Circulating hormone levels in menopausal women receiving different hormone replacement therapy regimens. A comparison

OBJECTIVE: To measure and compare plasma levels of sex hormones after the administration of different hormone replacement therapy (HRT) regimens. STUDY DESIGN: Ninety women with natural menopause were randomized into this comparative study. Eighty-five women completed one year of follow-up. Patients were randomly assigned to five groups. The first received 0.6 mg/d of conjugated equine estrogen (CEE) cyclically (n = 15). The second received 50 micrograms/d of transdermal estradiol (E2) cyclically (n = 17), and the third received 0.6 mg/d of CEE continuously (n = 17). All these groups also received 2.5 mg of medroxyprogesterone acetate (MPA) sequentially for the last 12 days of HRT, while the fourth therapy group received 0.625 mg/d of CEE and 2.5 mg/d of MPA continuously (n = 19). The fifth group constituted a treatment-free control group (n = 22). Levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), E2, estrone (E1), prolactin (PRL), testosterone (T), androstenedione (A4), dehydroepiandrosterone sulfate (DHEA-S) and sex hormone binding globulin (SHBG) were determined prior to HRT and during the last week of the 6th and 12th months of HRT, between days 21 and 24 of estrogen administration. RESULTS: After HRT we found decreases in FSH, LH and PRL levels, increases in E2, E1 and SHBG, and no modifications in T, A4 and DHEA-S plasma levels. There were no significant differences between the treatment groups in FSH, LH, E2, PRL, T, A4 or DHEA-S. E1 and SHBG were significantly higher in the groups with oral HRT. CONCLUSION: All the observed changes in hormone levels are to be expected after HRT except for the decrease in PRL levels. Finally, although MPA dosage was not the focus of the present study, our results suggest that the dosage of 2.5 mg/d of MPA in sequential regimens is clearly inadequate to protect the endometrium from hyperplastic changes.     

Studies on low-dose oral contraceptives: cervical mucus and plasma hormone changes in relation to circulating D-norgestrel and 17alpha ethynyl-estradiol concentrations

A study was undertaken to determine the effects of a low-dose oral contraceptive comprising 150 mug of D-norgestrel and 30 mug of 17alpha-ethynyl estradiol (Microgynon) on the plasma levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17BETA-ESTRADIOL, AND PROGESTERONE AND ON THE PHYSICAl properties of cervical mucus. Samples of blood and cervical mucus were obtained from three women during a treated cycle and the immediately-following "withdrawal" cycle. Specific radioimmunoassay methods were used to determine LH, FSH, 17beta-estradiol, and progesterone levels in treated and withdrawal cycles, and D-norgestrel and 17alpha-ethynyl estradiol in samples obtained during treated cycles. The concentration of synthetic steroids was also measured in blood samples obtained before and 1 hour after ingestion of the contraceptive to determine the maximal daily variation. The results indicated that the contraceptive action of this combined low-dose oral contraceptive is mediated through suppression of ovulation and by rendering the cervical mucus impenetrable to sperm. Plasma FSH levels appeared to be one of the most sensitive indices of suppression. Determination of D-norgestrel and 17alpha-ethynyl estradiol showed that 3 to 4 days were required to reach maximal plasma levels and that daily fluctuations were considerable. Withdrawal of the pill resulted in an immediate return to ovulatory cycles in all three subjects studied.     

Hypothalamic-pituitary-ovarian response to clomiphene citrate in women with polycystic ovary syndrome

