Decline In Estradiol Research Articles

Treatment with human chorionic gonadotropin (hCG) for ovulation induction is associated with an immediate 17β-estradiol decrease and a more rapid LH increase in mares

The effect of treatment with an ovulation-inducing dose of human chorionic gonadotropin (hCG) on 17β-estradiol (estradiol) and LH concentrations was studied in mares. In Experiment 1, treatment with hCG resulted in ovulation in approximately 48 h. The LH surge centralized to ovulation and the preovulatory decline in estradiol were not different between hCG-treated ( n = 15) and control ( n = 13) groups. In Experiment 2, concentrations of hCG decreased 92% between 1 and 48 h after hCG treatment, estradiol decreased ( P < 0.003) within 6 h, and LH increased at a greater ( P < 0.02) rate after 12 h ( n = 14). Results indicated: (1) hCG induced a decrease in estradiol and a subsequent greater rate of increase in LH and (2) when centralized to ovulation, the endogenous LH surge and the estradiol decrease were similar between hCG-treated and control groups.

Use of the australian crimson‐spotted rainbowfish (Melanotaenia fluviatilis) as a model test species for investigating the effects of endocrine disruptors

Few studies have investigated the potential reproductive effects of toxicants on Australian freshwater fish species. The present study uses the Australian rainbowfish (Melanotaenia fluviatilis) as a model for testing the potential effects of 17beta-estradiol. Groups of reproductively active rainbowfish were exposed to waterborne 17beta-estradiol (control, carrier control, and 30, 100, 300, and 1,000 ng/L) for 3- and 14-d periods. Biomarkers of both low ecological relevance (plasma estradiol and testosterone, phosphoprotein, gamma-glutamyltranspeptidase [GTP]) and high ecological relevance (egg counts, hatchability, larval lengths, histopathology) were measured and the relationships between these examined. Relative to the controls, exposed female rainbowfish had a decline in plasma estradiol. An increase in phosphoprotein (vitellogenin) also was observed after exposure to 1,000 ng/L after 3 d, and histological examination of the gonads showed an increase in oocyte atresia at 1,000 ng/L on days 3 and 14. Changes in egg production were observed at 300 and 1,000 ng/L. No changes were detected to egg hatchability and larval lengths of offspring. Although there were no changes in male rainbowfish plasma testosterone or the histological organization of testes, levels of phosphoprotein increased and GTP activities were increased after 3 d of exposure at all test concentrations, but these declined at day 14. The present study demonstrated that, though measurements at the biochemical level were responsive to 17beta-estradiol exposure, fewer changes were observed in markers of higher ecological relevance at the exposures concentrations and durations tested.

Clinical outcomes using a flexible regimen of GnRH-antagonists and a ‘step-up’ of additional gonadotropins in donor oocyte cycles

ABSTRACTObjective: To assess the impact of serum estradiol upon oocyte donor cycle stimulation characteristics and clinical outcomes using flexible GnRH-antagonist (GnRH‑ant) with additional FSH supplementation.Research design and methods: A retrospective chart review of 99 oocyte donor cycles using ovarian hyperstimulation with recombinant FSH (rFSH) and GnRH‑ant was analyzed. Following discontinuation of oral contraceptives, controlled ovarian hyperstimulation was begun using rFSH (150–300 IU daily). GnRH‑ant (ganirelix, Organon) and an additional 75 IU of FSH/day were begun when lead follicles were 13–14 mm in greatest diameter. Cycles were analyzed based on serum estradiol response following administration of GnRH‑ant (Group 1: progressive rise and Group 2: no rise or a decline). Primary endpoints were cycle stimulation characteristics based on serum estradiol following GnRH‑ant, clinical pregnancy and implantation rates.Results: A decline in serum estradiol was seen after GnRH‑ant administration in 45% of cycles. Clinical pregnancy rates per transfer (70 vs. 72%) and implantation rates (43 vs. 56%) were similar for each group.Conclusion: Flexible regimens of GnRH‑ant even with additional rFSH in a ‘step-up’ fashion frequently result in a decline in serum estradiol during ovulation induction. While our study is non-randomized, it does not appear to result in any adverse affect in clinical outcomes in donor oocyte cycles.

