Estrogen-treated Postmenopausal Women Research Articles

Morphometric, immunohistological and threedimensional evaluation of the endometrium of menopausal women treated by oestrogen and Crinone, a new slow-release vaginal progesterone

Recently advanced computerized technology was applied to the investigation of morphometric, immunohistological and three-dimensional changes of the endometrial mucosa in order to evaluate quantitatively the effects of three doses of a new slow-release vaginal progesterone on the endometrium in post-menopausal women. A total of 20 menopausal women, deprived of ovarian function, were given oestrogen for 12 days and a combined therapy of oestrogen (administered orally) and progesterone for another 12 day period. Progesterone was administered vaginally through a new gel (Crinone) utilizing a bioadhesive, biocompatible polymer as a base to achieve a sustained release effect. An endometrial biopsy was taken before treatment, after oestrogen-only treatment and after the oestro-progestogen therapy. Before treatment, all the patients exhibited an atrophic endometrium. After oestrogen-only treatment, typical proliferative changes occurred: an increase in the endometrium thickness, an increase in the mitotic index, numerous cylinder-like glands and no coiled glands, and high concentrations of oestrogen receptors (ER) and progesterone receptors (PR). After the oestro-progestogen therapy, whatever the dose of progesterone given, a secretory transformation of the endometrial mucosa occurred, mitotic activity decreased significantly, more ramified and coiled glands were observed, and a decrease in PR content was noted in epithelial and stromal nuclei, and a decrease in PR content was also observed in epithelial nuclei but not in stromal nuclei. Accurate new techniques of image analysis have shown that crinone therapy could eliminate the proliferative effects of oestrogen treatment in post-menopausal women, despite doses as low as 45 mg of progesterone administered vaginally every other day. The results suggest that the sustained release effects of Crinone are clinically relevant.

Coronary arteriography in estrogen-treated postmenopausal women

Four cross-sectional studies that used coronary arteriography to determine the extent of coronary atherosclerosis have provided some of the most convincing evidence that estrogen replacement reduces cardiovascular risk in postmenopausal women. One study of outcome in women undergoing coronary arteriography at baseline has found that the greatest improvement in total mortality occurred in women with significant coronary stenosis. Angiographic studies have also confirmed the importance of high-density lipoprotein in mediating the effect of estrogen and the beneficial effect of estrogen on endothelial function.

Diagnostic testing strategies for coronary artery disease: Special issues related to gender

