[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. Anasti JNLHBWKJ. 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. Dupont EKTMCVDSATSRDCACC. 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 <20 pg/mL. INTERVENTION(S): Daily topical application to both breasts of a gel containing a placebo, estradiol, progesterone, or a combination of estradiol and progesterone during the 14 days preceding esthetic breast surgery or excision of a benign lesion. MAIN OUTCOME MEASURE(S): Plasma and breast tissue concentrations of estradiol and progesterone. Epithelial cell cycles were evaluated in normal breast tissue by counting mitoses and performing quantitative proliferating cell nuclear antigen immunolabeling analyses. RESULT(S): Increasing the estradiol concentration enhanced the number of cycling epithelial cells, whereas increasing the progesterone concentration significantly limited the number of cycling epithelial cells. CONCLUSION(S): Exposure to progesterone for 14 days reduced the estradiol-induced proliferation of normal breast epithelial cells in vivo
[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 <.001), and we observed a 7% (95% CI, 2%-13%) increase in RR per year of use. We observed significantly elevated RRs with increasing duration of estrogen-only use across all strata of other ovarian cancer risk factors, including women with hysterectomy. The RR for estrogen-progestin use after prior estrogen-only use was 1.5 (95% CI, 0.91-2.4), but the RR for estrogen-progestin-only use was 1.1 (95% CI, 0.64-1.7). The RRs for less than 2 years and 2 or more years of estrogen-progestin-only use were 1.6 (95% CI, 0.78-3.3) and 0.80 (95% CI, 0.35-1.8), respectively, and there was no evidence of a duration response (P value for trend =".30)." CONCLUSION: Women who used estrogen-only replacement therapy, particularly for 10 or more years, were at significantly increased risk of ovarian cancer in this study. Women who used short-term estrogen-progestin-only replacement therapy were not at increased risk, but risk associated with short-term and longer-term estrogen-progestin replacement therapy warrants further investigation
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. 1996;(V)
[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. 7777;1998
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 |