Androgenic steroids as unexpected predictors of postpartum psychiatric disturbances

Postpartum psychiatric disorders develop in a significant number of otherwise healthy women. Because of the enormous decline in estradiol and progesterone after delivery, a relationship has been inferred between those changes and the onset of psychiatric symptoms. Little research has been done to characterize a broader range of hormone concentrations over the peripartal time frame and their potential causal relationship with emergent psychiatric disorders. This study investigated associations between nine psychiatric symptom clusters using the Symptom Checklist 90-R against changes in salivary progesterone, dehydroepiandrosterone sulfate (DHEAS), testosterone, estrone, estradiol and estriol concentrations in a cohort of 28 healthy, primigravid women. Concentrations of estradiol and progesterone declined as expected, but were not associated with postpartum psychiatric symptoms. Supra-physiological concentrations of DHEAS and diminished antenatal testosterone were significantly and consistently correlated with anxiety related symptoms and mild psychotic disturbances. These findings are consistent with the pharmacologic properties of these androgenic steroids and suggest that perinatal assessment of DHEAS and testosterone may be useful for prediction of and proactive intervention for postpartum psychiatric disturbances.

Reproductive tissue regression: Involvement of caspases, inducible nitric oxide synthase and nitric oxide during moulting in White Leghorn hens

Moulting is a natural physiological process where the reproductive system of birds undergoes complete remodeling in preparation for the next laying cycle. In domestic chickens, moulting is artificially induced by feed withdrawal to recycle the old laying flock for best profit margins. This has received severe criticism from animal welfare organizations, forcing several countries to stop this practice. Several alternative methods to feed withdrawal methods were developed but were found to produce inconsistent results. Understanding the actual mechanism of moulting would help in designing a new animal welfare friendly method. The present investigation attempted to study the molecular mechanism of moulting in White Leghorn hens. Eighty-four layers (75 weeks) were divided into two groups. The birds in the first group were subjected to moulting by feed withdrawal (FW) while the other group received high dietary Zn (ZnF) treatment for 10 days. Six birds from each group were sacrificed on 0, 1–4, 6 and 10 days of moulting and mRNA expression of caspases-1, -2 and iNOS, along with the apoptotic ladder pattern and nitric oxide (NO) in the ovary and oviduct, was investigated. The mRNA expression of iNOS was upregulated with a corresponding increase in NO levels. Caspases-1 and -2 were differentially upregulated in the ovary and oviduct of moulted birds. A constant decline in serum estradiol and progesterone levels was also observed. It can be concluded that the pattern of reproductive regression during moulting by the two methods is different, as the expression of genes studied in the present investigation is different.

Physiology and endocrinology of the menopause

Abstract The menopause is the permanent cessation of menstruation resulting from loss of ovarian follicular activity. Follicular granulosa cells produce estradiol and inhibins. An accelerated decline in follicle numbers occurs from about age 38 years, and the major initial change underlying the menopause is a selective, gradual decline in inhibin B, the major regulator of follicular phase follicle-stimulating hormone (FSH). It is produced by the granulosa cells of antral follicles during the early follicular phase. The inhibin B decline leads to increased FSH, which can maintain and even increase estradiol production for some years. Onset of menstrual irregularity after previously regular cycles marks the onset of the menopausal transition, when there is a substantial decline in inhibin B, with maintenance of estradiol. Anovulatory cycles increase as menstrual irregularity is established. The late menopausal transition is marked by 60–90 days of amenorrhoea and frequent prolonged and often anovulatory cycles. Estradiol levels decline and FSH is raised, but their concentrations vary considerably; measurements are of limited diagnostic value. At the time of the final menses, estradiol levels on average are 50% of those at mid-reproductive age; FSH is about 50% of the elevated concentrations finally reached postmenopausally. There is thus a profound decline (about 90%) in estradiol in the 3–4 years surrounding final menses, and this results in menopausal symptoms and bone loss. Testosterone levels decline by about 50% during mid-reproductive life, but show no significant change during the menopausal transition and in the early postmenopausal years.