OBJECTIVE: To examine the hypothalamic-pituitary sites of clomiphene citrate (CC) action in women with polycystic ovarian syndrome (PCOS). DESIGN: Prospective controlled trial. PATIENTS, PARTICIPANTS: Seventeen women with PCOS and 9 normal-cycling women. INTERVENTIONS: Subjects with PCOS received CC, 150 mg/d for 5 days. MAIN OUTCOME MEASURES: Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels and LH pulse characteristics and their response to gonadotropin-releasing hormone (GnRH, 10 micrograms) were examined before and after 3 days of CC in PCOS subjects during a 12-hour frequent sampling study (n = 8). Daily urinary estrone glucuronide and pregnanediol glucuronide levels after CC were compared with concentrations in normal-cycling women through one menstrual cycle. In another nine PCOS subjects, pituitary and ovarian hormonal cyclicity was monitored by daily blood sampling. RESULTS: Thirteen of 17 treated cycles were ovulatory with normal luteal phases. In the ovulatory cycles, serum LH, FSH, estradiol (E2), and estrone levels increased after CC. Luteinizing hormone pulse frequency was unchanged, but LH pulse amplitude increased significantly after CC. Both LH and FSH response to exogenous GnRH was significantly attenuated after CC treatment. In anovulatory cycles, serum LH, FSH, and E2 increased initially and then returned to baseline and remained unchanged for the ensuring 40 days. CONCLUSIONS: Clomiphene citrate-induced ovulation in women with PCOS is accompanied by increased secretion of LH and FSH with enhanced estrogen secretion. The increased LH pulse amplitude after CC, together with decreased pituitary sensitivity to GnRH, suggests a hypothalamic effect.     

Follicular fluid hormone concentrations after ovarian stimulation using gonadotropin preparations with different FSH/LH ratios. I. Comparison of an FSH-dominant and a purified FSH preparation

OBJECTIVE: A small amount of LH is necessary for 17beta-estradiol production in the ovarian follicle. Human menopausal gonadotropin (hMG) contains equal amounts of FSH and LH activity, whereas recombinant FSH is a gonadotropin preparation without LH. The aim of the present randomized study was to investigate whether ovarian stimulation treatment with recombinant FSH or hMG resulted in different steroidal composition of follicular fluid. METHODS: Antral fluid from mature follicles was collected in in vitro fertilization cycles and concentrations of testosterone, androstenedione, estrone, estradiol, progesterone, FSH, and LH were determined. Seven patients (27 samples) were treated with hMG, 6 patients (22 samples) with recombinant FSH. RESULTS: Androgen, estrogen, progesterone, and FSH concentrations in follicular fluid tended to be lower in the group treated with recombinant FSH, but the variation was large and differences were statistically not significant. CONCLUSION: Treatment with a gonadotropin preparation containing no LH resulted in adequate androgen and estrogen levels in antral fluid of the ovarian follicle in women with normal endocrine profiles, even during pituitary suppression by a GnRH agonist. Apparently, the amount of endogenous LH was sufficient for steroid production within the follicle.     

When is it safe to switch from oral contraceptives to hormonal replacement therapy?

Women may continue to use oral contraceptives (OCs) into their 40's and 50's, but to date no method has been evaluated to ascertain their ovarian status, i.e., whether fertility and estrogen production have diminished sufficiently so they could be safely switched to hormonal replacement therapy. A group of 12 postmenopausal women who had been, for long periods of time, on a regimen of 3 back-to-back packages (i.e., 63 days on, 7 days off) of low-dose oral contraceptives have been studied. Secondly, a group of 9 perimenopausal women aged 36 to 47 were examined in the same manner. The third group consisted of early reproductive age women (arbitrarily divided into subsets aged 17-25 and 26-35 using low-dose OCs in the customary regimen) as normal controls. Blood samples were obtained on the last day of a pill cycle and at 7 days off the pill. In some menopausal women, blood samples were obtained at both 7 and 14 days off OCs. Serum was assayed by RIA for estradiol, FSH and LH. As expected in the young reproductive age women, estradiol levels increase at one week off the pill, together with a rebound in FSH and LH to follicular phase levels. In the perimenopausal group, there was a sharp distinction based on age. The women over 40 showed a more marked rise in FSH while those aged 36-40 showed a distinctly lesser response. Estradiol levels were variable, but tended to show some age grouping. Little diagnostic separation was observed for LH. In postmenopausal women, FSH levels were not always elevated at one week post-pill, and even in a second trial with sampling at one and two weeks off the OC, not all postmenopausal women showed a "menopausal" increase in FSH. The more uniform feature was that estradiol levels never increased above basal values. The study found that serum estradiol levels increase after a week off the pill in controls, but are unchanged at one and two weeks in the menopausal group. FSH levels rebound normally in reproductive age women and usually, but not always, increase substantially in postmenopausal women. After two weeks off OCs, an increased FSH and/or no change in basal estradiol levels is strong evidence that it is now safe (contraceptively speaking) to switch from OCs to standard hormone replacement regimens.     

