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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