancer of the uterus and there are no other serious contraindications to hormone replacement therapy. Vasomotor flushes are almost entirely eliminated with estrogen-androgen replacement therapy. In addition, the androgen component of this regimen provides an increased healing effect because of its anabolic property. After 6 months we discuss whether estrogen-androgen replacement therapy should be continued or the therapy should be changed to estrogen replacement therapy only. Sexual desire and arousal, well-being, and energy level are enhanced by the addition of androgen. Side effects such as mild hirsutism are dose related and can be managed easily by dose reduction. Treatment with estrogen-androgen replacement therapy may be continued indefinitely if guidelines are followed and the patient is satisfied

Effect of ipriflavone--a synthetic derivative of natural isoflavones--on bone mass loss in the early years after menopause.

Gennari C, Agnusdei D, Crepaldi G, et al.

Menopause. 1998; 5(1):9-15.

OBJECTIVE: We studied whether oral administration of ipriflavone, a synthetic derivative of naturally occurring isoflavones, could prevent bone loss occurring shortly after menopause. DESIGN: Fifty-six women with low vertebral bone density and with postmenopausal age less than five years were randomly allocated to receive either ipriflavone, 200 mg three times daily, or placebo. All subjects also received 1,000 mg elemental calcium daily. RESULTS: Vertebral bone density declined after two years in women taking only calcium (4.9 +/- 1.1%, SEM, p = 0.001), but it did not change in those receiving ipriflavone (-0.4 +/- 1.1%, n.s.). A significant (p = 0.010) between-treatment difference was evidenced at both year 1 and year 2. At the end of the study, urine hydroxyproline/creatinine excretion was higher in the control group than in the ipriflavone group, as compared to no difference at baseline. Five patients taking ipriflavone and five taking placebo experienced gastrointestinal discomfort or other adverse reactions, but only one and four subjects, respectively, had to discontinue the study. CONCLUSIONS: Ipriflavone prevents the rapid bone loss following early menopause. This effect is associated with a reduction of bone turnover rate

Association of soy and fiber consumption with the risk of endometrial cancer.

Goodman MT, Wilkens LR, Hankin JH, et al.

Am J Epidemiol. 1997 Aug 15; 146(4):294-306.

The authors conducted a case-control study among the multi-ethnic population of Hawaii to examine the role of dietary soy, fiber, and related foods and nutrients on the risk of endometrial cancer. Endometrial cancer cases (n = 332) diagnosed between 1985 and 1993 were identified from the five main ethnic groups in the state (Japanese, Caucasian, Native Hawaiian, Filipino, and Chinese) through the rapid-reporting system of the Hawaii Tumor Registry. Population controls (n = 511) were selected randomly from lists of female Oahu residents and matched to cases on age (+/-2.5 years) and ethnicity. All subjects were interviewed using a diet history questionnaire that included over 250 food items. Non-dietary risk factors for endometrial cancer included nulliparity, never using oral contraceptives, fertility drug use, use of unopposed estrogens, a history of diabetes mellitus or hypertension, and a high Quetelet's index (kg/cm2). Energy intake from fat, but not from other sources, was positively associated with the risk of endometrial cancer. The authors also found a positive, monotonic relation of fat intake with the odds ratios for endometrial cancer after adjustment for energy intake. The consumption of fiber, but not starch, was inversely related to risk after adjustment for energy intake and other confounders. Similar inverse gradients in the odds ratios were obtained for crude fiber, non-starch polysaccharide, and dietary fiber. Sources of fiber, including cereal and vegetable and fruit fiber, were associated with a 29-46% reduction in risk for women in the highest quartiles of consumption. Vitamin A and possibly vitamin C, but not vitamin E, were also inversely associated with endometrial cancer, although trends were not strong. High consumption of soy products and other legumes was associated with a decreased risk of endometrial cancer (p for trend = 0.01; odds ratio = 0.46, 95% confidence interval 0.26-0.83) for the highest compared with the lowest quartile of soy intake. Similar reductions in risk were found for increased consumption of other sources of phytoestrogens such as whole grains, vegetables, fruits, and seaweeds. Ethnic-specific analyses were generally consistent with these results. The observed dietary associations appeared to be largely independent of other risk factors, although the effects of soy and legumes on risk were limited to women who were never pregnant or who had never used unopposed estrogens. These data suggest that plant-based diets low in calories from fat, high in fiber, and rich in legumes (especially soybeans), whole grain foods, vegetables, and fruits reduce the risk of endometrial cancer. These dietary associations may explain in part the reduced rates of uterine cancer in Asian countries compared with those in the United States

The effects of oral estriol on the endometrium in postmenopausal women.

Granberg S, Eurenius K, Lindgren R, et al.

Maturitas. 2002 Jun 25; 42(2):149-56.

OBJECTIVES: To study the long-term effects of oral estriol tablets on the endometrium of postmenopausal women by TVS and histology. METHOD: This was a cross sectional, parallel-group, multicenter trial of 241 postmenopausal women, out of whom 125 were treated with oral estriol and 116 were untreated controls. Endometrial histology using Pipelle biopsies and/or dilatation and curettage (D&C) was taken, endometrial thickness was assessed by use of transvaginal ultrasound (TVS), and the relation between endometrial thickness and histology was calculated. RESULTS: No statistically significant differences between the two groups were found in endometrial histology. There were found more polyps in the oral estriol group (14.0%) as compared with the control group (2.9%). The mean endometrial thickness in the oral estriol group was 3.0 mm compared with a mean value of 2.4 mm in the control group: P=0.01. CONCLUSIONS: No clinically relevant difference was found between the endometrium status (assessed by histology and TVS) of postmenopausal women on long-term oral estriol therapy and untreated controls. This trial supports the endometrial safety of maintenance treatment with oral estriol tablets. However, there are signs, not statistically significant, that may be associated with more endometrial polyps in postmenopausal women than if therapy is not given and that TVS is a useful instrument for the diagnosis

Effect of flaxseed consumption on urinary estrogen metabolites in postmenopausal women.

Haggans CJ, Hutchins AM, Olson BA, et al.

Nutr Cancer. 1999; 33(2):188-95.

Flaxseed, the richest known source of plant lignans, has been shown to have chemoprotective effects in animal and cell studies. Some of its effects may be mediated through its influence on endogenous hormone production and metabolism. Two competing pathways in estrogen metabolism involve production of the 2-hydroxylated and 16 alpha-hydroxylated metabolites. Because of the proposed differences in biological activities of these metabolites, the balance of the two pathways has been used as a biomarker for breast cancer risk. We examined the effects of flaxseed consumption on urinary estrogen metabolite excretion in postmenopausal women. Twenty-eight postmenopausal women were studied for three seven-week feeding periods in a randomized crossover design. During the feeding periods, subjects consumed their usual diets plus ground flaxseed (0, 5, or 10 g/day). Urinary excretion of the estrogen metabolites 2-hydroxyestrogen (2-OHEstrogen) and 16 alpha-hydroxyestrone (16 alpha-OHE1) as well as their ratio, 2/16 alpha-OHE1, was measured by enzyme immunoassay. Flaxseed supplementation significantly increased urinary 2-OHEstrogen excretion (p < 0.0005) and the urinary 2/16 alpha-OHE1 ratio (p < 0.05) in a linear, dose-response fashion. There were no significant differences in urinary 16 alpha-OHE1 excretion. These results suggest that flaxseed may have chemoprotective effects in postmenopausal women

The effect of an ipriflavone-containing supplement on urinary N-linked telopeptide levels in postmenopausal women.

Halpner AD, Kellermann G, Ahlgrimm MJ, et al.

J Womens Health Gend Based Med. 2000 Nov; 9(9):995-8.

Osteoporosis is a significant health concern to our aging population. We report here the results of a pilot placebo-controlled trial of a dietary supplement containing ipriflavone, calcium, and vitamin D on a urinary marker of bone breakdown in postmenopausal women. Seven postmenopausal women not currently receiving hormone replacement therapy received either an ipriflavone-containing supplement or placebo for 3 months. Urinary N-linked telopeptides, a marker of bone breakdown, declined by 29% in those receiving the supplement, whereas an increase in this marker was observed in the group receiving the placebo. No changes were observed in salivary hormone measurements. Although our sample size was small, to the best of our knowledge, this is the first report that demonstrates changes in N-linked telopeptide levels as a result of consuming an ipriflavone-containing product. Our findings confirm those of other researchers that demonstrate the usefulness of ipriflavone at slowing the progression of bone loss and suggest that measuring N-linked telopeptides may be a useful tool to assess therapeutic efficacy

Herbs of special interest to women.

Hardy ML.

J Am Pharm Assoc (Wash ). 2000 Mar; 40(2):234-42.

OBJECTIVE: To review the efficacy and safety of specific herbal medications that have been used traditionally to treat common conditions in women. DATA SOURCES: Current literature, with emphasis on more rigorously controlled studies. DATA SYNTHESIS: Herbal medicines have long been used in traditional healing systems to treat conditions of particular interest to women, such as premenstrual syndrome (PMS) and menopausal symptoms. For a select number of phytomedicines, including evening primrose oil, black cohosh root extract, dong quai, and chaste tree berry, scientific investigation is elucidating the pharmacologically active constituents, mechanism of action, and clinical value. CONCLUSION: Based on the available evidence, evening primrose oil and chaste tree berry may be reasonable treatment alternatives for some patients with PMS. Dong quai may have some efficacy for PMS when used in traditional Chinese multiple-herb formulas. For relief of menopausal symptoms, black cohosh root extract and dong quai have good safety profiles, but only black cohosh has demonstrated efficacy for this indication. Safety data, especially during pregnancy and lactation, are still largely lacking for many herbal medications, and recommendations for usage and dosage vary. Pharmacists who wish to recommend herbal products for women's health conditions need to evaluate the scientific literature in order to form their own opinions about appropriate use and safety

Soy and experimental cancer: animal studies.

Hawrylewicz EJ, Zapata JJ, Blair WH.

J Nutr. 1995 Mar; 125(3 Suppl):698S-708S.

Studies are reviewed that report consumption of soy protein diets inhibits the growth of various tumors in rats. The inhibitory effect has been attributed to the phytoestrogens (genistein and diadzein) or protein kinase inhibitor in soy protein products. Recent studies indicate that additional factors in soy protein products may also contribute to the inhibition of tumorigenesis, namely the deficiency of the essential amino acid methionine. Metastatic growth to the lungs of a primary rhabdomyosarcoma tumor was inhibited by feeding a soy protein diet. The effect was reversed by methionine fortification of the diet. Carcinogen-induced mammary tumor development was inhibited during the promotional phase in rats fed soy protein isolate diet and reversed with a methionine-supplemented diet. Additional studies demonstrated that after excision of the primary mammary tumor, growth of additional tumors was inhibited when the diet was changed from casein to soy protein isolate. Histopathologic evaluation of the mammary tumors revealed more benign fibroadenomas and lower-grade adenocarcinomas in the soy protein group. Before carcinogen administration (at 7 weeks of age), ornithine decarboxylase activity and polyamine concentrations in the rat mammary epithelium were significantly lower in the soy protein group. These data suggest an inhibitory effect on mammary epithelial growth in the soy-protein-fed group

Estriol: safety and efficacy.

Head KA.

Altern Med Rev. 1998 Apr; 3(2):101-13.

While conventional hormone replacement therapy provides certain benefits, it is not without significant risks. Estriol has been found to provide some of the protection without the risks associated with stronger estrogens. Depending upon the situation, estriol may exert either agonistic or antagonistic effects on estrogen. Estriol appears to be effective at controlling symptoms of menopause, including hot flashes, insomnia, vaginal dryness, and frequent urinary tract infections. Results of research on its bone-density-maintaining effects have been contradictory, with the most promising results coming from Japanese studies. Estriol's effect on cardiac risk factors has also been somewhat equivocal; however, unlike conventional estrogen prescriptions, it does not seem to contribute to hypertension. Although estriol appears to be much safer than estrone or estradiol, its continuous use in high doses may have a stimulatory effect on both breast and endometrial tissue

Vascular endothelial growth factor in premenopausal women--indicator of the best time for breast cancer surgery?

Heer K, Kumar H, Speirs V, et al.

Br J Cancer. 1998 Nov; 78(9):1203-7.

Timing of surgery in premenopausal patients with breast cancer remains controversial. Angiogenesis is essential for tumour growth and vascular endothelial growth factor (VEGF) is one of the most potent angiogenic cytokines. We aimed to determine whether the study of VEGF in relation to the menstrual cycle could help further the understanding of this issue of surgical intervention. Fourteen premenopausal women were recruited, along with three post-menopausal women, a woman on an oral contraceptive pill and a single male subject. Between eight and 11 samples were taken per person, over one menstrual cycle (over 1 month in the five controls) and analysed for sex hormones and VEGF165. Serum VEGF was significantly lower in the luteal phase and showed a significant negative correlation with progesterone in all 14 premenopausal women. No inter-sample variations of VEGF were noted in the controls. Serum from both phases of the cycle from one subject was added to MCF-7 breast cancer cells; VEGF expression in the supernatant was lower in the cells to which the luteal phase serum was added. The lowering of a potent angiogenic cytokine in the luteal phase suggests a possible decreased potential for micrometastasis establishment in that phase. This fall in VEGF may be an effect of progesterone and should be the focus of future studies

The decrease in bone mass associated with aging and menopause.

Heersche JN, Bellows CG, Ishida Y.

J Prosthet Dent. 1998 Jan; 79(1):14-6.

The human skeleton accumulates bone up to approximately age 30, after which bone is gradually lost. Although estrogen replacement therapy prevents postmenopausal bone loss, it is not certain that estrogen deficiency alone is responsible for the decrease in bone mass. Progesterone deficiency could also be a factor, and progesterone replacement therapy has been shown to prevent postmenopausal bone loss associated with ovarian dysfunction. This article reviews what is known about bone remodeling and bone loss as a function of age and gender, discusses evidence from studies in rats that progesterone plays an important role in regulating bone formation, and suggests directions for future studies in predicting the success or failure of implant therapy based on the number and kinds of osteoprogenitor cells present

Urinary 2/16 alpha-hydroxyestrone ratio: correlation with serum insulin-like growth factor binding protein-3 and a potential biomarker of breast cancer risk.

Ho GH, Luo XW, Ji CY, et al.

Ann Acad Med Singapore. 1998 Mar; 27(2):294-9.

Metabolism of estradiol occurs via two mutually exclusive hydroxylative pathways, yielding metabolites of divergent biological properties. 2-hydroxyestrone (2OHE1) is anti-estrogenic while 16 alpha-hydroxyestrone (16 alpha OHE1) is a potent estrogen. The ratio of 2OHE1 to 16 alpha OHE1 (2/16 alpha-OHE1 ratio) represents the net in vivo estrogenic activity. In this study, we sought to determine if the urinary 2/16 alpha-OHE1 ratio could be a predictor of breast cancer risk and the factors which influence this ratio. Variables analysed included age at diagnosis, menopausal status, parity, use of oral contraceptives, body mass index, serum levels of insulin-like growth factor-I (IGF-I), IGF binding proteins (BPs) and the presence of breast cancer. Serum and urine were collected from 65 breast cancer patients and 36 controls after an overnight fast. Urinary estrogen metabolites were measured by enzyme immunoassays while serum levels of IGF-I, BP-1 and BP-3 were determined by immunoradiometric assays. 2OHE1 levels and 2/16 alpha-OHE1 ratios were significantly lower (P < 0.05) while 16 alpha OHE1 levels were higher (P < 0.01) in cancer patients. Multiple linear regression analysis showed that levels of urinary metabolites were influenced by parity and breast carcinoma. 2/16 alpha-OHE1 ratio correlated positively with serum BP-3 level (P = "0.03)." By multiple logistic regression, 2/16 alpha-OHE1 ratio was the most significant factor predictive of breast cancer. The odds ratio for women with higher 2/16 alpha-OHE1 ratios was 0.10 (0.03-0.38, 95% confidence interval). In conclusion, the profile of urinary estradiol metabolites was distinctly altered in breast cancer patients. In addition, BP-3 may be a potential mechanism by which estradiol metabolites influence breast cancer progression. As 16 alpha OHE1 has been shown to initiate neoplastic transformation of mammary epithelial cells, the 2/16 alpha-OHE1 ratio may serve as a biomarker of increased risk of breast cancer

Effect of soy protein on bone metabolism in postmenopausal Japanese women.