Bilateral oophorectomy and premature menopause

The ovary is a complex metabolic organ. The follicles produce both androgens and estrogens, whereas the stromal tissue synthesizes androgens only. When menopause occurs, both androgen and estrogen levels decrease. The postmenopausal ovary remains a source of endogenous androgens that are converted to estrogen. The consequences of premature removal of the ovaries are not well known. The risks and benefits of menopausal hormone therapy (HT) in women with premature menopause have not been studied. Women who have had surgical menopause experience more severe symptoms and will need to stop estrogen therapy at some point in their lives. Intense symptoms such as hot flashes, night sweats, and insomnia will redevelop, so women should be given informed consent about the need for long-term use of HT and the greater difficulty in discontinuing therapy.

A Rapid Mid-Luteal Decline in Estradiol Concentrations does not Predict Poor Outcome in Assisted Reproduction

Both Progesterone and Estradiol have been show to play essential roles in the preparation and maintenance of the endometrium. It has been proposed that abrupt reductions in luteal phase estradiol may predict poor reproductive outcome either as a result of impaired follicular function or perhaps as a cause of sub-optimal endometrial preparation. We intended to identify the significance of a decline in mid luteal estradiol during cycles of assisted reproduction Retrospective analysis of assisted reproduction outcomes in a large academic facility A retrospective analysis was undertaken of 1127 women undergoing assisted reproduction using the down regulation protocol between August 2002 and December 2004. The indications for IVF were tubal (n=397), male (n=268), anovulation (n=102), endometriosis (n=86), ovarian dysfunction (84), and mixed (n=190). ICSI (n=395) was performed for couples with severe semen abnormalities (less than 106 motile spermatozoa recovered after sperm preparation, Kruger Morphology <4%, Motility <40%, or history of prior poor fertilization). ICSI was also performed in cases of testicular sperm extraction from the epididymis or testes. Variables analyzed included ratio of estradiol and time of hcg administration to midluteal estradiol, pregnancy rate, implantation rate, number of embryos transferred. Statistical analysis was then performed using the statistical software Statview (Berkeley Systems, California). Continuous variables were assessed by Student’s t-test or Wilcoxon rank sum test if data did not appear normally distributed. Categorical variables were assessed by Chi-square test or two-tailed Fisher’s exact test in the case of small cell frequencies. Multiple logistic regression was used to assess potentially confounding variables. A p-value of 0.05 was considered statistically significant. In cycles of ART using human chorionic gonadotropin for luteal support, the 25th, 50th, 75th, and 95th percentile of the ratio of day of HCG to the mid luteal estrogen were, 1.9, 3.1, 5.0, and 10.0 respectively. Hormonal parameters were not different between pregnant and non-pregnant cycles. Irrespective of estradiol ratio, pregnancy rates were similar in all groups. TableComparison of estradiol ratio (day of hcg to mid-luteal) in patients undergoing assisted reproduction and controlled ovarian hyperstimulation with down regulation. No decline in pregnancy rate could be determined in the group patients demonstrating a rapid mid luteal estrogen decline. Adequate endometrial preparation, hCG triggering, and luteal support, appears to compensate for follicular apparatus exhaustion and negative effects on the endometrium that may result from rapid declines in luteal estradiol levels.

Postmenopausal Bilateral Oophorectomy Is Not Associated With Increased Fracture Risk in Older Women

