Regional and total skeletal measurements in the early postmenopause.

In a cross-sectional study of 70 early postmenopausal women, regional bone measurements were compared with total body calcium (TBCa). Spinal and forearm trabecular bone were mainly related to age and time since menopause. In contrast, TBCa and forearm integral (cortical and trabecular) and cortical bone were unrelated to age, although the time since menopause also had some influence. Forearm integral and cortical bone measurements were quite well correlated with TBCa (r = 0.84 and 0.73, respectively, P less than 0.001). The correlation between spinal bone measurements and any of the forearm measurements, even purely trabecular bone, was weak (r less than 0.52, P less than 0.001). Our results show quite clearly that forearm bone measurements cannot be used to predict bone density in the vertebrae. Loss of ovarian function affects bone in general, and trabecular bone in particular. Bone measurements at specific anatomical sites are clearly necessary for studies of metabolic bone diseases and their response to treatment.

Psychological impact of screening for familial ovarian cancer.

BACKGROUND: Psychological distress following false-positive results could constitute a substantial disadvantage of cancer screening. PURPOSE: The purpose of this prospective study was to evaluate the psychological impact of true-negative and false-positive results in a high-risk group of women in a screening program to detect early familial ovarian cancer by ovarian ultrasound scan. The influence of coping style was also assessed. METHODS: Of 500 women who contacted the nationally advertised screening program, 302 received the scan and participated in the study. Before the screening, they were mailed a questionnaire concerning psychological state, coping style, and anxiety about risk of cancer. Transabdominal ultrasonography and transvaginal ultrasonography with color Doppler imaging were used to detect persistent ovarian lesions and changes in volume. Women were informed of any abnormality immediately and asked to return for another scan after 6 weeks. Those with a persistent ovarian mass were referred for hysterectomy and bilateral oophorectomy. The questionnaire was used to reassess psychological distress after the first ultrasound scan, after re-scanning, and after surgery. RESULTS: The first scan showed negative results for 233 of the 302 women; 69 (23%) had abnormalities in ovarian morphology. Sixty-four of the 69 had a second scan, with negative results for 32 and equivocal results for 12; 20 had surgery because the results of both scans were positive. None of the patients in the screening program were found to have ovarian cancer. After the first scan, psychological distress and worries about cancer were significantly reduced (P < .001) in the women who had negative results. Responses to positive results depended on the baseline coping style and the clinician's appraisal of malignancy potential at the time of the scan. Women who had information-seeking coping styles and those who were referred for surgery had higher levels of distress than other women. At follow-up, the anxiety scores of women who had positive results on both scans but negative results at surgery had returned to baseline levels. CONCLUSIONS: The findings suggest that false-positive results in screening are associated with increased distress in the short term, but these adverse effects do not appear to be severe or persistent. Women who had surgery appeared to welcome the certainty that they could never develop ovarian cancer. IMPLICATIONS: The issue of continued surveillance needs to be addressed, since many women expressed the desire to have the scan repeated regularly.

Effect of estrogen and progestin treatments on endometria from postmenopausal women.

PIP: This report describes experiments designed to answer several important questions about the biochemistry of estrogen-stimulated postmenopausal endometrium; in particular; how much estrogen enters the endometrium and the biological effectiveness of that estrogen in women receiving different forms of postmenopausal estrogenic therapy. To this end, nuclear and cytoplasmic estradiol receptor (ER) and cytoplasmic progesterone receptor (PR) were measured in curettage samples of endometria from women receiving, either sequentially or cyclically, Premarin, Harmogen, Progynova, or mestranol at either low or high doses. Cyclical treatment with estrogen alone was compared with sequential therapy with 3 weeks of estrogen plus 1 week of estrogen plus 1 week of estrogen plus northisterone. No difference in any of the receptor levels was found in samples obtained during the 3rd week of any of the 4-week treatment cycles. For 2-3 weeks of a treatment cycle, the receptor levels were similar to those seen in premenopausal, proliferative-phase endometrium, suggesting that postmenopausal endometrial cells are subjected to a very potent estrogenic stimulus for a considerable period. Norethisterone ingestion for 1 week decreased both the amount of nuclear ER and the percentage of total cellular ER that were in the nuclear fraction. Estradiol dehydrogenase was also induced by the progestin. The presence of this enzyme could result in lowered nuclear ER levels which were seen during the progestogenic phase of the treatment schedule. Nuclear ER was lower during Week 3 than Week 2 of estrogen treatment. In addition, PR was negatively correlated with nuclear ER in postmenopausal tissues obtained in Week 3 in contrast to positive correlations seen in premenopausal samples. Possibly a 3-week treatment with estrogen leads to a refractory condition. When receptor levels of normal, cystic hyperplastic, typical hyperplastic, and atypical hyperplastic tissues were compared, the endometria that had been returned to normal histology suggested that cells in atypical hyperplastic endometrial cells may be more estrogen sensitive than other types of endometrial tissues.^ieng