Horiuchi T, Onouchi T, Takahashi M, et al.

Osteoporos Int. 2000; 11(8):721-4.

We conducted a cross-sectional study of the effects of soybean protein intake on bone mineral density and biochemical markers in 85 postmenopausal Japanese women. Nutrients in the diet of postmenopausal Japanese women visiting the osteoporosis unit, including subjects with normal lumbar spine bone mineral density (L2-4 BMD), were investigated by questionnaire, and the calculated daily energy, protein, soy protein and calcium intake were obtained. L2-4 BMD was measured with dual-energy X-ray absorptiometry, and assays done of serum alkaline phosphatase (ALP) and serum intact osteocalcin (IOC) as bone formation markers and urinary pyridinoline (UPYR) and urinary deoxypyridinoline (UDPYR) as bone resorption markers. Soy protein intake was significantly associated with the Z-score for L2-4 BMD (r = 0.23,p = 0.038) and UDPYR (r = -0.23, p = 0.034). Stepwise multiple regression analyses showed that soy protein intake is significantly associated with the Z-score for L2-4 BMD (beta = 0.225, p = 0.04) and UDPYR (beta = -0.08, p = 0.03) among four nutritional factors. These results suggest that high soy protein intake is associated with a higher bone mineral density and a lower level of bone resorption, but further studies are needed to confirm the causal dynamic mechanisms

[Biological effect of estrogen metabolites in human breast cancer].

Imoto S.

Nippon Geka Gakkai Zasshi. 1992 May; 93(5):505-17.

In order to investigate the estrogen metabolism in human breast cancer, the estradiol 2- and 16 alpha-hydroxylase (2-, 16 alpha-OHase) activities were determined in the microsomal fractions of human breast tissues by using reverse-phase HPLC. The effects of estrogen metabolites on the cell proliferation were also examined by employing two human breast cancer cell lines. The 2-OHase activity was detected in most cancerous and noncancerous tissues, but the value in cancerous tissues was significantly lower than that in noncancerous tissues (p less than 0.05). Patients without lymph node metastases showed relatively higher activity than those with metastases (0.05 less than p less than 0.1). The 16 alpha-OHase activity was, however, found in only 23% of cancerous tissues. Among those, the activity was present in 52% of ER positive cancerous tissues, but almost absent in ER negative ones. The growth ER positive cell line, MCF-7, was suppressed with 2-hydroxyestrone and stimulated with 16 alpha-hydroxyestrone. The cell proliferation stimulated with 16 alpha-hydroxyestrone was not inhibited by the addition of tamoxifen, a strong antagonist of estradiol. Two metabolites had no effect on the growth of ER negative cell line, MDA-MB-231. These results suggest that estrogen metabolites influence the proliferation of human breast cancer cells as the endogenous regulatory factors and should be considered for the future endocrine therapy

Cognitive function in nondemented older women who took estrogen after menopause.

Jacobs DM, Tang MX, Stern Y, et al.

Neurology. 1998 Feb; 50(2):368-73.

Investigations of the effects of estrogen replacement on cognitive function in healthy older women have yielded disparate results. We evaluated the relationship between a history of estrogen use and cognitive test performance in 727 women participating in a large community-based study. Participants were followed longitudinally for an average of 2.5 years. Estrogen use history was obtained at baseline. Standardized tests of memory, language, and abstract reasoning were administered at baseline and at follow-up. Results indicate that women who had used estrogen replacement scored significantly higher on cognitive testing at baseline than nonusers, and their performance on verbal memory improved slightly over time. The effect of estrogen on cognition was independent of age, education, ethnicity, and APOE genotype. Results suggest that estrogen replacement therapy may help to maintain cognitive function in nondemented postmenopausal women

Urinary estrogen metabolites and breast cancer: a case-control study.

Kabat GC, Chang CJ, Sparano JA, et al.

Cancer Epidemiol Biomarkers Prev. 1997 Jul; 6(7):505-9.

Preliminary studies suggest that the estrogen metabolite 16 alpha-hydroxyestrone is associated with breast cancer, whereas 2-hydroxyestrone is not. However, epidemiological studies evaluating this relationship and taking established risk factors for breast cancer into account are lacking. The purpose of this study was to examine the association of the ratio of the urinary estrogen metabolites (2-hydroxyestrone and 16 alpha-hydroxyestrone) and of the individual metabolites with breast cancer. A spot urine sample, a brief history, and clinical data were collected from breast cancer cases (n = 42) and from women coming to the hospital for a routine mammogram or attending a free breast cancer screening (n = 64). 2-Hydroxyestrone and 16 alpha-hydroxyestrone were measured by enzyme immunoassay, and the estrogen metabolite ratio (EMR; 2-hydroxyestrone:16 alpha-hydroxyestrone) was computed. Cases and controls were similar in terms of age (mean age of cases, 53.8 +/- 15.1 years, versus 54.2 +/- 10.4 years for controls; P = 0.9) and demographics. Mean EMR was not associated with breast cancer overall (1.67 +/- 0.80 versus 1.72 +/- 0.66; P = 0.7). However, in postmenopausal women, the mean EMR was significantly lower in cases compared to controls (1.41 +/- 0.73 versus 1.81 +/- 0.71; P = 0.05). The multivariate adjusted odds ratios for the intermediate and lowest tertiles of the EMR relative to the highest among postmenopausal women were 9.73 (95% confidence interval, 1.27-74.84) and 32.74 (95% confidence interval, 3.36-319.09), respectively. The test for trend was highly significant (P = 0.003). Analyses of the individual metabolites indicated that 16 alpha-hydroxyestrone was a strong risk factor. The EMR did not show any consistent associations with age, race/ethnicity, age at first birth, parity, body mass index, family history of breast cancer, smoking, or alcohol intake. These data suggest a strong, inverse association of the EMR and a strong positive association of 16 alpha-hydroxyestrone with breast cancer in postmenopausal women. Larger studies are needed to confirm these results and to assess the relationship of the EMR and of the individual metabolites with breast cancer, with attention to menopausal status and clinical factors and with adjustment for known breast cancer risk factors

Women and menopause: beliefs, attitudes, and behaviors. The North American Menopause Society 1997 Menopause Survey.

Kaufert P, Boggs PP, Ettinger B, et al.

Menopause. 1998; 5(4):197-202.

OBJECTIVE: The main purpose in organizing this survey was to collect information relevant to The North American Menopause Society's (NAMS) educational mission and to document women's knowledge of, and attitudes toward, menopause. DESIGN: During June-July 1997, The Gallup Organization conducted 750 telephone interviews with a randomly selected sample of women 45-60 years of age from across the United States. Women were asked about their sources of information on menopause, what changes in health they anticipated as a result of menopause, why they used hormone therapy, and their attitudes toward menopause as a natural or a medical event. RESULTS: Women are more likely to believe that depression and irritability are associated with menopause than heart disease, but only a few associate menopause with an increasing vulnerability to either memory loss or Alzheimer's disease. Relief of physical symptoms of menopause was mentioned as the reason for starting hormone therapy more often than to protect against osteoporosis (25% relative to 15%), or to prevent stroke or a heart attack (10%), or to reduce the risk of developing Alzheimer's disease (2%). The single main source of women's information on menopause was a health professional (49%). The majority of women who were already menopausal or experiencing menstrual changes expressed an attitude toward menopause that was either neutral (42%) or positive (36%). CONCLUSIONS: Women are divided in their views of menopause, some seeing it as a medical condition requiring medical treatment, whereas others see it as a natural transition to be managed by "natural" means. Providing women with accurate, up-to-date information and enhancing communication between healthcare providers and menopausal women remain the challenges for NAMS

Inhibition of human estrogen synthetase (aromatase) by flavones.

Kellis JT, Jr., Vickery LE.

Science. 1984 Sep 7; 225(4666):1032-4.

Several naturally occurring and synthetic flavones were found to inhibit the aromatization of androstenedione and testosterone to estrogens catalyzed by human placental and ovarian microsomes. These flavones include (in order of decreasing potency) 7,8-benzoflavone, chrysin, apigenin, flavone, flavanone, and quercetin; 5,6-benzoflavone was not inhibitory. 7,8-Benzoflavone and chrysin were potent competitive inhibitors and induced spectral changes in the aromatase cytochrome P-450 indicative of substrate displacement. Flavones may thus compete with steroids in their interaction with certain monooxygenases and thereby alter steroid hormone metabolism

Monoclonal antibody-based enzyme immunoassay for simultaneous quantitation of 2- and 16 alpha-hydroxyestrone in urine.

Klug TL, Bradlow HL, Sepkovic DW.

Steroids. 1994 Nov; 59(11):648-55.

Alterations in the metabolism of estrogen have been implicated as an important factor in the etiology of diseases such as gynecological cancers and lupus erythematosus. The major metabolites of estradiol are hydroxylated at the C-2 or C-16 alpha position yielding products with estrogen antagonist and agonist activities, respectively. A sensitive and specific immunodiagnostic assay to determine the balance between these competing pathways might serve as a routine biomarker for management of estrogen-related diseases. We describe here the generation of high affinity, specific murine monoclonal antibodies to 2-hydroxyesterone and 16 alpha-hydroxyestrone by high efficiency fusion protocols. With these antibodies, we have developed a rapid and simple enzyme immunoassay (EIA) kit for the simultaneous quantitation of 2- and 16 alpha-hydroxyestrone in unextracted urine. Initial validation studies established that urinary metabolite 2- and 16 alpha-hydroxyestrone concentrations found by the EIA correlate well with values found by gas chromatography-mass spectroscopy. Preliminary studies with the EIA kit found total recovery of metabolites from spiked urine samples. The EIA inter- and intra-assay coefficients of variation for 2-hydroxyestrone and 16 alpha-hydroxyestrone and the ratio of 2-hydroxyesterone to 16 alpha-hydroxyestrone with the current EIA kit were consistently less than 9%. This kit, designated ESTRAMET 2/16 may provide an important new tool for research in estrogen-related diseases

Menopausal hormone replacement therapy and risk of ovarian cancer.

Lacey JV, Jr., Mink PJ, Lubin JH, et al.

JAMA. 2002 Jul 17; 288(3):334-41.

CONTEXT: The association between menopausal hormone replacement therapy and ovarian cancer is unclear. OBJECTIVE: To determine whether hormone replacement therapy using estrogen only, estrogen-progestin only, or both estrogen only and estrogen-progestin increases ovarian cancer risk. DESIGN: A 1979-1998 cohort study of former participants in the Breast Cancer Detection Demonstration Project, a nationwide breast cancer screening program. SETTING: Twenty-nine US clinical centers. PARTICIPANTS: A total of 44 241 postmenopausal women (mean age at start of follow-up, 56.6 years). MAIN OUTCOME MEASURE: Incident ovarian cancer. RESULTS: We identified 329 women who developed ovarian cancer during follow-up. In time-dependent analyses adjusted for age, menopause type, and oral contraceptive use, ever use of estrogen only was significantly associated with ovarian cancer (rate ratio [RR], 1.6; 95% confidence interval [CI], 1.2-2.0). Increasing duration of estrogen-only use was significantly associated with ovarian cancer: RRs for 10 to 19 years and 20 or more years were 1.8 (95% CI, 1.1-3.0) and 3.2 (95% CI, 1.7-5.7), respectively (P value for trend

Results of a 5 years prospective study of estriol succinate treatment in patients with climacteric complaints.

Lauritzen C.

Horm Metab Res. 1987 Nov; 19(11):579-84.

In a prospective study 911 patients were treated over a period of 5 years (M = 2.2) or a total of 2007 treatment years with estriol succinate oral (Synapause, 2-12 mg per day). The treatment was very effective in the removal of all typical climacteric complaints and of the atrophic genital changes caused by estrogen deficiency. Subjective side effects were seldom seen and without practical importance for the treatment. Objective, grave side effects were only few: one superficial phlebo-thrombosis, 2 cases of thrombophlebitis, one carcinoma in situ of the portio vaginalis uteri and 2 mammary cancers were seen. The carcinoma had probably no causal relationship to the treatment. Embolies, myocardial infarctions, cerebrovascular and liver-gall bladder complications did not occur during treatment. The rate of uterine bleedings was low. The incidence of all complications was not increased by estriol succinate; but was even lower than expected. Endometrial and ovarian cancers were not seen. Estriol succinate is accordingly a very effective and well tolerated preparation against climacteric complaints, exerting no significant side effects. It is remarkable that it does not proliferate the endometrium when given in one dose a day. Estriol succinate can therefore be characterized as the estrogen to be favoured for the treatment of postclimacteric women, who do not want to have uterine bleedings any longer.(ABSTRACT TRUNCATED AT 250 WORDS)

What Your Doctor May Not Tell You about Menopause.

Lee J.


[Clinical and endocrinologic studies of the treatment of ovarian insufficiency manifestations following hysterectomy with intact adnexa].

Lehmann-Willenbrock E, Riedel HH.

Zentralbl Gynakol. 1988; 110(10):611-8.

60 hysterectomized patients under 40 years old, who all had at least one intact ovary and still complained of climacteric symptoms, were treated with estriol, conjugated estrogens, estrogen-gestagen sequential therapy or an extract from cimicifuga racemosa after randomized distribution into 4 equal groups. Therapy was controlled after 4, 8, 12 and 24 weeks with a modified Kupperman-Index that also included trophic disorders of the genitals, and also by serum-FSH and -LH measurement. In all groups, the modified Kupperman-Index became significantly lower, the parallel decrease of gonadotropins could not be confirmed statistically, however. There were no significant differences between groups concerning therapy success

Clinical and experimental aspects of the anti-mammary carinogenic activity of estriol.

Lemon HM.

Front Horm Res. 1977; 5:155-73.

Intermittent implantation of 600--1,300 microgram estriol subcutaneously beginning 48 h before oral administration of 7,12-dimethylbenz(a)anthracene or procarbazine prevents development of 80--90% of carcinomas of the breast occurring during the natural life span of the intact female Sprague-Dawley rat. Some estriol precursors were less inhibitory of breast cancer development among 23 other estrogens and androgens, progestins and glucocorticoids tested. More frequent or lower estriol doses than 100--200 microgram/kg/24 h every 2 months were less inhibitory of breast carcinogenesis. No other types of neoplasms were reduced in incidence by estriol implants, which also reduced uterine weights by 20--25%. Intermittent substitution of estriol for estrone or estradiol in the nuclear receptor complexes of target cells probably accounts for these observations, which resemble the effect of castration in reducing breast cancer incidence. Human studies indicate excellent tolerance for oral estriol doses of 10--200 microgram/kg/24 h, which may correct subnormal estriol/estrone + estradiol urinary quotients associated with elevated risk of breast carcinogenesis in epidemiologic investigations

Pathophysiologic considerations in the treatment of menopausal patients with oestrogens; the role of oestriol in the prevention of mammary carcinoma.

