Is there evidence for preferential delivery of ovarian estradiol to the endometrium?

Objective: To determine the direction of delivery of E₂ in the female pelvis by assessing the ratio of endometrial to serum E₂ in women whose ovaries were stimulated to produce E₂ with women who received exogenous E₂.

Design: Prospective comparative study.

Setting: University-based ART program.

Patient(s): Oocyte donors and recipients of donor oocytes.

Intervention(s): Micronized E₂ administered by the oral or vaginal route and oocyte donation.

Main Outcome Measure(s): Serum and endometrial levels of E₂.

Result(s): Serum E₂ levels were significantly higher in women who underwent controlled ovarian hyperstimulation (COH) and women receiving exogenous E₂ by the vaginal route than in those who received oral E₂. Levels of E₂ in endometrial tissue were similar in women who underwent COH and those receiving oral E₂. Endometrial E₂ levels in women who underwent vaginal administration were significantly higher than those in the oral E₂ or COH groups. The ratio of endometrial to serum E₂ was highest in women who underwent vaginal E₂ and lowest in those undergoing COH.

Conclusion(s): Vaginal administration of micronized E₂ results in preferential absorption of E₂ into the endometrium, consistent with a “uterine first pass” effect. Since endogenous E₂ produced the smallest ratio of E₂ between the endometrium and serum, E₂ produced by the ovaries is not preferentially delivered to the uterus.     

Effect of sex steroids on β-endorphin levels at rest and during submaximal treadmill exercise in anovulatory and ovulatory runners

Objective: To examine the interaction between circulating β-endorphin levels and sex steroids during sustained submaximal exercise in runners who are either anovulatory and oligomenorrheic (AO) or ovulatory and eumenorrheic (EO).

Design: Controlled clinical study.

Setting: General clinical research center at an academic medical center.

Patient(s): Three AO and four EO runners.

Intervention(s): The athletes underwent 60 minutes of submaximal treadmill exercise on three separate occasions. Anovulatory and oligomenorrheic runners underwent exercise at baseline and after physiologic estrogen and combined estrogen and progesterone replacement. Ovulatory and eumenorrheic runners underwent exercise in the follicular and luteal phases and after GnRH agonist desensitization.

Main Outcome Measure(s): Serum cortisol, β-endorphin, progesterone, estrogen, and gonadotropin levels at rest and during exercise.

Result(s): Serum levels of E₂ increased in response to exercise in both EO and AO runners during sex steroid replacement. Baseline peripheral β-endorphin and cortisol levels were not different between the EO and AO groups. A significant increase in β-endorphin levels in response to exercise occurred only in the EO group after GnRH agonist desensitization.

Conclusion(s): Alterations in menstrual cyclicity and ovulation in conditioned runners probably are not due to an increase in opioid tone. The hypothalamic-gonadotropic axis appears to be intact in AO runners, as measured by the gonadotropic response to exogenous exposure to estrogen and progesterone. Sex steroid administration had no effect on basal β-endorphin levels, but this probably was not due to preexisting increased opioid tone.     

Substrate utilization and hormonal responses to moderate intensity exercise during pregnancy and after delivery