Plasma hormones in clomiphene citrate therapy

Daily plasma follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrone (E1), estradiol-17beta (E2), progesterone (P), androstenedione (A), and testosterone (T) were measured in six clomiphene citrate (Clomid) treated cycles. Three patients ovulated and 1 of them conceived during the study cycle. Three other patients failed to ovulate in spite of some evidence of ovarian response to clomiphene treatment in 2 of them. Plasma gonadotropin levels, of LH in particular, rose during the clomiphene therapy and reached a peak during Day 5 to Day 7 of therapy. Levels of plasma estrogens, both E1 and E2, gradually rose, reflecting follicular maturation in the ovary. When E2 reached a critical level as in the normal ovulatory cycle, it triggered an LH surge which consequently initiated ovulation. When the E2 level was inadequate or excessive, ovulation failed in spite of an LH surge. Following ovulation, plasma P rose and fell in a manner similar to the normal ovulatory cycle, with occasional values that exceeded the normal range. Levels of androgens, both A and T, rose during clomiphene therapy in some cases and T seemed to fluctuate in correlation with LH level. The possible local inhibitory influence of high E2 and T levels on follicular maturation in the ovary during clomiphene therapy is suspected in some cycles in which ovarian response was evident, but ovulation failed to occur.     

Development of aviation medicine in Germany

BACKGROUND: Despite some findings to the contrary, it would appear that pharmacological doses of progesterone and estrogen (alone or in combination) can influence intraocular pressure (IOP). The relationship between hormonal changes associated with the menstrual cycle and intraocular pressure is not clearly understood. After elimination of those factors that can affect IOP, the present study investigated whether physiological hormonal changes associated with the menstrual cycle have a correlation with intraocular pressure. METHODS: Intraocular pressure and the concentrations of circulating hormones, namely, the luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrone (E1), estradiol (E2), progesterone, and testosterone, of twenty married women of the same age groups were recorded daily throughout a menstrual cycle. None was taking any contraceptives in any form. The intraocular pressure was measured using a Goldmann applanation tonometer. RESULTS: The intraocular pressure values fluctuated in each of the twenty subjects at various times of the cycle; however, they were not definitely correlated with the different phases of the cycle. This study failed to find any correlation between IOP and progesterone or estradiol levels.     

Differences in urologist and patient assessments of health related quality of life in men with prostate cancer: results of the CaPSURE database

Premenstrual syndrome (PMS) is characterized by distressing somatic and behavioral symptoms that develop after ovulation, reach a maximum during the premenstrual days, and disappear within 4 days after the onset of menstruation. Corpus luteum formation is necessary for the presence of symptoms, but the role of luteal hormones is unclear. The aim of this work was to investigate the relationship between sex hormone serum concentrations and premenstrual symptom severity in patients with PMS. Mental and physical symptoms were marked on a validated visual analog scale by 30 PMS patients every evening. Daily blood samples were taken in the luteal phase and in most of the follicular phase. Estradiol, progesterone, FSH, and LH were analyzed. Symptom severity was calculated as the number of negative symptoms expressed per day and as summarized scores of negative ratings. Based on premenstrual hormone concentrations and using the median split method, patients were divided into groups with high and low hormone levels. The pattern of expressed symptoms and summarized scores during the menstrual cycle was similar for the 2 groups. High concentration of luteal-phase estradiol and LH were related to the severity of negative premenstrual symptoms.     