Lemon HM.

Acta Endocrinol Suppl (Copenh). 1980; 233:17-27.

At menopause, several abnormalities in oestrogen metabolism have been reported, which may increase the likelihood of cancer development in the breast or uterus following oestrone or oestradiol-17 beta supplementation. Occult hypothyroidism reduces the rate of oestrogen inactivation by C2 hydroxylation, and 15-20% of women have low rates of C16 hydroxylation to oestriol. Reduced sex hormone binding globulin concentration occurs in association with obesity, thereby increasing the biologically active unbound fraction of oestradiol in plasma. Since oestriol undergoes minimal metabolism after absorption, does not bind to sex hormone binding globulin, and has an anti-oestradiol action by decreasing the duration of nuclear binding of oestradiol-receptor proteins, it is less likely to induce proliferative changes in target organs of cancer-prone women than oestrone or oestradiol. Intermittent non-conjugated oestriol treatment has demonstrated the most significant anti-mammary carcinogenic activity of 22 tested compounds as well as anti-uterotropic activity in intact female Sprague Dawley rats fed either of two dissimilar carcinogens (7, 12 dimethylbenz(a) anthracene, procarbazine) and followed for their natural life span. The protective effect was specific for mammary carcinomas only and has been decreased in rats with a 20% increase in growth curves. Clinical experience thus far with oral oestriol therapy of post-menopausal women has indicated little hazard of cancer development

Inhibition of radiogenic mammary carcinoma in rats by estriol or tamoxifen.

Lemon HM, Kumar PF, Peterson C, et al.

Cancer. 1989 May 1; 63(9):1685-92.

Mammary carcinomas have been induced by 3.5 Gy whole-body gamma radiation administered at age 40 to 50 days to virgin female Sprague-Dawley rats. In 142 irradiated controls carcinoma incidence averaged 7.8% in survivors observed less than 300 days and 38.3% of those surviving longer (P less than 0.001 by t test). Mammary cancer promotion was inhibited by two methods: estriol (E3) 638 micrograms/month (2.2 microns/mo) subcutaneously for natural life span begun 2 weeks after exposure reduced cancer incidence from 76% in controls to 48% after 331 to 449 mean days observation until neoplasia was palpable (P less than 0.02 by chi-square analysis). Uterine weights were similar in control and treated groups, and were 15% to 18% greater than uteri of nonirradiated controls from other simultaneous experiments. Six monthly 638-micrograms doses of 17 alpha ethinyl estriol (EE3) reduced tumors from 88% in controls to 64% (P less than 0.05 by chi-square analysis) and delayed cancer onset (P less than 0.01-0.04 by life table analysis). Ethinyl estradiol (EE2) after 6 months' treatment similarly delayed mammary tumor development reducing incidence to 75% (NS), with a six-fold increase in nonmammary epithelial malignant tumors. Estriol administration begun between 3 days before to 5 days after radiation did not alter mammary cancer incidence in six experiments. Monthly implantation of 2.5 mg tamoxifen (4.44 microns/mo) started 2 weeks after radiation reduced mammary cancer incidence from 83% to 14% after 307 to 314 days' observation (P less than 0.001 by chi-square analysis). Treated rats had atrophic ovaries and uteri consistent with blockade of endogenous estradiol activity. Short-term parenteral E3 or EE3 therapy using 10 to 30 micrograms/kg/day (35-100 microns/kg/day) rapidly differentiated virgin rat mammary glands without impairment of subsequent estrus cycles and offers an alternative to castration or life-long antiestrogen therapy for reduction of risk of radiogenic mammary carcinoma

Clinical Study on the Use of Natural Progesterone Cream in the Prevention of Osteoporosis.

Leonetti H.


Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss.

Leonetti HB, Longo S, Anasti JN.

Obstet Gynecol. 1999 Aug; 94(2):225-8.

OBJECTIVE: To determine effectiveness of transdermal progesterone cream for controlling vasomotor symptoms and preventing postmenopausal bone loss. METHODS: We randomly assigned 102 healthy women within 5 years of menopause to transdermal progesterone cream or placebo. Study subjects and investigators were masked until data analysis was completed. An initial evaluation included complete history, physical examination, bone mineral density determination, and serum studies (TSH, FSH, lipid profile, and chemistry profile). Subjects were instructed to apply a quarter teaspoon of cream (containing 20 mg progesterone or placebo) to the skin daily. Each woman received daily multivitamins and 1200 mg of calcium and were seen every 4 months for review of symptoms. Bone scans and serum chemistries were repeated after 1 year. RESULTS: Thirty of the 43 (69%) in the treatment group and 26 of the 47 (55%) in the placebo group complained initially of vasomotor symptoms. Improvement or resolution of vasomotor symptoms, as determined by review of weekly symptom diaries, was noted in 25 of 30 (83%) treatment subjects and five of 26 (19%) placebo subjects (P < .001). However, the number of women who showed gain in bone mineral density exceeding 1.2% did not differ (alpha = ".05," power of 80%). CONCLUSION: Although we found no protective effect on bone density after 1 year, we did see a significant improvement in vasomotor symptoms in the treated group

Topical progesterone cream has an antiproliferative effect on estrogen-stimulated endometrium.

Leonetti HB, Wilson KJ, Anasti JN.

Fertil Steril. 2003 Jan; 79(1):221-2.

Therapeutic efficacy and safety of Cimicifuga racemosa for gynecologic disorders.

Liske E.

Adv Ther. 1998 Jan; 15(1):45-53.

The reproducible quality of phytopharmaceuticals--herbal medicines--is an essential prerequisite for good efficacy and tolerability in the treatment of functional disorders. In clinical trials and scientific investigations, standardized assessments (i.e., validated, internationally recognized and accepted scales) provide the basis for establishing clinical efficacy and tolerability. Extracts (ethanolic and isopropanolic aqueous, Remifemin) of the rootstock of the herb Cimicifuga racemosa (black cohosh) are active ingredients developed for the treatment of gynecologic disorders, particularly climacteric symptoms. Drug-monitoring and clinical studies documenting experience with C. racemosa rootstock extracts comprise the database of this herbal treatment for menopausal symptoms (e.g., hot flashes, profuse sweating, sleep disturbances, depressive moods). These studies show good therapeutic efficacy and tolerability profiles for C. racemosa. In addition, clinical and experimental investigations indicate that the rootstock of C. racemosa does not show hormone-like activity, as was originally postulated

Endocrine parameters and alpha-tocopherol therapy of patients with mammary dysplasia.

London RS, Sundaram GS, Schultz M, et al.

Cancer Res. 1981 Sep; 41(9 Pt 2):3811-3.

Patients with mammary dysplasia (17 patients) and controls (6 patients) were treated in a double-blind study with alpha-tocopherol acetate (600 units/day). Determination of serum alpha-tocopherol, estradiol, estriol., and progesterone were made from blood samples collected on Day 21 of the menstrual cycle before and during therapy. Eight-eight % of patients showed clinical response to therapy. Serum alpha-tocopherol concentrations rose after therapy in patients and controls. Serum estradiol and progesterone concentration were not statistically different in patients or controls after therapy, although patients showed a trend toward increased serum progesterone concentration. However, the ratio of progesterone to estradiol, which is abnormal in mammary dysplasia patients, rose from 30 +/- 7 (S.E.) to 53 +/- 11 in patients after alpha-tocopherol therapy (p less than 0.05). Control patients showed no significant change in progesterone/estradiol ratio. Results of this study indicate that alpha-tocopherol therapy may correct an abnormal progesterone/estradiol ratio in patients with mammary dysplasia, with implications on reducing future risk for malignant breast disease

The effect of a low fat diet on estrogen metabolism.

Longcope C, Gorbach S, Goldin B, et al.

J Clin Endocrinol Metab. 1987 Jun; 64(6):1246-50.

Women who consume a diet low in fat are at lower risk for breast cancer than women whose diet is relatively high in fat. To investigate the effects of a low fat diet on estrogen metabolism, six normal young women were studied while eating a Western-style high fat diet and again after 2 months of consuming a defined low fat diet. Both studies involved the simultaneous administration of [3H]estradiol [( 3H]E2) orally and [14C]E2 iv and the subsequent collection of multiple blood samples and urine for 96 h. The blood samples were analyzed for radioactivity as estrone (E1), E2, their glucuronides, and E1 sulfate. An aliquot of the pooled 96-h urine was analyzed for radioactivity as the glucuronides and sulfates of E1, E2, estriol, 16 alpha-hydroxyestrone (16 alpha-OHE1), and the catechol estrogens, i.e. 2-hydroxy and 2-methoxy metabolites of E1 and E2. The low fat diet resulted in a consistent and significant (P less than 0.05) decrease in urinary excretion of both 16-hydroxylated metabolites, estriol and 16 alpha-OHE1, expressed as a percentage of administered dose of [3H]E2 and [14C]E2, and an increase in the excretion of the catechol estrogens. These changes in metabolite excretion were not, however, mirrored by changes in the MCRs or conversion ratios of either [3H]E2 or [14C]E2. Thus, while neither the clearance of E2 from the blood nor its absorption from the intestinal tract was altered by a relatively short term decrease in dietary fat, there was a shift in the pattern of urinary metabolites away from the purported carcinogenic estrogen (16 alpha-OHE1) and toward the less active catechol estrogens. This may represent an important mechanism whereby low fat diets decrease the risk of breast cancer

Androgen metabolism and the menopause.

Longcope C.

Semin Reprod Endocrinol. 1998; 16(2):111-5.

The concentration of androgens in the blood peaks in early adulthood. While the concentrations of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) decline steadily, the concentrations of androstenedione (A) and testosterone (T) decline just before or at the menopause. DHEAS is bound strongly to albumin, resulting in a very low metabolic clearance rate (MCR) of about 12 L/day. DHEA and A are bound weakly to albumin and their MCRs are 1800 to 2000 L/day. T is bound strongly to sex hormone-binding globulin (SHBG), and the MCR of T is about 500 L/day. There are no significant changes in the MCRs at the menopause or with age. The pathways of metabolism are not altered at the menopause but aromatization of DHEA, A, and T to estrone and estradiol all increase with age. Thus, androgen metabolism in general is affected more by age than by the menopause itself

Megestrol acetate for the prevention of hot flashes.

Loprinzi CL, Michalak JC, Quella SK, et al.

N Engl J Med. 1994 Aug 11; 331(6):347-52.

BACKGROUND. Vasomotor hot flashes are a common symptom in women during menopause and in men who have undergone androgen-deprivation therapy for prostate cancer. Although treatment with estrogens in women and androgens in men can attenuate these symptoms, these hormones may be contraindicated in women with breast cancer and in men with prostate cancer. Pilot trials have suggested that the progestational agent megestrol acetate can ameliorate hot flashes in both groups of patients. METHODS. The patients included 97 women with a history of breast cancer and 66 men with prostate cancer who had undergone androgen-deprivation therapy. All patients had experienced bothersome hot flashes (median number per day at base line, 6.1 for the women and 8.4 for the men). After a one-week pretreatment observation period, the patients received megestrol acetate (20 mg twice daily) for four weeks, followed by placebo for four weeks, or vice versa in a double-blind manner as determined by pretreatment randomization. The patients documented the frequency and severity of hot flashes in daily symptom diaries. RESULTS. After four weeks, hot flashes were reduced by 21 percent in the group receiving placebo first and by 85 percent in the group receiving megestrol acetate first (P < 0.001). An intention-to-treat analysis of data for all eligible treated patients showed that 74 percent of the megestrol acetate group, as compared with 20 percent of the placebo group, had a decrease of 50 percent or more in the frequency of hot flashes during the first four weeks (P < 0.001). The degree of efficacy was similar in men and women. The only side effect was withdrawal menstrual bleeding in women, generally occurring one to two weeks after the megestrol acetate had been discontinued. CONCLUSIONS. Low-dose megestrol acetate is well tolerated and can substantially decrease the frequency of hot flashes in women and men

Increased urinary excretion of 2-hydroxyestrone but not 16alpha-hydroxyestrone in premenopausal women during a soya diet containing isoflavones.

Lu LJ, Cree M, Josyula S, et al.

Cancer Res. 2000 Mar 1; 60(5):1299-305.

Asian diets high in soy are associated with lower risk for breast cancer compared with Western diets. Moreover, higher levels of two putative carcinogenic metabolites of 17beta-estradiol, 4- and 16alpha-hydroxyestrogen, and lower amounts of anticarcinogenic metabolites, 2-hydroxyestrogens, have been associated with greater breast cancer risk. In this study, we tested the hypothesis that consumption of a soya diet containing the weakly estrogenic isoflavones genistein and daidzein may alter the metabolism of 17beta-estradiol to 2- and 16alpha-hydroxylated products. Eight pre-menopausal women were placed on a soya-containing, constant diet in a metabolic unit. The diet provided 400 kilocalories from soymilk and 113-202 mg/day (158 +/- 26 mg/day, mean +/- SD) isoflavones daily for a complete menstrual cycle. After a washout period of 4 months, the subjects consumed the same diet, but with soymilk that contained

Temporal actions of 16 alpha-hydroxyestrone in the rat: comparisons of lordosis dynamics with other estrogen metabolites and between sexes.

Lustig RH, Mobbs CV, Pfaff DW, et al.

J Steroid Biochem. 1989 Sep; 33(3):417-21.

16 alpha-Hydroxyesterone (16OHE1), a metabolite of estradiol (E2) and precursor of estriol (E3), binds to the estrogen receptor (ER) with low affinity (3% of E2), but is estrogenic in both in vitro and in vivo systems. This metabolite is able to bind in a non-dissociable manner to the ER. We examined these properties in vivo by assessing the temporal dynamics of estrogen metabolite action in the rat brain, using lordosis score (LS) to manual stimulation as a serial bioassay of estrogen effect. Male and female castrate Fisher rats were implanted with osmotic minipumps containing either vehicle, E2, 16OHE1, or E3. 16OHE1-induced LS was delayed in onset in both sexes relative to E2 and E3. Male LS reached a similar plateau for all metabolites, whereas female LS reached an initial LS plateau similar in amplitude to the male plateau. Over the next several days, female LS increased to reach a secondary plateau of higher amplitude, which persisted until pump removal. Upon pump removal, E2- and E3-stimulated LS fell to baseline quickly in both sexes, whereas 16OHE1-stimulated LS in males demonstrated a prolongation of maximal LS for 6 days following pump removal. These results suggest that 16OHE1 is estrogenic in the brains of both sexes. The delay of onset of LS with 16OHE1 is consistent with its poor ER affinity. Females were able to augment LS with prolonged exposure to all metabolites, while males could not. The ability of 16OHE1 to maintain maximal LS in the male long after its withdrawal is consistent with its ability to bind non-dissociably to the ER and promote prolonged estrogenic activation. However, females do not exhibit this response, suggesting a sex specificity in the dynamics of ligand-receptor action in the rat brain

Menses and breast cancer: does timing of mammographically directed core biopsy affect outcome?

Macleod J, Fraser R, Horeczko N.

