Triclosan (TCS), a chlorophenol, is widely used as a preservative in different types of commercial preparations. The reports on TCS-mediated endocrine disruption are controversial and the present study aimed to elucidate the probable mode of action of TCS as an antiandrogenic compound using a robust study design. Male albino rats, Rattus norvegicus, were treated with three doses of triclosan for a period of 60 days followed by the analysis of various biochemical parameters. RT-PCR analysis demonstrated a significant decrease in mRNA levels for testicular steroidogenic acute regulatory (StAR) protein, cytochrome P450(SCC), cytochrome P450(C17), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), 17beta-hydroxysteroid dehydrogenase (17beta-HSD) and androgen receptor (AR) in TCS treated rats (p<0.05). TCS also induced a perturbed translation of testicular StAR, and AR proteins as shown by Western blot analysis in treated groups of rats. A reduced level of StAR was further indicated by immunohistochemistry in testicular Leydig cells. Further, there was a significant decrease (p<0.05) in the level of serum lutenizing hormone (LH), follicle stimulating hormone (FSH), cholesterol, pregnenolone, and testosterone. In vitro assays demonstrated more than 30% decrease in testicular 3beta-HSD and 17beta-HSD enzyme activities in treated group of animals. Extensive histopathological malformations were observed in the testis and sex accessory tissues of the treated rats. Overall this study showed that TCS decreased the synthesis of androgens followed by reduced sperm production in treated male rats which could be mediated by a decreased synthesis of LH and FSH thus involving hypothalamo-pituitary-gonadal axis.

BACKGROUND

The potential benefit of adding recombinant human luteinizing hormone (r-hLH) to recombinant human follicle-stimulating hormone (r-hFSH) during ovarian stimulation is a subject of debate, although there is evidence that it may benefit certain subpopulations, e.g. poor responders.

METHODS

A systematic review and a meta-analysis were performed. Three databases (MEDLINE, Embase and CENTRAL) were searched (from 1990 to 2011). Prospective, parallel-, comparative-group randomized controlled trials (RCTs) in women aged 18-45 years undergoing in vitro fertilization, intracytoplasmic sperm injection or both, treated with gonadotrophin-releasing hormone analogues and r-hFSH plus r-hLH or r-hFSH alone were included. The co-primary endpoints were number of oocytes retrieved and clinical pregnancy rate. Analyses were conducted for the overall population and for prospectively identified patient subgroups, including patients with poor ovarian response (POR).

RESULTS

In total, 40 RCTs (6443 patients) were included in the analysis. Data on the number of oocytes retrieved were reported in 41 studies and imputed in two studies. Therefore, data were available from 43 studies (r-hFSH plus r-hLH, n=3113; r-hFSH, n=3228) in the intention-to-treat (ITT) population (all randomly allocated patients, including imputed data). Overall, no significant difference in the number of oocytes retrieved was found between the r-hFSH plus r-hLH and r-hFSH groups (weighted mean difference -0.03; 95% confidence interval [CI] -0.41 to 0.34). However, in poor responders, significantly more oocytes were retrieved with r-hFSH plus r-hLH versus r-hFSH alone (n=1077; weighted mean difference +0.75 oocytes; 95% CI 0.14-1.36). Significantly higher clinical pregnancy rates were observed with r-hFSH plus r-hLH versus r-hFSH alone in the overall population analysed in this review (risk ratio [RR] 1.09; 95% CI 1.01-1.18) and in poor responders (n=1179; RR 1.30; 95% CI 1.01-1.67; ITT population); the observed difference was more pronounced in poor responders.

CONCLUSIONS

These data suggest that there is a relative increase in the clinical pregnancy rates of 9% in the overall population and 30% in poor responders. In conclusion, this meta-analysis suggests that the addition of r-hLH to r-hFSH may be beneficial for women with POR.