Characterization of reproductive hormonal dynamics in the perimenopause

Medical therapy for women in the perimenopausal period is controversial, in part due to varying degrees of ovarian hormone secretion characteristic of this time of life. To extend our understanding of the reproductive endocrine milieu of perimenopausal women, we studied 6 cycling women, aged 47 yr and older, for 6 months with daily collections of first morning voided urine. Five additional older reproductive aged (43-47 yr old) women were studied with daily urine and serum sampling for a single menstrual cycle; their urinary hormone data were combined with the former group for menstrual cycle comparisons. Urine was assayed for LH, FSH, estrone conjugates, and pregnanediol glucuronide and normalized for creatinine (Cr). Eleven midreproductive aged (19-38 yr old) normally cycling women, 5 women with well defined premature ovarian failure, and 5 women aged 54 yr and older who were at least 1 yr postmenopausal were used for comparison. Perimenopausal women had shorter follicular phases (11 +/- 2 days vs. 14 +/- 1 days; P = 0.031) and, hence, shorter menstrual cycles than midreproductive aged controls. FSH excretion in perimenopausal women was greater than that in younger women (range of means, 4-32 vs 3-7 IU/g Cr; P = 0.0005). LH secretion was overall greater than that in younger normal subjects (range of means, 1.4-6.8 vs. 1.1-4.2 IU/g Cr; P < 0.026). Overall mean estrone conjugate excretion was greater in the perimenopausal women compared to that in the younger women [76.9 ng/mg Cr (range, 13.1-135) vs. 40.7 ng/mg Cr (range, 22.8-60.3); P = 0.023] and was similarly elevated in both follicular and luteal phases. Luteal phase pregnanediol excretion was diminished in the perimenopausal women compared to that in younger normal subjects (range for integrated pregnanediol, 1.0-8.4 vs. 1.6-12.7 microg/mg Cr/luteal phase; P = 0.015). Compared to postmenopausal women, perimenopausal women had more overall estrone excretion (2.5-6.2 ng/mg Cr in postmenopausal women; P = 0.02) and lower mean FSH (range of means for postmenopause, 24-85 IU/g Cr; P = 0.017) and LH (range for postmenopause, 4.3-14.8 IU/g Cr; P = 0.041). Compared to women with premature menopause, perimenopausal women again had lower FSH (range of means for premature menopause, 36-82 IU/g Cr; P = 0.0022), lower LH (range of means for premature menopause, 5.5-23.8 IU/g Cr; P = 0.0092), borderline higher mean estrone conjugates (range of means for premature menopause, 4-44 ng/mg Cr; P = 0.064), and far longer periods of ovarian activity (one to two cycles in prematurely menopausal women vs. three to six cycles in perimenopausal women). We conclude that altered ovarian function in the perimenopause can be observed as early as age 43 yr and include hyperestrogenism, hypergonadotropism, and decreased luteal phase progesterone excretion. These hormonal alterations may well be responsible for the increased gynecological morbidity that characterizes this period of life.     

Chronotropic competence in endurance trained heart transplant recipients: heart rate is not a limiting factor for exercise capacity

Soy isoflavones are hypothesized to be responsible for changes in hormone action associated with reduced breast cancer risk. To test this hypothesis, we studied the effects of isoflavone consumption in 14 premenopausal women. Isoflavones were consumed in soy protein powders and provided relative to body weight (control diet, 10 +/- 1.1; low isoflavone diet, 64 +/- 9.2; high isoflavone diet, 128 +/- 16 mg/day) for three menstrual cycles plus 9 days in a randomized cross-over design. During the last 6 weeks of each diet period, plasma was collected every other day for analysis of estrogens, progesterone, LH, and FSH. Diet effects were assessed during each of four distinctly defined menstrual cycle phases. Plasma from the early follicular phase was analyzed for androgens, cortisol, thyroid hormones, insulin, PRL, and sex hormone-binding globulin. The low isoflavone diet decreased LH (P = 0.009) and FSH (P = 0.04) levels during the periovulatory phase. The high isoflavone diet decreased free T3 (P = 0.02) and dehydroepiandrosterone sulfate (P = 0.02) levels during the early follicular phase and estrone levels during the midfollicular phase (P = 0.02). No other significant changes were observed in hormone concentrations or in the length of the menstrual cycle, follicular phase, or luteal phase. Endometrial biopsies performed in the luteal phase of cycle 3 of each diet period revealed no effect of isoflavone consumption on histological dating. These data suggest that effects on plasma hormones and the menstrual cycle are not likely to be the primary mechanisms by which isoflavones may prevent cancer in premenopausal women.     