Simple biochemical method to assess progestin effects on human endometrial DNA synthesis and its application to endometrial carcinoma.

Endometria of normal histology from postmenopausal women receiving either estrogen or estrogen plus a progestin have been analyzed for nuclear estradiol receptor, epithelial DNA synthesis, isocitric dehydrogenase, and estradiol dehydrogenase activities. Epithelial DNA synthesis correlated positively with nuclear estradiol receptor and negatively with both the dehydrogenases; this result was obtained regardless of whether the enzyme activity was related to the protein or DNA content of the samples. Thus, either of the dehydrogenases might provide an index of progestin effects on proliferative activity in endometrial carcinomata. Provera administered in vivo had no effect on either dehydrogenase activity in soluble estradiol receptor-poor carcinomata, whereas both dehydrogenase activities were high in some but not all soluble estradiol receptor-rich tumors. The enzyme activities in Provera-treated tumors have been compared with those in normal epithelium and endometrium from postmenopausal women taking estrogen plus progestin. The activities of both dehydrogenases were lower in soluble estradiol receptor-rich carcinomata than in either endometrium or epithelium from estrogen plus progestin-primed, normal postmenopausal women. This may indicate suboptimal progestin effects in the patients with carcinoma, and potential reasons for this are discussed.

Hormone replacement therapy and the cardiovascular system. Nonlipid effects.

Coronary heart disease (CHD) is the leading cause of death in women, and the risk of this disease rises markedly after loss of ovarian function. Hormone replacement therapy (HRT) can reduce the incidence of CHD in postmenopausal women by 50%. HRT causes changes in lipids and lipoproteins, but it is now clear that many other effects of gonadal steroid hormones have important influences on the cardiovascular system. These nonlipid effects include a variety of changes in other metabolic risk factors for CHD, as well as direct arterial effects. Insulin resistance and hyperinsulinaemia may be pivotal disturbances in the pathogenesis of CHD. Estradiol reverses the effects of menopause on glucose and insulin metabolism, resulting in an increase in pancreatic insulin secretion and a decrease in insulin resistance, although other types of estrogen may not do this. Androgenic progestogens may oppose this potentially beneficial effect on insulin resistance. Central obesity is linked with many CHD risk factors, and HRT reverses the increased fat distribution that results from loss of ovarian function at the menopause. HRT may also improve the balance between coagulation and fibrinolysis, resulting in a reduction in arterial thrombosis. Finally, estradiol acts directly on the arterial wall, modifying both endothelium-dependent and calcium-dependent processes. These actions result in improved blood flow and reduced blood pressure and, importantly, have the potential to reduce myocardial ischaemia.

Insulin resistance, secretion, and elimination in postmenopausal women receiving oral or transdermal hormone replacement therapy.