We studied whether oophorectomy performed after menopause is associated with an increased risk of hip or vertebral fractures in 6295 Study of Osteoporotic Fractures participants. There was no association between postmenopausal oophorectomy and the risk of hip or vertebral fractures. Bilateral oophorectomy after natural menopause has been associated with an increased risk of osteoporotic fractures, potentially because of a decline in serum estradiol and testosterone levels after the oophorectomy. We prospectively tested this hypothesis in the Study of Osteoporotic Fractures (SOF). We studied 6295 white women 65 years of age participating in the SOF who were not taking estrogen therapy at baseline. Hip fracture analyses included 708 hip fractures; vertebral fracture analyses included 267 incident vertebral fractures. Baseline serum estradiol and free testosterone values were available in a small subset of participants. There were no significant differences in age, weight, or BMD between the women who underwent postmenopausal oophorectomy (n = 583) and those who did not (n = 5712). Free testosterone levels were significantly lower among women who had a postmenopausal oophorectomy. A history of postmenopausal oophorectomy was not associated with an increased risk of hip (hazard ratio [HR] = 1.1; 95% CI = 0.9-1.5) or vertebral fracture (HR = 0.7; 95% CI = 0.5-1.2). The relationship between oophorectomy and hip fracture was not altered by adding serum estradiol level (HR = 1.3; 95% CI = 0.5-3.2) or serum free testosterone level (HR = 1.7; 95% CI = 0.8-3.7) to the model. In summary, postmenopausal oophorectomy was not associated with an increased risk of hip or vertebral fracture in this cohort. These results are in contrast to previous findings, suggesting that the relationship between postmenopausal oophorectomy and fractures is not fully elucidated and that incidental oophorectomy after menopause should still be considered carefully in each potential patient.

Estradiol and cognition during androgen deprivation in men with prostate carcinoma

The adverse effects of hormonal manipulation in prostate carcinoma need to be established in view of its increasing use as an adjuvant treatment. This prospective study investigated the association of androgen deprivation-induced estradiol decline with cognition in prostate carcinoma. Cognitive testing of prostate carcinoma patients was carried out at baseline and at 6 and 12 months on androgen deprivation (AD). Cognitive performances were evaluated with standardized measures of information processing, including working memory and attention, visual and verbal skills, and memory performances in 31 tests. Testosterone and estradiol changes during AD were measured with the DELFIA (PerkinElmer, Inc., Wellesley, MA) system. Associations between changes in cognitive performances and estradiol decline were studied. Cognitive performances, which were significantly associated with decline in estradiol, included visual memory of figures (r = -0.52; P = 0.022) and recognition speed of numbers, which were impaired, (r = -0.57; P = 0.030) at 6 months, and improvement in verbal fluency (r = -0.52; P = 0.019) at 12 months. Other cognitive domains appeared unaffected by estradiol decline. The character of change (impairment or improvement) depended on the magnitude of estradiol decline. The cognitive domains of verbal fluency, visual recognition, and visual memory were associated with decline in estradiol during androgen deprivation. The results suggest selective associations among testosterone decline, estradiol, and cognitive performance. Documentation of these associations has implications for informed patient support in hormonally treated prostate carcinoma.

In vitro effects of diethylstilbestrol, genistein, 4- tert-butylphenol, and 4- tert-octylphenol on steroidogenic activity of isolated immature rat ovarian follicles

Isolated rat ovarian follicles grow and produce steroid hormones in vitro and so provide a good model for studying the effects of hormonally active compounds on follicular steroidogenesis. We have evaluated the effects of diethylstilbestrol (DES), genistein (GEN) and two alkylphenols, 4- tert-butylphenol (BP) and 4- tert-octylphenol (OP) on the growth, survival, and steroid hormone and cAMP production by isolated 14-day-old rat (Sprague-Dawley) ovarian follicles. During a 5-day culture, FSH was obligatory for follicle growth and increased estradiol and testosterone secretion in a dose-dependent manner. DES (10 -6 M) caused the strongest decline in estradiol and testosterone levels but did not have detectable effects on either cAMP production or aromatase enzyme activity. GEN caused a prominent decrease in cAMP and testosterone levels without significant changes in secreted estradiol. The latter, apparently, was due to a dose-dependent stimulation of aromatase enzyme activity in the presence of genistein. Both BP and OP decreased estradiol and testosterone secretion in a dose-dependent manner while no effect on aromatase activity was observed. OP, unlike BP, decreased forskolin-induced cAMP levels. Xenoestrogens at the used concentrations did not interfere with the growth and survival of the follicles. The results indicate that isolated ovarian follicles representing intact morphological and functional units offer a sensitive model system for elucidating the female-specific reproductive effects of environmental chemicals.

GnRH antagonists followed by a decline in serum estradiol results in adverse outcomes in donor oocyte cycles.

