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.