Estrogen/progestin steroid combinations adversely affect glucose tolerance and insulin resistance, but their effects in combined hormone replacement therapy (HRT) have rarely been evaluated. We studied 61 untreated symptomatic postmenopausal women randomized to receive oral (conjugated equine estrogens, 0.625 mg/d continuous + levonorgestrel, 0.075 mg/d for 12 days of each 28-day cycle) or transdermal therapy (estradiol 17 beta, 0.05 mg/d continuous + norethindrone acetate, 0.25 mg/d for 14 days of each 28-day cycle). An untreated control group of 30 postmenopausal women not seeking HRT was also studied. Intravenous glucose tolerance tests (IVGTT) were performed at baseline and 3, 6, and 18 months later. Mathematical modeling analysis of plasma glucose, insulin, and C-peptide concentration profiles provided measures of insulin resistance, secretion, and elimination. There were no changes in glucose or insulin concentrations with transdermal therapy. Oral therapy caused a deterioration of glucose tolerance and an increased overall plasma insulin response, apparently due to a reduction in the immediate plasma insulin response to glucose. This may have resulted from increased hepatic insulin uptake, uncompensated for by an increase in first-phase pancreatic insulin secretion. Neither treatment caused significant insulin resistance compared with baseline, but with the oral treatment insulin resistance was greater during the combined phase compared with the estrogen-only phase. Thus the oral regimen affected both insulin delivery and insulin resistance. The transdermal regimen had relatively few effects on insulin metabolism.

Effects of oral and transdermal 17beta-estradiol with cyclical oral norethindrone acetate on insulin sensitivity, secretion, and elimination in postmenopausal women.

Few studies have examined the effects of 17beta-estradiol on parameters of insulin and glucose metabolism. We studied 42 healthy, untreated postmenopausal women seeking relief from menopausal symptoms. They were randomized to receive either oral 17beta-estradiol 2 mg daily combined with sequential oral norethindrone acetate (NETA) 1 mg daily from days 12 to 22, or transdermal 17beta-estradiol 0.05 mg daily combined with sequential oral NETA 1 mg daily from days 17 to 28. Intravenous glucose tolerance tests (IVGTTs) were performed at baseline and after 46 weeks (estrogen-alone phase) and 48 weeks (combined phase) of completed therapy. Mathematical modeling analysis of plasma glucose, insulin, and C-peptide concentration profiles provided measures of insulin resistance, secretion, and elimination. Both types of therapy were associated with a decrease in fasting insulin and glucose levels. Insulin sensitivity was increased by oral estradiol during the estrogen-alone phase but was reversed by the addition of NETA. Transdermal estradiol did not affect insulin sensitivity. Hepatic insulin uptake and insulin secretion were increased with both types of treatment. The oral regimen of estradiol therapy was favorable to both insulin elimination and sensitivity. Transdermal estradiol therapy had relatively few effects on insulin metabolism.

The role and use of progestogens.

Certain epidemiologic, histologic, and biochemical data on the effects of estrogens and progestogens on the endometrial, physical, psychological, and lipid status of postmenopausal women are reviewed. Unopposed estrogen replacement increases the risk of endometrial cancer not only while treatment is being taken but also for many years after it is discontinued. Strategies must be developed for posttreatment surveillance. The addition of a cyclic progestogen reduces this risk, but it is not clear whether the reduction is to, or below, that observed in an untreated population. Protective doses of C-19 (norethindrone) and C-21 (medroxy-progesterone acetate) progestogens are suggested. All progestogens may cause physical, psychological, and metabolic side effects. In addition, most women taking cyclic progestogens experience regular withdrawal bleeding. Continuous/combined therapy has been introduced to minimize these side effects and induce amenorrhea. Published data on the efficacy and safety of continuous combined therapy are few. Although the regimen is effective in relieving menopausal symptoms and inducing endometrial atrophy in most patients, side effects of progestogen are common and there is a high incidence of bleeding in the first few months, which is unacceptable to many patients. In our view, the effect of continuous combined therapy on lipids and lipoproteins has not been properly addressed. Based upon the available literature, we believe that the enthusiasm for continuous combined therapy is premature and we urge caution in its use until further, more conclusive, data become available.

Effect of continuous combined estrogen and desogestrel hormone replacement therapy on serum lipids and lipoproteins.