The aim of this retrospective study was to assess clinical outcomes using GnRH antagonists in oocyte donation cycles. Between July 2000 and June 2001, 40 recipient cycles generated from donor oocytes were evaluated. Controlled ovarian hyperstimulation (COH) was started on cycle day 2 using recombinant gonadotrophins (225 IU daily). GnRH antagonist was started on cycle day 6 of COH. All recipients were synchronized to donors using GnRH agonist followed by estrogen and progesterone supplementation. Main outcome measures were days of stimulation (DOS), number of ampoules used, peak serum estradiol, number of oocytes, fertilization rate, embryo score, clinical on-going pregnancy rate and implantation rate. Thirty-seven donor cycles (93%) underwent oocyte retrieval, resulting in 36 embryo transfers. Fourteen cycles (35%) had decreased serum estradiol after initiation of GnRH antagonist. No differences were seen in numbers of FSH ampoules, DOS, peak serum estradiol, number of retrieved oocytes, fertilization rate and embryo quality. However, clinical pregnancy rate per initiated cycle [14% (2/14) versus 54% (14/26)], ongoing pregnancy rate per initiated cycle [7% (1/14) versus 46% (12/26)] and implantation rate (4 versus 24%) were all significantly less (P <0.05) following a decrease in serum estradiol after initiation of GnRH antagonist. No clinical predictor, including donor age, basal day 2 FSH or estradiol, ovarian morphology or serum estradiol prior to GnRH antagonist, was predictive of a decline in serum estradiol following GnRH antagonist. These data demonstrate an adverse effect on clinical outcome in cycles, resulting in a decline in serum estradiol after GnRH antagonist administration. This effect was unpredictable and provided a simplified protocol for oocyte donation cycles; nonetheless, further study is needed to clarify the adverse effects of GnRH antagonists in oocyte donation cycles.

Identification of genes involved in follicular development by transcription gene profiling of ovaries from 5 and 15-day old mice

Objective: Identification of the genes involved in the transition from secondary to antral follicles. Design: In this study we used the Affymetrix gene chip to differentially profile genes involved in follicular development from secondary to antral follicles present in 5 and 15-day old mouse ovaries, respectively. At day 5 after birth, folliculogenesis has progressed no further than the secondary follicle stage and low levels of circulating gonadotropins are detected in plasma. At day 15 of age, follicles are at all stages of differentiation (including antral follicles), and the plasma levels of FSH, LH, estradiol and estrone are similar to the normal circulating levels present in the mature cycling animal. FSH, LH and estradiol decline abruptly by day 21 of age until the animal reaches cycling maturity. Therefore, gene expression profiling of ovaries from these two populations may identify genes involved in the secondary to antral follicle transition. Materials/Methods: Total ovarian RNA from 5-day old and 15-day old mice was isolated using TRIzol, DNAse treated, and then submitted to two rounds of cDNA synthesis. First strand cDNA synthesis was achieved with a modified oligo-dT primer containing the promoter sequence for T7 RNA polymerase, followed by the synthesis of double stranded cDNA, and this was then followed by in-vitro transcription using biotin-labeled NTPs to produce biotinylated cRNA. Biotinylated cRNA was submitted to fragmentation and used to hybridize the Murine 11KA and 11KB GenechipTM arrays from Affymetrix. The arrays were scanned and raw data analyzed using Affymetrix MicroArraySuite 4.0. Genes displaying an absolute intensity difference greater than 4-fold between ovaries of the 5- and 15-day old mice were selected for further analysis. Selection of genes was performed only on present probesets. The data were normalized with eleven bacterial genes added to the hybridization solution. Results: All genes involved in the conversion of cholesterol to estradiol through the delta-4 and delta-5 pathways were up-regulated in the 15-day old animals. We also found an increase in expression at day 15 of other genes known to be involved in folliculogenesis such as inhibin alpha, adrenodoxin, LH hormone receptor, prostaglandin E receptor, TGF beta I receptor, FGF, estrogen receptor beta, and prolactin receptor 1, ARF-1, Thrombospondin, among others. A 4-fold change in expression was also found in some genes not yet described in the ovary. Among these genes we found an up-regulation at day 15 of GBX-2, Secretagranin III, RHAMM, PAF-3, G- alpha 12, FKBP-65, Neuronatin, Protein Kinase C Delta, NEK-2 and SEK-1. We selected RHAMM and Secretagranin III for follow-up studies using Taqman to confirm the up-regulation of these genes at day 15 of age. By in-situ hybridization, RHAMM gene expression was localized to the granulosa cells of late antral follicles and in the corpus luteum of 60-day old female mouse ovaries. Conclusions: The transcriptional gene data generated by this approach validates the benefit of using 5-day and 15-day old mouse ovaries to identify possible candidate genes such as RHAMM, involved in the transition from secondary to late antral follicles. Supported by: Wyeth.

