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

Wagner JD; Cefalu WT; Anthony MS; Litwak KN; Zhang L; Clarkson TB
Comparative Medicine Clinical Research Center, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC 27157-1040, USA.
Metabolism: Clinical and Experimental (USA), 1997, 46/6 (698-705)

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

Daidzein sulfoconjugates are potent inhibitors of sterol sulfatase (EC 3.1.6.2)

Wong CK, Keung WM
Center for Biochemical and Biophysical Sciences and Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
Biochem Biophys Res Commun 1997 Apr 28;233(3):579-83

Recent studies have associated high dietary isoflavone intake with low incidence of breast cancer. Since estrogenic steroids are important factors in the evolution of breast cancer, and in breast tumors they are derived mainly from the sterol sulfatase pathway, we have therefore investigated effects of the isoflavone daidzein and its sulfoconjugates, daidzein-4'-O-sulfate and daidzein-7,4'-di-O-sulfate, on sterol sulfatase acitivity using dehydroepiandrosterone sulfate as substrate. While daidzein does not affect sterol sulfatase, its sulfoconjugates are potent inhibitors of this enzyme. Kinetic analyses reveal that daidzein-4'-O-sulfate and daidzein-7,4'-di-O-sulfa te inhibit sterol sulfatase competitively with respect to the steroid substrate and with K(i) values of 5.9 and 1 microM, respectively. Daidzein sulfo-conjugates also inhibit hydroxysteroid and phenol sulfotransferases but at much higher concentrations. These results provide a biochemical basis for the putative chemopreventive role of dietary isoflavones against breast cancer.

Adrenal puberty or adrenarche

Andrologie (France), 1997, 7/2 (165-186)

The androgens produced by the adrenal glands are mainly Deltleft arrow over right arrow steroids, first dehydroepiandrosterone (DHA) and its sulfate (DHAS). Adrenal androgens, very high at birth, decrease rapidly the first few months of life, remaining very low from 1 to 6 years of life. Adrenarche is defined as the changes in the pattern of adrenal secretions which occur several years before the onset of gonadal puberty (gonadarche). Developmental patterns of adrenal androgens differ markedly among species and only the chimpanzee exhibits an adrenarche comparable to that of man. Adrenarche starts in both sexes around age 7. The increase in DHA/DHAS has a rather abrupt onset and is thereafter progressive. Before the onset of gonadarche mean levels of DHA and DHAS have increased by about 10 and 20 fold respectively. The prepubertal rise in plasma Deltleft arrow over right arrow- androgens is accompanied by that of Delta4-androstenedione and 11B-hydroxy- Delta4-androstenedione occurring likely at about the same time but being very progressive and more modest are only significant after age 8 in both sexes. Adrenal androgens continue to rise during puberty. Plasma levels of DHA and DHAS continue to rise from pubertal stages 1 to 5 and remain similar in both sexes until age 15. At pubertal stage P5, plasma DHA levels are similar to that seen in young adults with no sex difference while that of DHAS continue to rise in boys and become significantly higher than in girls. Developmental changes in adrenal androgen secretions are also observed in the response to ACTH stimulation. Whether estimated as absolute levels or A of response, the rise in all unconjugated adrenal androgens to a short or prolonged ACTH stimulation, is greater with increasing age, with no sex difference, and is somewhat correlated to basal levels. Plasma levels of DHAS do not vary significantly the 2 hours following a bolus injection of ACTH (21, 34) but its response to long-term (3-days) ACTH stimulation is also increasing with age. Morphological and functional changes in the adrenal cortex also occur during development. Focal development of a Zona reticularis starts at 5 years of age, and progressively becomes continuous. The development of the zona reticularis is parallel to the increase in adrenal androgen secretions, and is completed only by age 15. This is accompanied by a rise in 17-hydroxylase and 17,20-desmolase activity in the adrenals. In a normal timing of physiological events, the onset of adrenarche occurs several years before the onset of gonadarche, 2-3 years in girls and 3-4 years in boys. This relation does not preclude that the processes are independent events. Indeed, the onset of adrenarche and gonadarche are dissociated in a variety of disorders of sexual maturation. Adrenal androgen secretions are under the control of ACTH, as shown by a series of observations. However, the specific increase of adrenal androgen secretions during development without any detectable change in ACTH stimulation, the dissociation between adrenarche and gonadarche in several conditions, have led to postulate that the biochemical differentiation of the zona reticularis may require the action of an <<adrenal factor>> in addition to ACTH. Among the proposed <<trophic>> factors of adrenal androgen secretion, LH/FSH and estrogens are no longer believed to be involved. The evidences for the existence of a separate and specific pituitary cortical androgen-stimulating hormone (CASH) are not yet convincing. Prolactin, linked to nutritional status, may stimulate the activity of the adrenal hydroxysteroid sulfotransferase. The functional zonal theory>> is attractive, but it does not explain why changes in adrenal androgens occur at a given age. Finally, the occurrence of familial cases of premature pubarche, the study of the changes in adrenal androgens in monozygotic or dizygotic twins and the observation that in idiopathic delayed puberty the delay in adrenarche is only one part of a generalized growth and developmental delay, strongly suggests that maturation of the adrenal cortex is regulated, at least in part, by genetic factors. The physiological importance of adrenal androgens remains a matter of controversy. Classical 'dogma' dictates that adrenal androgens are responsible for pubic hair development. It has also been suggested that they contribute to somatic growth or epiphyseal advancement in childhood. This is mainly based on the observation that premature adrenarche is accompanied by premature pubarche, tall stature and advanced bone age. However, adequate androgen secretion alone does not ensure normal sexual hair development in many patients with gonadal dysgenesis. Moreover, in children with a lack or delayed adrenarche long-term treatment with DHAS at dosages such as to restore normal levels for age, failed to induce growth of sexual hair or any change in growth rate, bone maturation velocity, or to advance puberty. Although new hypotheses favour the view that Deltleft arrow over right arrow-androgens, particularly Deltleft arrow over right arrow-androstenediol, have some characteristic properties of estrogens, the physiological role of adrenal androgens, if any, remains to be established. DHAS may well be only a prohormone. There are ample evidences that all tissues possess active sulfatases which transform it into DHA, asteroid with high turn-over. Administration of DHA to experimental animals has shown beneficial effects on various endocrine-metabolic parameters, enhanced immunoprotective functions and reduced carcinogenesis. DHA prevents diabetes in genetically diabetic and obese mice. The importance of in vivo and in vitro experimental findings is underscored by epidemiological data showing that low DHA levels are correlated with increased cardiovascular morbidity in men, breast cancer in women and a decline in immune competence. Human studies are at the moment controversial. It remains possible that DHAS influence breast cancer risk earlier in life, and/or that there are more complex interactions with other hormones or the intracellular metabolism of DHA/DHAS. Indeed, the tissue concentrations of DHAS may be important since it may act indirectly via its metabolism into estradiol or other steroids. Further long-term studies are needed to conclude whether DHA/DHAS are a youth fountain.

Urinary steroids at time of surgery in postmenopausal women with breast cancer

Juricskay S, Szabo I, Kett K
Central Research Laboratory, Medical University of Pecs, Hungary.
Jzsuzsa@main.pote.hu
Breast Cancer Res Treat 1997 May;44(1):83-9

Urinary steroid metabolites were measured by capillary gas chromatography in 22 postmenopausal women with operable breast cancer on day before the tumour excision and in 20 hospitalised control who were before an operation from other cause than cancer. Serum dehydroepiandrosterone-sulphat (DHEAS) and testosterone (T) level were measured by radioimmunassay in the same groups and same time. There was no significant difference in the level of urinary androgen metabolites. Pregnanediol level was significantly lower (P < 0.05) in cancer patients. In the 5 patients with positive axillary nodes the tetrahydrocortisol and alpha-cortolone levels were significantly (P < 0.05) higher than in node negative ones. There was no significant differences in the serum DHEAS and T levels. These results indicate that metabolic changes are existing in postmenopausal patients which may be a cause or a consequence of the disease.

Relation of serum levels of testosterone and dehydroepiandrosterone sulfate to risk of breast cancer in postmenopausal women

Zeleniuch-Jacquotte A, Bruning PF, Bonfrer JM, Koenig KL, Shore RE, Kim MY, Pasternack BS, Toniolo P
Nelson Institute of Environmental Medicine and Kaplan Comprehensive Cancer Center, New York University School of Medicine, NY 10010, USA.
Am J Epidemiol 1997 Jun 1;145(11):1030-8

The authors examined the relation between postmenopausal serum levels of testosterone and dehydroepiandrosterone sulfate (DHEAS) and subsequent risk of breast cancer in a case-control study nested within the New York University Women's Health Study cohort. A specific objective of their analysis was to examine whether androgens had an effect on breast cancer risk independent of their effect on the biologic availability of estrogen. A total of 130 cases of breast cancer were diagnosed prior to 1991 in a cohort of 7,054 postmenopausal women who had donated blood and completed questionnaires at a breast cancer screening clinic in New York City between 1985 and 1991. For each case, two controls were selected, matching the case on age at blood donation and length of storage of serum specimens. Biochemical analyses were performed on sere that had been stored at -80degreeC since sampling. The present report includes a subset of 85 matched sets, for whom at least 6 months had elapsed between blood donation and diagnosis of the case. In univariate analysis, testosterone was positively associated with breast cancer risk (odds ratio (OR) for the highest quartile = 2.7, 95% confidence interval (CI) 1.1-6.8, p < 0.05, test for trend). However, after including % estradiol bound to sex hormone-binding globulin (SHBG) and total estradiol in the statistical model, the odds ratios associated with higher levels of testosterone were considerably reduced, and there was no longer a significant trend (OR for the highest quartile = 1.2, 95% CI 0.4-3.5). Conversely, breast cancer risk remained positively associated with total estradiol levels (OR for the highest quartile = 2.9, 95% CI 1.0-8.3) and negatively associated with % estradiol bound to SHBG (OR for the highest quartile = 0.05, 95% CI 0.01-0.19) after adjustment for serum testosterone levels. These results are consistent with the hypothesis that testosterone has an indirect effect on breast cancer risk, via its influence on the amount of bioavailable estrogen. No evidence was found of an association between DHEAS and risk of breast cancer in postmenopausal women.

Role of glucose-6-phosphate dehydrogenase inhibition in the antiproliferative effects of dehydroepiandrosterone on human breast cancer cells

Di Monaco M, Pizzini A, Gatto V, Leonardi L, Gallo M, Brignardello E, Boccuzzi G
Department of Clinical Pathophysiology, University of Turin, Italy.
Br J Cancer 1997;75(4):589-92

Epidemiological and experimental studies suggest that dehydroepiandrosterone (DHEA) exerts a protective effect against breast cancer. It has been proposed that the non-competitive inhibition of glucose-6-phosphate dehydrogenase (G6PD) contributes to DHEA antitumour action. We evaluated the effects of DHEA on G6PD activity and on the in vitro proliferation of two human breast cancer cell lines, MCF-7 (steroid receptor positive) and MDA-MB-231 (steroid receptor negative), in a serum-free assay. DHEA inhibition of G6PD was only found to occur at concentrations above in 10 microM; at these high concentrations, the growth curve was parallel to the enzyme inhibition curve in both cell lines. In contrast, at concentrations in the in vivo breast tissue concentration range, neither cell growth nor enzyme activity was inhibited. The results failed to confirm DHEA's putative anti-tumour action on breast cancer through G6PD inhibition, as the enzyme blockade only becomes apparent at pharmacological concentrations of the steroid.

Effects of soya consumption for one month on steroid hormones in premenopausal women: Implications for breast cancer risk reduction

Lu LJ, Anderson KE, Grady JJ, Nagamani M
Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, TE 77555, USA.
Cancer Epidemiol Biomarkers Prev 1996 Jan;5(1):63-70

Soybean consumption is associated with reduced rates of breast, prostate, and colon cancer, which is possibly related to the presence of isoflavones that are weakly estrogenic and anticarcinogenic. We examined the effects of soya consumption on circulating steroid hormones in six healthy females 22- 29 years of age. Starting within 6 days after the onset of menses, the subjects ingested a 12-oz portion of soymilk with each of three meals daily for 1 month on a metabolic unit. Daily isoflavone intakes were similar100 mg of daidzein (mostly as daidzin) and similar100 mg of genistein (mostly as genistin). Serum 17beta-estradiol levels on cycle days 5-7, 12-14, and 20-22 decreased by 31% (P = 0.09), 81% (P = 0.03), and 49% (P = 0.02), respectively, during soya feeding. Decreases persisted for two to three menstrual cycles after withdrawal from soya feeding. The luteal phase progesterone levels decreased by 35% during soya feeding (P = 0.002). Dehydroepiandrosterone sulfate levels decreased progressively during soya feeding by 14-30% (P = 0.03). Menstrual cycle length was 28.3 plus or minus 1.9 days before soymilk feeding, increased to 31.8 plus or minus 5.1 days during the month of soymilk feeding (P = 0.06), remained increased at 32.7 plus or minus 8.4 days (P = 0. 11) at one cycle after termination of soymilk feeding, and returned to pre-soya diet levels five to six cycles later. These results suggest that consumption of soya diets containing phytoestrogens may reduce circulating ovarian steroids and adrenal androgens and increase menstrual cycle length. Such effects may account at least in part for the decreased risk of breast cancer that has been associated with legume consumption.

Chemoprevention by dietary dehydroepiandrosterone against promotion/progressi on phase of radiation-induced mammary tumorigenesis in rats

Inano H, Ishii-Ohba H, Suzuki K, Yamanouchi H, Onoda M, Wakabayashi K
First Research Group National Institute of Radiological Sciences, Chiba-shi, Japan.
J Steroid Biochem Mol Biol 1995 Jul;54(1-2):47-53

When pregnant rats received whole body irradiation with 260 cGy gamma-ray at day 20 of pregnancy, and were then implanted with a diethylstilbestrol (DES) pellet for an experimental period of 1 year under feeding of a control diet, a high incidence (96.2%) of mammary tumors was observed. Administration of dietary 0.6% dehydroepiandrosterone (DHEA) together with DES implantation significantly decreased the incidence (35.0%) of mammary tumors. The first appearance of palpable tumors in the DHEA-fed group was 4.5 months later than that in the control group. For clarification of the mechanism of the chemopreventive action, we measured hormone levels in the serum of DHEA-fed rats. In the DHEA diet rats, the concentration of estradiol-17beta exceeded, by approximately 6-fold, that in the control rats, while the levels of progesterone and prolactin were decreased by 30 and 45%, respectively, Interestingly, DHEA feeding prevented DES-induced hypertrophy of pituitary glands and DES-induced high level of prolactin in pituitary glands detected by immunohistochemical studies, but stimulated the development of mammary glands more than that in control rats treated with DES alone. These findings suggest that DHEA has a potent preventive activity against the promotion/progression phase of radiation-induced mammary tumorigenesis. The mechanism of chemoprevention by change of endocrinological environment is discussed.

Epidemiology of soy and cancer: Perspectives and directions

Persky V, Van Horn L
Epidemiology/Biostatics Program, University of Illinois, School of Public Health, Chicago 60612.
J Nutr 1995 Mar;125(3 Suppl):709S-712S

Previous epidemiologic studies of the effects of soy protein on cancer risk have been limited by small variations in soy intake, inability to separate soy from other dietary variables and difficulties inherent in relating dietary intake to the development of cancer several decades later. As a result, although existing data suggest that soy protein may be protective for cancer risk, results are overall inconclusive. There is also evidence that soy products may affect risk factors for cancer, such as endogenous hormone levels. Preliminary data from our group indicate that young Adventist women who are vegetarians with high soy intake and a lower risk of breast cancer may have higher levels of an adrenal androgen, dehydroepiandrosterone sulfate. Other groups have noted that soy protein may be associated with alterations in the regulation and binding of ovarian hormones. Additional studies examining effects of soy protein on risk factors for cancer would help, not only in delineating mechanisms of cancer development, but also in designing dietary programs aimed at cancer prevention.