OBJECTIVE: This study was undertaken to examine substrate utilization and hormonal responses to moderate intensity exercise in the same group of women across gestation. STUDY DESIGN: Glucose, triglyceride, insulin, glucagon, cortisol, growth hormone, and blood urea nitrogen levels were measured in 12 women at rest and after exercise. Heart rate, oxygen uptake, and respiratory exchange ratio were measured at rest and during exercise. Urine urea nitrogen levels, urine volume, and creatinine levels were measured 24 hours before and after exercise. Each woman completed a 30-minute treadmill walk at 65% of her predicted maximal heart rate at the same time of day during the 22nd and 33rd weeks of gestation and at 14 weeks after delivery. RESULTS: There were no significant differences between exercise trials in oxygen uptake, respiratory exchange ratio, or heart rate. Pregnancy elevated resting triglyceride levels but lowered plasma glucose levels. Exercise during pregnancy caused a reduction in plasma glucose levels but elevated circulating triglyceride levels (P <.05). Resting levels of cortisol, growth hormone, and insulin were elevated during pregnancy compared with after delivery, but resting glucagon levels were not affected by pregnancy. Exercise caused circulating levels of cortisol, growth hormone, and glucagon to increase (P <.05). The exercise-induced change in the cortisol level was greater during pregnancy than that after delivery. The exercise-induced changes in growth hormone and glucagon levels were greatest after delivery compared with those during pregnancy (P <.05). Exercise reduced insulin levels (P <.05), with the greatest reduction at 33 weeks' gestation. There were no significant differences in urine urea nitrogen excretion as a result of exercise. CONCLUSIONS: Certain substrate and hormonal responses to exercise are altered as pregnancy progresses. Quantitatively, protein appears to be a relatively unimportant fuel during a 30-minute bout of moderate intensity exercise in this group of women evaluated during pregnancy and after delivery. Furthermore, a 30-minute bout of moderate intensity exercise would not be expected to compromise fetal amino acid availability.     

Inhibin B response to EFORT is associated with the outcome of oocyte retrieval in the subsequent in vitro fertilization cycle

Objective: To examine whether the magnitude of the rise in inhibin B levels after gonadotropin challenge is associated with subsequent response to ovarian stimulation during IVF.

Design: Inhibin B serum levels after EFORT (exogenous follicle-stimulating hormone ovarian reserve test).

Setting: Academic clinical practice.

Patient(s): Serum samples from women who had undergone ovarian reserve screening with FSH in preparation for IVF. Thirteen of these women had a poor response in IVF (canceled cycle for low estradiol and/or no oocytes retrieved), and 19 had a good response (≥10 oocytes retrieved).

Intervention(s): EFORT test.

Main Outcome Measure(s): Baseline (day 3) serum E₂ (bE₂), FSH (bFSH), and inhibin B (bInhB) levels and inhibin B and E₂ levels 24 hours after EFORT (ΔInhB and ΔE₂).

Result(s): The mean bInhB and ΔInhB levels were significantly higher in good vs. poor responders. The odds ratio of having a good response for women with a ΔInhB of 202 pg/mL was 51.8 times (95% CI = 6.1–1,244) the corresponding odds for women with a ΔInhB of 49 pg/mL. As expected, ΔE₂ was also significantly higher in good vs. poor responders; however, combination of ΔE₂ plus ΔInhB did not improve the odds for predicting IVF response.

Conclusion(s): Our data suggest that ΔInhB after EFORT may provide a method for predicting ovarian response to hyperstimulation in a subsequent IVF cycle.     

Failure of the combination of sequential oral and transdermal estradiol plus norethisterone acetate to affect plasma homocysteine levels

Objective: A high level of plasma homocysteine may be deleterious to vascular health. We therefore compared the effect of combinations of sequential oral and transdermal estradiol plus norethisterone acetate on plasma homocysteine.

Design: Prospective, randomized study.

Setting: Outpatient department of obstetrics and gynecology in a university hospital.

Patient(s): Forty-two healthy, nonsmoking postmenopausal women starting hormone replacement therapy (HRT) to control climacteric symptoms.

Intervention(s): In a randomized order, the women started using either oral HRT (2 mg of estradiol on days 1–12, 2 mg of estradiol plus 1 mg of norethisterone acetate (NETA) on days 13–22, and 1mg of estradiol on days 23–28; N = 21) or transdermal HRT (50 μg/d of estradiol on days 1–28 and 250 μg/d of norethisterone acetate on days 15–28, N = 21) for 1 year.

Main Outcome Measure(s): Fasting plasma levels of homocysteine were measured before the treatment and during the combined estradiol-plus-NETA phases of the sixth and 12th treatment cycles.

Result(s): Basal homocysteine levels in the oral group (8.2 ± 3.1 μmol/L, mean plusmn;SD) and transdermal group (8.7 plusmn; 1.8 μmol/L, mean plusmn;SD) were not affected by the estradiol-plus-NETA combination.