A decline in midluteal estradiol of less than 50% is associated with a higher pregnancy rate in in-vitro fertilization

A decline in midluteal estradiol of less than 50% is associated with a higher pregnancy rate in in-vitro fertilization

Androgen replacement in aging men.

Serum testosterone and estradiol decline with advancing age in men, but the contribution of these changes to age-related bone loss remains unclear. Most studies show a closer relationship between bone density and serum estradiol than with serum testosterone. Nevertheless, hypogonadism is widely considered to be an important cause of male osteoporosis, occurring in up to 20% of men with vertebral fractures and 50% with hip fractures. Bone loss in hypogonadal men has been attributed to androgen and estrogen deficiency, low 1,25 dihydroxyvitamin D concentrations, malabsorption of calcium, and reduced circulating calcitonin. These abnormalities are corrected by testosterone replacement, which also decreases bone resorption and stimulates bone mineralization. Long-term testosterone replacement increases spine bone density by over 25%, although much of the improvement occurs in the first few years of treatment. There appears to be an inverse relationship between the basal serum testosterone and the increase in bone density observed with testosterone treatment, such that little change is seen in men with normal basal concentration. In contrast, an observational study in eugonadal men with vertebral fractures showed an increase in spine bone density of 5% after 6 months' treatment with testosterone, probably mediated by an increase in serum estradiol and a reduction in bone resorption. Although testosterone has beneficial effects on the skeleton, there may be adverse effects on the prostate and cardiovascular risk factors. Further studies are required to confirm the safety and efficacy of testosterone replacement in hypogonadal and eugonadal men with osteoporosis.

Decline in circulating estradiol during the periovulatory period is correlated with decreases in estradiol and androgen, and in messenger RNA for p450 aromatase and p450 17alpha-hydroxylase, in bovine preovulatory follicles.

The preovulatory surge of gonadotropins induces meiotic maturation of the oocyte, the follicular/luteal phase shift in hormone production, and ovulation. This complex and rapid series of developmental changes is difficult to study in large mammals, such as primates and ruminants, because variability in the length of individual reproductive cycles makes it virtually impossible to predict the time of the LH surge. We have validated an experimental model for inducing the LH surge and ovulation in cattle and used it to study the sequence of changes in hormone secretion and some of the mechanisms of these changes. Luteolysis and a follicular phase were induced by injection of prostaglandin F(2alpha); injection of a GnRH analogue 36 h later induced an LH surge and ovulation. The LH surge peaked 2 h after GnRH and ovulation followed 22-31 h after the surge, consistent with the periovulatory interval in natural cycles. The ensuing luteal phase was normal, both in length and in concentrations of circulating progesterone. In experiment I, the uteroovarian effluent was collected, via cannulation of the vena cava, at frequent intervals relative to GnRH injection. Circulating estradiol declined progressively after GnRH, reaching a nadir by 8-10 h before ovulation, whereas concentrations of androstenedione and testosterone remained constant. In experiment II, preovulatory follicles were obtained at 0, 3.5, 6, 12, 18, or 24 h after GNRH: Concentrations of androgens and estradiol were measured in follicular fluid and medium from cultures of follicle wall (theca + granulosa cells); steady-state levels of mRNA for 17alpha-hydroxylase (17alphaOH) and P450 aromatase were measured in follicular tissue. Shortly after the LH surge (3.5 h post-GnRH) there was an acute increase in the capacity of follicular tissue to secrete androstenedione, but not estradiol, in vitro. Thereafter, both androgens and estradiol declined, both in follicular fluid and in medium collected from cultures of follicle wall. Levels of mRNA for 17alphaOH and aromatase in follicle wall decreased significantly by 6 h after GnRH, suggesting that declining levels of these enzymes underlie the decreases in steroid production by follicular cells. These results show that in cattle the preovulatory decrease in follicular estradiol production is mediated by redundant mechanisms, because androgen production and the capacity of granulosa cells to convert androgens to estradiol decline coordinately, in concert with decreases in mRNA for 17alphaOH and P450 aromatase.