OBJECTIVE: To determine the effects of continuous combined hormone replacement therapy with desogestrel and 17 beta-estradiol (E2) on serum lipids and lipoproteins. METHODS: Fifty-seven healthy postmenopausal women of less than 60 years of age were studied prospectively and treated with oral desogestrel 0.15 mg/day and micronized 17 beta-E2 1 mg/day, both taken continuously. Fasting venous blood samples for serum lipids and lipoproteins were taken before and after 6 and 12 months of treatment. RESULTS: Thirty-two women completed the study. Levels of all serum lipids and lipoproteins fell significantly by 6 months and remained low at 12 months. The mean percentage reduction after 12 months of treatment was 12.8% for high-density lipoprotein (HDL) cholesterol, which largely resulted from a reduction in the HDL2 subfraction, which fell by 25.7%. The mean percentage reduction for both low-density lipoprotein (LDL) cholesterol and triglycerides was 7.7%. The median percentage reduction for lipoprotein (a) was 17.6%. CONCLUSIONS: This combination of hormone replacement therapy had profound effects on serum lipids and lipoproteins. According to current concepts, reductions in total and LDL cholesterol, triglycerides, and lipoprotein (a) may reduce cardiovascular disease risk. The reduction in HDL was unexpected, given the rise in HDL that has been demonstrated when desogestrel is combined with ethinyl estradiol in the contraceptive pill. The lowering of HDL observed in this study is undesirable and may be potentially harmful. Our results indicate that when desogestrel 0.15 mg/day is combined with micronized 17 beta-E2 1 mg/day in a continuous manner, the effects of the progestogen on HDL predominate and cause a reduction in HDL and the HDL2 subfraction.

Long-term effects of oral and transdermal hormone replacement therapies on serum lipid and lipoprotein concentrations.

OBJECTIVE: To see whether the short-term changes in serum lipid and lipoprotein concentrations induced by postmenopausal estrogen-progestin therapy are maintained in the long term. METHODS: Sixty-one healthy postmenopausal women were randomized to either oral therapy (continuous conjugated equine estrogens at 0.625 mg/day with sequential dl-norgestrel at 0.15 mg/day for 12 days each cycle) or transdermal therapy (patches delivering continuous 17 beta-estradiol [E2] at 0.05 mg/day with sequential norethindrone acetate at 0.25 mg/day for 14 days each cycle). Twenty-nine healthy postmenopausal women who did not request therapy served as a reference group. Fasting serum lipid and lipoprotein concentrations were monitored for 3 years. RESULTS: Studied in the estrogen-progestin phase, oral and transdermal therapies reduced serum total cholesterol concentrations by 12.1% (P < .001) and 8.4% (P < .001), respectively, and those of low-density lipoprotein (LDL) by 14.2% (P < .001) and 6.6% (P < .01), respectively. These changes, apparent at 3 months, were maintained over 3 years. Serum triglyceride concentrations fell by 2.5% (P < .05) and 16.4% (P < .01), respectively. These decreases were evident after 6 months in both groups but were maintained over 3 years only in the transdermal group. High-density lipoprotein (HDL) concentrations fell in women given oral therapy (7.8%, P < .05) and transdermal therapy (10.7%, P < .001), as well as in untreated women (7.0%, P < .05). CONCLUSIONS: The potentially beneficial effects of estrogen-progestin therapy on serum total and LDL cholesterol and on triglycerides were maintained over 3 years. Interpretation of the potentially detrimental effects on HDL concentrations was hindered by the changes seen in untreated women.

A risk-benefit assessment of estrogen therapy in postmenopausal women.

Estrogen therapy is extremely effective in relieving menopausal symptoms such as hot flushes, night sweats, urogenital atrophy and certain psychological symptoms. The short term side effects from this therapy are usually mild and self-limiting. They are more common in women who commence hormone replacement therapy some years after the menopause than in those who start treatment at about the time of the ovarian failure. Pre-existing gynaecological conditions such as fibroids and endometriosis can be worsened by estrogen therapy. The majority of published studies suggest a beneficial effect of postmenopausal estrogen therapy on cardiovascular and cerebrovascular disease. These effects may be mediated by favourable changes in lipids, but other mechanisms may also be involved. It is uncertain whether the adverse changes in lipids caused by progestogen therapy will reduce any of the benefits of estrogen therapy on the cardiovascular system. Osteoporosis is the major bone disease of the Western world; long term estrogen therapy will prevent its development in most postmenopausal women. The risk of endometrial carcinoma is increased with unopposed estrogen therapy; this increased risk appears to be abolished if a progestogen is added at an adequate dose and duration for each cycle. The risk of ovarian or cervical cancer is not increased with estrogen therapy. There may be an increased risk of breast carcinoma with long term postmenopausal estrogen use, but the studies show inconsistent results.