J Surg Oncol. 2000 Jul; 74(3):232-6.

BACKGROUND AND OBJECTIVES: Studies have shown molecular, genetic and cellular changes in breast cancer during the menstrual cycle. Changes in proliferative and metastatic potential of breast cancer cells during menses could explain improved survival when tumors are surgically removed in the luteal phase. This study examined if timing of mammography/core biopsy (MAM-CB) also affected breast cancer prognosis (histological tumor grade). METHODS: Eighty-five premenopausal women undergoing MAM-CB at one clinic between March 1995 and February 1998 were retrospectively studied. All patients had Stage I or II breast cancer surgically treated. Patients were grouped by phase of menses at MAM-CB: follicular (F, Days 0-14) or luteal (L, Days 15-35). Groups were comparable in age, menarche, family history, nulliparity, breastfeeding, and total percentage of clinically palpable tumors. Pathological characteristics of the tumors (tumor size, tumor type, estrogen and progesterone receptor status, axillary lymph node status, the presence of lymphatic or vascular invasion and extranodal metastasis) was also comparable across the 2 groups. RESULTS: Low-grade tumors were more frequent in the MAM-CB group L, whereas high-grade tumors were more common in the MAM-CB group F (P = 0.002, chi2(4) = 17.06). CONCLUSIONS: Timing of MAM-CB in relation to menses may be a factor influencing breast cancer outcome. Future studies examining the effect of menses on the outcome of breast cancer should consider the potential effect of the timing of MAM-CB

Do urinary oestrogen metabolites predict breast cancer? Guernsey III cohort follow-up.

Meilahn EN, De Stavola B, Allen DS, et al.

Br J Cancer. 1998 Nov; 78(9):1250-5.

This is the first prospective study of urinary measures of the two major competing pathways of oestrogen metabolism, 16alpha-hydroxyoestrone (16alpha-OHE1) and 2-hydroxyoestrone (2-OHE1), in relation to incident breast cancer risk. Experimental and case-control study results suggest that metabolism favouring the more oestrogenic 16alpha-OHE1 pathway may be linked to higher breast cancer risk. Women aged 35 and older from Guernsey (n = 5104) were surveyed in 1977-85 and have been continuously monitored for breast cancer and mortality up to the present (Guernsey III, Imperial Cancer Research Fund). Incident cases of breast cancer were matched to three control subjects for comparison of urinary oestrogen metabolite levels measured by enzyme immunoassay (EIA) in spot urine samples collected at baseline and stored frozen for up to 19 years. Consistent with case-control study results, post-menopausal (but not premenopausal) women at baseline who went on to develop breast cancer showed about a 15% lower 2:16alpha-OHE1 ratio than matched control subjects. Further, subjects with metabolite ratios in the highest tertile of 2:16alpha-OHE1 had about a 30% lower risk than women with ratios in the lowest two-thirds, although results were not statistically significant (OR = 0.71, 95% CI = 0.29-1.75). It is of potential importance that, in contrast to most risk factors for breast cancer, such as late age at first birth, oestrogen metabolism appears to be modifiable via diet and exercise, offering women the possibility of lowering breast cancer risk through non-pharmacological measures, although this remains to be tested

Reproducibility of plasma and urinary sex hormone levels in premenopausal women over a one-year period.

Michaud DS, Manson JE, Spiegelman D, et al.

Cancer Epidemiol Biomarkers Prev. 1999 Dec; 8(12):1059-64.

Although endogenous sex steroid hormones in premenopausal women may be associated with the risk of breast cancer and other illnesses, direct evidence to support this hypothesis is limited in large part by methodological issues in the conduct of relevant studies. One major unresolved issue is whether a single blood sample (such as is available in most epidemiological studies), collected in a specific phase of the menstrual cycle, reflects long-term levels in that phase. To address this issue, two sets of blood and urine samples were obtained from 87 premenopausal women over a 1-year period in both the follicular and luteal phases. Plasma estradiol, estrone, and estrone sulfate were measured in the blood samples obtained in both phases, whereas progesterone and urinary 2- and 16a-hydroxyestrone were measured in luteal-phase samples only. For all of the women combined, intraclass correlation coefficients (ICCs) ranged, with one exception, from 0.52 to 0.71 for the plasma estrogens and the urinary estrogen metabolites. The sole exception was for estradiol in the luteal phase (ICC = 0.19); inclusion of only women who were ovulatory in both cycles and who collected each sample 4-10 days before their next period resulted in a substantially higher ICC for estradiol in the luteal phase (ICC = 0.62; 95% confidence interval, 0.43-0.78). These data indicate that, for several plasma and urinary sex hormones, a single follicular- or luteal-phase measurement in premenopausal women is reasonably representative of hormone levels in that phase for at least a 1-year period

Increased estrogen 2-hydroxylation in obese women using oral indole-3-carbinol.

Michnovicz JJ.

Int J Obes Relat Metab Disord. 1998 Mar; 22(3):227-9.

OBJECTIVE: To investigate whether the dietary phytochemical, indole-3-carbinol (13C), influences the level of estradiol 2-hydroxylation in obese women. DESIGN: A clinical intervention study involving the ingestion of purified 13C, 400 mg, for two months. SUBJECTS: Five healthy, overweight, premenopausal women (age: 35-47 y, body mass index (BMI): 27-53 kg/m2). MEASUREMENTS: Two estrogen metabolites, 2-hydroxyestrone (2OHE1) and estriol (E3), were measured by radioimmunoassay in untimed overnight urine samples, before and after ingestion of 13C. RESULTS: The ratio of urinary estrogens, 2OHE1/E3, was significantly increased in obese women following 13C, reflecting induction of 2-hydroxylation in these women. CONCLUSIONS: Obese premenopausal women experience increased estrogen 2-hydroxylation in response to the dietary agent, 13C, similar to non-obese women. This response to 13C may result in a hormonal milieu that helps reduce estrogen-dependent cancer risk

[Vitex agnus castus extract in the treatment of luteal phase defects due to latent hyperprolactinemia. Results of a randomized placebo-controlled double-blind study].

Milewicz A, Gejdel E, Sworen H, et al.

Arzneimittelforschung. 1993 Jul; 43(7):752-6.

The efficacy of a Vitex agnus castus preparation (Strotan capsules) was investigated in a randomized double blind study vs. placebo. This clinical study involved 52 women with luteal phase defects due to latent hyperprolactinaemia. The daily dose was one capsule (20 mg) Vitex agnus castus preparation and placebo, respectively. Aim of the study was to prove whether the elevated pituitary prolactin reserve can be reduced and deficits in luteal phase length and luteal phase progesterone synthesis be normalized. Blood for hormonal analysis was taken at days 5-8 and day 20 of the menstrual cycle before and after three month of therapy. Latent hyperprolactinaemia was analysed by monitoring the prolactin release 15 and 30 min after i.v. injection of 200 micrograms TRH. 37 complete case reports (placebo: n = 20, verum: n = 17) after 3 month of therapy were statistically evaluated. The prolactin release was reduced after 3 months, shortened luteal phases were normalised and deficits in the luteal progesterone synthesis were eliminated. These changes were significant and occurred only in the verum group. All other hormonal parameters did not change with the exception of 17 beta-estradiol which rouse up in the luteal phase in patients receiving verum. Side effects were not seen, two women treated with the Vitex agnus castus preparation got pregnant. The tested preparation is thought to be an efficient medication in the treatment of luteal phase defects due to latent hyperprolactinaemia

Endometriosis: A Key to Healing Through Nutrition.

Mills DS.


Structure of the adduct of 16 alpha-hydroxyestrone with a primary amine: evidence for the Heyns rearrangement of steroidal D-ring alpha-hydroxyimines.

Miyairi S, Ichikawa T, Nambara T.

Steroids. 1991 Jul; 56(7):361-6.

16 alpha-Hydroxyestrone, a product of estrogen 16 alpha-hydroxylation in humans that is suspected to be implicated in cell transformation, has been found to form stable adducts with nuclear components. The stable covalent adduct formed from 16 alpha-hydroxyestrone with 2-methoxyethylamine via the Heyns rearrangement of the alpha-hydroxyimine was identified as 3-hydroxy-17 beta-(2-methoxyethylamino)estra-1,3,5(10)-trien-16-one. Since the same product was obtained from 16 beta-hydroxyestrone with the amine, the alpha-hydroxyenamine is the most likely intermediate of the Heyns rearrangement. The adduct was fairly stable at 37 C in phosphate buffer (pH 7.4)/methanol (1:1 v/v), while the adduct formed from 16-oxoestradiol was disrupted reversely and completely within 6 hours. The evidence suggests that N-(3-hydroxy-16-oxoestra-1,3,5(10-trien-17 beta-yl)amine is the partial structure of the stable adducts formed from D-ring alpha-ketol estrogens with proteins

Serum progesterone and prognosis in operable breast cancer.

Mohr PE, Wang DY, Gregory WM, et al.

Br J Cancer. 1996 Jun; 73(12):1552-5.

Several studies have now shown that women with operable breast cancer undergoing tumour excision during the luteal phase of the menstrual cycle have a better prognosis than those having surgery during the follicular phase. As part of a prospective study of prognostic factors in breast cancer, blood was taken at the time of surgery. Between 1975 and 1992 this was available from 289 premenopausal women within 3 days of tumour excision. All were treated by either modified radical mastectomy or breast conservation including axillary clearance and the date of last menstrual period (LMP) was known in 239 (80%) cases. Blood samples were assayed for both oestradiol (E2) and progesterone (P). Because of the wide inter-individual variation in E2 levels there was no clear relationship between E2 and LMP. However, using a running mean smoothing technique the expected cyclical variation could be discerned. There was no significant association between E2 and survival. Smoothing of the P data yielded a pattern similar to the normal hormone profile. Those cases with a progesterone level of 4 ng ml-1 or more had a significantly better survival than those with a level < 4 ng ml-1. This was especially clear in node-positive patients (P < 0.01). The possibility of misclassification of menstrual cycle status, because of misreported LMP, has been minimised by applying an independent hormonal measurement (P) of cycle activity. This parameter will also identify women who may be undergoing anovular cycles. Thus this study has confirmed that a raised level of progesterone at the time of tumour excision is associated with an improvement in prognosis for women with operable breast cancer

Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age.


J Clin Endocrinol Metab. 1995; 80(9):2799 (erratum).

Treatment of bone loss in oophorectomized women with a combination of ipriflavone and conjugated equine estrogen.

Nozaki M, Hashimoto K, Inoue Y, et al.

Int J Gynaecol Obstet. 1998 Jul; 62(1):69-75.

OBJECTIVE: We previously reported that 0.625 mg/day of conjugated equine estrogen (CEE) could not prevent acute bone loss in the first year after oophorectomy. The effect of additional administration of ipriflavone on bone mineral density (BMD) and biochemical indices of bone remodeling were studied to investigate whether concurrent use of CEE and ipriflavone prevent acute bone loss in the early stages following surgical menopause. METHODS: One-hundred and sixteen oophorectomized women were randomly divided into four groups according to treatment; group 1: placebo, n = 30; group 2: CEE (0.625 mg/day), n = 29; group 3: ipriflavone (600 mg/day), n = 30; group 4: CEE (0.625 mg/day) plus ipriflavone (600 mg/day), n = 27. Vertebral BMD was measured using dual energy X-ray absorptiometry (DEXA) and two biochemical indices of bone metabolism, urinary pyridinoline (Pyr) and serum intact human osteocalcin (hOC), were also measured before, 24 weeks, and 48 weeks after initiation of treatment. RESULTS: BMD was reduced 48 weeks after treatment by 6.1, 3.9 and 5.1% in groups 1-3, respectively, but by only 1.2% in group 4. Pyr decreased by 49.5, 32.0 and 41.5% in groups 2-4, respectively. hOC also decreased by 45.2 and 21.6% in groups 2 and 4, but increased by 40.5% in group 3, suggesting an inhibitory action of CEE and ipriflavone on the turnover of bone metabolism and stimulatory action of ipriflavone on bone formation. CONCLUSION: Concomitant use of ipriflavone with CEE from an early stage after oophorectomy inhibited bone loss and was considered to be effective in maintaining bone mass after oophorectomy

Upregulation of estradiol C16 alpha-hydroxylation in human breast tissue: a potential biomarker of breast cancer risk.

Osborne MP, Bradlow HL, Wong GY, et al.

J Natl Cancer Inst. 1993 Dec 1; 85(23):1917-20.

BACKGROUND: The biotransformation of the natural estrogen 17 beta-estradiol (E2) via the C16 alpha-hydroxylation pathway is elevated in patients with breast cancer, in subjects at increased risk for developing breast cancer, and in c-Ha-ras-initiated mouse mammary epithelial cells. PURPOSE: To determine whether differences in the extent of E2 C16 alpha-hydroxylation are related to the risk of developing breast cancer, we examined the extent of biotransformation of E2 via the C16 alpha-hydroxylation pathway in the mammary terminal duct lobular units (TDLUs), epithelial organoids that are a presumptive target site of human breast carcinogenesis, and in nontarget component mammary fat tissue. METHODS: Noninvolved mammary tissue was obtained from four patients undergoing reduction mammoplasty and from four undergoing mastectomy for breast cancer. A radiometric assay that measures 3H2O formation caused by stoichiometric 3H exchange from [C16 alpha-3H]E2 was utilized to compare the relative extent of C16 alpha-hydroxylation in explant cultures of TDLUs and mammary fat. RESULTS: The extent of E2 C16 alpha-hydroxylation was 1.83-fold higher (95% confidence interval [CI] = 1.71-1.97) in the TDLUs from reduction mammoplasty (i.e., "low-risk") patients and 7.96-fold higher (95% CI = 6.38-10.55) in the TDLUs from mastectomy (i.e., "high-risk") patients than in the corresponding values observed in the mammary fat. In the TDLUs obtained from the patients undergoing mastectomy for cancer, the extent of this metabolism was 4.56-fold higher (95% CI = 3.97-5.33) than that observed in TDLUs obtained from reduction mammoplasty patients who did not have cancer. CONCLUSION: The increase in the extent of C16 alpha-hydroxylation of E2 in the epithelial organoids of the human breast, TDLUs in particular, may be an important factor for breast cancer induction. This upregulation may represent an endocrine biomarker for the risk of developing breast cancer. IMPLICATION: A larger prospective study is required to confirm the clinical significance of this endocrine biomarker

Omega 3 fatty acids: modulation of estrogen metabolism and potential for breast cancer prevention.


Cancer Invest. 1988; 6(5):629-31.

Part 2: The role of soy in medicine. Presented at the Palais des Congress Conference, Brussels, Belgium, September 15-17, 1996; see also Life Extension Magazine March 1997.

Ostman C.


Androgens and estrogens in relation to hot flushes during the menopausal transition.

Overlie I, Moen MH, Holte A, et al.

Maturitas. 2002 Jan 30; 41(1):69-77.