Hormone patterns after induction of ovulation with clomiphene citrate: An age-related phenomenon

Since the introduction of clomiphene citrate (CC), more than three decades ago, a discrepancy has been observed between ovulation and pregnancy rates for which as yet no explanation exists. To investigate if ovulation disorders or abnormal hormonal patterns occur more often in CC-stimulated seemingly ovulatory cycles, we performed hormonal and sonographic monitoring in first cycles of oligo- or amenorrheic patients who were stimulated with 50 mg CC, and compared the hormonal patterns to those in natural cycles of age-matched proven fertile women. Twenty-four first CC cycles were monitored. Twelve cycles appeared to be ovulatory, eleven showed no follicle development and one cycle exhibited the luteinized unruptured follicle (LUF) phenomenon. Ten ovulatory cycles were compared with 27 unstimulated control cycles. In four cycles stimulated by CC, a temporary decline in estradiol levels was apparent. In these cycles, estradiol reached a higher level on cycle day (CD) 7 or 8 compared to cycles without a decline. Such an estradiol decline was seen in only one control cycle. Furthermore, the estradiol levels on CD 7 or 8 appeared to be age-related.We conclude that the estradiol decline in CC-stimulated ovulatory cycles may be a consequence of a sharp rise after CC stimulation, and such a rise may be age-related and coincide with a diminished follicle quality. If this phenomenon is associated with a suboptimal cycle, and so contributes to the suboptimal pregnancy rates after ovulation-induction treatment with clomiphene citrate, is still unknown.

Estradiol and progesterone regulate neuronal structure and synaptic connectivity in adult as well as developing brain

Until recently, it has been widely believed that the adult brain does not undergo changes in its structure, particularly in relation to the actions of circulating hormones. It has now become clear that estradiol and progesterone have important effects on adult brain structure and function. Single section Golgi silver staining and electron microscopy have been used to analyze numbers of spines on dendrites and to count synapses on dendritic spines. In the adult female rat brain, we find that dendrites of neurons in the ventromedial hypothalamus and CA1 region of the hippocampus sprout increased numbers of spines on dendrites and then lose them during the 4- or 5-day estrous cycle. Increased spine numbers are accompanied by increased numbers of synapses on spines. In the hippocampus, the loss of spines and spine synapses occurs during a 24-h period between the time of maximum sexual receptivity on the day of proestrus and the next day, the day of estrus. This loss is not due solely to the decline in estradiol; however, giving progesterone speeds up the decline, and administering the antiprogestin, Ru486, on proestrus blocks the natural decline of synapse density. The changes of synaptic density in the hypothalamus are responsible, at least in part, for the cyclicity of sexual behavior, whereas the cyclicity of synapses in the hippocampus may subnerve functions related to spatial learning and memory. In human subjects, cyclic fluctuations in gonadal hormones are associated with cyclic changes in performance on a variety of cognitive and motor tasks.