Prevention by dehydroepiandrosterone of the development of mammary carcinoma induced by 7,12-dimethylbenz(a)anthracene (DMBA) in the rat

Li S; Yan X; Belanger A; Labrie F
MRC Group of Molecular Endocrinology, CHUL Research Center, Quebec, Canada.
Breast Cancer Res Treat 1994 Feb;29(2):203-17

The concentration of serum dehydroepiandrosterone sulfate (DHEA-S) and DHEA decreases markedly during aging, and low circulating levels of DHEA have been associated with a higher incidence of breast cancer in women. Using 7,12- dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in the rat as model, we have studied the effect of increasing serum levels of DHEA released from Silastic implants on the incidence of these tumors in the rat. Treatment with increasing doses of DHEA leading to serum DHEA levels comparable to those observed in normal adult women (7.1plus or minus0.6 nM and 17.5plus or minus1.1 nM) caused a progressive inhibition of tumor development from 68% bearing tumors in control animals to 22% and 11%, respectively. The average tumor area per rat decreased from 2.81 cm2 in intact control animals to 0.96 and 0.09 cm2 in the groups treated with the same doses of DHEA, respectively. The present data indicate that circulating levels of DHEA similar to those found in normal adult premenopausal women exert a potent inhibitory effect on the development of DMBA-induced mammary tumors in the rat, thus suggesting the possibility of a new and more physiological approach for the prevention of breast cancer in women.

Serum sex hormone levels after menopause and subsequent breast cancer

Berrino F, Muti P, Micheli A, Bolelli G, Krogh V, Sciajno R, Pisani P, Panico S, Secreto G
Istituto Nazionale Tumori, Milan, Italy.
J Natl Cancer Inst 1996 Mar 6;88(5):291-6

Background: High levels of androgens and estrogens have been reported to be associated with breast cancer. However, the multiplicity of factors that influence hormone levels and methodologic issues complicate the study of the relationship between steroid sex hormones and breast cancer.

Purpose: Using an improved study design, we assessed prospectively the relationship between the principal steroid sex hormones in serum and the subsequent occurrence of invasive breast cancer in postmenopausal women. Methods: Four thousand fifty- three healthy postmenopausal women, aged 40-69 years, were enrolled from June 1987 through June 1992 in a prospective investigation of hormones and diet in the etiology of breast tumors (ORDET study) as part of a larger volunteer cohort of 10 788 premenopausal and postmenopausal women from Varese Province, northern Italy. At recruitment, blood samples were taken between 8:00 microM and 9:30 AM (after overnight fasting), and sera were preserved in -80 degreeC freezers. Women who had received hormone treatment in the 3 months prior to enrollment, who had a bilateral ovariectomy, or who had a history of cancer or liver disease were not recruited. Twenty-five women in the final eligible cohort of 4040 postmenopausal women developed histologically confirmed, invasive breast cancer during the first 3.5 years of follow-up for the cohort (13 537 woman-years). For each case subject, four control subjects were randomly chosen after matching for factors possibly affecting hormone preservation in serum. One case subject and eight control subjects were excluded because premenopausal hormonal patterns were found; thus, after also excluding the four control subjects matched to the ineligible case subject, we included 24 case and 88 control subjects. In the spring of 1994, stored sera of case and control subjects were assayed in a blinded manner for dehydroepiandrosterone sulfate and estradiol (E2) by in-house radioimmunoassay and for total and free testosterone and sex hormone-binding globulin by commercially available nonextraction iodination kits. Mean differences in risk factors were tested by analysis of variance for paired data. Relative risks (RRs) were estimated by conditional logistic regression analysis. All P values resulted from two-sided tests.

Results: Age-adjusted mean values of total tesrosterone, free testosterone, and E2 were significantly higher in case subjects than in control subjects: total testosterone, 0.34 ng/mL versus 0.25 ng/mL (P<.001); free testosterone, 1.07 pg/mL versus 0.77 pg/mL (P = .006); and E2, 25 pg/mL versus 22 pg/mL (P = .027). Age-adjusted RRs for breast cancer in increasing tertiles were as follows: for total testosterone, 1.0, 4.8, and 7.0 (P for trend = .026); for free testosterone, 1.0, 1.8, and 5.7 (P for trend = .005); and fur total E2, 1.0, 7.1, and 5.5 (P for trend = .128).

Conclusions and Implications: This prospective study provides further evidence in support of the already established association between elevated estrogen levels and breast cancer. Even more importantly, it provides new evidence that high serum testosterone levels precede breast cancer occurrence.

Relationship of serum dehydroepiandrosterone (DHEA), DHEA sulfate, and 5-androstene-3beta,17beta-diol to risk of breast cancer in postmenopausal women

Dorgan J.F.; Stanczyk F.Z.; Longcope C.; Stephenson H.E. Jr.; Chang L.; Miller R.; Franz C.; Falk R.T.; Kahle L.
USA
Cancer Epidemiology Biomarkers and Prevention (USA), 1997, 6/3 (177-181)

Laboratory evidence suggests a role for dehydroepiandrosterone (DHEA) and its metabolite 5-androstene-3beta,17beta-diol (ADIOL) in mammary tumor growth. Serum DHEA also has been related to breast cancer in postmenopausal women, but the relationship of ADIOL to risk has not been evaluated previously. To assess the relationship of serum DHEA, its sulfate (DHEAS), and ADIOL, with breast cancer risk in postmenopausal women, we conducted a prospective nested case-control study using serum from the Columbia, MO Breast Cancer Serum Bank. Cases included 71 healthy postmenopausal volunteers not taking replacement estrogens when they donated blood and who were diagnosed with breast cancer up to 10 years later (median, 2.9 years). Two randomly selected controls, who also were postmenopausal and not taking estrogens, were matched to each case on exact age, date (plus or minus1 year), and time (plus or minus2 h) of blood collection. Significant (trend P = 0.02) gradients of increasing risk of breast cancer were observed for increasing concentrations of DHEA and ADIOL, and women whose serum levels of these hormones were in the highest quartiles were at a significantly elevated risk compared to those in the lowest; their risk ratios were 4.0 (95% confidence interval (CI), 1.3- 11.8) and 3.0 (95% CI, 1.0-8.6), respectively. The relationship of DHEAS to breast cancer was less consistent, but women whose serum DHEAS concentration was in the highest quartile also exhibited a significantly elevated risk ratio of 2.8 (95% CI, 1.1-7.4). Results of this prospective study support a role for the adrenal androgens, DHEA, DHEAS, and ADIOL in the etiology of breast cancer.

Effects of oestrogen and progesterone on age-related changes in arteries of postmenopausal women.

Liang YL; Teede H; Shiel LM; Thomas A; Craven R; Sachithanandan N; McNeil JJ; Cameron JD; Dart A; McGrath BP
Department of Medicine, Monash University, Clayton, Victoria, Australia.
Clin Exp Pharmacol Physiol (Australia) Jun 1997, 24 (6) p457-9

1. Hormone replacement therapy (HRT) with oestrogen or oestrogen plus progestin may have different effects on arterial structure and function. To examine this question, carotid artery intima-medial thickness (IMT) and indices of systemic and carotid arterial compliance were measured in groups of older men, postmenopausal women not on HRT (non-HRT) and those women on long-term HRT with oestrogen alone (HRT-E) or oestrogen plus progestin (HRT-EP).

2. Sixty men, 90 postmenopausal women taking HRT and 91 not taking HRT participated in the study. The groups were similar for age, body mass index, numbers of smokers, physical activity, alcohol intake and blood pressure.

3. Plasma total cholesterol was reduced and high-density lipoprotein-cholesterol was increased in the HRT group compared with the non-HRT group; low-density lipoprotein-cholesterol, triglyceride and lipoprotein (a) values were similar in these two groups. Results for HRT-E and HRT-EP subgroups were similar.

4. Carotid IMT was significantly reduced in the HRT group compared with men and non-HRT groups. Results for HRT-E and HRT-EP subgroups were similar.

5. Mean systemic arterial compliance (SAC) was significantly greater in men than in women and was related to age; SAC was higher in both HRT-E and HRT-EP groups compared with the non-HRT group. Indices of carotid stiffness were similar in men and in non-HRT groups. The HRT-EP group showed increased carotid stiffness compared with the HRT-E group.

6. There is an apparent protective effect of long-term oestrogen therapy on carotid IMT and age-related changes in arterial stiffness. Progestin does not alter the IMT effects but may adversely influence arterial stiffness.

Hormone replacement therapy in postmenopausal women: urinary N-telopeptide of type I collagen monitors therapeutic effect and predicts response of bone mineral density.

Chesnut CH 3rd; Bell NH; Clark GS; Drinkwater BL; English SC; Johnson CC Jr; Notelovitz M; Rosen C; Cain DF; Flessland KA; Mallinak NJ
University of Washington Medical Center, Seattle 98195-6113, USA.
Am J Med (United States) Jan 1997, 102 (1) p29-37

PURPOSE: To assess the ability of the urinary N-telopeptide of type I collagen (NTx) to monitor and predict therapeutic effects of hormone replacement therapy (HRT) in postmenopausal women.

PATIENTS AND METHODS: To assess the relationship between baseline or change in NTx (predictive variable), and change in lumbar and hip bone mineral density (BMD; outcome variable), we conducted a 2-year randomized controlled study at academic university and private practice medical centers in 236 healthy women 1 to 3 years postmenopausal; 227 women completed the study. Women received estrogen plus progesterone plus calcium (treated group) or calcium alone (control group).

RESULTS: In the treated group NTx significantly (P < 0.0001) decreased, and spine and hip BMD significantly (P < 0.00001 and P < 0.005, respectively) increased; in the control group NTx did not change but BMD decreased significantly (P < 0.01). Subjects in the highest quartiles for baseline NTx (67 to 188 units) or decreasing NTx (-66% to -87%) through 6 months demonstrated the greatest gain in BMD in response to HRT (P < 0.05 and P < 0.005). For every increase of 30 units in baseline NTx the odds of gain in BMD in response to HRT increased by a factor of 5.0 (95% confidence interval [CI] 1.9 to 13.3); for every 30% decrease in NTx through 6 months, the odds of gaining BMD in response to HRT increased by a factor of 2.6 (95% CI 1.6 to 4.4). In the control group an increase of 30 units in mean NTx across the study indicated a higher odds of losing BMD by a factor of 3.2 (95% CI 1.6 to 6.5). A high baseline NTx (> 67 units) indicated a 17.3 times higher risk of BMD loss if not treated with HRT.

CONCLUSION: These data support the clinical utility of NTx to monitor the antiresorptive effect of HRT in recently postmenopausal women, and to predict changes in BMD in response to HRT.

Estrogen inhibits cuff-induced intimal thickening of rat femoral artery: effects on migration and proliferation of vascular smooth muscle cells.

Akishita M; Ouchi Y; Miyoshi H; Kozaki K; Inoue S; Ishikawa M; Eto M; Toba K; Orimo H
Department of Geriatrics, Faculty of Medicine, University of Tokyo, Japan.
Atherosclerosis (Ireland) Apr 1997, 130 (1-2) p1-10

The present study was performed to elucidate the mechanism underlying the anti-atherogenic action of estrogen. We investigated the effect of estrogen on intimal thickening of the rat femoral artery induced by cuff placement and further examined the effect of estrogen on migration and proliferation of vascular smooth muscle cells (VSMCs) in culture. Intimal thickening was significantly greater in males than in control females. Intimal thickening in females was increased to the level in males by ovariectomy. Estrogen replacement to ovariectomized rats reversed this effect. Proliferating cell nuclear antigen immunohistochemistry showed that in vivo proliferation of VSMCs contributed to the difference in intimal thickening. There was no difference in blood pressure and serum lipids, suggesting that estrogen directly acted on artery and inhibited intimal thickening. 17 beta-Estradiol (E2, 1-100 nmol/l) inhibited migration of cultured rat VSMCs, assayed using a microchemotaxis chamber, in a concentration-dependent manner. E2 (0.01-100 nmol/l), but not progesterone or testosterone, also inhibited [3H]thymidine incorporation in rat VSMCs in a concentration-dependent manner. Indomethacin, NG-monomethyl-L-arginine and methylene blue did not influence the inhibitory action of E2 on [3H]thymidine incorporation, suggesting that prostanoids and nitric oxide are not involved in the action of E2. E2 did not provoke VSMC injury, as measured by the release of incorporated [3H]2-deoxy-D-glucose. These results suggest that the inhibition of migration and proliferation of VSMCs contributes to the inhibitory effect of estrogen on intimal thickening.

Ovarian aging and hormone replacement therapy. Hormonal levels, symptoms, and attitudes of African-American and white women.

Pham KT; Grisso JA; Freeman EW
Division of General Internal Medicine, University of Pennsylvania, Philadelphia, USA.
J Gen Intern Med (United States) Apr 1997, 12 (4) p230-6

OBJECTIVES: To characterize reproductive hormone levels, symptoms, and attitudes related to menopause among healthy, menstruating white and African-American women aged 44 to 49 years.

DESIGN: Pilot study; cross-sectional survey.

SETTING: Community-based convenience sample of women in the Philadelphia metropolitan area.

PARTICIPANTS: Thirty-three African-American and 35 white women.

MEASUREMENTS: The survey instrument collected demographic data, medical and reproductive history, health practices and behaviors. It included previously validated function, depression, and quality-of-life instruments, and a Menopause Attitude Scale that included two factors, attitudes toward the menopause and attitudes toward medical therapy. Anthropometric measurements were taken at enrollment, and reproductive hormones and daily symptom logs were followed over two menstrual cycles.

MAIN RESULTS: The two groups were comparable in mean age (African-American 46.2 years, white 46.9 years). Serum levels of estradiol, follicle-stimulating hormone, dihydroepiandrosterone-sulfate, and progesterone were comparable. Symptoms were similar in type and frequency. However, the African-American women had significantly more positive attitudes toward menopause, were more likely to rely on family for information about menopause, and were less likely to have been recommended hormone replacement therapy by their physicians. A majority of women in each group expressed satisfaction with the care they had received.

CONCLUSIONS: Perimenopausal African-American and white women have different expectations of menopause and the role of medical care in menopause. This bears directly on women's acceptance of hormone replacement therapy. Conclusions are limited by the small sample size and convenience nature of the study population: further work with larger samples is needed to confirm these apparent differences.

In vivo estrogen regulation of epidermal growth factor receptor in human endometrium.

McBean JH; Brumsted JR; Stirewalt WS
Department of Obstetrics and Gynecology, University of Vermont College of Medicine, Burlington 05401, USA.
J Clin Endocrinol Metab (United States) May 1997, 82 (5) p1467-71

The effects of estrogen and progesterone on the expression of epidermal growth factor receptor (EGFR) in human endometrium were studied in hypogonadal women under conditions that simulated a normal menstrual cycle. All women received the same regimen of estrogen and progesterone and underwent serial biopsies. In one group of women (group I), a biopsy was obtained before receiving estrogen (CD0) and after 11 days (CD11) of estrogen replacement. A second group of women was biopsied on CD11 and CD21 to assess the combined effects of progesterone and estrogen (group II). Immunohistochemistry was used to test for the presence of EGFR, and a ribonuclease protection assay was used to assess the amounts of EGFR messenger ribonucleic acid (RNA) relative to ribosomal RNA in the tissue. In group I, a significant increase in EGFR messenger RNA from CD0 to CD11 was observed. A similar increase was observed to occur between CD11 and CD21 in group II. Immunostaining for EGFR was absent in all CD0 biopsies, but was present in all estrogen-exposed endometrium. No difference in immunostaining was noted between CD11 and CD21. We conclude that estrogen stimulates the synthesis of EGFR in human endometrium and that progesterone does not appear to modulate this effect. The examination of other parameters in hormone-replaced hypogonadal subjects will be valuable in understanding the complex physiological regulation of the human endometrium.