Assessment of the potency of orally administered progestins in women.

The effects of at least three doses of each of five orally administered progestins on estrogen-primed, postmenopausal endometrial biochemistry and morphologic features were analyzed. The progestins tested were norethindrone, medroxyprogesterone acetate (MPA), norgestrel, dydrogesterone, and progesterone. The dose required to elicit responses similar to those seen in premenopausal, secretory endometria was assessed for each of the parameters measured, and the relative potencies were calculated. Potencies, relative to a value of 1 for norethindrone, are L norgestrel 8 (D/L norgestrel 4), MPA 0.1, dydrogesterone 0.02, and progesterone 0.002. The dose of norethindrone required to elicit secretory phase activity was about 0.35 mg/day. These values agree with published data obtained with the use of different methods (delay of menstruation in premenopausal women, endometrial histologic features of estrogen-primed, ovariectomized women).

Absorption and metabolism of oral progesterone when administered twice daily.

The absorption, metabolism, and clearance of progesterone (P) from the peripheral circulation were investigated in five postmenopausal women after oral administration of 100 mg at 9:00 A.M. and 200 mg at 9:00 P.M. for 5 consecutive days. Mean peak plasma concentrations of P were observed 2 hours after ingestion of both the 100 and 200 mg doses and were 22.7 and 47.7 nmol/l, respectively. Of the three metabolites studied, the plasma concentrations of pregnanediol-3 alpha-glucuronide were most raised by treatment; those of 17-hydroxyprogesterone were least raised. Increases in the plasma levels of 20 alpha-dihydroprogesterone were more sustained than those of P, and the plasma concentrations remained elevated at approximately 20 nmol/l for at least 12 hours after P administration. We conclude that administration of oral P 100 mg in the morning and 200 mg at night increases the circulating concentrations of P and the biologically active metabolite 20 alpha-dihydroprogesterone, and that the duration of these increases is sufficient to evoke progestational responses in responsive end-organs.

The temporal effect of progestogen on uterine artery pulsatility index in postmenopausal women receiving sequential hormone replacement therapy.

OBJECTIVE: To determine the time relationship between the ingestion of progestogen during sequential hormone replacement therapy (HRT) and impedance to blood flow in the uterine arteries. DESIGN: Nine postmenopausal women who had already received HRT for at least 6 months were treated with either transdermal 17 beta-E2, 0.1 mg/d, or conjugated equine estrogens (Es), 1.25 mg/d, to which norethindrone, 0.7 mg/d, was added for 12 days in a single 28-day cycle of therapy. Transvaginal ultrasonography with color flow imaging was used to measure the pulsatility index (PI) in the uterine arteries every 3 to 5 days over one 28-day treatment cycle. RESULTS: The ingestion of norethindrone increased the mean uterine artery PI by 30% (SE 16.4%). The PI fell significantly within 4 days of ceasing norethindrone. CONCLUSION: Progestogen addition in sequential HRT causes changes in the uterine arterial tone, but the effect subsides within 4 days of progestogen withdrawal.

Hormone excretion during early pregnancy following spontaneous and clomiphene citrate-induced ovulation.

Endocrine changes during early pregnancy have been studied in 12 patients between days 35 and 91 from the last menstrual period. Ovulation had occurred spontaneously in five patients and was induced with clomiphene citrate (CC) in the remaining seven women. All the patients collected daily samples of early morning urine throughout the period of study; on each sample, human chorionic gonadotropin (hCG), pregnanediol-3-alpha-glucuronide (PGDG) and estrone-3-glucuronide (E1G) were measured by chemiluminescence immunoassay. No significant difference was observed between the two groups of patients with respect to the concentrations of hCG and PGDG. The excretion of E1G, however, was significantly higher in patients treated with CC. These data suggest that the induction of ovulation with CC may affect estrogen production in early pregnancy.

The optimal dose of oral norethindrone acetate for addition to transdermal estradiol: a multicenter study.