Early reports of the prevalence, diagnosis, and outcomes of coronary artery disease (CAD) in women have led to the acceptance of several myths concerning noninvasive diagnostic studies in women. Many of the myths can be explained by age-related differences in prevalence, methodological errors that exclude women from enrollment, worse clinical baseline risk profiles, comorbid diseases at the time of interventions, and smaller coronary vessels. Awareness of these age-related prevalence factors in women and the potential for delaying the onset of CAD by estrogen treatment in postmenopausal women must be considered in assessing the accuracy of diagnostic studies. The critical role of noninvasive testing in women is to diagnose CAD accurately in a population with a lower prevalence of disease prior to the development of more severe clinical manifestations when therapeutic interventions have a higher risk and a poor outcome. Exercise radionuclide ventriculography has lower specificity in women, which may be due to gender differences in the response to excercise. Radionuclide perfusion imaging for the detection of CAD is accurate, there is extensive published literature, and it is used widely. High-dose dipyridamole in combination with echocardiography is not widespread in the United States; most pharmacologic echocardiographic studies are performed using dobutamine, and there are no reports on gender differences using dobutamine echocardiography. At this time, however, there is a paucity of published data on accuracy and no information on the prognostic value of this method. Both perfusion imaging and echocardiography have a better diagnostic accuracy than electrocardiographic stress testing. Myocardial perfusion imaging with thallium-201 or Tc-99m sestamibi identifies not just the presence or absence of CAD, it also prognostically identifies those patients with more severe disease who may benefit from invasive diagnostic testing and possible therapeutic interventions. Technetium-99m perfusion agents offer several advantages over thallium-201 : less attenuation, the ability to measure first-pass ejection fraction, and gated image acquisition. All 3 of these characteristics are expected to improve both sensitivity and specificity in women. Early reports of the prevalence, diagnosis, and outcomes of coronary artery disease (CAD) in women have led to the acceptance of several myths concerning noninvasive diagnostic studies in women. Many of the myths can be explained by age-related differences in prevalence, methodological errors that exclude women from enrollment, worse clinical baseline risk profiles, comorbid diseases at the time of interventions, and smaller coronary vessels. Awareness of these age-related prevalence factors in women and the potential for delaying the onset of CAD by estrogen treatment in postmenopausal women must be considered in assessing the accuracy of diagnostic studies. The critical role of noninvasive testing in women is to diagnose CAD accurately in a population with a lower prevalence of disease prior to the development of more severe clinical manifestations when therapeutic interventions have a higher risk and a poor outcome. Exercise radionuclide ventriculography has lower specificity in women, which may be due to gender differences in the response to excercise. Radionuclide perfusion imaging for the detection of CAD is accurate, there is extensive published literature, and it is used widely. High-dose dipyridamole in combination with echocardiography is not widespread in the United States; most pharmacologic echocardiographic studies are performed using dobutamine, and there are no reports on gender differences using dobutamine echocardiography. At this time, however, there is a paucity of published data on accuracy and no information on the prognostic value of this method. Both perfusion imaging and echocardiography have a better diagnostic accuracy than electrocardiographic stress testing. Myocardial perfusion imaging with thallium-201 or Tc-99m sestamibi identifies not just the presence or absence of CAD, it also prognostically identifies those patients with more severe disease who may benefit from invasive diagnostic testing and possible therapeutic interventions. Technetium-99m perfusion agents offer several advantages over thallium-201 : less attenuation, the ability to measure first-pass ejection fraction, and gated image acquisition. All 3 of these characteristics are expected to improve both sensitivity and specificity in women.

Diagnostic testing strategies for coronary artery disease: Special issues related to gender

Early reports of the prevalence, diagnosis, and outcomes of coronary artery disease (CAD) in women have led to the acceptance of several myths concerning noninvasive diagnostic studies in women. Many of the myths can be explained by age-related differences in prevalence, methodological errors that exclude women from enrollment, worse clinical baseline risk profiles, comorbid diseases at the time of interventions, and smaller coronary vessels. Awareness of these age-related prevalence factors in women and the potential for delaying the onset of CAD by estrogen treatment in postmenopausal women must be considered in assessing the accuracy of diagnostic studies. The critical role of noninvasive testing in women is to diagnose CAD accurately in a population with a lower prevalence of disease prior to the development of more severe clinical manifestations when therapeutic interventions have a high risk and a poor outcome. Exercise radionuclide ventriculography has lower specificity in women, which may be due to gender differences in the response to exercise. Radionuclide perfusion imaging for the detection of CAD is accurate, there is extensive published literature, and it is used widely. High-dose dipyridamole in combination with echocardiography is not widespread in the United States; most pharmacologic echocardiographic studies are performed using dobutamine, and there are no reports on gender differences using dobutamine echocardiography.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgenic progestogens oppose the decrease of insulin-like growth factor I serum level induced by conjugated oestrogens in postmenopausal women. Preliminary report