Replacing GnRH agonist cotreatment for the prevention of a premature rise in LH during ovarian stimulation for in vitro fertilization (IVF) by the late follicular phase administration of GnRH antagonist may render supplementation of the luteal phase redundant, because of the known rapid recovery of pituitary function after antagonist cessation. This randomized two-center study was performed to compare nonsupplemented luteal phase characteristics after three different strategies for inducing final oocyte maturation. Forty patients underwent ovarian stimulation using recombinant (r-)FSH (150 IU/d, fixed) combined with a GnRH antagonist (antide; 1 mg/d) during the late follicular phase. When at least one follicle above 18 mm was observed, patients were randomized to induce oocyte maturation by a single injection of either r-human (h)CG (250 microg) (n = 11), r-LH (1 mg) (n = 13), or GnRH agonist (triptorelin; 0.2 mg) (n = 15). Retrieved oocytes were fertilized by either IVF or intracytoplasmatic sperm injection, depending on sperm quality. Embryo transfer was performed 3-4 d after oocyte retrieval. No luteal support was provided. Serum concentrations of FSH, LH, estradiol (E(2)), progesterone (P), and hCG were assessed at fixed intervals during the follicular and luteal phase. The median duration of the luteal phase was 13, 10, and 9 d for the r-hCG, the r-LH, and the GnRH agonist group, respectively (P = 0.005). The median area under the curve per day (from 4 d post randomization until the onset of menses) for LH was 0.50, 2.34, and 1.07 for the r-hCG, the r-LH, and the GnRH agonist group, respectively (P = 0.001). The median area under the curve per day for P was 269 vs. 41 and 16 for the r-hCG, the r-LH, and the GnRH agonist group, respectively (P < 0.001). Low pregnancy rates (overall, 7.5%; range, 0-18% per started cycle) were observed in all groups. In conclusion, the nonsupplemented luteal phase was insufficient in all three groups. In the patients receiving r-hCG, the luteal phase was less disturbed, compared with both other groups, presumably because of prolonged clearance of hCG from the circulation and the resulting extended support of the corpus luteum. Despite high P and E(2) concentrations during the early luteal phase in all three groups, luteolysis started prematurely, presumably because of excessive negative steroid feedback resulting in suppressed pituitary LH release. Hence, support of corpus luteum function remains mandatory after ovarian stimulation for IVF with GnRH antagonist cotreatment.

Follicle-Stimulating Hormone (FSH) at a wide range of doses is routinely added to culture media during in vitro maturation (IVM) of oocytes, but the effects on oocyte health are unclear. The suggestion that superovulation may cause aneuploidy and fetal abnormalities prompted us to study the potential role of FSH in the genesis of chromosomal abnormalities during meiosis I. Mouse cumulus-oocyte complexes (COCs) isolated from the antral follicles of unprimed, sexually immature B6CBF1 mice were cultured in increasing concentrations of FSH. Following culture, matured oocytes were isolated, spread, stained with DAPI, and the numbers of chromosomes counted. Significantly increased aneuploidy, arising during the first meiotic division, was observed in metaphase II oocytes matured in higher concentrations of FSH >> or =20 ng/ml). The effect of FSH on spindle morphology and chromosome alignment during metaphase I was then explored using immunocytochemistry and three-dimensional reconstruction of confocal sections. High FSH had no effect on gross spindle morphology but did alter chromosome congression during prometaphase and metaphase, with the spread of chromosomes across the spindle at this time being significantly greater in oocytes cultured in 2000 ng/ml compared with 2 ng/ml FSH. Analysis of three-dimensional reconstructions of spindles in oocytes matured in 2000 ng/ml FSH shows that chromosomes are more scattered and farther apart than they are following maturation in 2 ng/ml FSH. These results demonstrate that exposure to high levels of FSH during IVM can accelerate nuclear maturation and induce chromosomal abnormalities and highlights the importance of the judicious use of FSH during IVM.