Profound suppression of plasma estrogens by megestrol acetate in postmenopausal breast cancer patients

Twelve postmenopausal women suffering from advanced breast cancer had plasma estrogens, androgens, cortisol, and gonadotropins determined before therapy and during treatment with megestrol acetate (MA) in oral doses escalated from 40 to 160 mg. The plasma clearance and production rate of estrone and estrone sulfate were determined before treatment and after 4 weeks of therapy with 160 mg MA. Treatment with MA suppressed plasma levels of dehydroepiandrosterone sulfate, androstenedione, and cortisol in a dose-dependent manner to <10% of pretreatment values. Plasma testosterone, estradiol, estrone, and estrone sulfate were suppressed to 18-29% of pretreatment values, whereas the gonadotropins were suppressed to 35-52%. The plasma clearance rates of estrone and estrone sulfate were increased by a mean value of 23.7% (P < 0.01) and 23.5% (P < 0.025), whereas the production rates were reduced by 76.7% (P < 0.0005) and 76.1% (P < 0.0005), respectively. Our findings indicate that MA causes profound suppression of adrenal steroid production but in addition suppresses ovarian secretion of androgens in postmenopausal breast cancer patients. The reduction in plasma estrogens is comparable to values obtained with commonly used aromatase inhibitors and may be responsible for its antitumor effects in breast cancer.     

Neuroendocrine aspects of primary endogenous depression--XIV. Gonadotropin secretion in female patients and their matched controls

To determine the extent of dysregulation of gonadotropin secretion in depressed women, we measured nocturnal and diurnal serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) concentrations and the responses of these hormones to gonadotropin releasing hormone (LHRH) in 20 Research Diagnostic Criteria primary, definite endogenous female depressives and in 20 individually matched female normal controls. Fourteen patients and 14 controls were premenopausal, and six patients and six controls were peri/postmenopausal or panhysterectomized. None of the latter was receiving estrogen replacement therapy. The premenopausal patients showed no significant differences in basal nocturnal or diurnal gonadotropin concentrations and no significant differences in hormone concentrations post-LHRH compared to their premenopausal matched controls. In contrast, in the postmenopausal subjects there were (1) significantly increased diurnal vs. nocturnal serum FSH concentrations in the depressives; (2) marginally increased nocturnal, diurnal, and LHRH-stimulated LH concentrations and highly significantly increased LHRH-stimulated FSH concentrations in the depressives compared to their controls; and (3) positive correlations between the LH measures and ratings of depression severity in the patients. These results suggest a dysregulation of the HPG axis in peri/postmenopausal and panhysterectomized female endogenous depressives.     

Purified urinary follicle stimulating hormone induces different hormone profiles compared with menotrophins, dependent upon the route of administration and endogenous luteinizing hormone activity