The perimenopausal hot flash: epidemiology, physiology, and treatment.

Shaw CR
Marquette University College of Nursing, Milwaukee, Wis, USA.
Nurse Pract (United States) Mar 1997, 22 (3) p55-6, 61-6

The "hot flash" (HF), or vasomotor instability, is experienced by 75% of perimenopausal and menopausal women in the United States. The experience for some women is a minor annoyance but for others, the HF is an intensely unpleasant sensation that is disruptive to their lives. The HF is thought to be triggered by a number of external and internal stimuli such as anxiety, stress, ambient high temperatures, caffeine, and alcohol. The thinner woman tends to experience more severe and frequent HFs than the woman with more adipose tissue, probably because of the ability of adipose tissue to transform androstenedione to estrone and estradiol. Smoking history also tends to be associated with the experience of HFs at an earlier age. The etiology of HFs in the decreasing estrogen state is related to the downward resetting of the hypothalamic thermoregulating mechanism, probably by the action of norepinephrine, which is usually modulated by estrogen. The body attempts to dissipate unwanted body heat by vasodilation, thus causing the sensation of the HF. The most successful treatment modalities have been hormone replacement therapy with estrogen and progesterone. Alpha 2-adrenergic blockers have also shown some limited effectiveness. Many alternative therapies such as vitamin E, primrose oil, dong quai, and black cohash have anecdotal support but have not been thoroughly studied. Relaxation, exercise, avoidance of triggering factors, and control of external environment have all been utilized with some success by women.

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Effects of hormone replacement modalities on low density lipoprotein composition and distribution in ovariectomized cynomolgus monkeys.

Manning JM; Campos G; Edwards IJ; Wagner WD; Wagner JD; Adams MR; Parks JS
Department of Comparative Medicine, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC 27157, USA.
Atherosclerosis (Ireland) Apr 5 1996, 121 (2) p217-29

This study was designed to determine the effect of several hormone replacement therapies on LDL size, density, heterogeneity, and composition in surgically postmenopausal cynomolgus monkeys fed an atherogenic diet. Groups (n = 5 each) of ovariectomized cynomolgus monkeys were untreated (control), or treated with conjugated equine estrogens, medroxyprogesterone acetate (progesterone), combined estrogen-progesterone, or tamoxifen for 9 weeks. There were no differences among treatment groups in total plasma, LDL, or HDL cholesterol or triglyceride concentrations. Plasma LDL were isolated by ultracentrifugation and size exclusion chromatography and subfractionated by density gradient centrifugation for subsequent chemical analysis. Estrogen treatment was associated with significantly smaller (measured as LDL molecular weight, 3.9 +/- 0.2 g/mu mol) and denser plasma LDL (1.034 g/ml peak density) compared with control (4.5 +/- 0.1 g/mu mol; 1.030 g/ml peak density) or progesterone-treated animals (4.6 +/- 0.2; 1.029 g/ml peak density). LDL from the estrogen group were relatively enriched in protein and triglyceride and poor in cholesteryl ester and apolipoprotein F (apoE) compared to the control group. Triglyceride enrichment with estrogen treatment occurred predominantly in the lighter, larger LDL subfractions (d = 1.015-1.025 g/ml), which were reduced in concentration (26 +/- 10 mg cholesterol/dl) compared to control (61 +/- 19mg/dl) or progesterone treated animals (67 +/- 16 mg/dl). Combined estrogen-progesterone or tamoxifen treatment resulted in changes in LDL that followed the same trend as those observed with estrogen treatment. We conclude that short-term estrogen treatment of ovariectomized cynomolgus monkeys results in changes in plasma LDL size, density, and composition while having no apparent effect on overall plasma lipid concentrations.

Cause-specific mortality in women receiving hormone replacement therapy.

Schairer C; Adami HO; Hoover R; Persson I
Environmental Epidemiology Branch, National Cancer Institute, Rockville, MD 20892-7374, USA.
Epidemiology (United States) Jan 1997, 8 (1) p59-65

To assess the risks and benefits of menopausal hormone replacement therapy, we followed a 23,346-member, population-based cohort of Swedish women who were prescribed menopausal estrogens for an average of 8.6 years for mortality. Compared with the general population, the standardized mortality ratio for all-cause mortality in this cohort was 0.77 (95%confidence limits = 0.73, 0.81). Deaths in each of the 12 major categories of causes of death except for injuries occurred 12% to 86% less frequently than expected. We examined in detail four specific causes of death according to the type of hormone prescribed, namely weak estrogens (primarily estriol), more potent estrogens (primarily estradiol and conjugated estrogens) in combination with a progestin, and more potent estrogens without a progestin. Mortality from endometrial cancer was not related to the prescription of weak estrogens or an estrogen-progestin combination, but mortality was 40% higher in women prescribed more potent estrogens without a progestin. Women prescribed weak estrogens, more potent estrogens, and the combined estrogen-progestin regimen were at reduced risk of death from ischemic heart disease (standardized mortality ratios of 0.7, 0.6, and 0.4, respectively). The more potent estrogens and the estrogen-progestin combination were associated with a marked reduction in risk of intracerebral hemorrhage (standardize mortality ratios of 0.4 and 0.6, respectively) and "other" cerebrovascular disease, but not other types of stroke. The concern that use of progestins would lead to psychic disorders related to suicide received no support from our results. Breast cancer results are described elsewhere. These data provide little evidence of an adverse effect of the combined estrogen-progestin regimen as compared with estrogens alone on mortality. They do indicate, however, that both selection factors and biology may contribute to the almost across-the-board-reduction in mortality associated with hormone replacement therapy.

Hormone replacement therapy increases trabecular and cortical bone density in osteoporotic women.

Bagur A; Wittich A; Ghiringhelli G; Vega E; Mautalen C
Departamento de Medicina, Hospital de Clinicas Jose de San Martin, Facultad de Medicina, Universidad de Buenos Aires, Argentina.
Medicina (B Aires) (Argentina) 1996, 56 (3) p247-51

Twenty five postmenopausal Caucasian women with established osteoporosis or severe osteopenia were treated with continuous combined estrogen/progesterone (2 mg 17 beta estradiol and 5 mg medroxiprogesterone) and 1000 mg of calcium daily. The mean age of the patients was 57 +/- 6 years (range 44 to 69 years), and the average postmenopausal interval was of 10.7 +/- 4.2 years. The bone mineral density (BMD) of the lumbar spine and proximal femur was determined using DXA densitometer at baseline, 12 and 24 months of treatment. Serum and urine measurements were done at baseline and 12 months. After 24 months of treatment bone mineral density increased at the trochanter 10.2% p < 0.001, lumbar spine 9.6% p < 0.001, Ward's triangle 8.6% p < 0.005 and femoral neck 5.7% p < 0.001 in comparison to basal levels. In the first year of treatment serum alkaline phosphatase and urinary hydroxiproline diminished significantly in comparison to basal levels (p < 0.001, for both). In conclusion, this study indicates that continuous combined estrogen progesterone therapy decreases bone turnover and increases BMD of the spine, femoral neck and trochanter in established osteoporosis.

DHEA: a hormone with multiple effects.

Khorram O
Department of Obstetrics and Gynecology, University of Wisconsin Medical School, Madison 53792, USA.
Curr Opin Obstet Gynecol (United States) Oct 1996, 8 (5) p351-4

Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) represent the major androgens secreted by the adrenal gland. Various functions including metabolic, immune, and cognitive effects have been attributed to this steroid and are reviewed here. Since the levels of DHEA correlate with general good health, and aging is associated with a decline in the secretion of this steroid, a growing interest in replacement of DHEA in elderly people has developed. The findings from recent studies of replacement of DHEA in elderly people are discussed.

Mammographic changes in women on hormonal replacement therapy.

Erel CT; Seyisoglu H; Senturk ML; Akman C; Ersavasti G; Benian A; Uras C; Altug A; Ertungealp E
Department of Obstetrics and Gynecology, Cerrahpasa School of Medicine, Istanbul University, Turkey.
Maturitas (Ireland) Aug 1996, 25 (1) p51-7

OBJECTIVES: In the present retrospective study, we aimed to determine the frequency and the types of mammographic changes of breast parenchyma in women receiving hormone replacement therapy (HRT). We also investigated whether there was an association between mammographic changes and some clinical and hormonal characteristics of the women on HRT.

METHODS: One-hundred and eight women were included into the study. Of the 108 women, 19 were climacteric, four premature menopause, 50 spontaneous menopause and 35 surgical menopause. Prior to the start of HRT, an initial mammography was performed and it was repeated at 6- to 18-month intervals according to the women's status. Estrogen alone was started for 35 surgical menopause women and a combination of estrogen plus progesterone for the remaining 73 women.

RESULTS: Group I consisted of 96 women with no parenchymal changes or a decrease in parenchymal density on mammography, whereas group II consisted of 12 women with an increase in parenchymal density (11%) during the mean period of 24 months. Endogenous E2 levels were significantly higher in group II than in group I (52.4 +/- 42.3 pg/ml vs. 32.3 +/- 29.3 pg/ml, P < 0.05). Climacterium or types of menopause did not affect the mammographical density changes. Neither the type nor the duration of HRT had an effect on mammographic density increase.

CONCLUSIONS: We concluded that the endogenous E2 level might be an important role in screening the women mammographically. Long-term follow-up studies were concluded to be needed in order to evaluate the effects of HRT on mammographic changes.

Androgen replacement therapy in women: myths and realities.

Casson PR; Carson SA
Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA.
Int J Fertil Menopausal Stud (United States) Jul-Aug 1996, 41 (4) p412-22

In recent years, much attention has been directed at the potential of androgen replacement in the menopausal woman. Testosterone (T) replacement, in various forms, is widely used. However, evidence is lacking for a profound T deficiency state with natural menopause. Data confirming efficacy are also scant, and side effects have been demonstrated with prolonged therapy. The adrenal androgens, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S), also in contradistinction to T, decline substantially with age. Preliminary studies involving replacement of physiologic levels of DHEA have demonstrated some potential benefits: enhancement of the immune system and enhancement of the growth hormone axis. However, long-term trials have not been performed to date, so this modality of androgen replacement remains in the realm of clinical investigation. Ovarian and adrenal androgen replacement in menopausal women, while theoretically appealing, remains imperfect to date and should be used judiciously, if at all.

Sequential addition of low dose of medrogestone or medroxyprogesterone acetate to transdermal estradiol: a pilot study on their influence on the endometrium.

Pansini F; De Paoli D; Albertazzi P; Bonaccorsi G; Campobasso C; Zanotti L; Pisati R; Giulini NA
Menopause and Osteoporosis Center, University of Ferrara, Italy.
pan@dns.unife.it
Eur J Obstet Gynecol Reprod Biol (Ireland) Sep 1996, 68 (1-2) p137-41

We evaluated bleeding pattern and endometrium following the administration of two of the most common types of progestogens used in hormone replacement therapy, medroxyprogesterone acetate (MPA) and medrogestone acetate. Twenty eight patients in spontaneous menopause were randomly allocated to two groups. Group 1 (n = 14) received 5 mg/day of of MPA and group 2 (n = 14) received 5 mg/day of medrogestone: both the progestogens were sequentially added for the last 12 days of a 21-day period of transdermal estradiol administration (50 micrograms per day). A 7-day treatment-free period completed the cycle. The study treatments were administered for 6 cycles. The endomtria were checked for their thickness by transvaginal ultrasound before starting treatment and at 6th treatment cycle (days 6-10 of the estrogen-only phase and during the period between days 8 and 12 of the progestogen addition). Endometrial biopsies were performed before starting treatment only in the patients with a positive progesterone challenge test and in all the patients at the end of the study during the addition of the progestogen. The bleeding pattern was closely monitored. MPA is accompanied by a thick endometrium with full secretory transformation in all cases. On the contrary, the same dose of medrogestone induced a consistent decrease of estrogen primed endometrium with only 4 cases of full secretory transformation. Four medrogestone-treated patients dropped out due to unscheduled bleeding. A low dose of medrogestone added to transdermal estradiol induced incomplete transformation of endometrium and oligo-amenorrhea more frequently than MPA, but it increased the chances of irregular bleeding. MPA fully transformed the endometrium: periods were thus heavier but regular. None of the patients in either group had endometrial hyperplasia.

Hormone replacement therapy: clinical benefits and side-effects.

de Lignieres B
Service d'Endocrinologie et Medecine de la Reproduction, Hospital Necker, Paris, France.
Maturitas (Ireland) May 1996, 23 Suppl pS31-6

Beside well-established clinical benefits, the current doses of oestrogens may induce clinical side-effects leading to non-compliance and loss of efficacy. During a normal menstrual cycle the incidence of any cyclic discomfort is consistently reported to be lowest during the mild-follicular phase when plasma E2 remains between 60 and 150 pg/ml. The incidence of pregnancy-like symptoms such as bloating, breast tenderness and mood swings tends to increase in mid-luteal phase when E2 increases upto 150 pg/ml. On the other hand incidence of asthenia, sleep disturbances, depressive mood, headaches and migraines increase during perimenstrual days when E2 drops to 40 pg/ml or below. Accordingly experimental and human studies in castrated animals and postmenopausal women suggest that plasma E2 around 100 pg/ml is optimal for treatment of hot flushes, prevention of bone loss and cardiovascular protection. Due to large interindividual variation in estrogen clearance rate, it is unlikely that any standardized unique dose of oral or non-oral formulations will reproduce the optimal levels in all postmenopausal users. Efforts for individual titration are mandatory to improve compliance and actual efficacy on a long term. Because older postmenopausal women tend to have a better clinical tolerance to low E2 levels, objective markers of efficacy should also be identified when the aim of HRT is the prevention of osteoporosis or vascular diseases. In addition clinical and metabolic side-effects related to added progestins can be substantially reduced by the use of lower dose inducing amenorrhea and by progesterone instead of synthetic steroids.

Progestins.

Hirvonen E
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Finland.
Maturitas (Ireland) May 1996, 23 Suppl pS13-8

The history of progesterone and hormone replacement therapy goes back to 1934 when Butenandt obtained crystalline progesterone and Kaufmann started to treat ovariectomized women with both estrogens and progesterone (Table 1). Today synthetic perorally active 19-nortestosterone and 17-alpha-hydroxyprogesterone derivatives are used in addition to contraception and hormone replacement therapy in a variety of gynecological disorders. In hormone replacement therapy progestin is added only to prevent development of hyperplasia of the endometrium and its consequences. However, because progestins may cause both subjective and metabolic adverse effects minimum effective antiproliferative doses are recommended. The duration of the progestin phase cannot be shortened to less than 10 days whereas the frequency of administration apparently can be reduced without increased risk of hyperplasia. Development of new modes of administration may further help in reduction of the doses.

Evidence for primary and secondary prevention of coronary artery disease in women taking oestrogen replacement therapy.