Conclusion(s): Neither an oral nor a transdermal combination of sequential estradiol and NETA causes significant changes in plasma homocysteine in Finnish postmenopausal women with normal baseline homocysteine levels.     

Elevated Levels of Basal Estradiol-17β Predict Poor Response in Patients with Normal Basal Levels of Follicle-Stimulating Hormone Undergoing In Vitro Fertilization

Objective: To evaluate whether the predictive ability of a normal FSH level on cycle day 3 can be enhanced by levels of estradiol-17β (E₂) on cycle day 3.

Design: Prospective cohort study.

Setting: University hospital–based, tertiary care infertility center.

Patient(s): Two hundred thirty-one consecutively seen patients who attended the center for their first IVF attempt.

Intervention(s): Blood samples were collected on day 3 of the cycle preceding IVF; IVF was performed in all patients.

Main Outcome Measure(s): Patient’s age, number of ampules of hMG, cancellation rate, number of oocytes, fertilization rate, and clinical pregnancy rate.

Result(s): In patients with elevated FSH levels on cycle day 3, a low oocyte yield was achieved (7 versus 11) and a high number of ampules of hMG was necessary (56 versus 33). Their cancellation rate was high (67% versus 16%). In patients with normal basal FSH levels, high E₂ levels predicted a high cancellation rate (56%, versus 13% in patients with low E₂ levels) and a low oocyte yield (9, versus 11 in patients with low E₂ levels). Patients with both normal FSH levels and low E₂ levels on cycle day 3 fared best.

Conclusion(s): The basal E₂ level on cycle day 3 is a useful prognosticator of response to stimulation in IVF patients with normal basal FSH levels.     

Acute Changes in Endometrial Thickness After Aspiration of Functional Ovarian Cysts

Objective: To evaluate the influence of aspiration of functional ovarian cysts on endometrial thickness.

Design: Prospective study.

Setting: An IVF Unit of an academic medical center.

Patient(s): Twenty-two patients from our IVF program, in whom administration of a gonadotropin-releasing hormone agonist preparation in the “long protocol” failed to induce pituitary desensitization, as evidenced by a serum E₂ concentration of >55 pg/mL and the presence of an ovarian cyst of >20 mm in diameter.

Intervention(s): Transvaginal ultrasonographic-guided cyst aspiration was performed, and 2 days later, serum E₂ concentration and endometrial thickness were reassessed.

Main Outcome Measure(s): The values of serum E₂ concentration and endometrial thickness before and after cyst aspiration were compared.

Result(s): Two days after ovarian cyst aspiration, the serum E₂ concentration dropped from a mean (±SD) of 203 ± 93 to 37 ± 34 pg/mL. The mean (±SD) endometrial thickness was 9.6 ± 2.0 mm before cyst aspiration and decreased to 5.9 ± 2.4 mm after the procedure.

Conclusion(s): Within 48 hours after ovarian cyst aspiration, a significant reduction in endometrial thickness occurs concomitant with a sharp decline in serum E₂ levels. The phenomenon of acute reduction in endometrial thickness in response to acute estrogen withdrawal has not been described previously. The exact mechanism and endometrial component involved in the “shrinking” process should be further investigated.     

Pharmacokinetics and pharmacodynamics of transdermal dosage forms of 17 beta-estradiol: comparison with conventional oral estrogens used for hormone replacement

This open-label, multiple-crossover study compared the pharmacokinetics and pharmacodynamics of transdermal 17 beta-estradiol and two oral forms of estrogen replacement therapy in postmenopausal women. The transdermal systems delivered either 0.025, 0.05, or 0.1 mg/day; oral dosages were 2 mg of micronized 17 beta-estradiol or 1.25 mg of conjugated equine estrogens. Transdermal estradiol provided serum and urinary levels of estradiol conjugates typical of the early follicular phase of the premenopausal woman and an estradiol/estrone ratio that approximated 1. The increments of both serum and urinary estradiol showed dose proportionality. Serum levels of estradiol obtained 24 hours after oral administration of estrogens were in a range similar to the steady-state levels obtained with transdermal estradiol delivery. Oral estrogens, however, induced an excessive rise in estrone to levels far beyond those observed in premenopausal women. Continuous application of transdermal estradiol over 3 weeks did not result in any accumulation of estradiol or estradiol conjugates. After only three doses of oral estrogens, there were signs of retention of estrogens. Suppression of gonadotropins by oral and transdermal administration of estrogens was in a similar range. This observation supports the conclusions that levels of circulating estradiol are relevant to efficacy, and that excessively high levels of estrone after oral administration of estrogens merely represents a nonphysiologic precursor or metabolite pattern.     