The effects of treatment of patients with gonadotrophin-releasing hormone analogue (GnRHa) combined with purified follicle stimulating hormone (FSH) for in-vitro fertilization (IVF) were investigated in detail to determine the influences of different administration routes and the degree of suppression of luteinizing hormone (LH). Responses to exogenous gonadotrophins were studied in infertile women (n = 60) with normal menstrual rhythm whose endogenous gonadotrophin activity was suppressed using a GnRHa in a long protocol. They were randomized to receive i.m. administration of human menopausal gonadotrophins (HMGim, Pergonal) or purified follicle stimulating hormone (FSH, Metrodin High Purity) administered either i.m. (MHPim) or s.c. (MHPsc). Responses were assessed by measuring plasma FSH, LH, oestradiol, testosterone and progesterone. After stimulation day 4, the MHPsc group showed significantly higher circulating concentrations of FSH than either the MHPim or HMGim group. However, the HMG group showed significantly higher oestradiol concentrations after stimulation day 5 than either MHP group. The differences in circulating oestradiol concentrations in the MHP-treated patients appeared to be strongly influenced by the mean circulating concentrations of LH in the follicular phase. The patients who showed mean follicular phase LH concentrations of < 1 IU/l showed longer follicular phases, lower circulating oestradiol and testosterone concentrations and also lower follicular fluid concentrations of oestradiol and testosterone, indicating a reduction in the normal follicular metabolism of progesterone to androgens and oestrogens under these conditions. This group of patients also showed longer follicular phases, which may have consequences for future clinical management.     

Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women

BACKGROUND: A positive relationship has generally been observed between plasma estrogen levels and breast cancer risk in postmenopausal women, but most of these studies have been small and few have evaluated specific estrogen fractions (such as percent bioavailable estradiol). In addition, few studies have evaluated plasma androgen levels in relation to breast cancer risk, and their results have been inconsistent. We prospectively evaluated relationships between sex steroid hormone levels in plasma and risk of breast cancer in postmenopausal women by use of a case-control study nested within the Nurses' Health Study. METHODS: Blood samples were collected during the period from 1989 through 1990. Among postmenopausal women not using hormone replacement therapy at blood collection (n = 11,169 women), 156 women were diagnosed with breast cancer after blood collection but before June 1, 1994. Two control subjects were selected per case subject and matched with respect to age, menopausal status, month and time of day of blood collection, and fasting status at the time of blood collection. RESULTS: From comparisons of highest and lowest (reference) quartiles, we observed statistically significant positive associations with risk of breast cancer for circulating levels of estradiol (multivariate relative risk [RR] = 1.91; 95% confidence interval [CI] = 1.06-3.46), estrone (multivariate RR = 1.96; 95% CI = 1.05-3.65), estrone sulfate (multivariate RR = 2.25; 95% CI = 1.23-4.12), and dehydroepiandrosterone sulfate (multivariate RR = 2.15; 95% CI = 1.11-4.17). We found no substantial associations with percent free or percent bioavailable estradiol, androstenedione, testosterone, or dehydroepiandrosterone. The positive relationships were substantially stronger among women with no previous hormone replacement therapy. CONCLUSION: Our data, in conjunction with past epidemiologic and animal studies, provide strong evidence for a causal relationship between postmenopausal estrogen levels and the risk of breast cancer.     

Thrombin activates MAPKAP2 kinase in vascular smooth muscle

OBJECTIVE: To study the effects of estradiol and progesterone on the proliferation of normal human breast epithelial cells in vivo. DESIGN: Double-blind randomized study. SETTING: Departments of gynecology and of cell biology at a university hospital. PATIENT(S): Forty postmenopausal women with untreated menopause and documented plasma FSH levels of >30 mIU/mL and estradiol levels of <20 pg/mL. INTERVENTION(S): Daily topical application to both breasts of a gel containing a placebo, estradiol, progesterone, or a combination of estradiol and progesterone during the 14 days preceding esthetic breast surgery or excision of a benign lesion. MAIN OUTCOME MEASURE(S): Plasma and breast tissue concentrations of estradiol and progesterone. Epithelial cell cycles were evaluated in normal breast tissue by counting mitoses and performing quantitative proliferating cell nuclear antigen immunolabeling analyses. RESULT(S): Increasing the estradiol concentration enhanced the number of cycling epithelial cells, whereas increasing the progesterone concentration significantly limited the number of cycling epithelial cells. CONCLUSION(S): Exposure to progesterone for 14 days reduced the estradiol-induced proliferation of normal breast epithelial cells in vivo.     