In this paper, the association of hormones to vasomotor complaints during the menopausal transition is discussed. Fifty-seven regularly menstruating women without history of hormone replacement therapy (HRT) were selected for a longitudinal, prospective study around the menopausal transition. The mean age at the start of the study was 51.3 (+/-2.0) years. At intervals of 12 months all women went through a semi-structured interview and filled in questionnaires. Venous blood samples were collected every 12-month for analyses of estradiol (E2), testosterone, androstendione, dehydroepiandrosterone-sulphate (DHEA-S), follicle stimulating hormone (FSH), thyrotropin (TSH), and luteinizing hormone (LH). Vasomotor complaints were tested using questions about hot flushes and bouts of sweating in terms of occurrence, frequency and degree of distress. Forty-six percent of the subjects reported hot flushes and bouts of sweating before menopause, increasing to 67% during the first year after menopause and 49% in the second year postmenopause. Low levels of estradiol and high levels of FSH were associated with vasomotor complaints before menopause. During menopause high levels of TSH were related to vasomotor complaints. The first year after menopause, women, who at this point achieved hot flushes, were characterised by high levels of E2, but declining and low levels of FSH, but increasing. Postmenopausal, high levels of testosterone and DHEA-S seemed to protect against vasomotor symptoms. Our most important finding was, that among women who achieved hot flushes at the first assessment postmenopause, the high androgen levels was a significant predictor of recovery from hot flushes at the last assessment, 1 year later

NIH Research and Other Efforts Related to the Menopausal Transition.


2002;2002 Apr 22

Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women.

Potter SM, Baum JA, Teng H, et al.

Am J Clin Nutr. 1998 Dec; 68(6 Suppl):1375S-9S.

The effects of soy protein (40 g/d) containing moderate and higher concentrations of isoflavones on blood lipid profiles, mononuclear cell LDL receptor messenger RNA, and bone mineral density and content were investigated in 66 free-living, hypercholesterolemic, postmenopausal women during a 6-mo, parallel-group, double-blind trial with 3 interventions. After a control period of 14 d, during which subjects followed a National Cholesterol Education Program Step I low-fat, low-cholesterol diet, all subjects were randomly assigned to 1 of 3 dietary groups: Step I diet with 40 g protein/d obtained from casein and nonfat dry milk (CNFDM), Step I diet with 40 g protein/d from isolated soy protein containing 1.39 mg isoflavones/g protein (ISP56), or Step I diet with 40 g protein/d from isolated soy protein containing 2.25 mg isoflavones/g protein (ISP90). Total and regional bone mineral content and density were assessed. Non-HDL cholesterol for both ISP56 and ISP90 groups was reduced compared with the CNFDM group (P < 0.05). HDL cholesterol increased in both ISP56 and ISP90 groups (P < 0.05). Mononuclear cell LDL receptor mRNA was increased in subjects consuming ISP56 or ISP90 compared with those consuming CNFDM (P < 0.05). Significant increases occurred in both bone mineral content and density in the lumbar spine but not elsewhere for the ISP90 group compared with the control group (P < 0.05). Intake of soy protein at both isoflavone concentrations for 6 mo may decrease the risk factors associated with cardiovascular disease in postmenopausal women. However, only the higher isoflavone-containing product protected against spinal bone loss

Hormone replacement in women with a history of breast cancer.

Pritchard KI.

Oncologist. 2001; 6(4):353-62.

Estrogen used alone (estrogen replacement therapy [ERT]) or with the addition of progesterone (hormone replacement therapy [HRT]) is known to be effective in reducing menopausal symptoms including hot flashes, vaginal dryness and urinary symptoms. It has been traditionally contraindicated, however, in women with a previous diagnosis of breast cancer because of fear that it may increase the risk of recurrence. There are considerable basic scientific data but little methodologically strong observational data and none from randomized studies concerning the use of ERT in women with a prior diagnosis of breast cancer. From our knowledge of the physiology of breast cancer, however, estrogen and/or progestational agents should be used with caution in women with a previous diagnosis of breast cancer. There are currently many alternatives to ERT/HRT in the prevention of menopausal symptoms such as vitamin E, clonidine and selective serotonin reuptake inhibitor antidepressants such as venlafaxine. There are also a variety of other approaches to the prevention of osteoporosis and cardiovascular disease including bisphosphonates, diet, and exercise; and diet, exercise, and statins, respectively. Other suggested beneficial effects of estrogen such as colon cancer prevention can be approached by the use of aspirin or the non-steroidals. Several trials of ERT/HRT used for 2 years versus no therapy in menopausal women with a previous diagnosis of breast cancer are ongoing in Europe and Britain, and should give us stronger data as to the role of HRT in this setting

Long term use of megestrol acetate by cancer survivors for the treatment of hot flashes.

Quella SK, Loprinzi CL, Sloan JA, et al.

Cancer. 1998 May 1; 82(9):1784-8.

BACKGROUND: Hot flashes are often a troublesome symptom in breast carcinoma survivors and men with prostate carcinoma who have undergone androgen deprivation therapy. A previous clinical study demonstrated that, on a short term basis, low dose megestrol acetate markedly reduced hot flashes and was well tolerated. Little information has been available regarding the long term use of low dose megestrol acetate for hot flashes. METHODS: Patients previously enrolled on a randomized placebo-controlled trial that evaluated the short term use of megestrol acetate for hot flashes were contacted and interviewed by telephone. RESULTS: A total of 132 persons were contacted. Nine percent of the patients discontinued megestrol acetate after resolution of their hot flashes. Forty-five percent of the patients contacted were continuing to utilize megestrol acetate approximately 3 years beyond the conclusion of the 1992 study. Three-quarters of these patients were utilizing < or ="20" mg of megestrol acetate per day. Potential toxicities attributed to megestrol acetate included episodes of chills, appetite stimulation/weight gain, vaginal bleeding, and carpal tunnel syndrome symptoms. CONCLUSIONS: A substantial proportion of patients continue to use megestrol acetate for periods of up to 3 years or longer with continued control of hot flashes. This treatment appears to be relatively well tolerated

Modulation of bcl-2 and cytotoxicity by licochalcone-A, a novel estrogenic flavonoid.

Rafi MM, Rosen RT, Vassil A, et al.

Anticancer Res. 2000 Jul; 20(4):2653-8.

Herbal therapies are commonly used by patients with cancer, despite little understanding about their clinical and biological activity. We recently demonstrated that the herbal combination PC-SPES, which contains licorice root, had potent estrogenic activity in vitro, in animals, and in patients with prostate cancer. Licochalcone-A (LA) is one flavonoid extracted from licorice root with antiparasitic and anti-tumor activity, but the effect on the human estrogen receptor and mechanism of anti-tumor activity is unknown. Recent studies demonstrated that the mechanism of cytotoxic effect by some estrogens may involve modulation of the anti-apoptotic protein bcl-2. In the present study, we determined if LA had estrogenic activity, anti-tumor activity, and modulated the apoptotic protein bcl-2 in human cell lines derived from acute leukemia, breast cancer, and prostate cancer. A yeast growth-based assay under the control of the human estrogen receptor (hER) demonstrated that LA was a phytoestrogen. A cell viability assay demonstrated that LA had anti-tumor activity in all cell lines tested and enhanced the effect of paclitaxel and vinblastine chemotherapy. LA induced apoptosis in MCF-7 and HL-60 cell lines, as demonstrated by cleavage of PARP, the substrate of ICE-like proteases. Immunoblot analysis demonstrated that LA decreased the anti-apoptotic protein bcl-2 and altered the bcl-2/bax ratio in favor of apoptosis. In contrast, the parent compound chalcone or estradiol did not decrease bc1-2 expression. Therefore, these data demonstrate that LA is a phytoestrogen with anti-tumor activity and is capable of modulating bcl-2 protein expression. The modulation of bcl-2 may be dependent on specific structural differences between LA and the parent compound chalcone and independent of LA estrogenicity

Natural Hormone Balance for Women: Look Younger, Feel Stronger, and Live Life with Exuberance.

Reiss U.


Estrogen replacement therapy and longitudinal decline in visual memory. A possible protective effect?

Resnick SM, Metter EJ, Zonderman AB.

Neurology. 1997 Dec; 49(6):1491-7.

Estrogen replacement therapy (ERT) is increasingly recommended for postmenopausal women due to its beneficial effects on physical health in older women. Recent studies have suggested that ERT may have a protective effect on cognitive function and may reduce the risk of Alzheimer's disease. In the present study we test the hypothesis that ERT may have a protective effect on memory in nondemented women. Data on hormonal status and memory were examined in 288 postmenopausal women in the Baltimore Longitudinal Study of Aging. One hundred sixteen women who reported that they were receiving ERT during a cognitive assessment were compared with 172 women who had never received ERT. Women who were receiving ERT had fewer errors on the Benton Visual Retention Test (BVRT), a measure of short-term visual memory, visual perception, and constructional skills. Furthermore, ERT appeared to protect against age changes in BVRT performance in a subgroup of 18 women for whom BVRT data were available before and during treatment with ERT. These findings suggest that ERT may protect against memory decline in nondemented postmenopausal women and offer further support for a beneficial role of estrogen on cognitive function in aging women

Estrogen replacement therapy and fatal ovarian cancer.

Rodriguez C, Calle EE, Coates RJ, et al.

Am J Epidemiol. 1995 May 1; 141(9):828-35.

The authors examined the relation between use of estrogen replacement therapy and ovarian cancer mortality in a large prospective mortality study of 240,073 peri- and postmenopausal women, none of whom had a prior history of cancer, hysterectomy, or ovarian surgery at enrollment in 1982. During 7 years of follow-up, 436 deaths from ovarian cancer occurred. Cox proportional hazard regression was used to adjust for other risk factors. Ever use of estrogen replacement therapy was associated with a rate ratio for fatal ovarian cancer of 1.15 (95% confidence interval (CI) 0.94-1.42). The mortality rate ratio increased with duration of use prior to entry to this study to 1.40 (95 CI% 0.92-2.11) with 6-10 years of use and 1.71 (95% CI 1.06-2.77) with > or = 11 years of use. The increase in mortality associated with > or = 6 years of use was observed in both current users (rate ratio (RR) = 1.72, 95% CI 1.01-2.90) and former users at study entry (RR = 1.48, 95% CI 0.99-2.22), relative to never users. Risk associated with use was not modified by any of the other risk factors. These data suggest that long-term use of estrogen replacement therapy may increase the risk of fatal ovarian cancer

Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis.

Rosen CA, Woodson GE, Thompson JW, et al.

Otolaryngol Head Neck Surg. 1998 Jun; 118(6):810-5.

OBJECTIVE: We report the preliminary results of a phase I trial using indole-3-carbinol for the treatment of recurrent respiratory papillomatosis. Indole-3-carbinol is a chemical that is found in high concentrations in cruciferous vegetables and has been shown to alter the growth pattern of recurrent respiratory papillomatosis cell cultures and to be effective in an in vivo animal model of recurrent respiratory papillomatosis. METHODS: Eighteen patients were treated with oral indole-3-carbinol and had a minimum follow-up of 8 months and a mean follow-up of 14.6 months. All patients received indole-3-carbinol, and outcome measures included a change in papilloma growth rate and the need for surgery during treatment compared with before treatment. All patients had serial examinations with videoendoscopy to document papilloma location and growth rate. RESULTS: Thirty-three percent (6 of 18) of the study patients had a cessation of their papilloma growth and have not required surgery since the start of the study. Six patients have had reduced papilloma growth rate, and 6 (33%) patients have shown no clinical response to indole-3-carbinol. Indole-3-carbinol affects the ratio of hydroxylation of estradiol; changes in the ratios of urinary 2-hydroxylation and 16-hydroxylation of estradiol caused by indole-3-carbinol correlated well with clinical response. No major complications or changes in the children's growth curve were noted. CONCLUSIONS: The preliminary results of treating recurrent respiratory papillomatosis with indole-3-carbinol holds promise. Longer follow-up of this patient group and a blinded, controlled trial are required. We conclude that indole-3-carbinol appears to be safe and well tolerated and may be an efficacious treatment for recurrent respiratory papillomatosis

Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial.

Rossouw JE, Anderson GL, Prentice RL, et al.

JAMA. 2002 Jul 17; 288(3):321-33.

CONTEXT: Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain. OBJECTIVE: To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States. DESIGN: Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998. INTERVENTIONS: Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102). MAIN OUTCOMES MEASURES: The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes. RESULTS: On May 31, 2002, after a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 person-years. CONCLUSIONS: Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD

Psychosexual effects of menopause: role of androgens.

Sarrel PM.

Am J Obstet Gynecol. 1999 Mar; 180(3 Pt 2):S319-S324.

Ovarian hormones-estrogens, androgens, and progesterone-produce a myriad of effects in the nervous system. The effects of androgens in the brain are mediated through androgen-specific receptors and by the aromatization of testosterone to estradiol. Alterations in the circulating levels of androgens play an important role in psychologic and sexual changes that occur after menopause. The effects of short-term estrogen therapy in improving psychologic symptoms, maintaining vaginal lubrication, decreasing vaginal atrophy, and increasing pelvic blood flow in postmenopausal women are well documented. However, some patients require more than estrogen alone to improve psychologic dysfunction, decreased sexual desire, or other sexual problems associated with menopause. Results from clinical studies show that hormone replacement therapy with estrogen plus androgens provides greater improvement in psychologic (eg, lack of concentration, depression, and fatigue) and sexual (eg, decreased libido and inability to have an orgasm) symptoms than does estrogen alone in naturally and surgically menopausal women

Abnormal oxidative metabolism of estradiol in women with breast cancer.

Schneider J, Kinne D, Fracchia A, et al.

Proc Natl Acad Sci U S A. 1982 May; 79(9):3047-51.

The three dominant oxidative biotransformations of estradiol were examined in 10 normal women and 33 females with breast cancer by using a recently devised radiometric method. Estradiol tracers, labeled with 3H specifically in the 17 alpha, C-2, or 16 alpha position, were used to measure both the rate and extent of 17 beta-ol oxidation (the initial metabolic step) and the subsequent 2- and 16 alpha-oxidative reactions. The mean +/- SEM values for the extent of extradiol metabolism at these three specific sites for the extent of estradiol metabolism at these three specific sites were 76.9 +/- 5.3%, 31.1 +/- 4.0%, and 9.3 +/- 0.8%, respectively in normal subjects. Corresponding data in patients with breast cancer--i.e., 73.0 +/- 4.2%, 32.7 +/- 2.7%, and 14.9 +/- 1.5%--revealed a significantly greater extent of 16 alpha-hydroxylation in the latter population. Because the 16 alpha-hydroxylated compounds (including estriol) are themselves potent estrogens, these changes may have important hyperestrogenic consequences that could have a bearing on the etiology of the disease

Antiestrogen action of 2-hydroxyestrone on MCF-7 human breast cancer cells.

Schneider J, Huh MM, Bradlow HL, et al.

J Biol Chem. 1984 Apr 25; 259(8):4840-5.

The estrogen responsive human breast cancer MCF-7 cell culture was examined for its response to 2-hydroxyestrone a principal metabolite of estradiol. Addition of 2-hydroxyestrone to the cell cultures in concentration of 10(-9) - 10(-6) M had no effect on cell growth and proliferation because of rapid O-methylation of the catechol estrogen by catechol O-methyltransferase which is highly active in these cells. In the presence of quinalizarin, a potent catechol O-methyltransferase inhibitor which reduces the O-methylation of the steroid, 10(-7) M and 10(-8) M 2-hydroxyestrone markedly suppresses the growth and proliferation of the cells. The tumor cell growth-inhibitory action of the catechol estrogen was neutralized by the presence of 10(-9) M estradiol. The catechol estrogen inhibition of cell growth is not observed in the estrogen receptor-negative human breast cancer cell lines MDA-MB-231 and MDA-MB-330 providing evidence that the inhibition is specific and is estrogen receptor-mediated. In contrast, the 16 alpha-hydroxylated metabolites of estradiol, estriol and 16 alpha-hydroxyestrone, are effective stimulators of MCF-7 cell proliferation with the latter exhibiting potency in excess of that expected from its estrogen receptor affinity. The present results represent the first observation of a specific receptor-mediated antiestrogenic action of 2-hydroxyestrone and suggest that the physiological regulation of the agonist activity of the primary estrogen may involve in situ generation of catechol estrogen

Estrogen metabolite ratios and risk assessment of hormone-related cancers. Assay validation and prediction of cervical cancer risk.