The effects of adding one of three doses (0.5, 0.75, or 1.0 mg/d) of norethindrone acetate for 12 days each month to continuous, transdermal estradiol (0.05 mg/d) have been determined in a prospective, randomized, multicenter study. Significant symptomatic and psychological improvements were observed and, with one exception, were not opposed by the added progestogen. Distinct redness at the site of last patch application was reported by 10% of patients and faint erythema by 30%. However, less than 5% of patients discontinued treatment because of skin problems. Breakthrough bleeding occurred infrequently and all three doses of norethindrone acetate induced a regular pattern of bleeding with secretory transformation in the endometrium. There was no hyperplasia or carcinoma.

Is Provera the ideal progestogen for addition to postmenopausal estrogen therapy?

In a dose-ranging study, medroxyprogesterone acetate, 2.5, 5, or 10 mg daily, was given for 12 days of each calendar month to postmenopausal women also receiving conjugated estrogens, 0.625 mg daily, continuously. Endometrial biopsy specimens were taken on the sixth day of combined therapy for histologic, ultrastructural and biochemical evaluation. Medroxyprogesterone acetate induced secretory and ultrastructural changes within the endometrium, but the responses were variable and inconsistent. Suppression of epithelial deoxyribonucleic acid synthesis appeared dose-dependent. The levels of nuclear estradiol receptor, although reduced to within the secretory phase range, were not significantly lower than the values observed during the estrogen-only phase of treatment. Induction of both estradiol and isocitrate dehydrogenase activities was to within the secretory phase ranges, but the magnitude of these responses appeared less than those observed previously with other progestogens. Both morphologically and biochemically, medroxyprogesterone acetate, even at high dosage, produced suboptimal responses. Further studies are required to establish whether this is a dose-related effect.

Differential effects of transdermal estradiol and sequential progestogens on impedance to flow within the uterine arteries of postmenopausal women.

OBJECTIVE: To investigate the relationship between estradiol (E2), progestogen, and impedance to blood flow in the uterine artery. SUBJECTS: Twelve postmenopausal women treated for two cycles with transdermal E2, 0.05 mg/d, with either norethindrone acetate, 0.7 mg, or medroxyprogesterone acetate, 10 mg added sequentially. MEASUREMENTS: Transvaginal ultrasonography and color flow imaging were used to measure the pulsatility index in the uterine arteries before and during the E2-only and combined E2/progestogen phases. RESULTS: The mean pulsatility index fell to 53% of its pretreatment value within 12 days E2 administration (P < or = 0.0001) and was 66% of its pretreatment value in the combined phase (P < 0.005). Similar changes were seen in cycle 2. Time since menopause was correlated with the pretreatment pulsatility index (r = 0.674, P < 0.05) and change in pulsatility index on treatment (r = 0.856, P < 0.001). CONCLUSION: Gonadal hormones have a profound effect on arterial tone in postmenopausal women; this action may help explain some of the beneficial effects of estrogen on arterial disease risk.

The effects of oestrogens and progestogens on the postmenopausal endometrium.

Cyclical regimens of unopposed oestrogens are associated with the development of endometrial hyperplasia and the incidence of hyperplasia is dose-related. As no pattern of vaginal bleeding serves as a reliable indicator of underlying endometrial pathology and as hyperplasia can develop subsequent to the finding of a normal endometrium and at any time from 2 to 35 mth after the start of treatment, serial biopsies are required on every patient. Oral oestrone and oestradiol complexes both give rise in the plasma principally to oestrone and therefore the term "Hormone replacement therapy" is inappropriate. The incidence of hyperplasia during sequential oestrogen/progestogen therapy is greatly reduced and therefore progestogens are capable of protecting against the development of this condition. Sequential regimens can also reverse oestrogen-related hyperplasia to normal endometrium.

Sex and menopause: defining the issues.

This is a study of 185 women attending a menopause clinic in London, England. Individual interviews carried out by a gynecologist trained in sex therapy found a variety of psychosexual problems affected the lives of a large majority of the women. Sex problems existing prior to menopause were exacerbated. For most of the women, however, problems developed during the years immediately preceding and following menopause. Problems included disorders of sexual desire, sexual response and sexual behavior. Menopause clinic staff should be alert to the presence of sex problems and should play a role in diagnosis, treatment and/or referral.