A prospective randomized comparison between long and discontinuous-long protocols of gonadotropin-releasing hormone agonist for in vitro fertilization

Objective: To investigate the efficacy of a discontinuous-long protocol in an IVF program.

Design: Prospective randomized study.

Setting: University hospital.

Patient(s): One hundred thirty-seven IVF cycles of 92 patients in an outpatient IVF program from April 1995 to December 1995.

Intervention(s): In the discontinuous-long protocol group (n = 68), GnRH agonist (GnRH-a) was administered from the luteal phase until cycle day 7, when pure FSH administration was begun. In the long protocol group (n = 69), GnRH-a was administered until the day before hCG administration.

Main Outcome Measure(s): Serum LH and ovarian steroid hormone levels, and IVF outcome.

Result(s): The period and the total dosage of hMG were increased in the discontinuous-long protocol group. Although the fertilization rate was similar under both protocols, the number of embryos transferred was smaller and the cancellation rate was higher in the discontinuouslong protocol group because of the greater failure of oocyte retrieval and fertilization. Serum E₂ levels in the late follicular phase were lower in the discontinuous-long protocol group.

Conclusion(s): Early discontinuation of GnRH-a is not beneficial because of its adverse effects on follicular development.     

Young Low Responders Protected from Untoward Effects of Reduced Ovarian Response

Objective(s): To correlate fertilization and clinical pregnancy rates (PRs) in low responders with their E₂ levels (<500, 500–800, >800–1,000 pg/mL), age (20–30, 31–40, >40 years), number of follicles, and number of oocytes retrieved.

Design: A retrospective study.

Setting: The IVF unit of an academic hospital.

Patient(s): One hundred forty-three women who failed to attain E₂ levels of 1,000 pg/mL on the day of hCG administration.

Intervention(s): Controlled ovarian hyperstimulation, blood E₂ and progesterone measurements, ultrasonographic scanning of ovarian follicles, oocyte retrieval after hCG administration, and ET.

Main Outcome Measure: Clinical PR.

Result(s): Although E₂ levels, fertilization rates, age, and number of oocytes did not differ significantly between the three age groups, the PR achieved in the youngest group was approximately three times as high (19.3%) as that achieved in the two older groups.

Conclusion: Young low responders represent a unique subset in that their age protects them from the deleterious effects of poor ovarian response.     

中药养巢方治疗卵巢功能减退疗效及对性激素水平、卵泡发育的影响

目的 探讨中药养巢方治疗卵巢功能减退疗效及对患者性激素水平、卵泡发育的影响.方法 选取80例卵巢功能减退患者,按照随机数字表法分为对照组与治疗组,每组40例.对照组采用雌二醇片雌二醇地屈孕酮片复合片(芬吗通)治疗,治疗组采用中药养巢方治疗.比较两组临床疗效、治疗前后性激素水平、排卵率、3、6个月内妊娠率、子宫内膜厚度及...     

The clinical therapeutic window for luteinizing hormone in controlled ovarian stimulation

Objective: To discuss the clinical therapeutic window for LH during the follicular phase.

Design: Review of selected papers that were retrieved through a Medline search and a review of clinical trials, the results of which are in the process of publication.

Patient(s): Women undergoing infertility treatment.

Intervention(s): Recombinant human LH (r-hLH) was administered SC as a supplement to FSH during controlled ovarian hyperstimulation.

Main Outcome Measure(s): Follicular development, E₂ production, and endometrial thickness.