Sepkovic DW, Bradlow HL, Ho G, et al.

Ann N Y Acad Sci. 1995 Sep 30; 768:312-6.

Phytoestrogens: the biochemistry, physiology, and implications for human health of soy isoflavones.

Setchell KD.

Am J Clin Nutr. 1998 Dec; 68(6 Suppl):1333S-46S.

The importance of estrogens in homeostatic regulation of many cellular and biochemical events is well illustrated by the pathophysiologic changes that occur with estrogen deficiency. Many of the major diseases of Western populations are hormone dependent and epidemiologic data have shown a strong association between their incidence and diet. In particular, the importance of a plant-based diet is evident from the current dietary recommendations that emphasize an increase in the proportion and amount of fruit and vegetables that should be consumed. Although interpretation of the role of individual components of the diet is difficult from epidemiologic and dietary studies, it is recognized that there are many plant-derived bioactive nonnutrients that can confer significant health benefits. Among these phytochemicals is the broad class of nonsteroidal estrogens called phytoestrogens, and in the past decade there has been considerable interest in the role of isoflavones because of their relatively high concentrations in soy protein. The isoflavones in modest amounts of ingested soy protein are biotransformed by intestinal microflora, are absorbed, undergo enterohepatic recycling, and reach circulating concentrations that exceed by several orders of magnitude the amounts of endogenous estrogens. These phytoestrogens and their metabolites have many potent hormonal and nonhormonal activities that may explain some of the biological effects of diets rich in phytoestrogens

Bioavailability of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements.

Setchell KD, Brown NM, Desai P, et al.

J Nutr. 2001 Apr; 131(4 Suppl):1362S-75S.

The pharmacokinetic behavior of naturally occurring isoflavones has been determined for the first time in healthy adults. We compared plasma kinetics of pure daidzein, genistein and their beta-glycosides administered as a single-bolus dose to 19 healthy women. This study demonstrates differences in the pharmacokinetics of isoflavone glycosides compared with their respective beta-glycosides. Although all isoflavones are efficiently absorbed from the intestinal tract, there are striking differences in the fate of aglycones and beta-glycosides. Mean time to attain peak plasma concentrations (t(max)) for the aglycones genistein and daidzein was 5.2 and 6.6 h, respectively, whereas for the corresponding beta-glycosides, the t(max) was delayed to 9.3 and 9.0 h, respectively, consistent with the residence time needed for hydrolytic cleavage of the glycoside moiety for bioavailability. The apparent volume of distribution of isoflavones confirms extensive tissue distribution after absorption. Plasma genistein concentrations are consistently higher than daidzein when equal amounts of the two isoflavones are administered, and this is accounted for by the more extensive distribution of daidzein (236 L) compared with genistein (161 L). The systemic bioavailability of genistein [mean AUC = 4.54 microg/(mL x h)] is much greater than that of daidzein [mean AUC = 2.94 microg/(mL x h)], and bioavailability of these isoflavones is greater when ingested as beta-glycosides rather than aglycones as measured from the area under the curve of the plasma appearance and disappearance concentrations. The pharmacokinetics of methoxylated isoflavones show distinct differences depending on the position of the methoxyl group in the molecule. Glycitin, found in two phytoestrogen supplements, underwent hydrolysis of the beta-glycoside moiety and little further biotransformation, leading to high plasma glycitein concentrations. Biochanin A and formononetin, two isoflavones found in one phytoestrogen supplement, were rapidly and efficiently demethylated, resulting in high plasma genistein and daidzein concentrations typically observed after the ingestion of soy-containing foods. These differences in pharmacokinetics and metabolism have implications for clinical studies because it cannot be assumed that all isoflavones are comparable in their pharmacokinetics and bioavailability. An analysis of 33 phytoestrogen supplements and extracts revealed considerable differences in the isoflavone content from that claimed by the manufacturers. Plasma concentrations of isoflavones show marked qualitative and quantitative differences depending on the type of supplement ingested. These studies indicate a need for improvement in quality assurance and standardization of such products

Estrogenic effects on memory in women.

Sherwin BB.

Ann N Y Acad Sci. 1994 Nov 14; 743:213-30.

Sufficient evidence now exists to support the contention that estrogen influences cognitive functioning in women. Moreover, the data strongly suggest that estrogen exerts a specific and not a global effect on cognitive functions. Whereas estrogen enhances and/or maintains aspects of verbal memory, it is without effect, or possibly even has a negative influence on spatial memory. Indeed, there is some preliminary evidence that progesterone may enhance visual-spatial skills in women but this needs to be confirmed. Estrogen also exerts a positive effect on sexually dimorphic cognitive skills in which females typically excel such as verbal articulation and fine motor skills. While the weight of the evidence supports the above conclusion, findings across studies are not entirely consistent. Some of the methodological problems that weaken these studies include generalizing from one or two cognitive tasks to the entire realm of cognitive functions, neglecting to assay plasma levels of estradiol to confirm cycle phase or compliance with hormone administration and neglecting to consider the differential availability to the brain of the various estrogen preparations and the effects of different routes of administration. Although, for the most part, the menstrual cycle studies and the postmenopausal studies in healthy women show that estrogen maintains verbal memory, the effect size is modest. There is no reason to believe, for example, that verbal memory is truly impaired in women during phases of the menstrual cycle marked by low levels of estrogen. Nor are 45-year-old untreated, surgically menopausal women clinically impaired to any degree that affects their daily functioning in the real world. In both cases, however, decrements in performance occur reliably in the laboratory. This raises the issue, therefore, of the clinical meaningfulness of these findings. One way to address the clinical relevance of the relationship between estrogen and memory and thus, on cognitive functioning of the brain, is to examine what is known of estrogenic effects on other physiological systems where we already have substantial information. For example, the vast majority of women experience bone loss following the menopause and many develop osteopenia (bone density more than two standard deviations below mean peak bone mass levels) which is asymptomatic. Then, with advancing age, some women with osteopenia develop osteoporosis, predisposing them to fractures following minimal trauma. It has been estimated that 40 per cent of women who live to age 80 will develop spinal fractures and 33 per cent of women who live to age 90 will experience a hip fracture.(ABSTRACT TRUNCATED AT 400 WORDS)

Role of human hepatic cytochrome P450 1A2 and 3A4 in the metabolic activation of estrone.

Shou M, Korzekwa KR, Brooks EN, et al.

Carcinogenesis. 1997 Jan; 18(1):207-14.

The metabolic activation of estrone (E1), a potent estrogen was investigated using recombinant human cytochrome P450 enzymes, 1A2, 2B6, 2C8, 2C9, 2C9R144C, 2E1, 3A4, 3A5 and liver microsomes from 14 human organ donors. At least five products of E1 were detected and quantitated by HPLC and gas chromatography-mass spectrometry (GC-MS). Among these metabolites, 16alpha-OH-E1, 2-OH-E1 and 4-OH-E1, which are believed to be associated with estrogen carcinogenesis in animals, were definitively identified. Of all P450s examined, 1A2 and 3A4 exhibited the highest activities with turnovers of 3.4 and 2.5 nmol/min/nmol P450 for the total metabolism of E1, respectively, while 3A5, 2C9 and 2C9R144C showed moderate activities. 2B6, 2E1 and 2C8 did not produce any significant amount of products. 1A2 formed almost exclusively the 2-OH-E1 at a rate of 3.3 nmol/min/nmol but 3A4 preferentially formed the metabolite X1 (an unknown hydroxylation product) and 16alpha-OH-E1. Kinetic characterization showed that the Km values of 1A2, 3A4 and 3A5 were 14, 95 and 64 microM and Vmax were 5.43, 0.68 and 0.35 min(-1), respectively. All human liver microsomes were capable of metabolizing estrone and a 4-fold variation was seen between individuals. The relative amount of metabolites formed was generally 2-OH-E1 > metabolite X1 > 4-OH-E1 > 16alpha-OH-E1 > metabolite X2. 3A4/5 enzyme complex was assessed by inhibitory monoclonal antibody specific for 3A4/5 to contribute 60-88% to the formation of individual metabolites in human liver except for 2-OH-E1 (3%). The formation of 2-OH-E1 and 16alpha-OH-E1 by 14 human liver microsomes was significantly correlated with caffeine 3-demethylation supported by 1A2 (r2 = 0.87) and with testosterone 6beta-hydroxylation by 3A4 (r2 = 0.66), respectively. Thus the metabolic patterns exhibited by human liver are likely due to the combined activities of the P450 1A2 and 3A4 enzymes

Hormone replacement therapy: cardiovascular benefits for aging women.

Sites CK.

Coron Artery Dis. 1998; 9(12):789-93.

Observational studies suggest that hormone replacement therapy (HRT) reduces the risk of coronary artery disease by approximately 50%. This review focuses on possible mechanisms for this reduction in disease risk. HRT reverses many of the lipid and lipoprotein change associated with menopause, and the route of hormone delivery influences these changes. Oral HRT improves serum markers of clotting, although it may increase the risk of deep vein thrombosis. Endothelial function, particularly endothelium-dependent vasodilation, improves with estrogen. Central body fat appears to be reduced with oral HRT, possibly reducing the risk of coronary artery disease. Insulin sensitivity, which worsens after menopause, may be improved with HRT. Global systolic function, as measured by ejection fraction, may improve with oral HRT. Understanding how HRT regimens influence cardiovascular risk may allow physicians to make intelligent choices about HRT for particular patients

Risks of menopausal androgen supplementation.

Slayden SM.

Semin Reprod Endocrinol. 1998; 16(2):145-52.

There is increasing interest in the use of menopausal androgen replacement therapy (MART) in symptomatic women undergoing natural or surgical menopause. However, the efficacy of MART in alleviating these symptoms compared to traditional estrogen/progestin hormone replacement therapy remains a subject of debate. Accordingly, attention must be focused on the side-effects of the various MART preparations. The dose, alkylation, and route of administration of these compounds influences the development of side effects. While all androgens are potential virilizing agents, alkylated compounds have an additional risk of inducing severe hepatic consequences, regardless of their route of administration. Fortunately, the lower doses administered to women compared to men has not resulted in significant hepatic events. Generation of an adverse lipoprotein profile is possible but is not addressed in this article. Thus, virilizing and cutaneous side effects remain the primary concern. While some observational studies indicate acne and/or hirsutism are evident in up to 38% and 36% of oral methyltestosterone-treated patients, respectively, other studies performed in a prospective fashion suggest a much lower incidence of approximately 5%. Other reported virilizing effects include deepening of the voice and clitoromegaly. Additional concerns are related to risks of developing endometrial hyperplasia when MART is used in conjunction with estrogens. Fortunately, concomitant progestin administration is protective. Finally, there is a theoretical concern that MART may increase the risk of developing breast cancer but this has not been demonstrated in clinical practice. Overall, the safety profile of MART appears to be acceptable when dosing avoids supraphysiologic testosterone levels

Twenty-year follow-up of the breast cancers diagnosed during the Breast Cancer Detection Demonstration Project.

Smart CR, Byrne C, Smith RA, et al.

CA Cancer J Clin. 1997 May; 47(3):134-49.

This study reports on the 20-year follow-up of the women diagnosed with breast cancer in the Breast Cancer Detection Demonstration Project (BCDDP) between 1973 and 1980. This project provided 5 years of screening with physical examination and two-view mammography for 280,000 volunteer women across the United States. Based on a 96% follow-up from 1993 to 1995 of the 4,051 women with breast cancer available for analysis, 2,658 (66%) were alive and 1,393 (34%) were dead. A high proportion of the cancers were detected by mammography alone, and 28.6% of all the cancers were smaller than 1.0 cm. Survival rates were calculated by life table method with deaths from breast cancer as the outcome. The adjusted survival rate for the entire group was 80.5%, and the observed survival rate was 61.7%. Adjusted and observed survival rates were 97.2% and 78.5%, respectively, for women with non-invasive cancers and 78.2% and 59.3%, respectively, for those with invasive cancers. Lymph node status and the size of the cancer at diagnosis were prognostic indicators of survival in the BCDDP Women with invasive cancers and negative lymph nodes had an 85.5% breast cancer survival rate and a 65.6% observed survival rate. Adjusted survival rates for women with invasive breast cancers were 90.2% for cancers smaller than 1 cm, 80.5%, for cancers 1.0 to 1.9 cm, 70.5% for cancers 2.0 to 4.9 cm, and 60.6% for cancers larger than 5 cm. Women 40 to 49 years of age demonstrated a greater survival with noninvasive or invasive cancers smaller than 5.0 cm compared with women 50 to 59 and 60 to 69 years of age at diagnosis. These results from the BCDDP are discussed in the context of the recent decline in breast cancer incidence and mortality in the United States

[Principles of hormone replacement therapy in climacteric].

Smetnik VP.

Vestn Ross Akad Med Nauk. 1997;(2):34-8.

With age-specific diminished and excluded ovarian function and estrogen deficiency, 60% of females may develop various systemic disorders (the menopausal syndrome, urogenital and cardiovascular diseases, osteoporosis). In the past 10-15 years, hormone replacement treatment regimens have been developed for climacteric females. Numerous epidemiological surveys have indicated that hormone replacement therapy shows a 50% reduction in the incidence of stroke, myocardial infarction, bone fractures. Therefore, post-menopausal hormone therapy is indicated both for therapeutical and prophylactic purposes, which may increase female longevity

Estrogen 2-hydroxylase oxidation and menstrual function among elite oarswomen.

Snow RC, Barbieri RL, Frisch RE.

J Clin Endocrinol Metab. 1989 Aug; 69(2):369-76.

We monitored the estrogen metabolism and menstrual function of two groups of elite oarswomen as they progressed from a phase of low intensity training (phase I), to high intensity training (phase II), and back to low intensity training (phase III). Each phase lasted 3 months. The two groups of oarswomen included five oarswomen (group A) who experienced no menstrual dysfunction during the training year, even during the phase of high intensity training, and five oarswomen (group B) who experienced normal menses during phases of low intensity training but disrupted menses during the phase of high intensity training. Four nonathletic controls were also studied. Menstrual function was monitored throughout the training year by assay for pregnanediol glucuronide in overnight 12-h urine samples collected twice weekly. Repeated measures of the extent of estradiol metabolized by 2-hydroxylase oxidation, total body water, and nutrient intake of group A and B oarswomen were made at the three phases of the training year; the extent of estradiol metabolized by 2-hydroxylase oxidation was evaluated by radiometric analysis; total body water was measured by deuterium oxide dilution and bioimpedance analysis; and nutrient intake was evaluated by food frequency questionnaire. The group B oarswomen were found to metabolize a significantly greater fraction of administered [2-3H]estradiol by 2-hydroxylase oxidation than group A oarswomen (chi 2(1) = 6.57; P = 0.01). The extent of estradiol metabolized by 2-hydroxylase oxidation among group A oarswomen did not differ from that among nonathletic controls. The extent of 2-hydroxylase activity did not change significantly with the intensity of training among either group A or group B oarswomen. Oarswomen in groups A and B lost body weight and became leaner during the phase of high intensity training (phase II). Group A and B oarswomen did not differ in the degree of weight loss or in relative fatness during phase II. Over all subjects, the extent of estradiol metabolized by 2-hydroxylase oxidation was positively correlated with the extent of leanness. These data suggest that elevated estradiol 2-hydroxylase oxidation among elite oarswomen is associated with the occurrence of menstrual disturbances during phases of high intensity training and increased relative leanness

Soy intake related to menopausal symptoms, serum lipids, and bone mineral density in postmenopausal Japanese women.