Bush TL
JHU Womens Research Core, Lutherville, MD, USA.
Eur Heart J (England) Aug 1996, 17 Suppl D p9-14

The increasing use of oestrogen replacement therapy in women has focussed attention on the cardioprotective properties it has demonstrated. Historically, it has been shown that women enjoy a certain protection from heart disease, a phenomenon, however, which has not been studied extensively. Women at every age have less coronary artery disease (CAD) than men, even when various risk factors are accounted for, although the presence of diabetes carries equal mortality for both sexes. However, women who do develop CAD have a greater risk of mortality than men with CAD. Other gender differences include a later age of onset of CAD for women, and a difference in the type of atherosclerotic lesions developed. Most striking is the fact that, in women, high-density lipoprotein (HDL) seems to be a more potent predictor of major cardiovascular events than low-density lipoprotein (LDL), or total cholesterol. The Postmenopausal Oestrogen and Progesterone Interventions (PEPI) Trial looked at changes in HDL, fibrinogen, blood pressure and serum insulin resulting from oestrogen use. Four regimens were compared against placebo in 875 women. The results showed that HDL was increased significantly, LDL decreased significantly, fibrinogen levels decreased significantly, and blood pressure and serum insulin levels were essentially unaffected by oestrogen and oestrogen/progestin interactions. The Heart and Oestrogen/Progestin Replacement (HERS) Study, currently underway, is a secondary prevention trial testing the protective effect of hormone therapy in women with documented CAD. This trial may definitively answer the question of whether hormones protect against CAD. After HERS, it may be unethical to continue conducting placebo-controlled trials in a therapy that has such documented cardioprotective benefit.

Practical aspects of preventing and managing athersclerotic disease in post-menopausal women.

Sullivan JM
Department of Medicine, University of Tennessee, Memphis 38163, USA.
Eur Heart J (England) Aug 1996, 17 Suppl D p32-7

Factors that exacerbate the risk of atherosclerotic plaque formation include cigarette smoking, hypertension, hypercholesterolaemia, sedentary lifestyle, and oestrogen deficiency. The potentially important role of oestrogen deficiency in this process is evidenced by the significant increase in cardiovascular risk observed in women after menopause, and in the marked reduction in cardiovascular events observed in women who take hormone replacement therapy. Oestrogen replacement therapy, through an effect on the blood vessel wall and on serum lipids, also appears to stabilize existing atherosclerotic plaques. The combination of oestrogen and progesterone reduces risk of endometrial cancer while possibly delivering the same benefits as oestrogen alone. Other measures, such as antithrombotic therapy, exercise, and smoking cessation, also contribute to reduced risk of cardiovascular disease in older women.

Hormone replacement therapy is associated with improved arterial physiology in healthy post-menopausal women.

McCrohon JA; Adams MR; McCredie RJ; Robinson J; Pike A; Abbey M; Keech AC; Celermajer DS
Department of Cardiology, Royal Prince Alfred Hospital, Camperdown, Sydney, Australia.
Clin Endocrinol (Oxf) (England) Oct 1996, 45 (4) p435-41

OBJECTIVE: Oestrogen replacement therapy is associated with a marked reduction in coronary event rates in post-menopausal women. As older age is associated with progressive arterial endothelial damage, a key event in atherosclerosis, we assessed whether hormone replacement therapy (HRT) with oestrogen alone, or oestrogen and progesterone combined, is associated with improved endothelial function in healthy women after the menopause.

DESIGN: Using high resolution external vascular ultrasound, brachial artery diameter was measured at rest and in response to reactive hyperaemia, with increased flow causing endothelium-dependent dilatation (flow-mediated dilatation).

PATIENTS: We investigated 135 healthy women; 40 were pre-menopausal (mean +/- SD age/26 +/- 6 years, group 1), 40 were post- menopausal and had never taken HRT (aged 58 +/- 3 years; group 2) and 55 were age-matched post-menopausal women who had taken HRT for > or = 2 years, from within 2 years of the menopause (aged 57 +/- 4 years; group 3). In group 3, 40 women were on combined oestrogen and progesterone and 15 on oestrogen-only HRT.

RESULTS: In group 2, flow-mediated dilatation was significantly reduced compared with group 1 (4.4 +/- 3.4 vs 9.6 +/- 3.6%, P< 0.001), consistent with a decline in arterial endothelial function after the menopause. In group 3, however, flow-mediated dilatation was significantly better than group 2 (6.2 +/- 3.3 vs 4.4 +/- 3.4%, P = 0.01), suggesting a protective effect of HRT. Flow-mediated dilatation was similar in women taking oestrogen alone and in those on combined HRT (5.5 +/- 2.8 vs 6.5 +/- 3.4%, P = 0.40).

CONCLUSIONS: Long-term HRT is associated with improved arterial endothelial function in healthy post-menopausal women. This benefit was observed in both the combined hormone replacement and unopposed oestrogen therapy groups. This may explain some of the apparent cardioprotective effect of HRT after the menopause.

An examination of the effect of combined cyclical hormone replacement therapy on lipoprotein(a) and other lipoproteins.

Haines CJ; Chung TK; Masarei JR; Tomlinson B; Lau JT
Department of Obstetrics and Gynaecology, Chinese University of Hong Kong, New Territories.
Atherosclerosis (Ireland) Jan 26 1996, 119 (2) p215-22

Lipoprotein(a) (Lp(a)) is an independent marker of cardiovascular disease which is relatively unresponsive to treatment with most of the commonly prescribed lipid lowering drugs. Concentrations of Lp(a) increase after the menopause, and the primary aim of this study was to determine whether combined hormone replacement therapy was effective in lowering levels of Lp(a) in postmenopausal women. An open longitudinal study was conducted among 42 women who had undergone a spontaneous menopause and were attending the outpatient clinic of the Prince of Wales Hospital, Hong Kong. All subjects were treated with 2 mg oral estradiol daily and 5 mg medroxyprogesterone acetate for 12 days each calendar month. Fasting blood samples for lipoprotein measurement were taken before the commencement of treatment and at 6 and 12 months. Lp(a) levels showed a skewed distribution with a median value before treatment of 9.45 mg/dl (range 1.47-95.62 mg/dl). After 6 months, there was a reduction to 7.70 mg/dl (1.12-72.59 mg/dl) (P < 0.01), and after 12 months the median concentration was 7.14 mg/dl (0.63-69.23 mg/dl) (P < 0.001 0-12 months). There were also significant reductions in the concentrations of apo B from 116.13 to 111.62 mg/dl and LDL-C from 3.02 to 2.74 mmol/l (P < 0.05), plus a lowering of TC of borderline significance. Apo A-I increased from 162.56 to 173.35 mg/dl (P < 0.01), but there were no significant changes in HDL-C or the HDL-C subfractions. TC, LDL-C, apo B and TG concentrations were higher and HDL-C and HDL2-C concentrations were lower when blood was sampled during combined treatment with estrogen and progesterone than when estrogen was being taken alone. Levels of Lp(a) were also lower during the estrogen only phase of treatment, but none of these differences were statistically significant. This study demonstrates that combined cyclical hormone replacement therapy is effective in reducing concentrations of Lp(a). The trend towards a more atherogenic lipid profile during the combined phase of treatment suggests that attention should be given to the timing of blood sampling in future studies of this nature.

Effects of estrogens and progestogens on the renin-aldosterone system and blood pressure.

Oelkers WK
Department of Medicine, Klinikum Benjamin Franklin (Steglitz), Freie Universitat Berlin, Germany.
Steroids (United States) Apr 1996, 61 (4) p166-71

Endogenous 17 beta-estradiol (E2) and low parenteral doses of exogenous E2 are vasodilators. High dose estrogens, especially ethinylestradiol (EE) and mestranol, stimulate the synthesis of hepatic proteins including coagulation factors, sex hormone binding globulin, and angiotensinogen (Aogen). In the steady state, high plasma levels of Aogen produce only a very small increase of angiotensin II (AII) and plasma renin activity, because AII inhibits the secretion of renin and lowers plasma renin concentration. However, the increase in AII is sufficient for a slight reduction in renal blood flow and a slight increase in exchangeable sodium and blood pressure; in susceptible women, blood pressure may rise considerably. Effects of estrogens on the brain may also be involved in blood pressure changes. Endogenous progesterone is a mineralocorticoid receptor antagonist. Endogenous or exogenous progesterone leads to sodium loss and a compensatory increase in renin secretion, plasma renin activity, AII, and plasma aldosterone, e.g. in the second half of the menstrual cycle. Synthetic progestogens are commonly devoid of the mineralocorticoid receptor antagonistic effect of progesterone, and some are weak estrogen receptor agonists. Combined use of EE and synthetic progestogens may therefore enhance estrogen effects on body sodium and blood pressure. A new progestogen (Drospirenone) with an antimineralocorticoid effect like that of progesterone is described that slightly lowers body weight and blood pressure in a contraceptive formulation together with EE. An almost ideal oral contraceptive would be progestogen like Drospirenone together with a low dose natural estrogen that does not stimulate Aogen synthesis. Since most oral formulations for postmenopausal estrogen replacement also stimulate hepatic protein synthesis (including Aogen) to some extent, the transdermal route of E2 application for contraceptive purposes should also be investigated, since it has reduced potential for undesirable side effects.

Effects of progestogens on haemostasis.

Kuhl H
Department of Obstetrics and Gynecology, J.W. Goethe University Frankfurt, Germany.
Maturitas (Ireland) May 1996, 24 (1-2) p1-19

Epidemiological data suggested an involvement of the progestogen component in the pathomechanism of venous and arterial diseases during intake of oral contraceptives. The influence of progestogens on haemostasis parameters depend on type and dose of the progestogen, the presence of an estrogen, the route of application, and the duration of use. Treatment of women with progestogen-only preparations caused only minor effects on coagulation and fibrinolysis. Similarly, during hormone replacement therapy with natural estrogens, the additional application of progestogens induced no unfavourable changes on haemostasis. In contrast, the use of ovulation inhibitors resulted in an acceleration of coagulation and fibrinolysis. This is primarily induced by the marked action of ethinylestradiol on hepatic and vascular function. Progestogens with androgenic properties may counteract the estrogen-induced changes in the hepatic synthesis of platelet aggregation and readiness for coagulation. Estrogen and progesterone receptors are localized in endothelial and smooth muscle cells of the vessel wall, but there are differences in the response of veins and arteries to sex steroids. Estrogens and progestogens may influence collagen and elastin synthesis, and the release of vasoactive compounds and of factors controlling fibrinolysis from endothelium. In veins, progestogens may increase distensibility and capacitance resulting in a decreased blood flow. In predisposed women, this may lead to venous stasis and thrombosis. In arteries, progestogens may act as vasoconstrictors, and may enhance vasospasms at sites of injured endothelium which finally may lead to ischemic diseases.

Effects of hormone therapy on bone mineral density: results from the postmenopausal estrogen/progestin interventions (PEPI) trial. The Writing Group for the PEPI

JAMA (United States) Nov 6 1996, 276 (17) p1389-96
Contract/Grant No.: U01-HL40154, HL, NHLBI; U01-HL40185, HL, NHLBI; U01-HL40195, HL, NHLBI
Comment in JAMA 1996 Nov 6;276(17):1430-2

OBJECTIVE: To assess the effects of hormone therapy on bone mineral density (BMD) in the spine and hip of postmenopausal women.

DESIGN: A 3-year, multicenter, randomized, double-blinded, placebo-controlled clinical trial.

PARTICIPANTS: A total of 875 healthy women aged 45 to 64 years recruited at 7 clinical centers.

INTERVENTIONS: Treatments were (1) placebo; (2) conjugated equine estrogens (CEE), 0.625 mg/d; (3) CEE, 0.625 mg/d plus medroxyprogesterone acetate (MPA), 10 mg/d for 12 d/mo; (4) CEE, 0.625 mg/d plus MPA, 2.5 mg/d daily; or (5) CEE, 0.625 mg/d plus micronized progesterone (MP), 200 mg/d for 12 d/mo.

MAIN OUTCOME MEASURES: Bone mineral density at baseline, 12 months, and 36 months. RESULTS: Participants assigned to the placebo group lost an average of 1.8% of spine BMD and 1.7% of hip BMD by the 36-month visit, while those assigned to active regimens gained BMD at both sites, ranging from 3.5% to 5.0% mean total increases in spinal BMD and a mean total increase of 1.7% of BMD in the hip. Changes in BMD for women assigned to active regimens were significantly greater than those assigned to placebo. Women assigned to CEE plus continuous MPA had significantly greater increases in spinal BMD (increase of 5%) than those assigned to the other 3 active regimens (average increase, 3.8%). Findings were similar among those adhering to assigned therapy, although, among adherent participants, there were no significant differences in BMD changes among the 4 active treatment groups. Older women, women with low initial BMD, and those with no previous hormone use gained significantly more bone than younger women, women with higher initial BMD, and those who had used hormones previously.

CONCLUSIONS: Postmenopausal women assigned to placebo demonstrated decreased BMD at the spine and hip, whereas women assigned to estrogen therapy increased BMD during a 36-month period. These findings demonstrate that estrogen replacement therapy increases BMD at clinically important sites.

Transdermal estrogen replacement therapy in normal perimenopausal women: effects on pituitary-ovarian function.

De Leo V; Lanzetta D; D'Antona D; De Palma P
Department of Obstetrics and Gynecology, University of Siena, Italy.
Gynecol Endocrinol (England) Feb 1996, 10 (1) p49-53

The effects of 6 months of hormone replacement therapy by transdermal estradiol patches (0.05 mg/day for 21 days) and oral progestogens (10mg/day for 10 days) on hypothalamic-pituitary-ovarian function was evaluated in 32 perimenopausal women, aged 42-47 years, with irregular anovulatory cycles and menopausal symptoms. Hormone levels evaluated on the 8th and 24th day of the cycle preceding therapy showed follicle-stimulating hormone (FSH) levels above 15 mIU/ml, estradiol less than 45 pg/ml and progesterone less than 800 pg/ml. During therapy, there was an improvement in menopausal symptoms, a decrease in luteinizing hormone (LH) and FSH levels, an increase in estradiol levels and the transdermal patches were well tolerated. At the end of therapy, 19 women continued to have regular ovulatory cycles with progesterone levels similar to those in luteal phase. FSH and LH concentrations were significantly lower than before therapy. This study shows that hormone replacement therapy not only improves menopausal symptoms but may also restore the hypothalamic-pituitary-ovarian function.

The effects of androgens and other sex hormones on serum lipoproteins

Reiner Z
Klinika za unutarnje bolesti KBC Rebro, Zagreb.
Lijec Vjesn (Croatia) Mar 1996, 118 Suppl 1 p33-7

This review summarizes recent data on the effects of endogenous and exogenous androgens, estrogens and progesterone on serum lipoproteins levels and composition in humans. Sex steroid hormones modulate serum lipoprotein metabolic mechanisms and influence atherosclerosis and coronary heart disease. In general, androgens lower HDL and raise LDL levels and Lp(a) thus promoting the atherogenic process. As it is true with estrogens, the lipoprotein effects of androgens are more pronounced with oral than with parenteral administration. Millions of women use oral contraception and postmenopausal women use more and more some form of hormone replacement therapy. The HDL-raising effect of estrogen replacement seems to be mediated by an increase in apoprotein AI production and not by a decrease in the clearance rate. Estrogens lower LDL levels by accelerating the rate of LDL catabolism which is due to an increase in the number of hepatic LDL receptors. They also improve endothelium-dependent vasodilatation which might be mediated by an antioxidant action of estrogens. These facts could explain well known cardioprotective effects of estrogens. Androgen progestins, especially older such as norgestrel, lower HDL and raise LDL thus diminishing or eliminating the benefits of estrogens on cardiovascular system while newer progestins have a lesser effect on circulating lipoproteins. (55 Refs.)

Hormonal and environmental factors affecting cell proliferation and neoplasia in the mammary gland.