Result(s): Optimal follicular maturation is the result of both FSH and LH stimulation. In patients with hypogonadotropic hypogonadism, 75 IU of r-hLH and 150 IU of FSH per day resulted in more follicles and provided sufficient E₂ for optimal endometrial proliferation. Additional r-hLH (>250 IU/day), in patients with either hypogonadotropic hypogonadism or polycystic ovary disease, may precipitate a series of deleterious physiological actions leading to atresia of developing follicles. Adding r-hLH to FSH in women treated with GnRH agonist showed no benefits in terms of number of mature oocytes, fertilization, and cleavage. However, those who experience profound pituitary desensitization may benefit from adding LH to the stimulation protocol. No obvious clinical criteria have been established to define this group of patients.

Conclusion(s): A “threshold” and “ceiling” level for LH (therapeutic window) is proposed, below which E₂ production is not adequate and above which LH may be detrimental to follicular development.     

不同临床特征IHH女性患者相关激素含量特征的风险

目的 探究不同临床特征特发性低促性腺激素性性腺功能减退症(IHH)女性相关激素含量的特征.方法 选取100例IHH女性患者为研究组,另选取同期68例健康女性为健康组.比较两组血清睾酮(T)、孕酮(P)、雌二醇(E2)、25羟维生素D[25(OH)D]含量及研究组不同临床特征IHH女性患者T、P、E2、25(OH)D含量...     

Phytoestrogens and reproductive biology

Phytoestrogens are naturally occurring plant substances that can either mimic or antagonize the action of endogenous estrogens. This is because of the similarity of the functional structure of phytoestrogens and endogenous estrogens. In premenopausal women, phytoestrogen intake might induce a decrease in luteinizing hormone, follicle-stimulating hormone and estradiol (E₂), which are associated with a longer follicular phase. The circulating transport protein, sex hormone-binding globulin, is increased, resulting in less cellular availability of E₂. Phytoestrogens inhibit the activities of E₂ synthetic enzymes through adenylate cyclase and tyrosine kinase cascades. This might decrease of risk of hormone dependent cancers. A phytoestrogen-rich diet might reproduce normal body composition, affecting the course of polycystic ovary syndrome (PCOS). Some herbs used in traditional Japanese medicine contain phytoestrogens that influence endogenous hormone levels to directly regulate the pituitary-ovarian system, in particular, the chemotactic effects on ovaries. (Reprod Med Biol 2005; 4 : 225 –229)     

Basal 17β-estradiol did not correlate with ovarian response and in vitro fertilization treatment outcome

Objective: To verify the correlation of basal 17β-E₂ with ovarian response to stimulation and outcome of in vitro fertilization (IVF).

Design: Retrospective observational study.

Setting: The Assisted Conception Unit, University College London Hospitals.

Patient(s): Three hundred five women undergoing IVF and IVF with intracytoplasmic sperm injection.

Intervention(s): Basal follicle-stimulating hormone (FSH) and 17β-E₂ were assessed. The cutoff level for day 2 E₂ established was 250 pmol/L. Each patient was noted for below (group A) or above (group B) the cutoff point according to her basal E₂ level.

Main Outcome Measure(s): Basal E₂, age, duration of infertility, cycle day 2 FSH, number of ampules of gonadotropin used, number of days of stimulation, number of retrieved oocytes, fertilization rate, number of embryos transferred, number of cycles with embryo freezing, cancellation rate, clinical pregnancy rate, and implantation rate were compared between the two groups.

Result(s): No differences were found between group A and group B in the number of oocytes retrieved (8.8 ± 4.2 vs. 9.3 ± 4.8), embryos transferred (2.5 ± 0.8 vs. 2.7 ± 0.7), cancellation (9.1% vs. 6.9%), pregnancy (24.8% vs. 30%), and implantation rate (12.3% vs. 15.6%). Correlation coefficient and coefficient of determination showed no significant correlation between basal E₂ and the number of oocytes retrieved, age, and basal FSH.

Conclusion(s): In our study population, basal E₂ was not a sensitive predictor of ovarian response to stimulation and did not correlate with IVF outcome.     