Oral oestrogen treatment in postmenopausal women causes a decrease of insulin-like growth factor I (IGF-I) serum level, probably through a hepatocellular effect. To explore the possibility that the androgenic progestogens oppose this effect, serum IGF-I and sex hormone binding globulin (SHBG) were evaluated in two groups of patients treated respectively with oral conjugated oestrogens (oCE) or transdermal oestradiol (tdE 2), in a first phase with the addition of dydrogesterone (DYDR), a non-androgenic progestogen, and subsequently with the addition of norethisterone acetate (NETA). With respect to basal values, treatment with oCE + DYDR caused an increase of SHBG ( P < 0.002) and a decrease of IGF-I serum levels ( P < 0.05); the shift to NETA addition opposed both effects: SHBG levels decreased partially but significantly ( P < 0.01 vs. oCE + DYDR) and IGF-I returned to basal values with a significant increase with respect to the oCE + DYDR phase ( P < 0.02). No changes were observed in the tdE 2 + DYDR treated women; in this group the shift to NETA addition caused a significant decrease of SHBG values ( P < 0.001 vs. before treatment and vs. tdE 2 + DYDR phase) and a slight increase of IGF-I values. These differential effects on IGF-I and SHBG serum levels might be relevant as far as breast cancer risk is concerned.

Estrogen protection against bone resorbing effects of parathyroid hormone infusion. Assessment by use of biochemical markers.

Because parathyroid hormone (PTH) stimulates bone resorption, resistance to its actions might help maintain bone mass. We tested the hypothesis that the effects of estrogen on bone are accomplished in part by decreasing the sensitivity of the skeleton to the resorbing effects of PTH. Comparison of response to PTH infusion in untreated and estrogen-treated postmenopausal women with osteoporosis. (1-34) human PTH, 0.55 U/(kg.h), was infused intravenously over 20 hours. The inpatient clinical research unit of a referral hospital. Women with primary postmenopausal osteoporosis who were untreated (n = 15) or treated with estrogen (n = 17). Skeletal turnover indices including hydroxyproline, deoxypyridinoline, pyridinoline, tartrate-resistant acid phosphatase, alkaline phosphatase, bone Gla protein, and insulin-like growth factor-1. All basal indices were higher in untreated than in estrogen-treated women, but statistical differences were seen only for deoxypyridinoline and pyridinoline. During the 20-hour infusion, hydroxyproline/creatinine increased 0.023 mumol/mumol in untreated women but only 0.010 mumol/mumol in estrogen-treated women (P < 0.05). Corresponding changes for deoxypyridinoline/creatinine were 14.6 mumol/mumol and 3.5 mumol/mumol (P = 0.06). Tartrate-resistant acid phosphatase and pyridinoline increased only in untreated group. A circadian rhythm in circulating bone Gla protein was seen in both groups without clear PTH-induced effects or differences between groups. Alkaline phosphatase levels decreased and insulin-like growth factor-1 levels increased in both groups with no distinction between untreated and estrogen-treated women [corrected]. The estrogenized postmenopausal osteoporotic skeleton is less sensitive to the bone resorbing effects of acutely administered PTH. There are no differential effects on bone formation.

Plasma BGP: an indicator of spontaneous bone loss and of the effect of oestrogen treatment in postmenopausal women

One hundred and ninety-one healthy early postmenopausal women, aged 45-54 years, were randomized to 2 years of treatment with (a) percutaneous 17 beta-oestradiol combined with progesterone (n = 29) or placebo (n = 28); (b) oral oestradiol valerate combined with cyproterone acetate (n = 37) or placebo (n = 39); (c) 24R, 25 (OH)2D3 (n = 29) or placebo (n = 29). We measured the plasma bone Gla-protein (BGP), bone mineral content of the proximal forearms (BMC), bone mineral density in the spine (BMDspine) and total body bone mineral (TBBM) in all the women before, and during, the study. In the groups of women receiving the oestrogen preparations, the plasma BGP decreased highly significantly (P less than 0.001) to a premenopausal level. The initial plasma BGP concentration was significantly related to the loss of BMC (P less than 0.001) in the placebo groups. The changes in plasma BGP were an indicator of the oestrogen response on BMC. We conclude that serial determinations of plasma BGP are useful for determination of the effect of oestrogen therapy in groups of patients, and that plasma BGP measured at the time of the menopause indicates what the rate of bone loss will be.