Snedeker SM; Diaugustine RP
Hormone and Cancer Workgroup, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Prog Clin Biol Res (United States) 1996, 394 p211-53

Although estrogens have been identified as key endocrine hormones in the control of early mitogenesis and development in the mammary gland, local control of cell proliferation during ductal morphogenesis may be regulated by polypeptides such as TGF-alpha or TGF-beta. Many breast tumors are estrogen dependent, and some breast tumor cell lines are known to produce TGF-alpha, suggesting that the mitogenic pathways controlling early normal mammary growth and the growth of some breast tumors may be similar. While progesterone does not appear to be important in the early program of ductal growth, progesterone and estrogen are necessary for the cyclic proliferation of mammary ductal cells that occurs during the menstrual cycle, and for lobuloalveolar growth during pregnancy. Since increased cell division enhances the chances for the formation of a malignant phenotype in the breast, exogenous hormones containing estrogen alone or estrogen and progesterone may increase breast cancer risk. While DES is no longer prescribed to prevent abortions, it demonstrates that high doses of an estrogen during a period of mammary proliferation can affect breast cancer risk. Whether the addition of progestogens to estrogen replacement therapy enhances breast cancer risk in postmenopausal women remains an unanswered question because of the lack of large, well-controlled prospective studies. There currently is no evidence to indicate that the progestogen-containing subdermal contraceptive Norplant increases breast cancer risk. However, it has not been determined if the elevation of serum estrogens reported in some Norplant users affects breast cancer risk. There is little evidence that combined OCAs enhance breast cancer risk in most women. More research is needed to substantiate the findings that OCA use in young women, especially before a first full-term pregnancy, may enhance breast cancer risk. Animal studies indicate that there are critical periods of susceptibility to chemical carcinogens, since the number and malignancy of tumors are increased when carcinogens are administered to young virgin animals during the proliferative period of ductal morphogenesis. Since the breast appears to be most susceptible to the carcinogenic effects of ionizing radiation during the first decade of life, exposure to other carcinogenic agents during the period of early breast development may be important in determining breast cancer risk. Therefore, more studies are needed to confirm the observation that heavy drinkers and heavy smokers are at higher risk for developing breast cancer when they start smoking or drinking at an early age. The observation that serum and urinary estrogen levels increase with alcohol consumption may provide a basis for the higher risk of developing breast cancer in heavy drinkers. While the restriction of methyxanthine intake may alleviate the symptoms associated with fibrocystic breast disease in some women, there is not enough evidence to suggest that a reduction in caffeine intake will reduce breast cancer risk. Evidence for an association between electromagnetic radiation and breast cancer is limited. Electromagnetic radiation may only pose a risk in certain occupations with exposure to very high levels for extended periods of time. It is not known whether exposure to PCBs transplacentally or though the lipid fraction of human milk can affect breast cancer rates in female offspring. The higher risk of breast cancer in women with elevated DDE levels in their blood underscores the importance of determining the extent to which environmental contaminants affect breast cancer risk.

The menopause and hormone replacement therapy: lipids, lipoproteins, coagulation and fibrinolytic factors.

Tikkanen MJ
Department of Medicine, Helsinki University Central Hospital, Finland.
Maturitas (Ireland) Mar 1996, 23 (2) p209-16

OBJECTIVES: To review the recent literature concerning the effects of the menopause and hormone replacement therapy (HRT) on the plasma lipoprotein and hemostatic system, as well as on the interaction between these two coronary heart disease (CHD) risk factor systems.

METHODS. Collection of information from relevant scientific journals, and by the use of Medline and Current Contents.

RESULTS: The mainly beneficial effects of unopposed oral estrogen replacement on the plasma lipoprotein pattern are preserved to different degrees after addition of progestin to the regimen. Nortestostorone-derived progestins tend to lower HDL cholesterol levels more than progesterone derivatives. The slight triglyceride-elevating effect on conjugated equine estrogens was in a large study not significantly counteracted by progesterone derivatives but can, according to other studies, be reversed by nortestosterone-derived progestins. A limited number of studies on transdermal administration of estradiol has suggested that the effects on plasma lipoproteins are smaller than during oral administration. There is no convincing evidence that currently used HRT regimens would significantly increase the risk of thrombosis. Nevertheless, the finding in some studies that plasma triglyceride elevations could in theory be associated with impaired fibrinolysis and enhanced coagulation merit further attention as some HRT regimens tend to increase plasma triglyceride levels. From a theoretical point of view, transdermal estrogen delivery would be preferable in women at risk for thrombosis, as they have less pronounced effects on liver functions, including production of hemostatic factors and very-low-density lipoprotein triglycerides.

CONCLUSIONS: While the numerous existing HRT regimens provide many alternative and useful possibilities, further studies are needed concerning (a) novel progestins with minimal HDL cholesterol lowering effects, (b) transdermal and other non-oral routes for HRT, 8 possible antioxidative properties of estrogen and (d) metabolic links between the lipoprotein and hemostatic risk factor systems.

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Hormonal therapy and genital tract cancer.

Wren B
Centre for the Management of the Menopause, Royal Hospital for Women, Paddington, Sydney, NSW, Australia.
Curr Opin Obstet Gynecol (United States) Feb 1996, 8 (1) p38-41

The use of hormonal replacement therapy following genital tract cancer is often denied to women because of the fear of increasing the risk of recurrence or new growth. The paucity of articles written on this subject during the past decade is an indication of the attitude of the medical profession to the needs of women suffering from symptoms of sex hormone deficiency. During 1994-1995 there were few articles published on the use of hormonal therapy to treat menopausal symptoms following genital tract cancer. Several articles, however, reviewed the relationship between hormones and genital tract cancer, some explored the value of antioestrogens in controlling recurrent or secondary disease, and a few others discussed the risk of developing uterine cancer when tamoxifen was used to manage postmenopausal breast cancer. Some suggestions are made that will allow women suffering from symptoms of hormone deficiency to receive alternative regimens of hormonal therapy. Maintaining quality of life without reducing the potential length of life is paramount in reaching a decision on the use of hormonal therapy following genital tract cancer.

Health consequences of short- and long-term postmenopausal hormone therapy.

Weiss NS
University of Washington, Seattle 98195, USA
nweiss@u.washington.edu
Clin Chem (United States) Aug 1996, 42 (8 Pt 2) p1342-4

Some women take an estrogen preparation for as long as several years to ease symptoms of the menopause. Such women appear to have little or no alteration in their risk of endometrial cancer, especially if they are also taking a progestogen, and no alteration in their risk of breast cancer. Similarly, the incidenc of fractures is unaffected by relatively short-term hormone use. The risk of ischemic heart disease also is reduced among women who currently take estrogens (with or without a progestogen), but the influence of duration of use on this association is uncertain. Postmenopausal women who take estrogens for an extended period of time (e.g., a decade or more) incur a sharply increased risk of cancer of the endometrium. This is largely abated by use of a progestogen for at least 10 days per month. Such long-term estrogen use, whether accompanied by a progestogen or not, may increase the risk of breast cancer slightly, but this is an area of great controversy, at present unresolved. The incidence of both myocardial infarction and fracture is substantially reduced in long-term users of menopausal hormones.

Current concepts in postmenopausal hormone replacement therapy.

Mayeaux EJ Jr; Johnson C
Department of Family Medicine, Lousiana State University Medical Center, Shreveport, USA.
J Fam Pract (United States) Jul 1996, 43 (1) p69-75

As more women are living longer, there is an increasing need for women to discuss hormone replacement therapy (HRT) with their physicians. This task is complicated by areas of scientific uncertainty and evolving data concerning the risks and benefits of HRT. Benefits of HRT that are supported by strong scientific evidence include relief from menopausal symptoms such as hot flashes, prevention of osteoporosis, cardioprotective effects, relief of urogenital atrophy, and decreased urinary incontinence. Benefits supported by observational evidence include improvement of emotional lability and depression, improved sense of well-being in patients with rheumatoid arthritis, increased dermal and total skin thickness, improved verbal memory skills, and decreased risk of colon cancer. Risks to consider include a possible increase in the incidence of breast cancer and an increase in endometrial cancer in women who have an intact uterus and do not receive a progestin. Women in various risk groups, such as those at risk for coronary artery disease, osteoporosis, or breast cancer, must consider the risk-to-benefit ratio for their own individual circumstances.

Regulation of estrogen/progestogen receptors in the endometrium.

Casper RF
Department of Obstetrics and Gynecology University of Toronto, Ontario, Canada.
Int J Fertil Menopausal Stud (United States) Jan-Feb 1996, 41 (1)p16-21

Patient acceptance of standard cyclic hormonal replacement therapy (HRT) has been poor. One major cause of non-acceptance is thought to be the resumption of menses as a result of induced withdrawal bleeding. In order to prevent bleeding, continuous combined estrogen and progestin HRT has been utilized. However, most publications report irregular breakthrough bleeding in a majority of patients receiving the continuous HRT regimen. The cause of the irregular bleeding remains unclear at present. It is known that the continuous presence of progestin causes down-regulation of estrogen and progestin receptors and endometrial atrophy. Endometrial atrophy may result in withdrawal of stromal support for blood vessels leading to dilatation and extravasation of blood. In addition, progestin has been implicated in neovascularization, possibly by stimulation of vascular endothelial growth factor (VEGF). Finally, programmed cell death and apoptosis appear to occur in endometrial stroma after prolonged exposure to progesterone and may contribute to breakthrough bleeding. We have developed a novel interrupted progestin HRT regimen in which estrogen is given continuously, but with progestin administered in a 3-days-on and 3-days-off schedule. The rationale for this regimen is to prevent total receptor down-regulation by allowing estrogen to up-regulate estrogen and progestin receptors during the progestin-free periods. Interrupting the progestin may also prove to be favorable in reducing neo-angiogenesis. Clinically, we have demonstrated low bleeding rates in menopausal women, and in premenopausal women on long-term GnRH-agonist treatment for endometriosis or severe PMS, in whom the interrupted regimen has been used for addback HRT. Further basic and clinical studies, preferably in prospective randomized trials, are required to demonstrate reduced bleeding and improved patient acceptance compared to continuous combined HRT.

Hormone replacement therapy and breast cancer risk.

Gambrell RD Jr br> Department of Physiology and Endocrinology, Medical College of Georgia, Augusta, USA.
Arch Fam Med (United States) Jun 1996, 5 (6) p341-8

The role of estrogen therapy in the risk of breast cancer has been a concern for both physicians and patients. There is some evidence that women taking estrogen who develop breast cancer have a better prognosis. During 8 to 18 years of follow-up of 256 postmenopausal women with breast cancer from our hospital, median survival time was 84 months for those who never used estrogen, 80 months for past users, and 143 months for current users. More than 50 studies have shown that there is no increased risk of breast cancer even with long-term estrogen use, while some studies suggest an increased risk. Several studies indicate that when progestogens are added to estrogen therapy, there is a significant reduction in the risk of breast carcinoma. Indirect evidence is accumulating to show why added progestogen should decrease the risk of breast cancer. Preliminary studies further indicate that estrogen therapy, which has been contraindicated in breast cancer survivors in the past, may be safe, and added progestogens may decrease recurrences and deaths. Some medical oncologists and surgeons now advocate estrogen use in women with previous carcinoma of the breast.

Hormone replacement therapy, hormone levels, and lipoprotein cholesterol concentrations in elderly women.

Paganini-Hill A; Dworsky R; Krauss RM
Department of Preventive Medicine, University of Southern California School of Medicine, Los Angeles 90031, USA.
Am J Obstet Gynecol (United States) Mar 1996, 174 (3) p897-902

OBJECTIVE: Our purpose was to assess the relationships of lipid and lipoprotein cholesterol levels to hormone replacement therapy and hormone levels in elderly women.

STUDY DESIGN: A sample of 292 postmenopausal women 55 to 99 years old (mean 76 years) was drawn from Leisure World Laguna Hills, California, an upper-middle-class, white independent-living population. We compared 84 women receiving unopposed estrogen replacement therapy and 38 women taking combination hormone replacement therapy with 170 women who had never used hormone replacement therapy. Nonparametric tests for differences in lipid and lipoprotein cholesterol levels among groups and multiple stepwise regression models were used.

RESULTS: Estrogen users (with and without progestin) had lower total and low-density lipoprotein cholesterol and higher high-density lipoprotein and high-density lipoprotein subfraction types 2, 2a, and 2b cholesterol levels. High density lipoprotein type 3 subfractions were lower in combination hormone replacement therapy users but higher in unopposed estrogen users relative to nonusers. The conjugated equine estrogen dose was negatively correlated with total (p = 0.0009) and low-density lipoprotein cholesterol (p <0.0001) levels and positively correlated to high-density lipoprotein cholesterol (p = 0.002) and its subfractions. The medroxyprogesterone acetate dose showed no consistent effect on cholesterol levels.

CONCLUSION: The associations found here reaffirm the significant role of estrogen replacement therapy on lipid and lipoprotein cholesterol levels and provide no evidence of a reduction in the beneficial effect of estrogen with the addition of a progestational agent to the replacement regimen.

Hormone replacement therapy as treatment of breast cancer--a phase II study of Org OD 14 (tibilone).

O'Brien M; Montes A; Powles TJ
Breast Unit, Royal Marsden Hospital, Sutton, Surrey, UK.
Br J Cancer (England) May 1996, 73 (9) p1086-8

Org OD 14 (tibilone) is a synthetic steroid, designed to combine the favourable effects of oestrogens, progestagens and androgens into a single substance for use as hormone replacement therapy (HRT). Given its antiovulatory properties, the ability to control menopausal symptoms and blocking action on progesterone receptors, Org OD 14 was considered as an agent with potential anti-cancer activity while at the same time helping existing menopausal symptoms. In this phase II study, 14 post-menopausal women with advanced or metastatic breast cancer, who had failed on tamoxifen, were treated with Org OD 14. The median duration of treatment was 12 weeks and all patients stopped because of progressive disease with or without toxicity. Vaginal bleeding occurred in four patients, three of whom had recently stopped tamoxifen. One response was seen: an 82-year-old patient had a partial response in an axillary soft tissue mass, improvement in liver function tests and an improvement in her performance status that lasted over 6 months. One patient with progressive disease on Org OD 14 improved on stopping the drug. In view of the vaginal bleeding, Org OD 14 should not be given to patients who have recently stopped tamoxifen.

Postmenopausal hormone therapy and breast cancer.

Speroff L
Department of Obstetrics and Gynecology, Oregon Health Sciences University, Portland, USA.
Obstet Gynecol 1996 Feb;87(2 Suppl):44S-54S

Given the magnitude of the older female population, the possibility that postmenopausal hormone therapy is associated with an increased risk of breast cancer is an issue of great public and individual importance. Epidemiologic evidence indicates the possibility of a slightly increased risk of breast cancer associated with long durations of postmenopausal estrogen use. However, in a review of the literature, it is apparent that the epidemiologic data are contradictory and do not yield uniform and consistent results. It is further apparent that adding a progestin to a postmenopausal hormone program does not alter the findings compared with the use of estrogen alone. Reasons for this disagreement and lack of definitive evidence are detailed, and it is suggested that any impact of postmenopausal hormone therapy on the risk of breast cancer is unlikely to be great. Finally, the question of whether a woman who has had breast cancer should use postmenopausal hormones is addressed.

Future aspects of hormone-replacement therapy

Huber J.C.
Abt Gynakologische Endokrinologie, Sterilitatsbehandlung, Universitatskli nik Frauenheilkunde, Wahringer Gurtel 18-20, A-1090 Wien Austria
Acta Chirurgica Austriaca (Austria), 1996, 28/5 (282-284)

Background: The last 30 years' hormon-replacement therapy has mostly been directed towards substituting estrogen and progestogen.