Chronic hypertension, pregnancy-induced hypertension, and low birthweight

Menstrual and hormone patterns were investigated in 10 fertile women (median age 37, range 25-43 years) with locally advanced cervical cancer treated with neoadjuvant chemotherapy (CT). CT consisted of two cycles of high-dose cisplatin (CDDP, 40 mg/m2, Days 1 to 4) and bleomycin (B, 15 mg/m2, Days 1 and 8) separated by an interval of 21 days. Menstrual patterns before and during CT were recorded. FSH, LH, estradiol, and progesterone were assayed on the day that treatment was begun, after 2 and 4 days of CDDP administration, and weekly between and after the two cycles. Hormone assays during the first week of CT showed no significant change in hormone levels. After the first course of CT, five patients showed hypergonadotrophic amenorrhea and five patients maintained menses, two showing ovulatory and three showing follicular phase hormone patterns. After the second course of CT, one more patient become amenorrheic, and endocrine follow-up showed that two patients maintained hypergonadotrophic amenorrhea, four with hypergonadotrophic amenorrhea had a return of hormone levels to the follicular range of 7-9 weeks after, three maintained follicular phase hormone patterns until operation, and one ovulated. Gonadal dysfunction should be included among the side effects of high-dose CDDP and B regimens.     

Plasma levels of fractionated estrogens and pituitary hormones in endometrial carcinoma

Plasma levels of estrone (E1), estradiol-17beta (E2), and estriol (E3), as well as follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin were measured in 30 control subjects and in 20 postmenopausal patients with adenocarcinoma of the endometrium. Within the sensitivity of the assay (5 to 10 pg.), no E3 was found. Mean levels of E1 and E2 in the patients with carcinoma (42.64+/-3.8 (S.E.M.) and 17.3+/-1.7 (S.E.M.) pg. per mililiter) were significantly higher than those measured in the control subjects (E1=26.97+/-2.4 (S.E.M.) pg. per mililiter, p less than 0.001; E2=12.08+/-1.2 (S.E.M.) pg. per milliliter, p less than 0.02). Effects of age, diabetic status, and obesity were taken into consideration. Significant differences in FSH and marginally significant differences in prolactin levels were observed between the two groups. Mean levels of FSH, LH, and prolactin in the control group and the group with adenocarcinoma, respectively, were as follows: FSH=152.3+/-7.0 (S.E.M.) versus 98.1+/-8.9 (S.E.M.) mI.U. per milliliter, p less than 0.001; LH=64.7+/-3.1 (S.E.M.) versus 66.5+/-5.2 mI.U. per milliliter, difference not significant; and prolactin=14.3+/-0.9 (S.E.M.) versus 17.8+/1.7 (S.E.M.) ng. per milliliter, p less than 0.06. These results, as well as previously reported alterations in human growth hormone secretion, suggest aberrations in hypothalamic function in endometrial carcinoma.     

Diagnosis and management of transient ischaemic attacks in accident and emergency

AIM: Are there any changes in hypophyseal and gonadal hormones levels during the naloxone test in the degenerative changes of the seminiferous tubules? MATERIAL AND METHODS: The naloxone test (0.4 mg i.v.) was performed in 13 patients with degenerative changes of the seminiferous tubules. The plasma FSH, LH, prolactin, testosterone and estradiol levels were determined before and 30, 60, 90, 120 minutes after the administration of the drug. RESULTS: In the examined group of patients the plasma FSH, prolactin and estradiol levels were significantly higher, testosterone levels significantly lower and LH levels were in the same range compared with the patients with azoospermia and normal spermatogenesis. The plasma FSH, prolactin and testosterone levels did not change significantly their values during the test. The plasma estradiol levels decreased significantly and plasma LH levels increased significantly during the test. CONCLUSION: Elevated plasma FSH, prolactin and estradiol levels, diminished testosterone levels and the decrease of plasma estradiol levels and the increase plasma LH levels during the naloxone test indicate the degenerative changes of the seminiferous tubules in the cases of azoospermia.     