Somekawa Y, Chiguchi M, Ishibashi T, et al.

Obstet Gynecol. 2001 Jan; 97(1):109-15.

OBJECTIVE: To evaluate the effects of dietary isoflavones in soy products on menopausal symptoms, lipid profiles, and bone mineral densities in postmenopausal Japanese women. METHODS: We estimated the daily intakes of isoflavones in the diets of 478 postmenopausal Japanese women who reported soy consumption. We recorded serum values of fasting total cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and apolipoproteins. Bone mineral density was measured at the lumbar spine (L2-L4) by dual energy x-ray absorptiometry. Women were assigned to two groups according to years since menopause (early and late postmenopausal groups), and each group was subcategorized into four groups according to dietary isoflavone intake. Relationships between isoflavone intake, menopausal symptoms, lipid profiles, and bone mineral density were examined in each group. RESULTS: The mean estimated intake of isoflavones among 478 women was 54.3 mg/day. With stepwise regression analysis we found that weight and years since menopause were significant independent predictors of bone mineral density. Bone mineral densities adjusted to years since menopause and weight were significantly different in the highest intake compared with lowest intake category (P

Isoflavone-rich or isoflavone-poor soy protein does not reduce menopausal symptoms during 24 weeks of treatment.

St Germain A, Peterson CT, Robinson JG, et al.

Menopause. 2001 Jan; 8(1):17-26.

OBJECTIVE: We examined the change in menopausal symptoms in response to 24 weeks of isoflavone-rich (80.4 mg/day) and isoflavone-poor (4.4 mg/day) soy protein isolate treatment in perimenopausal women. DESIGN: In this double-blind 24-week study, 69 women were randomized to treatment: isoflavone-rich soy protein (n = 24), isoflavone-poor soy protein (n = 24), or whey protein control (n = 21). A Menopausal Index was used to assess change in hot flushes and night sweats, as well as other symptoms, at baseline, week 12, and week 24. RESULTS: Repeated measures analysis of variance indicated no treatment effect on change in hot flush (p = 0.18) and night sweat (p = 0.92) frequency, whereas there was a significant decline in hot flush (p = 0.0003) and night sweat (p = 0.0007) frequency with time in all treatment groups. Chi2 analyses indicated no treatment effect on severity of hot flushes or night sweats at any time point, as well as no treatment effect on frequency or severity of other vasomotor symptoms. At the completion of the study, we found no treatment effect on retrospective perception of frequency, duration, or severity of hot flushes or night sweats. Since time had a significant effect on symptoms with all groups reporting a decline in overall symptoms, this indicated either a placebo effect or simply an improvement in symptoms during the study. CONCLUSION: In this study, we found no evidence that isoflavone-rich or isoflavone-poor soy protein provided relief of vasomotor or of other menopausal symptoms

Approach to menopausal symptoms in women with breast cancer.

Stearns V, Hayes DF.

Curr Treat Options Oncol. 2002 Apr; 3(2):179-90.

Hot flashes represent one of the most bothersome complaints in breast cancer survivors. In the last two decades, studies investigated several agents and natural compounds to treat these symptoms. Hormones such as estrogens and progestins remain the most beneficial treatment. However, many physicians and patients are reluctant to use these therapies because of the controversy regarding the hormonal effects on tumor growth and progression. Unfortunately, most natural and nonconventional remedies that have been scientifically investigated appear disappointing. Selective serotonin re-uptake inhibitors and other agents that seem to work in similar ways have been investigated over the last few years in Phase II and III trials. Mature results from two prospective, randomized, placebo-controlled trials reveal that selective serotonin re-uptake inhibitors are well tolerated, reduce hot flashes by 50%-60%, and improve sleep and libido. Selective serotonin re-uptake inhibitors should be considered as a first-line nonhormonal pharmacologic therapy for women with menopausal symptoms

An alternative to treat menopausal complaints.

Stolze H.

Gynecology. 1982;(3):14-6.

Covalent binding of the endogenous estrogen 16 alpha-hydroxyestrone to estradiol receptor in human breast cancer cells: characterization and intranuclear localization.

Swaneck GE, Fishman J.

Proc Natl Acad Sci U S A. 1988 Nov; 85(21):7831-5.

The interactions of 16 alpha-hydroxyestrone (16 alpha-OHE1), a metabolite of estradiol (E2), with estrogen receptors (ERs) were compared in this study to the classic E2-receptor mechanism in human breast cancer cells MCF-7 in culture. When MCF-7 cells were incubated with radioinert 16 alpha-OHE1 or its 3H-labeled form for 4 weeks, the estrogen bound extensively and irreversibly in a time-dependent fashion to nuclear protein species that correspond to the ER. Here we show that the interactions of 16 alpha-OHE1 with the ER are different from those of E2 with the receptor. Dissociation of tritiated E2-ER or 16 alpha-OHE1-ER complexes, salt extraction, DNase and proteinase K digestion, and ethanol treatment demonstrated that the binding of 16 alpha-OHE1 to the ER corresponds to two different forms: a classical noncovalent interaction similar to that of E2, and a covalent adduct formation between the metabolite and the ER. These complexes localized preferentially in nuclear matrix components as revealed by cell fractionation and probing with a monoclonal anti-ER antibody. [3H]16 alpha-OHE1-ER complexes analyzed by polyacrylamide gel electrophoresis demonstrated a radiolabeled band at approximately 66 kDa that was absent when the exposure of cells was done in the presence of E2 in competition and that was also absent in [3H]E2 incubations. The present results when considered together with our previous findings of elevated activities of estrogen 16 alpha-hydroxylase, the enzyme responsible for the formation of 16 alpha-OHE1, in breast cancer patients and in women at enhanced risk for the disease, suggest that covalent modification of the ER may be one mechanism of malignant transformation in estrogen target tissues

Efficacy and safety of oral estriol for managing postmenopausal symptoms.

Takahashi K, Manabe A, Okada M, et al.

Maturitas. 2000 Feb 15; 34(2):169-77.

OBJECTIVE: to assess the therapeutic efficacy and safety of oral estriol for the treatment of climacteric symptoms in postmenopausal women. METHODS: 68 postmenopausal women with climacteric symptoms received oral estriol, 2 mg/day, daily for 12 months. We evaluated the degree of climacteric complaints with estriol therapy; serum levels of gonadotropins, estradiol (E2) and lipids; biochemical markers of bone metabolism; blood pressure; and side effects both at baseline and during treatment. Climacteric symptoms were assessed according to the menopausal index (MI), a version of the Kupperman index that had been modified for Japanese women. RESULTS: oral estriol therapy significantly reduced total MI scores. The greatest relief was noted for hot flushes, night sweats, and insomnia. Estriol treatment significantly lowered serum follicle stimulating hormone (FSH) and luteinizing hormone (LH) concentrations but did not affect any of the other parameters (lipids, bone, liver and blood pressure) during the study period. Slightly vaginal bleeding occurred in 14.3% of those who underwent natural menopausal women. Histologic evaluation of the endometrium and ultrasound assessment of the breasts following 12 months of estriol treatment found normal results in all women. CONCLUSION: Estriol is a safe and effective alternative for relieving climacteric symptoms in postmenopausal Japanese women

Safety and efficacy of oestriol for symptoms of natural or surgically induced menopause.

Takahashi K, Okada M, Ozaki T, et al.

Hum Reprod. 2000 May; 15(5):1028-36.

To assess the safety and efficacy of oestriol in relieving post-menopausal symptoms 53 post-menopausal Japanese women with climacteric symptoms, 27 with natural menopause (group I) and 26 with surgically induced menopause (group II), received oral oestriol, 2 mg daily for 12 months. Clinical parameters including Kupperman index (KI) and the degree of satisfaction with symptomatic relief; serum concentrations of oestradiol, FSH and LH; serum lipids; blood pressure; bone mineral density, serum calcium (Ca), alkaline phosphatase (ALP), and urinary Ca were compared between the two groups. Oestriol improved KI in groups I and II by 49 and 80% respectively. Satisfaction with treatment was 85% in group I and 93% in group II. For both parameters, values were significantly different between groups I and II (P < 0.05 for both). Serum concentrations of oestradiol, FSH and LH changed in group I versus group II 6 months after initiation. A significant decrease in serum ALP and Ca/Cr was observed in group I at 6 months. Except for serum triglycerides, oestriol had no significant effect on lipids. Systolic and diastolic blood pressures were significantly decreased in group I at 3 months versus baseline. Slight vaginal bleeding occurred in 14.3% of group I. Histological evaluation of the endometrium in all women of group I and ultrasound assessment of the breasts following 12 months of oestriol treatment found normal results in all women. Therefore, oestriol appeared to be safe and effective in relieving symptoms of menopausal women. The beneficial biochemical effects of oestriol were marked in the natural menopause. Overall, oestriol may serve as a good choice for hormone replacement therapy to protect against other climacteric symptoms in post-menopausal women who do not need medication for osteoporosis or coronary artery disease

[Effect of shakuyaku-kanzo-to, shakuyaku, kanzo, paeoniflorin, glycyrrhetinic acid and glycyrrhizin on ovarian function in rats].

Takeuchi T.

Nippon Naibunpi Gakkai Zasshi. 1988 Nov 20; 64(11):1124-39.

It is known that amenorrhea, oligomenorrhea, irregular menstrual cycles, luteal insufficiency and infertility are frequently associated with hyperandrogenism. It has been reported in previous studies that the traditional herbal medicine, Shakuyaku-Kanzo-To(SKT) can lower high serum testosterone levels in oligomenorrheic or amenorrheic women, and that some of these sterile women conceive. SKT contains Shakuyaku (S) and Kanzo (K) in equal amounts. The main component of S and K is paeoniflorin and glycyrrhizin, respectively. This study was designed to investigate the mechanism in lowering serum testosterone (T) levels by SKT. Experiment I: Female Wistar rats were injected subcutaneously with 500 micrograms of testosterone propionate at the age of 2 days, becoming androgen-sterilized rats (ASR). Fifty-six-day-old ASR were given orally SKT (22.5, 45, 90 and 180 mg/kg body weight), S or K (11.25, 22.5, 45 and 90 mg/kg b.w.) in water through a tube every day for 2 weeks. Control ASR were given only water. Each group consisted of 10 rats. Serum total and free T levels in SKT and S groups were significantly lower than those in the controls, and these decreases were dose-dependent. Experiment II: Female Wistar rats were oophorectomized at the age of 60 days. From one week later they were given orally SKT (90 and 180 mg/kg b.w.), S or K (45 and 90 mg/kg b.w.) every day for 2 weeks. Control rats were given only water. Each group consisted of 11 rats. There was no change in serum T, LH and FSH levels in either groups. The results from experiment I and II suggest that SKT influences the T production by ovaries but not by adrenal glands. Experiment III: The minced tissues of one ovary obtained from proestrous Wistar rats were incubated with media containing Paeoniflorin(P), Glycyrrhetinic acid(GA) or Glycyrrhizin(GL) (GL) (1, 50 and 100 micrograms/ml, respectively, n = 5 in each group) for 270 minutes at 37 degrees C under an atmosphere of 95%O2 and 5%CO2. The T production by ovaries was significantly decreased in each treated group in comparison with the control, and this decrease was dose-dependent. However, the delta 4-androstenedione (delta 4-A) production by ovaries was increased in each treated group. The ratio of T to delta 4-A was significantly lower in each treated group than in the control. The estradiol(E2) production by ovaries in each treated group was not changed in comparison with the control.(ABSTRACT TRUNCATED AT 400 WORDS)

Estrogenic and antiproliferative properties of glabridin from licorice in human breast cancer cells.

Tamir S, Eizenberg M, Somjen D, et al.

Cancer Res. 2000 Oct 15; 60(20):5704-9.

There is an increasing demand for natural compounds that improve women's health by mimicking the critical benefits of estrogen to the bones and the cardiovascular system but avoiding its deleterious effects on the breast and uterus. The estrogenic properties of glabridin, the major isoflavan in licorice root, were tested in view of the resemblance of its structure and lipophilicity to those of estradiol. The results indicate that glabridin is a phytoestrogen, binding to the human estrogen receptor and stimulating creatine kinase activity in rat uterus, epiphyseal cartilage, diaphyseal bone, aorta, and left ventricle of the heart. The stimulatory effects of 2.5-25 microg/animal glabridin were similar to those of 5 microg/animal estradiol. Chemical modification of glabridin showed that the position of the hydroxyl groups has a significant role in binding to the human estrogen receptor and in proliferation-inducing activity. Glabridin was found to be three to four times more active than 2'-O-methylglabridin and 4'-O-methylglabridin, and both derivatives were more active than 2',4'-O-methylglabridin. The effect of increasing concentrations of glabridin on the growth of breast tumor cells was biphasic. Glabridin showed an estrogen receptor-dependent, growth-promoting effect at low concentrations (10 nM-10 microM) and estrogen receptor-independent antiproliferative activity at concentrations of > 15 microM. This is the first study to indicate that isoflavans have estrogen-like activities. Glabridin and its derivatives exhibited varying degrees of estrogen receptor agonism in different tests and demonstrated growth-inhibitory actions on breast cancer cells

Estrogen metabolite 16a hydroxyestrone induces genotoxic damage and aberrant cell proliferation in mouse mammary epithelial cells in culture.


J Natl Cancer Inst. 1992;(82):634-8.

[Bioavailability of soy isoflavones in supplements for menopausal women].

Thomas JL, Couston S, Joubrel G, et al.

Presse Med. 2001 Jan 20; 30(2):63.

Estriol in the management of the menopause.

Tzingounis VA, Aksu MF, Greenblatt RB.

JAMA. 1978 Apr 21; 239(16):1638-41.

Estriol was administered for a six-month period as estrogen replacement therapy to 52 symptomatic postmenopausal women. Assays of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrone, and estradiol were performed before and during therapy. During this period of administration, vaginal cytology, cervical mucus, and endometrial studies were performed. Clinical effectiveness was directly related to dosage (2 to 8 mg/day). Estriol (8 mg/day) failed to induce endometrial proliferation and proved a poor suppressor of FSH and LH. This agent's capacity to relieve vasomotor instability and improve vaginal maturation without notable side effects is sufficient reason to include this drug in the management of the postmenopausal syndrome

Urinary 2-hydroxyestrone/16alpha-hydroxyestrone ratio and risk of breast cancer in postmenopausal women.

Ursin G, London S, Stanczyk FZ, et al.

J Natl Cancer Inst. 1999 Jun 16; 91(12):1067-72.