Methods: A survey trying to demonstrate the therapeutic significance of replacing other hormones is given.

Results: The third sexual hormone, testosterone, was largely disregarded. As this steroid has a number of physiologic functions to fulfill it should be made use of in future replacement therapies. Another future aspect is to substitute not only sexual hormones but other hormones, which diminish with increasing age, as well. Among them are the growth hormone, dehydroepiandrosterone, and melatonin.

Conclusions: Sexual steroids are involved in many biologic compartments. Intensified, future, interdisciplinary cooperation with other fields could create therapeutic possibilities for a causative treatment of immunologic, dermatologic and ophthalmologic diseases that have so far not been linked with sexual steroids.

Neuroendocrine aspects of the menopause and hormone replacement therapy

Genazzani A.R.; Stomati M.; Spinetti A.; Bertolini S.; Nappi L.; Taponeco F.; Cela V.; D'Ambrogio G.; Hesch
Dept. of Obstetrics and Gynaecology, University of Pisa, Pisa Italy
Journal of Cardiovascular Pharmacology (USA), 1996, 28/Suppl. 5 (S58-S60)

Hypergonadotrophic hypogonadism in postmenopausal women induces neuroendocrine changes involving hypothalamic functions and secretion of pituitary hormones. Specific receptors for oestrogen, progestogen, and androgen are localized in the central nervous system, and sex steroid hormones exert a modulatory effect on the synthesis, release, and metabolism of neuroactive transmitters and their receptors. In particular, noradrenaline, dopamine, serotonin, acetylcholine, GABA, opioid peptides, neuropeptide Y, galanin, melatonin, and corticotrophin-releasing factor are influenced by sex steroids. Several disturbances originate from the withdrawal of sex steroids which, in the menopause, is associated with vasomotor instability, anxiety, insomnia, mood changes, migraine/headache, depression, loss of libido, reduced motor activity, loss of memory, and Alzheimer's disease. These represent possible clinical expressions of neuroendocrine modifications. There is particular interest in the higher prevalence of Alzheimer's dementia in postmenopausal women than in men. Hormone replacement therapy improves the cognitive performance and short- term memory of women with Alzheimer's type dementia. In fact, oestrogens increase the activity of acetylcholine transferase, which is the most important enzyme in the synthesis of acetylcholine. Therefore, the levels of acetylcholine are reduced, which is an important sign of Alzheimer's disease. Moreover, oestrogens improve dopaminergic tone, playing a protective role against Parkinson's disease in postmenopausal women.

Hormone therapy and phytoestrogens

Lien L.L.; Lien E.J.
Dept. of Pharmaceutical Sciences, USC School of Pharmacy, Los Angeles, CA 90033 USA
Journal of Clinical Pharmacy and Therapeutics (United Kingdom), 1996, 21/2 (101-111)

As ageing progresses the levels of sex hormones decrease in the human body. In the male population, the decrease or absence of testosterone leads to decreased strength and stamina, thin bones and a low sex drive

(1). In the female population, the immediate symptoms of menopause include irregular periods, painful sexual intercourse due to vaginal dryness, hot flushes and night sweats

(2). Lack of oestrogen also leads to the risk of developing osteoporosis and cardiovascular diseases. In this report, the authors will mainly discuss the effects of hormone therapy (HT) in menopausal women. Available current clinical data on the effects of calcium supplementation with and without HT, exercise, exercise plus calcium and exercise with HT on bone loss are presented. The effects of transdermal and oral oestrogen therapy (OT) on serum lipids are discussed. Commercially-available HT products, their indications, dosages, contra-indications, side-effects and drug interactions are compared. Alternative therapies for menopausal symptoms with Chinese traditional herbs, and a comparison of the molecular structures of phytoestrogens with estradiol and diethylstilbestrol are examined

(3, 4). A list of medicinal herbs and foods reported toelicit an oestrogenic response in animals is compiled.

The effects of hormone replacement therapy on plasma vitamin E levels in post-menopausal women

Wu J.; Norris L.A.; Wen Y.C.; Sheppard B.L.; Feely J.; Bonnar J.
Department of Obstetrics/Gynaecology, Trinity College Centre, St. James's Hospital, Dublin 8 Ireland
European Journal of Obstetrics Gynecology and Reproductive Biology (Ireland), 1996, 66/2 (151-154)

Objective: To measure vitamin E levels in post-menopausal women before and after HRT, compared with levels in pre-menopausal women.

Design: Post-menopausal women (n = 21) had plasma vitamin E levels measured before treatment and after 6 and 12 months treatment with HRT (2 mg 17-beta-oestradiol and 1 mg norethisterone acetate). The pre-menopausal group (n = 20) had plasma vitamin E levels measured at day 15-18 of the menstrual cycle.

Results: There was no significant difference in vitamin E levels between the pre-menopausal group and the post-menopausal group. Plasma vitamin E levels were not significantly altered by 12 months HRT, Conclusion: Post-menopausal women did not have altered levels of vitamin E compared with pre-menopausal women. Similarly HRT has no effect on plasma vitamin E levels. We conclude therefore that HRT does not reduce vitamin E levels in a similar manner to oral contraceptives and consequently post-menopausal women are unlikely to need a vitamin E supplement.

Effects of hormonal therapies and dietary soy phytoestrogens on vaginal cytology in surgically postmenopausal macaques

Cline J.M.; Paschold J.C.; Anthony M.S.; Obasanjo I.O.; Adams M.R.
Department of Comparative Medicine, Bowman Gray School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1040 USA
Fertility and Sterility (USA), 1996, 65/5 (1031-1035)

Objective: To evaluate the effects of conjugated equine estrogens, medroxyprogesterone acetate (MPA), conjugated equine estrogens combined with MPA, tamoxifen, and soybean estrogens on vaginal cytology in surgically postmenopausal cynomolgus macaques (Macaca fascicularis).

Design: Randomized long-term experimental trial.

Setting: Cytologic samples were taken from animals in two long-term randomized studies of the effects of hormonal and dietary effects on atherosclerosis.

Patients: Surgically postmenopausal cynomolgus macaques. Interventions: Conjugated equine estrogens, MPA, conjugated equine estrogens combined with MPA, tamoxifen, and soybean estrogens were given via the diet, at doses scaled from those given to women.

Main Outcome Measure: Vaginal cytologic maturation index.

Results: Conjugated equine estrogens elicited a marked maturation effect, which was antagonized partially by the addition of MPA. Tamoxifen produced a lesser estrogenic response. The cytologic pattern in animals given soybean estrogens or MPA alone did not differ from that of controls.

Conclusion: Soybean estrogens at the doses given do not exert an estrogenic effect on the vagina of macaques. Conjugated equine estrogens are potent inducers of vaginal keratinization in this model; tamoxifen has a lesser effect. Medroxyprogesterone acetate partially antagonizes the effects of conjugated equine estrogens, and has no effect when given alone. The results support the possibility that soybean estrogens may be a 'tissue-selective' estrogen with minimal effects on the reproductive tract.

Dietary and behavioral determinants of menopause

Gold E.B.
Community/International Health Dept., School of Medicine, University of California, Davis, CA 95616 USA
Clinical Consultations in Obstetrics and Gynecology (USA), 1996, 8/1 (21-26)

1. Black and Hispanic women have been observed to experience natural menopause at an earlier age than white women, despite increased body mass, whereas Asian women have been observed to have a lower frequency of hot flushes than white women, despite lower serum estradiol levels.

2. Women who smoke have consistently been shown to experience menopause earlier than nonsmokers and to have a shorter perimenopause, and a dose-response relationship in this association has been shown. Little is known about the relationship of passive smoke exposure to age at menopause or whether smoking increases the frequency or severity of menopausal symptoms.

3. Although some studies show that increased body mass and upper body fat are associated with later age at menopause, some studies do not confirm this. Further research is needed on the independent effects of body mass and composition on frequency and severity of menopausal symptoms.

4. Shorter and more variable menstrual cycles in early adulthood and increased parity and oral contraceptive use have all been associated with later age at menopause.

5. Age at menarche, previous spontaneous abortions, age at first birth, and history of breast- feeding have all been shown not to be associated with age at menopause.

6. The effect of physical activity on age at menopause is unknown, but participation in an exercise program reduced the vasomotor symptoms associated with menopause.

7. Lower social class has been associated with earlier menopause, but nothing is known about the relationship of occupational exposures to age at menopause or frequency or severity of menopausal symptoms.

8. Dietary phytoestrogens have estrogenic activity and may compete with estradiol for binding to estrogen receptors and affect plasma estradiol, FSH and LH levels in premenopausal women and have been shown to reduce hot flashes in one small study of postmenopausal women.

A review of the clinical effects of phytoestrogens

Knight D.C.; Eden J.A.
Frank Rundle House, Royal Hospital for Women, 188 Oxford Street, Paddington, NSW 2021 Australia
Obstetrics and Gynecology (USA), 1996, 87/5 II Suppl. (897-904)

Objective: To review the sources, metabolism, potencies, and clinical effects of phytoestrogens on humans.

Data Sources: The MEDLINE data base for the years 1980-1995 and reference lists of published articles were searched for relevant English-language articles concerning phytoestrogens, soy products, and diets with high-phytoestrogen content.

Methods of Study Selection: We identified 861 articles as being relevant. Human cell line studies, human epidemiologic studies (case-control or cohort), randomized trials, and review articles were included. Animal studies regarding phytoestrogens were included when no human data were available concerning an important clinical area.

Tabulation, Integration, and Results: Included were studies containing information considered pertinent to clinical practice in the areas of growth and development, menopause, cancer, and cardiovascular disease. When findings varied, those presented in this study reflect consensus. All studies concurred that phytoestrogens are biologically active in humans or animals. These compounds inhibit the growth of different cancer cell lines in cell culture and animal models. Human epidemiologic evidence supports the hypothesis that phytoestrogens inhibit cancer formation and growth in humans. Foods containing phytoestrogens reduce cholesterol levels in humans, and cell line, animal, and human data show benefit in treating osteoporosis.

Conclusion: This review suggests that phytoestrogens are among the dietary factors affording protection against cancer and heart disease in vegetarians. With this epidemiologic and cell line evidence, intervention studies are now an appropriate consideration to assess the clinical effects of phytoestrogens because of the potentially important health benefits associated with the consumption of foods containing these compounds.

Molecular effects of genistein on estrogen receptor mediated pathways

Wang T.T.Y.; Sathyamoorthy N.; Phang J.M.
Lab Nutritional Molecular Regulation, NCI-Frederick Cancer Res Dev Ctr, NIH, Frederick, MD 21702-1201 USA
Carcinogenesis (United Kingdom), 1996, 17/2 (271-275)

Genistein, a component of soy products, may play a role in the prevention of breast and prostate cancer. However, little is known about the molecular mechanisms involved. In the present study, we examined the effects of genistein on the estrogen receptor positive human breast cancer cell line MCF-7. We observed that genistein stimulated estrogen-responsive pS2 mRNA expression at concentrations as low as 10-8 M and these effects can be inhibited by tamoxifen. We also showed that genistein competed with (3H)estradiol binding to the estrogen receptor with 50% inhibition at 5 X 10-7 M. Thus, the estrogenic effect of genistein would appear to be a result of an interaction with the estrogen receptor. The effect of genistein on growth of MCF-7 cells was also examined. Genistein produced a concentration-dependent effect on the growth of MCF-7 cells. At lower concentrations (10-8-10-6 M) genistein stimulated growth, but at higher concentrations (>10-5 M) genistein inhibited growth. The effects of genistein on growth at lower concentrations appeared to be via the estrogen receptor pathway, while the effects at higher concentrations were independent of the estrogen receptor. We also found that genistein, though estrogenic, can interfere with the effects of estradiol. In addition, prolonged exposure to genistein resulted in a decrease in estrogen receptor mRNA level as well as a decreased response to stimulation by estradiol.

Rationale for the use of genistein-containing soy matrices in chemoprevention trials for breast and prostate cancer

Barnes S.; Peterson T.G.; Coward L.
Department of Pharmacology, Birmingham Medical Center, University of Alabama, 1670 University Boulevard, Birmingham, AL 35294-0019 USA
J Cell Biochem Suppl 1995;22:181-7

Pharmacologists have realized that tyrosine kinase inhibitors (TKI) have potential as anti-cancer agents, both in prevention and therapy protocols. Nonetheless, concern about the risk of toxicity caused by synthetic TKIs restricted their development as chemoprevention agents. However, a naturally occurring TKI (the isoflavone genistein) in soy was discovered in 1987. The concentration of genistein in most soy food materials ranges from 1-2 mg/g. Oriental populations, who have low rates of breast and prostate cancer, consume 20-80 mg of genistein/day, almost entirely derived from soy, whereas the dietary intake of genistein in the US is only 1-3 mg/day. Chronic use of genistein as a chemopreventive agent has an advantage over synthetic TKIs because it is naturally found in soy foods. It could be delivered either in a purified state as a pill (to high-risk, motivated patient groups), or in the form of soy foods or soy-containing foods. Delivery of genistein in soy foods is more economically viable ($1.50 for a daily dose of 50 mg) than purified material ($5/day) and would require no prior approval by the FDA. Accordingly, investigators at several different sites have begun or are planning chemoprevention trials using a soy beverage product based on SUPRO(TM), an isolated soy protein manufactured by Protein Technologies International of St. Louis, MO. These investigators are examining the effect of the soy beverage on surrogate intermediate endpoint biomarkers (SIEBs) in patients at risk for breast and colon cancer, defining potential SIEBs in patients at risk for prostate cancer, and determining whether the soy beverage reduces the incidence of cancer recurrence. These studies will provide the basis for formal Phase I, Phase II and Phase III clinical trials of genistein and soy food products such as SUPRO(TM) for cancer chemoprevention.

Dietary flour supplementation decreases post-menopausal hot flushes: Effect of soy and wheat

Murkies A.L.; Lombard C.; Strauss B.J.G.; Wilcox G.; Burger H.G.; Morton M.S.
Brighton Medical Clinic, 26 Carpenter St., Brighton, Vic. 3186 Australia
Maturitas (Ireland), 1995, 21/3 (189-195)

Plants contain compounds with oestrogen-like action called phytoestrogens. Soy contains daidzin, a potent phytoestrogen, and wheat flour contains less potent enterolactones. We aimed to show in 58 postmenopausal women (age 54, range 30-70 years) with at least 14 hot flushes per week, that their daily diet supplemented with soy flour (n = 28) could reduce flushes compared with wheat flour (n = 30) over 12 weeks when randomised and double blind. Hot flushes significantly decreased in the soy and wheat flour groups (40% and 25% reduction, respectively <0.001 for both) with a significant rapid response in the soy flour group in 6 weeks (P < 0.001) that continued. Menopausal symptom score decreased significantly in both groups (P < 0.05). Urinary daidzein excretion confirmed compliance. Vaginal cell maturation, plasma lipids and urinary calcium remained unchanged. Serum FSH decreased and urinary hydroxyproline increased in the wheat flour group.

Soy and experimental cancer: Animal studies

Hawrylewicz E.J.; Zapata J.J.; Blair W.H.
Department of Research, Mercy Hospital/Medical Center, Chicago, IL 60616 USA
Journal of Nutrition (USA) , 1995, 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.