Study Type - Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Hypogonadism is a prevalent problem, increasing in frequency as men age. It is most commonly treated by testosterone supplementation therapy but in younger patients this can lead to testicular atrophy with subsequent exogenous testosterone dependency and may impair spermatogenesis. Clomiphene citrate (CC) may be used as an alternative treatment in these patients with hypogonadism when maintenance of fertility is desired. This study shows that CC is a safe and efficacious drug to use as an alternative to exogenous testosterone. Not only have we validated previous findings of other papers but have proven our findings over a much longer period (mean duration of treatment 19 months). This prospective study is the largest to date assessing both the objective hormone response to CC therapy as well as the subjective response based on a validated questionnaire.

OBJECTIVE

• To prospectively assess the andrological outcomes of long-term clomiphene citrate (CC) treatment in hypogonadal men.

METHODS

• We prospectively evaluated 86 men with hypogonadism (HG) as confirmed by two consecutive early morning testosterone measurements <300 ng/dL. • The cohort included all men with HG presenting to our clinic between 2002 and 2006 who, after an informed discussion, elected to have CC therapy. CC was commenced at 25 mg every other day and titrated to 50 mg every other day. The target testosterone level was 550 ± 50 ng/dL. • Testosterone (free and total), sex hormone binding globulin, oestradiol, luteinizing hormone and follicle stimulating hormone were measured at baseline and during treatment on all patients. Once the desired testosterone level was achieved, testosterone/gonadotropin levels were measured twice per year. • To assess subjective response to treatment, the androgen deficiency in aging males (ADAM) questionnaire was administered before treatment and during follow-up.

RESULTS

• Patients' mean (standard deviation [sd]; range) age was 29 (3; 22-37) years. Infertility was the most common reason (64%) for seeking treatment. The mean (sd) duration of CC treatment was 19 (14) months. • At the last evaluation, 70% of men were using 25 mg CC every other day, and the remainder were using 50 mg every other day. • All mean testosterone and gonadotropin measurements significantly increased during treatment. • Subjectively, there was an improvement in all questions (except loss of height) on the ADAM questionnaire. More than half the patients had an improvement in at least three symptoms. • There were no major side effects recorded and the presence of a varicocele did not have an impact on the response to CC.

CONCLUSIONS

• Long-term follow-up of CC treatment for HG shows that it appears to be an effective and safe alternative to testosterone supplementation in men wishing to preserve their fertility.

This study was undertaken to investigate stem cells in adult mouse ovary, the effect of chemotherapy on them and their potential to differentiate into germ cells. Very small embryonic-like stem cells (VSELs) that were SCA-1+/Lin-/CD45-, positive for nuclear octamer-binding transforming factor 4 (OCT-4), Nanog, and cell surface stage-specific embryonic antigen 1, were identified in adult mouse ovary. Chemotherapy resulted in complete loss of follicular reserve and cytoplasmic OCT-4 positive progenitors (ovarian germ stem cells) but VSELs survived. In ovarian surface epithelial (OSE) cell cultures from chemoablated ovary, proliferating germ cell clusters and mouse vasa homolog/growth differentiation factor 9-positive oocyte-like structure were observed by day 6, probably arising as a result of differentiation of the surviving VSELs. Follicle-stimulating hormone (FSH) exerted a direct stimulatory action on the OSE and induced stem cells proliferation and differentiation into premeiotic germ cell clusters during intact chemoablated ovaries culture. The FSH analog pregnant mare serum gonadotropin treatment to chemoablated mice increased the percentage of surviving VSELs in ovary. The results of this study provide evidence for the presence of potential VSELs in mouse ovaries and show that they survive chemotherapy, are modulated by FSH, and retain the ability to undergo oocyte-specific differentiation. These results show relevance to women who undergo premature ovarian failure because of oncotherapy.