Safety, activity and estrogen inhibition by exemestane in postmenopausal women with advanced breast cancer: a phase I study

Exemestane is an irreversible, steroidal, oral aromatase inhibitor under evaluation in postmenopausal women with advanced breast cancer. A phase I study was conducted in 27 postmenopausal patients who were candidates for hormone therapy because they had advanced breast cancer and estrogen receptor-positive or unknown status. Most patients were moderately or heavily pretreated. Cohorts of at least three patients received sequentially escalating daily oral doses of 5-600 mg. The median duration of exemestane treatment was 13 weeks (range: 3-166 weeks). The maximal tolerated dose was not reached because of lack of treatment-related grade 3 or 4 toxicity. The most common adverse events, including those not related to treatment, were mild to moderate headache (44% of patients), dizziness (33%), nausea (33%), hot flushes (30%) and tumor-related pain (30%). There were three complete and four partial responses for an objective response rate of 26% (95% CI: 11.1-46.3%) in the intent-to-treat population; the median duration of response was 74 weeks (95% CI: 48-99 weeks). Exemestane, at the dose of 25 mg, maximally suppressed estradiol, estrone and estrone sulfate serum levels to 13, 5 and 10% of baseline, respectively. Exemestane appears to suppress estrogen, be well tolerated and have antitumor activity in postmenopausal women with advanced breast cancer. A large, safe therapeutic window of up to 600 mg was defined. In view of its safety and estrogen-suppression profiles, the most favorable effects were observed at the 25 mg daily dose.     

Experimental studies on the positive feedback effect of progesterone, 17 alpha-hydroxyprogesterone and 20 alpha-dihydroprogesterone on the pituitary release of LH and FSH in the human female. The estrogen priming of the progesterone feedback on pituitary gonadotropins in the eugonadal woman

Administration of progesterone eugonadal women during the midfollicular phase of the menstrual cycle failed to induce a positive feedback effect on the serum concentrations of LH and FSH. The levels of estradiol in serum decreased following the injection of progesterone without a parallel change in LH and FSH concentrations indicating a direct ovarian effect of the exogenous progesterone. In the late follicular phase of the cycle, when preovulatory levels of estradiol were present in serum, or under a ethinyl estradiol treatment progesterone was able to induce an LH discharge indicating the requirement of an estradiol priming of the positive feedback of progesterone in eugonadal women. In order to establish the time required for a sufficient estrogen priming with preovulatory levels of estradiol in serum 3 mg of estradiol-benzoate were administered i.m. 1, 12 and 24 h prior to the administration of 30 mg of microcristalline progesterone in the midfollicular phase of the menstrual cycle, when progesterone alone did not cause an LH surge. Only when estradiol-benzoate was injected 24 h prior to the progesterone administration an LH surge reproducible in time course and magnitude occurred. Administration of estradiol-benzoate alone under these conditions did not cause an LH surge within the elapse of time after the injection when the progesterone induced LH surge occurred. Thus, these experiments demonstrate that a defined estrogen priming is required for the positive feedback effect of progesterone on the gonadotropin release in eugonadal women. Furthermore, progesterone levels in serum of about only 1--2 ng/ml were required for the induction of an LH surge indicating that under physiological conditions progesterone may have an supplementory effect on the primarily estradiol induced LH midcycle peak. 17-hydroxyprogesterone administered during the mid follicular phase of the menstrual cycle and under pretreatment with ethinyl estradiol failed to induce a positive feedback effect on the serum concentrations of LH and FSH, indicating that this steroid does not play a regulatory role on the midcycle LH release in women. 20alpha-dihydroprogesterone administered under the same experimental conditions as 17-hydroxyprogesterone seems to be able to induce an LH surge in serum provided there is an adequate estrogen priming.