BACKGROUND: It has been suggested that women who metabolize a larger proportion of their endogenous estrogen via the 16alpha-hydroxylation pathway may be at elevated risk of breast cancer compared with women who metabolize proportionally more estrogen via the 2-hydroxylation pathway. However, the supporting epidemiologic data are scant. Consequently, we compared the ratio of urinary 2-hydroxyestrone (2-OHE1) to 16alphahydroxyestrone (16alpha-OHE1) in postmenopausal women with breast cancer and in healthy control subjects. METHODS: Estrogen metabolites were measured in urine samples obtained from white women who had participated in a previous population-based, breast cancer case-control study at our institution. All P values are from two-sided tests. RESULTS: All of the urinary estrogens measured, with the exception of estriol, were higher in the 66 case patients than in the 76 control subjects. The mean value of urinary 2-OHE1 in case patients was 13.8% (P = .20) higher than that in control subjects, 16alpha-OHE1 was 12.1% (P = .23) higher, estrone was 20.9% higher (P = .14), and 17beta-estradiol was 12.0% higher (P = .36). The ratio of 2-OHE1 to 16alpha-OHE1 was 1.1% higher in the patients (P = .84), contrary to the hypothesis. Compared with women in the lowest third of the values for the ratio of urinary 2-OHE1 to 16alpha-OHE1, women in the highest third were at a nonstatistically significantly increased risk of breast cancer (odds ratio = 1.13; 95% confidence interval = 0.46-2.78), again contrary to the hypothesis. CONCLUSION: This study does not support the hypothesis that the ratio of the two hydroxylated metabolites (2-OHE1/16alpha-OHE1) is an important risk factor for breast cancer

Glycyrrhizic acid: the assessment of a no effect level.

van Gelderen CE, Bijlsma JA, van Dokkum W, et al.

Hum Exp Toxicol. 2000 Aug; 19(8):434-9.

Because from earlier experiments in rats and a pilot study in humans a no-effect level of glycyrrhizic acid could not be established, a second experiment was performed in healthy volunteers. The experiment was performed in females only, because the effects were most marked in females in the pilot study. Doses of 0, 1, 2 and 4 mg glycyrrhizic acid/kg body weight were administered orally for 8 weeks to 39 healthy female volunteers aged 19-40 years. The experiment lasted 12 weeks including an adaptation and a "wash-out" period. A no-effect level of 2 mg/kg is proposed from the results of this study, from which an acceptable daily intake (ADI) of 0.2 mg/kg body weight can be extrapolated with a safety factor of 10. This means consumption of 12 mg glycyrrhizic acid/day for a person with a body weight of 60 kg. This would be equal to 6 g licorice a day, assuming that licorice contains 0.2% of glycyrrhizic acid. The proposed ADI is below the limit advised by the Dutch Nutrition Council of 200 mg glycyrrhizic acid/day. This reflects the relatively mild acute toxicity of glycyrrhizic acid, which is also emphasised by the "generally recognised as safe" (GRAS) status of glycyrrhizic acid in the USA in 1983. However, the long-term effects of a mild chronic intoxication (causing, for example, a mild hypertension), although not immediately lethal, justify special attention to the amount of glycyrrhizic acid used daily

Opposite effects of estrogen and catecholestrogen on hormone-sensitive breast cancer cell growth and differentiation.

Vandewalle B, Lefebvre J.

Mol Cell Endocrinol. 1989 Feb; 61(2):239-46.

Catecholestrogens and especially 2-hydroxyestrone (2OH-E1) are estradiol metabolites locally formed in breast cancer cells. The present study demonstrates that the two parent compounds, estradiol (E2) and its metabolite 2OH-E1, exert opposite effects on hormone-sensitive breast cancer cell growth assessed by cell counts and transferrin receptor levels, and also on cell differentiation assessed by secreted proteins such as alpha-lactalbumin and gross cystic disease fluid protein (GCDFP-15). The present findings may highlight estradiol regulation in hormone-sensitive breast cancer cells

Soy isoflavones: are they useful in menopause?

Vincent A, Fitzpatrick LA.

Mayo Clin Proc. 2000 Nov; 75(11):1174-84.

In October 1999, the US Food and Drug Administration authorized the use on food labels of health claims associated with soy protein and the reduced risk of coronary heart disease. Several studies have indicated that a total daily intake of 25 g of soy protein paired with a low-fat diet resulted in clinically important reductions of total cholesterol and low-density lipoprotein (LDL) cholesterol levels. Soybeans are a rich source of isoflavones, a class of phytoestrogens found predominantly in legumes and beans. Soy isoflavones are heterocyclic phenols with structural similarity to estradiol-17beta and selective estrogen receptor modulators. Actions at the cellular level depend on the target tissue, receptor status of the tissue, and the level of endogenous estrogen. Studies of soy-based diets evaluating the relation between soy consumption and serum lipid concentrations revealed that soy consumption significantly decreased total cholesterol, LDL cholesterol, and triglyceride levels. However, the soy isoflavones do not increase high-density lipoprotein cholesterol or triglyceride levels. The effects of soy protein on other target tissues reflect estrogenlike agonist and antagonist effects. Epidemiological studies suggest a protective effect of soy protein on breast tissue as evidenced by the lower rates of breast cancer in East Asian countries where soy is a predominant part of the diet. Data available from human studies on the effect of isoflavones on osteoporosis are limited, and additional studies are needed to support a role in osteoporosis prevention. Thus far, there is no evidence for a stimulatory effect of isoflavones on the endometrium. A few studies reveal a minimal effect of soy on hot flashes, with soy reducing hot flashes 45% and placebo causing a 30% reduction compared with an approximate 70% reduction in hot flashes with estrogen replacement therapy. Evidence from laboratory studies reveals neither a positive nor a negative effect of soy isoflavones on cognition. To date, no adverse effects of short- or long-term use of soy proteins are known in humans. The only adverse effects known are those reported in animals (infertility in sheep and quails grazing on phytoestrogen-rich pastures). In conclusion, soy isoflavones are biologically active compounds. Current data are insufficient to draw definitive conclusions regarding the use of isoflavones as an alternative to estrogen for hormone replacement in postmenopausal women. Although epidemiological and basic laboratory studies allude to the possible protective effects of soy isoflavones at specific target tissues, randomized, placebo-controlled clinical trials are necessary to address these important issues

Dietary soy protein and estrogen replacement therapy improve cardiovascular risk factors and decrease aortic cholesteryl ester content in ovariectomized cynomolgus monkeys.

Wagner JD, Cefalu WT, Anthony MS, et al.

Metabolism. 1997 Jun; 46(6):698-705.

Estrogen replacement therapy (ERT) decreases the progression of coronary artery atherosclerosis in monkeys. Dietary soy protein also retards the progression of atherosclerosis relative to animal proteins such as casein. Soy protein contains weakly estrogenic compounds called isoflavones or phytoestrogens that may be responsible for the cardioprotective effects. This study was designed as a 2 x 2 factorial to determine the magnitude of soy protein's effects on cardiovascular risk factors relative to casein and lactalbumin, with or without estradiol treatment. Ovariectomized female monkeys were randomized to four treatment groups based on past dietary cholesterol consumption, their origin, and past reproductive history, and studied for 7 months. The animals were divided into (1) a group fed casein and lactalbumin as the protein source (n = 14), (2) a group fed casein and lactalbumin as the protein source plus 17 beta-estradiol (E2) (n = 13), (3) a group fed soybean protein isolate as the protein source (n = 11), and (4) a group fed soybean protein isolate as the protein source plus E2 (n = 10). Soy protein compared with casein consumption resulted in a significant improvement in plasma lipid and lipoprotein concentrations, a significant improvement in insulin sensitivity and glucose effectiveness as determined by minimal-model analyses, and a decrease in arterial lipid peroxidation. E2-treated monkeys had a significant reduction in fasting insulin levels and insulin to glucose ratios, total body weight, and amounts of abdominal fat, and had smaller low-density lipoprotein (LDL) particles. In addition, E2 treatment resulted in a significant reduction (P = .001) in aortic cholesteryl ester content. A similar trend (P = .14) was found for soy protein compared with casein. There also was a significant interaction (P = .02) with soy and E2, such that animals consuming soy protein +E2 had the least arterial cholesteryl ester content. These results suggest that both ERT and dietary soybean protein have beneficial effects on cardiovascular risk factors. Interestingly, the two treatments affected different risk factors and together resulted in the greatest reduction in arterial cholesterol content. Further studies are needed to determine the active component of the soy protein and to assess its long-term effects on the cardiovascular system and other organ systems (such as the bones and reproductive system)

Using phyto-treatment to influence menopause symptoms.

Warnecke G.

Med Welt. 1985;(36):871-4.

Hormone replacement therapy regimens and breast cancer risk(1).

Weiss LK, Burkman RT, Cushing-Haugen KL, et al.

Obstet Gynecol. 2002 Dec; 100(6):1148-58.

Hormone replacement therapy (HRT) has increased in the United States over the past 2 decades in response to reports of long-term health benefits. A relationship between HRT and breast cancer risk has been observed in a number of epidemiological studies. In 2002, the Women's Health Initiative Randomized Controlled Trial reported an association between continuous combined HRT and breast cancer risk. The objective of this study was to examine the association between breast cancer risk and HRT according to regimen and duration and recency of use.A multicenter, population-based, case-control study was conducted in five United States metropolitan areas from 1994 to 1998. Analyzed were data from 3823 postmenopausal white and black women (1870 cases and 1953 controls) aged 35-64 years. Odds ratios (ORs) were calculated as estimates of breast cancer risk using standard, unconditional, multivariable logistic regression analysis. Potential confounders were included in the final model if they altered ORs by 10% or more. Two-sided P values for trend were computed from the likelihood ratio statistic.Continuous combined HRT was associated with increased breast cancer risk among current users of 5 or more years (1.54; 95% confidence interval 1.10, 2.17). Additionally, a statistically significant trend indicating increasing breast cancer risk with longer duration of continuous combined HRT was observed among current users (P =.01). There were no positive associations between breast cancer risk and other HRT regimens.Our data suggest a positive association between continuous combined HRT and breast cancer risk among current, longer term users. Progestin administered in an uninterrupted regimen may be a contributing factor. Risk dissipates once use is discontinued

Differential effects of estrogen metabolites on bone and reproductive tissues of ovariectomized rats.

Westerlind KC, Gibson KJ, Malone P, et al.

J Bone Miner Res. 1998 Jun; 13(6):1023-31.

The effects of 17 beta-estradiol and the important estrogen metabolites, 2-hydroxyestrone (2-OHE1) and 16 alpha-hydroxyestrone (16 alpha-OHE1) on bone, mammary gland, and uterine histology, and on blood cholesterol were investigated in ovariectomized growing rats. Rats were treated with 200 micrograms/kg of body weight/day of each of the test compounds for 3 weeks. Ovariectomy resulted in uterine and mammary gland atrophy, increased body weight, bone turnover and tibia growth, and hypercholesterolemia. 17 beta-estradiol treatment prevented these changes, with the exception that this high dose of estrogen did not prevent hypercholesterolemia. 2-OHE1 had no effect on any of the measurements. 16 alpha-OHE1 resulted in bone measurements that did not differ from the 17 beta-estradiol-treated rats and prevented the increase in serum cholesterol. In contrast, 16 alpha-OHE1 resulted in increases in uterine weight, uterine epithelial cell height, and mammary gland cell proliferation that were significantly less than the 17 beta-estradiol treatment. These findings demonstrate that 16 alpha-hydroxylation of estrone results in tissue-selective estrogen agonistic activity, whereas 2-hydroxylation resulted in no measured activity. Furthermore, they suggest that factors that modulate the synthesis of these metabolites could selectively influence estrogen target tissues

The effect of diurnal and menstrual cyclicity and menopausal status on estrogen metabolites: implications for disease-risk assessment.

Westerlind KC, Gibson KJ, Wolfe P.

Steroids. 1999 Mar; 64(3):233-43.

It has been proposed that the ratio of two estrogen metabolites, 2-hydroxyestrone (2-OHE1) and 16alpha-hydroxyestrone (16alpha-OHE1), may represent a marker to predict a woman's risk for developing breast cancer and other estrogen-related disease. The present studies evaluated the potential confounders of type of sample, diurnal rhythm, menstrual cycle phase, and menopausal status on the ratio of 2/16alpha-OHE1 using an urine-based monoclonal antibody enzyme immunoassay. Two initial studies to compare a 24-h urine collection with a first-morning void and to evaluate diurnal variation were performed. Subsequently, urine samples were collected every other day for 2 months from five premenopausal subjects to assess the impact of the menstrual cycle. Spot urine samples were then obtained from a total of 67 pre, peri-, early post-, and late post-menopausal women to assess the effect of menopausal status. No significant difference in the ratio of 2/16alpha-OHE1 was found between a 24-h and first-morning void or over a 24-h period. No significant difference in the mean ratio of 2/16alpha-OHE1 was found with the menstrual phase. Intra-individual variability was observed in the ratio of 2/16alpha-OHE1, which was attributable to small fluctuations in the small denominator, 16alpha-OHE1. No difference in the ratio of 2/16alpha-OHE1 was observed in groups of women of different menopausal status. The data suggest that a first-morning void is representative of a 24-h collection and that the 2/16alpha-OHE1 ratio is constant throughout a 24-h period. Moreover, menstrual phase and menopausal status do not appear to significantly influence the ratio of 2/16alpha-OHE1

Natural Hormone Replacement for Women Over 45.

Wright JV.


Interaction of histones with estrogens. Covalent adduct formation with 16 alpha-hydroxyestrone.

Yu SC, Fishman J.

Biochemistry. 1985 Dec 31; 24(27):8017-21.

Disturbed estrogen metabolism leading to increased 16 alpha-hydroxyestrone (16 alpha-OHE) has been described in patients with systemic lupus erythematosus and mammary carcinoma. Previous studies showed the formation of covalent complexes between 16 alpha-OHE and nonspecific cellular membrane proteins. The present study is concerned with the interaction of 16 alpha-OHE and histones. Covalent adduct formation between 16 alpha-OHE and individual histones was maximal with H1 histone. Other endogenous estrogens such as estrone, estradiol, and estriol did not interact with histones and form covalent adducts, nor did they interfere with the interaction of 16 alpha-OHE with these nuclear proteins. The evidence supports that the adduct formation between 16 alpha-OHE and histones proceeds via a stabilized Schiff base and subsequent rearrangement. This adduct formation which may have in vivo analogues may represent a mechanism for cellular transformation by this estrogen metabolite

Is 2-methoxyestradiol an endogenous estrogen metabolite that inhibits mammary carcinogenesis?

Zhu BT, Conney AH.

Cancer Res. 1998 Jun 1; 58(11):2269-77.

Catechol estrogens (2- or 4-hydroxyestradiol and 2- or 4-hydroxyestrone) are chemically reactive estrogen metabolites that are O-methylated to less polar monomethyl ethers by catechol-O-methyltransferase, an enzyme present in many tissues such as the liver, kidney, brain, placenta, uterus, and mammary gland. In the present report, we review recent studies on the antitumorigenic and antiangiogenic effects of exogenously administered 2-methoxyestradiol in vitro and in vivo. We also discuss data that suggest that endogenous formation of 2-methoxyestradiol (and its 2-hydroxyestradiol precursor) may have a protective effect on estrogen-induced cancers in target organs. Although the molecular mechanism of action of 2-methoxyestradiol is not clear, we suggest that some unique effects of 2-methoxyestradiol may be mediated by a specific intracellular effector or receptor that is refractory to the parent hormone, estradiol. Additional research is needed to identify factors that regulate the metabolic formation and disposition of 2-methoxyestradiol in liver and in target cells and to evaluate the effects of modulating 2-methoxyestradiol formation on estrogen-induced carcinogenesis