Endocrine and chronobiological effects of fasting in women

OBJECTIVE: To determine whether fasting in women would suppress GnRH/LH drive in a high- versus low-gonadal steroid milieu. DESIGN: Case-control study. SETTING: Academic clinical research center. PATIENT(S): Eleven eumenorrheic women and eleven women taking combined oral contraceptives. INTERVENTION(S): Seven of the eleven women in each group underwent an acute 72-hour fast. Blood samples were obtained at 15-minute intervals for 24 hours before the fast and during the last 24 hours of fasting. MAIN OUTCOME MEASURE(S): Twenty-four-hour profiles of LH, cortisol, and melatonin were assessed. Ovarian activity was tracked with estradiol and progesterone levels, and metabolic responses were gauged by measuring thyroid hormone and beta-hydroxy-butyric acid levels. RESULT(S): Fasting increased beta-hydroxy-butyric acid and reduced free thyronine. Fasting in the midfollicular phase had no effect on LH pulsatility or on FSH, estradiol, or subsequent luteal-phase progesterone levels. However, fasting elevated cortisol and resulted in a phase advance in melatonin secretion of 81 minutes in both the midfollicular and luteal phases. CONCLUSION(S): Fasting in women elicited expected metabolic responses and apparently advanced the central circadian clock without compromising reproductive function.     

Effect of age on the response of the hypothalamo-pituitary-ovarian axis to a combined oral contraceptive

Objective: To examine the effect of age on the response to treatment with a combined oral contraceptive.

Design: Prospective, controlled clinical study.

Setting: Reproductive medicine unit in a tertiary care university medical center.

Patient(s): Twenty-six healthy female volunteers aged 21–45 years.

Intervention(s): After a control cycle, all the women were given a combined oral contraceptive containing 20 μg of ethinylestradiol with 75 μg of gestodene for three cycles. The women were examined through the posttreatment cycle.

Main Outcome Measure(s): Pituitary and ovarian activity was assessed with ultrasound and measurement of ovarian steroids.

Result(s): Follicular activity was observed in all treatment cycles, although ovulation was inhibited. Ovarian suppression was maximal in cycle 1. Mean endogenous E₂ levels were lower during cycles 2 and 3 in the older group. Serum FSH levels were higher in the control cycle and on day 28 of the treatment cycles in the older group. Most women ovulated during the posttreatment cycle.

Conclusion(s): Combined oral contraceptives did not inhibit all ovarian activity; maximal suppression was seen in cycle 1. Less follicular activity was observed in cycles 2 and 3 in the older group. Raised FSH levels with age reflect increasing ovarian resistance to follicular development.     

Effects of estrogen and estrogen–progestogen therapy on homocysteine levels and their correlation with carotid vascular resistance

Objective. To evaluate the correlation between homocysteine levels and carotid vascular resistance in menopausal women submitted to estrogen and estrogen–progestogen therapy.

Methods. Eighty-six women with a mean age of 52 years were enrolled in a prospective, randomized, double-blind, 6-month study. Patients were allocated to use one of three oral therapies: placebo (n = 26), micronized estradiol 2 mg/day (n = 30) or micronized estradiol 2 mg/day plus norethisterone acetate 1 mg/day (n = 30). Evaluation of homocysteine levels and Doppler sonography of the common carotid artery, used to calculate pulsatility index (PI), were carried out prior to initiating therapy and at the end of the study. The correlation between these two parameters was evaluated using Pearson's coefficient of correlation.

Results. There was a significant reduction in homocysteine levels in the groups treated with estrogen alone or estrogen combined with norethisterone. PI was significantly lower only in users of estrogen alone; however, no significant correlation was found between homocysteine measurements and PI.

Conclusion. No significant correlation was found between homocysteine levels and carotid vascular resistance following hormone therapy.     

Ryudocan expression by luteinized granulosa cells is associated with the process of follicle atresia

Objective: To evaluate the presence of ryudocan in follicular fluid (FF) and its possible correlation with FF E₂ and P, and to study the levels of ryudocan in granulosa-lutein cells stimulated with hCG.