Evaluation of the urethral mucosa before and after oestrogen treatment in postmenopausal women with a new sampling technique.

Using a new type of nylon brush (Cytobrush) for sampling of cells, the state of the urethral mucosa was evaluated before and after oestrogen treatment in 10 patients suffering from urinary incontinence. In 4 other patients the results obtained were compared with those using the conventional cotton swab technique. The brush specimens were found to be much more cellular and consequently more informative than those obtained with the conventional technique. The cytologic examination based on brush samples also demonstrated that oestrogen treatment within 3 weeks induced a proliferation of the atrophic urethral mucosa in postmenopausal women suffering from urinary incontinence.

Avoidance of Endometrial Hyperstimulation in Estrogen-Treated Postmenopausal Women

Avoidance of Endometrial Hyperstimulation in Estrogen-Treated Postmenopausal Women

THE ROLE OF HORMONES IN THE ETIOLOGY OF BREAST AND ENDOMETRIAL CANCER

Despite many years of extensive investigation, there has been neither a clear-cut pattern of hormonal production nor milieu found in women with breast cancer. Estrogen replacement therapy for menopause does not significantly increase the risk of breast cancer and one study indicated that estrogen users have a lower incidence of breast cancer than that observed in untreated women. Some studies have shown that the mortality rate from breast cancer is lower in estrogen-treated postmenopausal women. Only one investigator has found any significantly increased risk of breast cancer in oral contraceptive users. In that report, increased duration of birth control pill use decreased the risk of breast carcinoma. Several studies were unable to find an increased risk of breast cancer from oral contraceptives while one investigation observed a lower incidence in birth control pill users than that expected. The mortality from carcinoma of the breast in oral contraceptive users was lower than in non-users, most likely due to earlier detection. Although some retrospective studies have indicated that estrogen use increases the risk of endometrial cancer, a prospective investigation found only an insignificant increase. Progestogens afford some protection from cancer in estrogen-treated postmenopausal women. The incidence of endometrial adenocarcinoma is lower than that observed in untreated postmenopausal women. Combination oral contraceptives are protective against developing adenocarcinoma of the endometrium but sequential birth control pills may afford less protection.

The Role of Hormones in Endometrial Cancer

In this review article the author evaluated current information and clinical data concerning sex hormones in endometrial cancer and offers the following conclusions. 1) Postmenopausal women with above normal estrogen production (increased androstenedione to estrone conversion as seen in obesity liver disease and polycystic ovaries) are at an increased risk for developing adenocarcinoma of the endometrium. 2) Despite conflicting data patients treated with estrogen replacement therapy alone probably have an increased risk for endometrial cancer (Tables 1-3; Figure 1). 3) Progestogens can prevent endometrial malignancy in both estrogen-treated postmenopausal women and patients with increased endogenous estrogens (Figure 2). 4) Synthetic progestogens can reverse hyperplasia of the endometrium a precancerous lesion to normal endometrium in most patients (Tables 4-5; Figure 3). 5) Oral contraceptives of the combined type can prevent endometrial cancer while sequential birth control pills are less protective. This may be due to the potency or bioavailability of synthetic progestogens in these contraceptives. 6) Since androgens reduce withdrawal bleeding in estrogen-progestogen treated postmenopausal women (Table 6) they may help prevent adenocarcinoma of the endometrium by endometrial suppression. However there is insufficient evidence to support this theory.

Disturbance of tryptophan metabolism and its correction during oestrogen treatment in postmenopausal women

A relative pyridoxine deficiency was found in all of 12 women using conjugated oestrogens unopposed by progestagens. This was due to disturbed tryptophan metabolism, expressed in increased xanthurenic acid (XA) excretion (⩾60 μmol/8 h) during 8 h following oral administration of 2 g L-tryptophan. The intake of synthetic oestrogens such as ethinyl oestradiol has already been found to lead to a disturbance of tryptophan metabolism and to a deficiency of vitamin B6. Now we have evidence that this is the case not only in women taking oestrogens in oral contraceptives but also as replacement therapy during the postmenopause. This disturbance is clear after 1 yr of oestrogen treatment. Xanthurenic acid excretion was only slightly increased in 3 women who used progestagens in high dosages at the same time. The biochemical changes induced could easily be corrected by administration of vitamin B6. Our cyclic treatment regimen now consists of 25 days of oestrogens per month. In the remaining days a 250 mg tablet per day of vitamin B6 is prescribed.