OBJECTIVE

To determine whether cortisol levels change prospectively during the menopausal transition (MT); whether these changes are associated with changes in the hypothalamic-pituitary-ovarian axis (follicle-stimulating hormone [FSH] and estrone glucuronide [E1G]), stressors, or menopause symptoms; and whether women who experienced a rise in cortisol levels during the transition had behavioral practices, stressors, vasomotor symptoms, or mood or sleep disturbances that affected hypothalamic-pituitary-adrenal axis function.

METHODS

One hundred sixty-nine women in the middle or late MT or early postmenopause stages provided monthly urine specimens for cortisol, FSH, and E1G, and rated symptoms and stress levels as part of a longitudinal study of the MT. Of these women, 91 completed a transition to the next MT stage: from early to middle (n = 30), middle to late (n = 39), or late to postmenopause (n = 22) and were eligible for inclusion in the analyses.

RESULTS

Cortisol increased from 7 to 12 months before the late MT stage to 7 to 12 months after onset of the late MT stage. There were no differences before and after the middle MT stage or the final menstrual period. Women with increased cortisol (>10 ng/mg creatinine) during the late MT stage had more severe vasomotor symptoms than those without changes, but did not differ in terms of age, body mass index, levels of FSH or E1G, health practices, exercise, mood, sleep, cognition, or stress levels.

CONCLUSIONS

Cortisol levels rise with age, but have not been linked to stages of the MT. Increased cortisol levels during the late MT stage, when menstrual irregularities are greatest, suggests increases in adrenal androgens and intraabdominal fat with menopause, and may influence risk of cardiovascular disease, vasomotor symptoms, mood, cognition, and bone loss.

The alterations in morphology and function of the ovarian follicle as it matures, ovulates, and becomes a corpus luteum are dramatic. A variety of steroid and polypeptide hormones influence these processes, and the ovary in turn produces specific hormonal signals for endocrine regulation. One such signal is inhibin, a heterodimeric protein that suppresses the secretion of follicle-stimulating hormone from pituitary gonadotrophs. Rat inhibin complementary DNA probes have been used to examine the levels and distribution of inhibin alpha-and beta A-subunit messenger RNAs in the ovaries of cycling animals. Striking, dynamic changes have been found in inhibin messenger RNA accumulation during the developmental maturation of the ovarian follicle.

Inhibin B and FSH levels in 289 idiopathic infertile men were compared with reference materials consisting of 303 proven fertile men (reference group 1) and 307 healthy men from the general population with unknown fertility status (reference group 2). The diagnostic power of these two serum markers of spermatogenesis was evaluated by the use of receiver operating characteristic plot analysis, and an example of how both markers can be used simultaneously in a bivariate reference chart is presented. Inhibin B levels were significantly lower and FSH levels were significantly higher in the infertile men, compared with either reference group, but with significant overlap, especially with reference group 2. Nevertheless, approximately 50% of the infertile men had an inhibin B or FSH, respectively, below the 2.5 percentile or above the 97.5 percentile of reference group 1, whereas only approximately 25% of the infertile men had an inhibin B or FSH, respectively, below the 2.5 percentile or above the 97.5 percentile of reference group 2. Fourteen and 11% of reference group 2 had an inhibin B or FSH, respectively, below the 2.5 percentile or above the 97.5 percentile of reference group 1, suggesting that a significant number of individuals from the general population with unknown fertility but otherwise healthy may actually be subfertile. In conclusion, 1) proven fertile men constitute the most appropriate reference group in the evaluation of the FSH-inhibin B axis; the sensitivity of these markers to identify infertility increased by approximately 20% when fertile men rather than men from the general population were used as control group; 2) FSH alone had a slightly higher positive predictive value than inhibin B alone, but the positive predictive value were highest when both markers of spermatogenesis were used in an inhibin B/FSH ratio; and 3) a bivariate reference chart is a valuable objective tool in the simultaneous evaluation of FSH and inhibin B as two interrelated markers.