Aromatase in bone cell: Association with osteoporosis in postmenopausal women

Nawata H.; Tanaka S.; Tanaka S.; Takayanagi R.; Sakai Y.; Yanase T.; Ikuyama S.; Haji M.
Third Dept. of Internal Medicine, Faculty of Medicine, Kyushu University, Maidashi 3-1-1, Fukuoka 812 Japan
Journal of Steroid Biochemistry and Molecular Biology (United Kingdom), 1995, 53/1-6 (165-174)

To clarify the possible action of adrenal androgen on bone cell, the existence, characteristics and regulation of aromatase in human osteoblast-like osteosarcoma cells (HOS) and primary cultured osteoblast-like cells from normal human bones (HO) were examined in this study. Significant positive correlation between bone mineral density (BMD) and serum dehydroepiandrosterone sulfate (DHEA-S) was found in 120 postmenopausal women (51-99 years old) but no correlation was seen between BMD and serum estradiol (E2). In subset analysis, strongly positive correlation of serum DHEA-S and estrone (E1) with BMD was observed in postmenopausal women aged less than 69 years old. Administration of DHEA to ovariectomized rat significantly increased BMD and decreased relative osteoid volume in femur. These in vivo findings strongly suggested that serum adrenal androgen may be converted to estrogen in peripheral organ, especially, osteoblast and be important steroids to maintain BMD. (3H)DHEA was converted to (3H)androstenedione and (3H)androstenedione to (3H)estrone in primary cultured human osteoblast. Osteoblast-like cells showed aromatase activity, and an apparent K(m) and the V(max) were 4.74 plus or minus 0.78 nM (mean plus or minus SD, n = 3) and 0.83 plus or minus 0.79 fmol/mg protein/h for HOS, and 4.6 plus or minus 2.9 nM and 279 plus or minus 299 fmol/mg protein/h (mean plus or minus SD, n = 19) for HO, respectively. The aromatase activity was significantly increased by dexamethasone in a dose-dependent manner. Reverse transcription-polymerase chain reaction analysis revealed that dexamethasone increased the transcript of P450(AROM) gene. Osteoblast-specific promoters were also determined. Dexamethasone and 1alpha,25-dihydroxyvitamin D3 synergistically enhanced aromatase activity and P450(AROM) mRNA expression. These results demonstrate that adrenal androgen, DHEA, is converted to E1 in osteoblast by P450(AROM) which is positively regulated by glucocorticoid and 1alpha,25-dihydroxyvitamin D3 and important to maintain BMD in the 6 to 7th decade, after menopause.

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Estrogen replacement therapy and fatal ovarian cancer.

Rodriguez C, Calle EE, Coates RJ, Miracle-McMahill HL, Thun MJ, Heath CW Jr
Division of Epidemiology, Emory University School of Public Health, Atlanta, GA, USA.
Am J Epidemiol 1995 May 1;141(9):828-35

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

Inhibition of breast cancer cell growth by combined treatment with vitamin D3 analogues and tamoxifen.

Vink-van Wijngaarden T, Pols HA, Buurman CJ, van den Bemd GJ, Dorssers LC, Birkenhager JC, van Leeuwen JP
Department of Internal Medicine III, Erasmus University, Rotterdam, The Netherlands.
Cancer Res 1994 Nov 1;54(21):5711-7

The steroid hormone 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] has potential to be used as an antitumor agent, but its clinical application is restricted by the strong calcemic activity. Therefore, new vitamin D3 analogues are developed with increased growth inhibitory and reduced calcemic activity. In the present study, we have examined the antiproliferative effects of four novel vitamin D3 analogues (CB966, EB1089, KH1060, and 22-oxa-calcitriol) on breast cancer cells, either alone or in combination with the antiestrogen tamoxifen. The estrogen-dependent ZR-75-1 and estrogen-responsive MCF-7 cell lines were used as a model. It was shown that, with EB1089 and KH1060, the same growth inhibitory effect as 1,25-(OH)2D3 could be reached at up to 100-fold lower concentrations, whereas CD966 and 22-oxa-calcitriol were nearly equipotent with 1,25-(OH)2D3. The growth inhibition by the vitamin D3 compounds could be augmented by combined treatment with tamoxifen. At the maximal effective concentrations of the vitamin D3 compounds, the effect of combined treatment was addictive (MCF-7 cells) or less than additive (ZR-75-1 cells). Tamoxifen increased the sensitivity of the cells to the vitamin D3 compounds 2- to 4000-fold, which was expressed by a shift to lower median effective concentration values. Thereby, the vitamin D3 compounds may be used at even lower dosages in combination therapy with tamoxifen. A major problem of tamoxifen therapy is the development of tamoxifen resistance. We have observed that tamoxifen-resistant clones of ZR-75-1 cells retain their response to the vitamin D3 compounds. Regulation of the growth-related oncogene c-myc (mRNA level) and the estrogen receptor (protein level) were studied but appeared not to be related to the antiproliferative action of the vitamin D3 compounds. Together, our data point to a potential benefit of combination therapy with 1,25-(OH)2D3 or vitamin D3 analogues and tamoxifen for the treatment of breast cancer.

Melatonin modulation of estrogen-regulated proteins, growth factors, and proto-oncogenes in human breast cancer.

Molis TM; Spriggs LL; Jupiter Y; Hill SM
Department of Anatomy, Tulane University School of Medicine, New Orleans, LA 70112, USA.
J Pineal Res 1995 Mar;18(2):93-103

The growth-inhibitory actions of the pineal hormone, melatonin, on human breast tumor cells and the possible association between this inhibition and melatonin's down-regulation of the estrogen receptor (ER) expression were examined in the ER-positive, estrogen-responsive MCF-7 human breast tumor cell line. As previously reported, melatonin dramatically inhibits the growth of these breast tumor cells and down-regulates ER levels in these cells, suggesting that the modulation of ER may be an important mechanism by which melatonin inhibits breast cancer cell growth. In the present studies, Northern blot analysis was used to examine the expression of estrogen-regulated transcripts known to be involved in estrogen's mitogenic actions. Melatonin, at a physiologic concentration (10(-9) M), rapidly, significantly, and, in some cases, transiently elevated the steady-state mRNA levels of growth stimulatory products such as TGF alpha, c-myc, and pS2, which are normally up-regulated in response to estrogen. Conversely, melatonin decreased the expression of other factors normally up-regulated by estrogen, such as progesterone receptor and c-fos. Significant stimulation of the expression of the growth-inhibitory factor TGF beta was seen with melatonin treatment, potentially supporting the concept that melatonin's growth-inhibitory activity is mediated through the breast tumor cells' estrogen-response pathway. The early regulation of many of these products by melatonin suggests that mechanisms more rapid than the down-regulation of ER are important in melatonin's modulation of their expression. However, the long-term modulation of these transcripts (12-48 hr) may be heavily influenced by melatonin's down-regulation of ER expression. These results clearly define the need for additional in depth studies to dissect the cellular events leading to melatonin-induced growth inhibition in breast tumor cells.

Melatonin inhibition of MCF-7 human breast-cancer cells growth: influence of cell proliferation rate.

Cos S, Sanchez-Barcelo EJ
Department of Physiology and Pharmacology, School of Medicine, University of Cantabria, Santander, Spain.
Cancer Lett 1995 Jul 13;93(2):207-12

We have studied whether the cell proliferation rate modifies the inhibitory actions of melatonin on MCF-7 cell growth. The proliferative rate of cells was altered by plating them at different densities (5 x 10(4) to 100 x 10(4) cells/dish) in media with low charcoal-stripped serum concentrations. In this way, population doubling time ranged from 33 h (for density = 100 x 10(4) cells/dish) to 75 h (for density = 5 x 10(4) cells/dish). Melatonin (10(-9)M) only inhibited fast proliferating MCF-7 cells, increasing their cell doubling time, and did not significantly modify the length of doubling time in the cultures with low proliferation rate, in which doubling time was already long. These data clearly show that there is a direct relation between proliferative rate of cells and melatonin inhibitory actions on MCF-7 cells.

Modulation of cancer endocrine therapy by melatonin: a phase II study of tamoxifen plus melatonin in metastatic breast cancer patients progressing under tamoxifen alone.

Lissoni P, Barni S, Meregalli S, Fossati V, Cazzaniga M, Esposti D, Tancini G
Divisione di Radioterapia Oncologica, San Gerardo Hospital, Monza, Milan, Italy.
Br J Cancer 1995 Apr;71(4):854-6

Recent observations have shown that the pineal hormone melatonin (MLT) may modulate oestrogen receptor (ER) expression and inhibit breast cancer cell growth. On this basis, we have evaluated the biological and clinical effects of a concomitant MLT therapy in women with metastatic breast cancer who had progressed in response to tamoxifen (TMX) alone. The study included 14 patients with metastasis who did not respond (n = 3) to therapy with TMX alone or progressed after initial stable disease (SD) (n = 11). MLT was given orally at 20 mg day-1 in the evening, every day starting 7 days before TMX, which was given orally at 20 mg day-1 at noon. A partial response was achieved in 4/14 (28.5%) patients (median duration 8 months). The treatment was well tolerated in all cases, and no MLT-induced enhancement of TMX toxicity was seen; on the contrary, most patients experienced a relief of anxiety. Mean serum levels of insulin-like growth factor 1 (IGF-1), which is a growth factor for breast cancer, significantly decreased on therapy, and this decline was significantly higher in responders than in patients with SD or progression. This pilot phase II study would suggest that the concomitant administration of the pineal hormone MLT may induce objective tumour regressions in metastatic breast cancer patients refractory to TMX alone.

Modulation of estrogen receptor mRNA expression by melatonin in MCF-7 human breast cancer cells.

Molis TM, Spriggs LL, Hill SM
Department of Anatomy, Tulane University School of Medicine, New Orleans, Louisiana 70112.
Mol Endocrinol 1994 Dec;8(12):1681-90

Melatonin, the hormonal product of the pineal gland, has been shown to inhibit the development of mammary tumors in vivo and the proliferation of MCF-7 human breast cancer cells in vitro by mechanisms not yet identified. However, previous studies have demonstrated that melatonin significantly decreased estrogen-binding activity and the expression of immunoreactive estrogen receptor (ER) in MCF-7 breast cancer cells. To determine the mechanism(s) by which melatonin regulates ER expression in MCF-7 cells, the relationship between the level of steady state ER mRNA and the rate of ER gene transcription were examined in response to melatonin. Physiological concentrations of melatonin decreased steady state levels of ER mRNA expression in a dose- and time-specific manner. This decrease was not dependent upon the presence of estrogen since similar decreases in steady state ER mRNA levels were seen in MCF-7 cells cultured in both complete and estrogen-depleted media. The decreased expression of ER mRNA in response to melatonin appears to be directly related to the suppression of transcription of the ER gene. This regulation is independent of the synthesis of new proteins, as cycloheximide was unable to block the melatonin-induced decrease of steady-state ER mRNA levels. The down-regulation of ER by melatonin appears to not be mediated via a direct interaction with the ER and subsequent feedback on its own expression, since melatonin treatment did not alter the transcriptional regulatory ability of the fully activated wild type ER or a constitutively active hormone-binding domain-deleted ER variant. In addition, the stability of the ER transcript was unaffected by melatonin. Thus, it appears that the antiproliferative actions of this pineal indoleamine are mediated, at least in part, through the suppression of the transcription of the ER gene in MCF-7 human breast cancer cells.

Melatonin modulates growth factor activity in MCF-7 human breast cancer cells.

Cos S, Blask DE
Department of Physiology and Pharmacology College of Medicine, University of Cantabria, Santander, Spain.
J Pineal Res 1994 Aug;17(1):25-32

Melatonin has been shown to have direct oncostatic actions on estrogen-responsive, MCF-7 human breast cancer cells in culture. In the present study, we examined whether these inhibitory actions on cell growth may be mediated through actions on bioassayable growth factor activity. In order to test this hypothesis, we estimated the growth factor activity of conditioned medium (CM) from estradiol (E2), or melatonin-treated cells, in the presence or absence of melatonin on MCF-7 cell growth. We also determined whether melatonin inhibits the action of epidermal growth factor (EGF) action in the absence of E2. The addition of melatonin (10(-9) M) to the cultures of MCF-7 cells with CM from E2 (10(-8) M)-treated cells significantly inhibited the growth stimulatory activity of CM, suggesting that melatonin inhibited cell proliferation by blocking the action of E2-induced autocrine growth stimulatory factors. Conditioned medium from melatonin-treated cells significantly inhibited cell proliferation, while an additional supply of melatonin to these cultures had an even greater inhibitory effect. Melatonin was also active in the complete absence of serum as long as cell growth was stimulated by EGF, an E2-inducible growth factor. The inhibitory effect of melatonin increased as the dose of EGF increased. This non-antiestrogenic inhibitory effect of melatonin was reversed by E2, but not by EGF itself, suggesting that melatonin requires accessible estrogen receptor sites for its inhibitory activity on the growth stimulating action of EGF. Taken together, these findings suggest that melatonin may inhibit the action and/or release of growth stimulatory factors as well as stimulate the release of growth inhibitory factors in culture.

Role of pineal gland in aetiology and treatment of breast cancer.

Cohen M, Lippman M, Chabner B
Lancet 1978 Oct 14;2(8094):814-6

The hypothesis that diminished function of the pineal gland may promote the development of breast cancer in human beings is suggested by the relation between breast cancer and prolonged oestrogen excess, and by the observation that the pineal secretion, melatonin, inhibits ovarian oestrogen production, pituitary gonadotrophin production, and sexual development and maturation. The hypothesis is supported by the following points.

(1) Pineal calcification is commonest in countries with high rates of breast cancer and lowest in areas with a low incidence; the incidences of pineal calcification and of breast cancer are moderate among the black population in the United States.

(2) Chlorpromazine raises serum-melatonin; there are reports that psychiatric patients taking chlorpromazine have a lower incidence of breast cancer.

(3) Although information is lacking on breast cancer, the pineal and melatonin may influence tumour induction and growth in experimental animals.

(4) The demonstration of a melatonin receptor in human ovary suggests a direct influence of this hormone on the ovarian function, and possibly oestrogen production.

(5) Impaired pineal secretion is believed to be an important factor triggering puberty (early menarche is a risk factor for breast cancer).

3beta-hydroxysteroid dehydrogenase/isomerase and aromatase activity in primary cultures of developing zebra finch telencephalon: Dehydroepiandrosterone as substrate for synthesis of androstenedione and estrogens

Vanson A.; Arnold A.P.; Schlinger B.A.
Department of Psychology, University of California, Los Angeles, CA 90024 USA
General and Comparative Endocrinology (USA), 1996, 102/3 (342-350)

3beta-hydroxysteroid dehydrogenase/Deltleft arrow over right arrow-Delta4 isomerase (3beta-HSD) activity was measured in primary dissociated cell cultures prepared from telencephalons of developing zebra finches. 3beta-HSD activity was confirmed after cultures were incubated with (7-3H)pregnenolone (Preg) or (1,2,6,7- 3H-) dehydroepiandrosterone (DHEA) and 3H-progesterone (Prog) and 3H- androstenedione (AE) were detected in the medium. Product identity was confirmed by recrystallizations and by HPLC analysis. When DHEA was used as substrate, 3H-estradiol and 3H-estrone were also detected in the culture medium, presumably derived from the aromatization of 3H-AE or 3H-T produced from 3H-DHEA. To test this idea, cultures were incubated with 3H-DHEA together with radioinert AE or with fadrozole HCl, a potent and specific aromatase inhibitor. In the presence of radioinert AE, 3H-AE increased but metabolites of 3H-AE decreased in the media; in the presence of fadrozole, 3H-estrogens decreased but 3H-AE and its androgenic metabolite 3H-5beta- androstanedione increased. These data demonstrate 3beta-HSD activity in the songbird brain. The presence of Prog and estradiol in these cultures suggest that Preg and DHEA can potentially serve as substrates for the ultimate formation of active sex steroids in the songbird telencephalon.