Estrogen Treatment of Postmenopausal Women

Estrogen treatment of postmenopausal women is effective in relieving the symptoms of vasomotor instability and urogenital atrophy; estrogen treatment is effective in preventing accelerated bone loss and osteoporosis in young women following castration, but in postmenopausal women aging is a more important determinant of accelerated bone loss than is decreased estrogen secretion. Low-dose estrogen treatment of postmenopausal women neither prevents nor increases the risk of arteriosclerotic cardiovascular disease or cerebral vascular disease. It cannot be definitively established that estrogen treatment of postmenopausal women causes an increased incidence of breast tumors, but it is clear that such treatment does not prevent these tumors. It is established that estrogen treatment of postmenopausal women increases the risk ratio of endometrial carcinoma.

Estrogen treatment of postmenopausal women. Benefits and risks

Estrogen treatment of postmenopausal women. Benefits and risks

Secretory endometrium associated with breakthrough bleeding in estrogen-treated postmenopausal women

Paradoxical secretory changes are described in benign endometria curetted for breakthrough bleeding in postmenopausal women on cyclic low dosage Premarin therapy. This purely histologic study, though favoring progesterone mediation, provides no definitive answer to the problem of pathogenesis. Future correlative morphologic and endocrine investigations are clearly indicated.

THE INFLUENCE OF OESTROGENS ON THE WELLBEING AND MENTAL PERFORMANCE IN CLIMACTERIC AND POSTMENOPAUSAL WOMEN

Studies were conducted on the effect of estrogen on the mental and psychosomatic disorders and mental performance in 27 patients with climacteric symptoms and 25 postmenopausal women who had been amenorrheic for at least 1 year. Both groups were treated with estrogen and a progestogen cyclically for 6 months. A group of 21 postmenopausal women were divided into 2 subgroups 11 were treated with estrogen and 10 received placebo in a double-blind procedure. Social status parity education and occupation were similar in all groups. All patients received a general physical and gynecological examination and metabolic screening. Each patient was examined by means of a series of psychological tests inventories and rating scales for degree of neuroticism distress depression sexual function information-processing capacity and psychosomatic complaints. There was a decrease of follicle stimulating hormone and luteinizing hormone in the estrogen-treated postmenopausal women at 3 and 6 months of treatment; levels in estrogen-treated premenopausal women and in the placebo group were unchanged. Climacteric and postmenopausal patients initially showed a higher than standard degree of neuroticism as measured by the Eysenck Personality Inventory. Estrogen-treated patients showed a statistically significant decrease in contrast to an increase in placebo patients. In the Hamilton Rating Scale for Depression and Sabbatsberg Distress Self-Rating Scale estrogen-treated groups improved significantly while the placebo group showed a deterioration. Performance tests of estrogen-treated patients particularly in complex tasks showed improved information-processing capacity. An improvement was noted on the Sabbatsberg General Symptoms Rating Scale and Sabbatsberg Sexual Self Rating Scale. In self-report estrogen-treated patients considered themselves improved while placebo patients reported the opposite. These findings suggest that estrogen deficiency should be treated to restore somatic mental and social well-being.