Regulation of Ovarian Steroid Biosynthesis by Estrogen during Proestrus in the Rat*

Studies were performed to test the hypothesis that the rapid decline in estradiol (E2) levels on proestrus before ovulation was due to a reduction in androgen substrate for aromatase, and that this decline in androgen was regulated by an estrogen receptor-mediated mechanism. Aromatase activity, concentrations of E2, androstenedione (A), testosterone (T), and progesterone (P4) in follicular, corpora lutea, and ovarian homogenates as well as peripheral E2, A, P4, and LH were measured in cycling rats from 1400-2000 h on proestrus. These parameters were also recorded after the expected E2 surge in animals treated at 1900 h on diestrous day 2 with the antiestrogen keoxifene (20 mg/kg), with or without an ovulatory dose of PMSG at 1600 h on proestrus. In a second experiment, P-450-17 alpha-hydroxylase/C17,20-lyase (P-450(17 alpha] activity was measured in a group of control rats at 1500, 1700, and 1900 h. Aromatase activity remained unchanged, even though serum and ovarian E2 levels were reduced from peak values at 1500 h to basal values at 1800 h (P less than 0.01). Peripheral A as well as ovarian androgens (specifically follicular but not luteal) A and T were also reduced over this time period (P less than 0.01). Although total ovarian P4 remained unchanged, follicular levels rose from 1400-2000 h (P less than 0.01). These reductions in androgens and E2 levels coincided with a marked reduction in follicular P-450(17 alpha) activity. Treatment with keoxifene with or without PMSG prevented the fall in peripheral E2 and A and the increase in peripheral P4 seen in controls. Ovarian and follicular E2, A, and to a lesser extent T were also remained at values similar to those during the E2 surge. Follicular P4 was reduced by both treatments. Neither treatment had any effect on aromatase. These results indicate that the fall in peripheral and ovarian E2 levels before ovulation was due to a decline in aromatizable androgen, through an inhibition of follicular P-450(17 alpha) enzyme activity, which appears to be mediated by an estrogen receptor-regulated mechanism.

Variable Ovarian Response to Gonadotropin-Releasing Hormone Antagonist-Induced Gonadotropin Deprivation during Different Phases of the Menstrual Cycle

The gonadotropin dependence of ovarian follicular maturation and corpus luteum function can now be examined in women using antagonistic analogs of GnRH. We studied the responses of three groups of women throughout a control cycle and during the administration of a potent GnRH antagonist, detirelix ([N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Trp3,D-hArg(Et2)6,D-Ala10++ +] GnRH, Syntex Research). Detirelix (10 mg, sc) was administered for 3 consecutive days during the midfollicular phase (n = 4), preovulatory phase (n = 4), and early luteal phase (n = 4). The pituitary response to detirelix was similar throughout the three phases of the menstrual cycle. Immunoreactive LH concentrations decreased to 35% (mean +/- SEM) of pretreatment values within 8 h after the initial injection and remained suppressed for 72 h after discontinuance of treatment. Immunoreactive FSH concentrations decreased to 73 +/- 3% of pretreatment levels within 8 h and returned to baseline within 24 h after the third injection. In contrast, the ovarian response to detirelix varied markedly during different phases of the cycle. Midfollicular phase treatment was associated with a decline in estradiol (E2) levels from pretreatment values of 246 +/- 48 to 81 +/- 15 pmol/L within 24 h of the last injection. Vaginal bleeding ensued in three of four women. Follicular recruitment was then reinitiated, and an ovulatory LH surge occurred 18.2 +/- 2.9 days after the last injection. Similarly, treatment during the early luteal phase produced a decline in E2 concentrations from 286 +/- 29 to 70 +/- 7 pmol/L and a decline in progesterone concentrations from 20 +/- 1.6 to 1.9 +/- 0.3 nmol/L within 24 h after the last injection. Luteolysis was associated with menstrual bleeding in all four women. The subsequent ovulatory LH surge occurred 16.5 +/- 1.0 days after discontinuance of treatment. In contrast, treatment during the preovulatory phase resulted in a decline in E2 concentrations from 844 +/- 66 to 429 +/- 132 pmol/L during the first 48 h of treatment. Gonadotropin and E2 concentrations subsequently recovered from suppression, growth of the dominant follicle resumed, and a LH surge occurred 5.8 +/- 1.4 days after the last injection. These data indicate that the GnRH antagonist detirelix produces rapid and consistent suppression of pituitary gonadotropin secretion. The magnitude of suppression and preferential suppression of LH vs. FSH are similar throughout the cycle. In contrast, the ovarian response to gonadotropin deprivation varies during the menstrual cycle.(ABSTRACT TRUNCATED AT 400 WORDS)