Abnormal production of androgens in women with breast cancer

Secreto G.; Zumoff B.
Div of Endocrinology and Metabolism, Department of Medicine, Beth Israel Medical Center, New York, NY USA
Anticancer Res. (Greece), 1994, 14/5 B (2113-2117)

Two long and broad streams of medical literature, from the 1950's to date have established the existence of two unrelated abnormalities of androgen production in women with breast cancer: One is the genetically determined presence of subnormal production of adrenal androgens (i.e. DHEA and DHEAS) in women with premenopausal breast cancer and their sisters, who are at increased risk for breast cancer: The other is excessive production of testosterone, of ovarian origin, in subsets of women with either premenopausal or postmenopausal breast cancer and women with atypical breast-duct hyperplasia, who are at increased risk for breast cancer; along with the hypertestosteronism, there is frequently chronic anovulation in the premenopausal patients. The combination of ovarian hypertestosteronism and chronic anovulation is characteristic of the polycystic ovary syndrome and is also frequently seen in women with abdominal ('android') obesity; both PCOS and abdominal obesity are known to be characterized by high risk for postmenopausal cancer. The elevated testosterone levels and the increased levels of insulin, IGF-I, and IGF-II that are seen in PCOS and abdominal obesity could favor the development of breast cancer in several ways, all of which have been demonstrated experimentally binding of testosterone to cancer cells bearing testosterone receptors, with direct stimulation; intratissular aromatization of testosterone to estradiol, with stimulation of estrogen-sensitive cells; stimulation of the production of epithelial growth factor (EGF) by testosterone, with direct mitogenic effect of EGF on cancer cells; stimulation of aromatase by insulin and IGF-I; direct mitogenic stimulation of cancer cells by insulin, IGF-I, and IGF-II; and stimulation by IGF-I and IGF-II of the intratissular reduction of estrone to estradiol. Since PCOS is probably largely genetically determined, and abdominal obesity may also be, the hypertestosteronism of these conditions may represent a second genetically determined hormonal risk factor for breast cancer.

Endogenous sex hormones: Impact on lipids, lipoproteins, and insulin

Haffner S.M.; Valdez R.A.
Department of Medicine, Univ. of Texas Hlth. Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284-7873 USA
Am. J. Med. (USA), 1995, 98/1 A (40S-47S)

Estrogen use has been reported to decrease triglyceride and low-density lipoprotein cholesterol (LDL-C) and increase high-density lipoprotein cholesterol (HDL-C). Estrogen use increases the secretion of large, very low- density lipoprotein cholesterol (VLDL-C) and also stimulates the uptake of VLDL-C by the liver and increases the catabolism of LDL-C in the liver. Sex hormones may affect several enzymes involved in the metabolism of HDL-C and triglyceride and may also affect lipolysis. In both pre- and postmenopausal women, several studies have shown that increased glucose and insulin concentrations are associated with increased free testosterone and decreased sex hormone binding globulin. The temporal direction of this relationship in premenopausal women is not clear, however. In contrast to women, increased androgen concentrations in men do not seem to be associated with increased cardiovascular risk factors, although testosterone concentrations are associated with increased HDL-C and decreased insulin concentrations. Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) appear to be associated with improved cardiovascular risk factors in men, but this connection in women is less clear.

Dehydroepiandrosterone antiestrogenic action through androgen receptor in MCF-7 human breast cancer cell line

Boccuzzi G.; Di Monaco M.; Brignardello E.; Leonardi L.; Gatto V.; Pizzini A.; Gallo M.
Dipartimento Fisiopatologia Clinica, Universita di Torino, Via Genova 3, 10126 Torino Italy
Anticancer Res. (Greece), 1993, 13/6 A (2267-2272)

The possible mechanisms of the inhibitory effect of dehydroepiandrosterone (DHEA) on the estrogen-induced growth of MCF-7 human breast cancer cells were explored. The impairment of metabolic pathways via the inhibition of glucose-6-posphate dehydrogenase (G6PD) activity was excluded: G6PD activity in MCF-7 homogenate was reduced by DHEA only at a very high concentration (50 microM) while no inhibitory action on the enzyme activity was detected when DHEA was added at the antimitotic concentrations (0.02-0.5 microM). A steroid receptor mediated effect was explored: DHEA might either activate androgen receptors (AR) or partially displace E2 from estrogen receptor (ER). The pure antiandrogens Flutamide and Hydroxyflutamide reversed the inhibitory effect of DHEA on MCF-7 cell growth, whereas both the nonsteroidal estrogen Diethylstilbestrol and the antiestrogen Tamoxifen were ineffective. Results demonstrate that the AR activation plays a pivotal role in the inhibitory action of DHEA on the E2-induced MCF-7 growth.

Effect of flax seed ingestion on the menstrual cycle

Phipps W.R.; Martini M.C.; Lampe J.W.; Slavin J.L.; Kurzer M.S.
Department of Obstetrics-Gynecology, Rochester University Medical Center, Box 668, 601 Elmwood Avenue, Rochester, NY 14642 USA
J. Clin. Endocrinol. Metab. (USA), 1993, 77/5 (1215-1219)

Lignans are a group of phytochemicals shown to have weakly estrogenic and antiestrogenic properties. Two specific lignans, enterodiol and enterolactone, are absorbed after formation in the intestinal tract from plant precursors particularly abundant in fiber-rich food and are excreted in the urine. We evaluated the effect of the ingestion of flax seed powder, known to produce high concentrations of urinary lignans, on the menstrual cycle in 18 normally cycling women, using a balanced randomized cross-over design. Each subject consumed her usual omnivorous, low fiber (control) diet for 3 cycles and her usual diet supplemented with flax seed for another 3 cycles. The second and third flax cycles were compared to the second and third control cycles. Three anovulatory cycles occurred during the 36 control cycles, compared to none during the 36 flax seed cycles. Compared to the ovulatory control cycles, the ovulatory flax cycles were consistently associated with longer luteal phase (LP) lengths (mean plus or minus SEM, 12.6 plus or minus 0.4 vs. 11.4 plus or minus 0.4 days; P = 0.002). There were no significant differences between flax and control cycles for concentrations of either estradiol or estrone during the early follicular phase, midfollicular phase, or LP. Although flax seed ingestion had no significant effect on LP progesterone concentrations, the LP progesterone/estradiol ratios were significantly higher during the flax cycles. Midfollicular phase testosterone concentrations were slightly higher during flax cycles. Flax seed ingestion had no effect on early follicular phase concentrations of DHEA-S, PRL, or sex hormone-binding globulin. Our data suggest a significant specific role for lignans in the relationship between diet and sex steroid action, and possibly between diet and the risk of breast and other hormonally dependent cancers.

Estrogen and nerve growth factor-related systems in brain. Effects on basal forebrain cholinergic neurons and implications for learning and memory processes and aging

Gibbs R.B.; Jones K.J.; Moorjani B.; Luine V.
Department Pharmacy and Therapeutics, University of Pittsburgh, School of Pharmacy, Pittsburgh, PA 15261 USA
Ann. New York Acad. Sci. (USA), 1994, 743/- (165-199)

Estrogen replacement can significantly affect the expression of ChAT and NGF receptors in specific basal forebrain cholinergic neurons. The time-course of the effects is consistent with a direct up-regulation of ChAT followed by either direct or indirect down-regulation of p75(NGFR) and trkA NGF receptors, possibly due to increased cholinergic activity in the hippocampal formation and cortex and a decrease in hippocampal levels of NGF. Current evidence suggests ChAT, p75(NGFR) trkA, and NGF all play a role in regulating cholinergic function in the hippocampal formation and cortex. In addition, all have been implicated in the maintenance of normal learning and memory processes as well as in changes in cognitive function associated with aging and with neurodegenerative disease. It is possible that estrogen may affect cognitive function via effects on NGF-related systems and basal forebrain cholinergic neurons. Effects of estrogen on cognitive function have been reported, as has some preliminary evidence for beneficial effects of estrogen in decreasing the prevalence of and reducing some cognitive deficits associated with Alzheimer's disease. Whether these effects are related to effects on NGF-related systems or basal forebrain cholinergic neurons is currently unknown. Indirect evidence suggests that estrogen interacts with NGF-related systems and that changes in circulating levels of estrogen can contribute to age-related changes in hippocampal levels of NGF. These findings have important implications for consideration of estrogen replacement therapy in pre- and post-menopausal women. Further studies examining effects of different regimens of estrogen replacement as well as estrogen combined with progesterone on NGF and basal forebrain cholinergic neurons in young and aged animals are required. Prospective studies correlating aging and estrogen replacement with numbers of basal forebrain cholinergic neurons and hippocampal and cortical levels of NGF also need to be performed to better assess the potential benefits of estrogen replacement in reducing age- and disease-related cognitive decline.

Postmenopausal estrogen replacement: A long-term cohort study

Lafferty F.W.; Fiske M.E.
University Suburban Health Center, 1611 South Green Road, Cleveland, OH 44121 USA
Am. J. Med. (USA), 1994, 97/1 (66-77)

To assess the long-term effects of estrogen replacement therapy (ERT) in 157 postmenopausal women, a prospective, nonrandomized, cohort study was conducted from 1964 to 1989. ERT consisted of 0.625 mg of conjugated equine estrogen daily for the first 25 days of each month without oral progesterone from 1964 to 1984. From 1984 to 1989 5 mg of medroxyprogesterone was added from day 14 to 25 of every sixth month in subjects with an intact uterus. The mean loss of height was significantly less among the ERT subjects after age 65 years and remained at 0.08 cm/year from age 56 to 80 years, whereas the loss of height accelerated among the control subjects to 0.19 cm/year from age 66 to 70, to 0.22 cm/year from age 71 to 75, and to 0.30 cm/year from age 76 to 80. The mean cortical bone density at the distal third of the radius was significantly greater among the ERT subjects compared to the control subjects with the difference representing a 12.0% higher bone density with ERT.

Impact of the menopause on the epidemiology and risk factors of coronary artery heart disease in women

Gorodeski G.I.
Department of Obstetrics/Gynecology, University MacDonald Womens Hospital, 2074 Abington Road, Cleveland, OH 44106 USA
Exp. Gerontol. (USA), 1994, 29/3-4 (357-375)

Cardiovascular disease is the leading cause of morbidity and mortality in women, and coronary artery heart disease (CHD) is the largest single component of fatal cardiovascular disease. Gender-related differences are observed in the symptomatology, natural course and outcome, and in the management of the acute coronary event. More women, compared to men, have angina as their first manifestation of CHD, and they are less likely to have serious stenosis. Women undergo less invasive diagnostic procedures, but have an overall prognosis that is worse than that of men. Rates of CHD in women increase after the fifth-sixth decades of life, suggesting that young women have a protective factor that is lost after the fifth decade. Because most women become menopausal during this age range, it is speculated that the protective factor may the female hormone, estrogen. This conclusion is supported by results of epidemiological studies indicating an increased risk of CHD in women with early-onset menopause and a reduced risk in postmenopausal women treated with estrogen replacement therapy. The impact of the menopausal transition on other CHD risk factors is still not fully understood. Reduced estrogen levels resulting from the menopausal transition have been implicated in adverse effects on obesity and fat distribution, plasma lipid profile, and rheological properties of plasma and platelet function. Postmenopausal estrogen deficiency may also aggravate preexisting diabetes mellitus and hypertension, and have an overall negative effect on the reaction to stress. These data suggest that estrogen deficiency can directly and indirectly promote CHD in women. More research is needed to clarify and differentiate menopause-related from aging-related effects on the risk of CHD women.

Hormone therapy and endometrium cancer

Bergeron C.
Reprod Hum. Horm. (France), 1994, 7/4 (137-139)

Endometrial carcinomas are hormone-dependent by the presence of estrogen and progesterone receptors in the neoplastic proliferation. Treatment with estrogen alone is associated with an increase risk of endometrial carcinoma but those carcinomas are discovered at an early stage and have an excellent prognosis. Estrogen replacement therapy following treatment for stage I endometrial carcinoma is no more a contraindication and is associated with a better prognosis by the benefit on bone and cardiovascular system. Progestogens suppress the risk of endometrial carcinoma by their antiestrogenic effect and lead to a secretory or atrophic endometrium. They may be used as adjuvant therapy in advanced endometrial carcinomas which have retained progesterone receptors in the neoplastic proliferation. Tamoxifen may have an estrogenic effect on the endometrial mucosa but the increase risk for development of endometrial carcinoma with tamoxifen (20 mg/j) remains hypothetical. Tamoxifen is mostly associated with an atrophic mucosa or with cystic and atrophic polyps.

Progestin replacement in the menopause: Effects on the endometrium and serum lipids

Williams D.B.; Moley K.H.
Curr. Opin. Obstet. Gynecol. (USA), 1994, 6/3 (284-292)

The benefits of estrogen replacement therapy (ERT) in the menopause have been well demonstrated and are of significant importance, particularly with regard to prevention of osteoporosis and reduction in cardiovascular morbidity and mortality. The addition of a progestin to ERT is advocated in patients with a uterus to minimize the risk of endometrial hyperplasia and cancer. Although progestins can have adverse effects on serum lipids, it is unclear whether or not these effects negate the cardioprotective effects of estrogen. Progestins are an important part of hormone replacement therapy (HRT) regimen in patients with an intact uterus. The minimum dose and duration should be given to offset potential adverse effects on serum lipids while affording adequate protection of the endometrium. Both continuous and sequential progestin regimens appear to be efficacious. The newer progestins may offer increased flexibility in minimizing progestin side-effects while protecting the endometrium. Other regimens, such as less than monthly progestin administration, may offer another alternative to achieve these goals. Future studies in these areas are warranted.

Effects of hormone replacement therapy on lipoprotein(a) and lipids in postmenopausal women

Chee Jeong Kim; Hak Chul Jang; Dong Hee Cho; Yong Ki Min
Internal Medicine, Cheil General Hospital, 1-23 Mookchung-Dong, Chung-Ku, Seoul 100-380 South Korea
Arterioscler. Thromb. (USA), 1994, 14/2 (275-281)

High concentrations of lipoprotein(a) (Lp(a)), an independent risk factor for atherosclerosis, cannot be managed by the usual lipid-lowering agents. It has been suggested that Lp(a) levels are related to female sex hormones. Estrogen replacement therapy makes the lipid profiles favorable for delaying atherosclerosis in postmenopausal women. The effects of the combination therapy of estrogen and progesterone on lipids are controversial. This study was designed to evaluate the effect of female sex hormones on the concentration of Lp(a) and to clarify the influence of progesterone on the effect of estrogen in postmenopausal women. Postmenopausal women (n=184) were divided into four groups: control; 0.625 mg conjugated equine estrogen (CEE) plus 10 mg medroxy-progesterone acetate (MPA); 0.625 mg CEE plus 5 mg MPA; and 0.625 mg CEE only. Medication for 2 months lowered the concentrations of Lp(a) by 20% in all treated groups. The decrease was more pronounced in subjects with a relatively higher basal Lp(a) concentration. Estrogen replacement therapy raised the concentration of high-density lipoprotein cholesterol and decreased low-density lipoprotein cholesterol without changing total cholesterol. The combination therapy of estrogen and progesterone abolished the effect of estrogen on high-density lipoprotein cholesterol. Hormone replacement therapy lowered Lp(a) levels in postmenopausal women. The effect was prominent in subjects with high basal Lp(a) levels. This decrease may be one of the mechanisms of the cardioprotective effects of estrogen. The cardioprotective effect of estrogen cannot be applied to the combination therapy due to the adverse effect of progesterone on high-density lipoprotein cholesterol.