Design: Controlled clinical study and in vitro experiment.

Setting: University teaching hospital.

Patient(s): One hundred seven patients undergoing IVF.

Intervention(s): The FF and granulosa-lutein cells were aspirated from follicles 34 hours after an ovulatory gonadotropin bolus.

Main Outcome Measure(s): FF ryudocan, E₂, and P levels as well as hCG-mediated induction of ryudocan.

Result(s): Ryudocan was abundant in the FF; the concentration of ryudocan in human FF was estimated to be 305.5 ± 200.8 ng/mL (mean ± SD). Atretic follicles had higher concentrations of ryudocan (559.1 ± 156.5 ng/mL). FF ryudocan levels were inversely correlated with FF E₂ (r = −0.5023) and P concentrations (r = −0.4459). A detectable amount of ryudocan was found in pooled granulosa-lutein cells. Ryudocan production was augmented by surge levels of hCG.

Conclusion(s): Ryudocan is expressed in luteinized granulosa cells in vitro. The higher concentrations of ryudocan in FF of atretic follicles suggest an involvement of ryudocan in the process of atresia.     

Endocrine, neuroendocrine and behavioral effects of oral dehydroepiandrosterone sulfate supplementation in postmenopausal women.

Aging in women and men is characterized by a progressive decline of circulating dehydroepiandrosterone (DHEA) levels and its sulfate ester (DHEAS). The improvement of wellbeing described in postmenopausal women treated with DHEA suggests that this steroid may exert specific actions on the central nervous system (CNS). The postmenopausal period is associated with several neuroendocrine modifications. The decrease of circulating levels of beta-endorphin is considered a hormonal marker of those changes. The aim of the present study was to investigate neuroendocrine and behavioral effects of three months of DHEAS supplementation in postmenopausal women. Postmenopausal women (n = 22) were divided in three groups: the first group was treated with oral DHEAS (n = 8) (50 mg/day), the second treated with the same dose of oral DHEAS + transdermal estradiol (n = 8) (DHEAS) 50 mg/day, estradiol 50 micrograms/patch) and the third with transdermal estradiol alone (n = 6) (50 micrograms/day). Before and after 1, 2 and 3 months of therapy, the following circulating steroid and protein hormone levels were evaluated: DHEA, DHEAS, androstenedione, testosterone, estrone, estradiol, 17-hydroxyprogesterone, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), luteinizing hormone (LH), beta-endorphin, growth hormone (GH) and cortisol, and a Kupperman score was performed. Before and after treatments, plasma beta-endorphin levels were evaluated in response to three neuroendocrine tests: (a) clonidine, an alpha 2-presynaptic adrenergic agonist (1.25 mg i.v.) (b) naloxone, an opioid receptor antagonist (4 mg i.v.) and (c) fluoxetine, a serotonin selective reuptake inhibitor (30 mg p.o.). In both groups of women treated with DHEAS, mean basal serum DHEA, DHEAS, androstenedione, and testosterone levels significantly increased after treatment, while no changes were shown in the group receiving estradiol alone. Serum estradiol, estrone, GH and plasma beta-endorphin levels significantly increased progressively for the three months of treatment, with higher levels for estrone and estradiol in subjects receiving estradiol alone or plus DHEAS. Serum SHBG, cortisol, and 17-hydroxyprogesterone did not show significant variations under any treatment. Serum LH and FSH levels showed a significant decrease in groups treated with estradiol alone or plus DHEAS at the second and third months. The Kupperman score showed that all treatments were associated with similar and progressive improvement. Before therapy clonidine, naloxone and fluoxetine stimuli failed to modify circulating beta-endorphin levels. After each of the treatments, the beta-endorphin response was completely restored and was similar, independent of the kind of therapy. Restoration of the beta-endorphin response to specific stimuli suggests that DHEAS and/or its active metabolites modulates the neuroendocrine control of pituitary beta-endorphin secretion, which may support the therapeutic efficacy of the DHEAS on behavioral symptoms.