Progestin receptors in human tissues: Concentrations and binding kinetics

Progestin receptor level was measured from myometrial cytosol samples obtained from normally menstruating women (group I), postmenopausal women (group II) and postmenopausal women after 1 week's treatment with estrogens (group III). The following receptor levels were found: Group I, 63–722 fmol/mg cytosol protein; group II, below 100 fmol/mg, and group III, 350–3600 fmol/mg. Estrogen treatment of postmenopausal women preferentially promoted formation of the 7S progestin receptor in the myometrial cytosol. By contrast, the binding of [ 3H]-progesterone occurred only to the 4S component in the myometrial cytosol samples from normally menstruating women. During the menstrual cycle, progestin receptor level in the myometrial cytosol correlated directly to the cytosol estradiol-17β content and inversely to progesterone concentration in both the myometrial cytosol and serum. Interaction of the partially purified myometrial progesterone receptor at +4°C with the following [ 3H]-labeled progestins was studied: Progesterone (P), norethisterone (NET), 16α-ethyl-21-hydroxy-19-nor-4-pregnene-3, 20-dione (ORG 2058), 17,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione (R 5020) and 13-ethyl-11-methylene-18,19-dinor-17α-4-pregnen-20-yn-17-ol (ORG 2969). The rate of association of ORG 2969, lacking the 3-keto group, was much slower ( k a = 0.23 × 10 5 1 × mol −1 × s −1) than that of other progestins ( k a range 1.9–4.6 × 10 5 1 × mol −1 × s −1). The rate of dissociation was fastest for P ( k d = 13.0 × 10 −5 s −1, t 1 2 90 min) followed by NET and ORG 2969 ( t 1 2 205 and 235 slower rates of dissociation were recorded for R 5020 and ORG 2058 ( t 1 2 620 and 1000 min). The apparent intrinsic dissociation constants ( K D) calculated from the kinetic parameters were: P 0.56, NET 0.3, ORG 2058 0.04, R 5020 0.04 and ORG 2969 2.5 nmol × 1 −1. These values were about 5–15 times lower than those obtained in the equilibrium binding studies. In the myometrial cytosol of estrogen-treated women, the potent progestins were bound to both 4S and 7S components, although they preferred association with the latter. The low rate of dissociation of ORG 2058 and minimal binding to non-receptor sites render it very suitable for progestin receptor measurements also from non-uterine tissues. This is exemplified by results obtained in assays of progestin receptors from human breast cancer tissue.

Oestrogen-induced progesterone receptor in human uterus

High affinity progesterone binding proteins having the characteristics of steroid receptors were found in the endometrial and myometrial cytosols of human uteri obtained after hysterectomy from fertile females and estrogen-treated postmenopausal women. Only traces, if any, of this type of binding protein were present in the uterine cytosols of untreated postmenopausal women. The steroid-binding properties of the progesterone receptors in both uterine compartments were very similar. Both proteins were capable of binding a great variety of potent progestins, derivatives of 19-norprogesterone and norethisterone, whereas cortisol was not bound by either receptor. The following physicochemical characteristics were determined at +4°C for the myometrial progesterone receptor(s): Sedimentation rate 3.8S and 7.5S (hypoionic medium), 3.8S (hyperionic medium, 0.3 M KCl); equilibrium association constant 1–4 × 10 9 l/mol; rate of association 6.7 × 10 4 l/mol × s −1; rate of dissociation 4.4 × 10 −5 s −1; isoelectric points at pH 4.8 and 5.2. The binding process was heat and acid labile had a pH optimum of 8.3. An involvement of SH-groups in the steroid binding process was indicated by a loss of binding ability in the presence of p-hydroxymercuribenzoate. Furthermore, some divalent cations interfered with hormone binding, possibly by interacting with SH-groups on the protein. In the myometria of estrogen-treated postmenopausal women, the binding site concentration varied from 0.35 to 3.6 × 10 −12 mol/mg of cytosolic protein. In fertile females, the concentration was 0.06-0.55 × 10 −12 mol/mg protein. In normally menstruating women, the myometrial binding site concentration seemed to correlate directly with plasma estradiol-17β and indirectly with plasma progesteone concentrations, as in some animal species.