Epidermal growth factor (EGF) stimulates the proliferation of various mammalian cells in culture, but its physiological role is not well defined. In mature male mice, large amounts of EGF are produced in the submandibular gland; it is present in the circulation at approximately 5 nanograms of EGF per milliliter of plasma. Sialoadenectomy (removal of the submandibular glands) decreased the amount of circulating EGF to an undetectable level but did not affect the circulating levels of testosterone or follicle-stimulating hormone. The number of mature sperm in the epididymis decreased by as much as 55 percent; the number of spermatids in the testis decreased by 40 to 50 percent; and the number of spermatocytes increased by about 20 percent. Administration of EGF to sialoadenectomized mice restored both the sperm content of the epididymis and the number of spermatids in the testis to normal. Thus, EGF may play a role in male reproductive function by stimulating the meiotic phase of spermatogenesis.

FSH is produced by the pituitary gonadotrope to regulate gametogenesis. Steroid hormones, including androgens, progestins, and glucocorticoids, have all been shown to stimulate expression of the FSHbeta subunit in primary pituitary cells and rodent models. Understanding the molecular mechanisms of steroid induction of FSHbeta has been difficult due to the heterogeneity of the anterior pituitary. Immortalized LbetaT2 cells are a model of a mature gonadotrope cell and express the endogenous steroid receptor for each of the three hormones. Transient transfection of each receptor, along with ligand treatment, stimulates the mouse FSHbeta promoter, but induction is severely diminished using receptors that lack the ability to bind DNA, indicating that induction is likely through direct DNA binding. All three steroid hormones act within the first 500 bp of the FSHbeta promoter where six putative hormone response elements exist. The -381 site is critical for FSHbeta induction by all three steroid hormones, whereas the -197 and -139 sites contribute to maximal induction. Interestingly, the -273 and -230 sites are also necessary for androgen and progestin induction of FSHbeta, but not for glucocorticoid induction. Additionally, we find that all three receptors bind the endogenous FSHbeta promoter, in vivo, and specifically bind the -381 site in vitro, suggesting that the binding of the receptors to this element is critical for the induction of FSHbeta by these 3-keto steroid hormones. Our data indicate that androgens, glucocorticoids, and progestins act via their receptors to directly activate FSHbeta gene expression in the pituitary gonadotrope.

Inhibin, a gonadal hormone capable of preferential suppression of pituitary follicle-stimulating hormone (FSH) secretion, has recently been purified. The major form of this protein is an alpha beta heterodimer encoded by two separate genes. In contrast to the FSH-suppressing action of the alpha beta heterodimer, the beta beta homodimer stimulates FSH secretion. Luteinizing hormone (LH)-secreting pituitary cells and gonadal androgen-producing cells have long been shown to form a closed-loop feedback axis. Based on recent studies demonstrating the FSH stimulation of inhibin biosynthesis by ovarian granulosa and testis Sertoli cells, an additional closed-loop feedback axis exists between pituitary FSH- and gonadal inhibin-producing cells. Because uncharacterized Sertoli cell factors have been suggested to either stimulate or inhibit androgen production by testicular Leydig cells, we have tested the intragonadal paracrine actions of heterodimers and homodimers of inhibin subunits. In primary cultures of testis cells, the alpha beta heterodimer of inhibin enhances Leydig cell androgen biosynthesis stimulated by LH, whereas the beta beta homodimer suppresses androgen production. Furthermore, similar modulatory actions of inhibin-related proteins were found in cultured ovarian theca-interstitial cells and theca explants treated with LH. In contrast, treatment with the inhibin-related proteins alone did not affect gonadal steroidogenesis. Our data indicate that the inhibin-related gene products synthesized by Sertoli and granulosa cells may form heterodimers or homodimers to serve as intragonadal paracrine signals in the modulation of LH-stimulated androgen biosynthesis and allow cross-communication between the two feedback loops.

Steroid hormones regulate levels of gonadotropin mRNA in the pituitary, and gonadotropic hormones in plasma. To determine whether estrogen receptor alpha (ERalpha) mediates steroid negative feedback, wild type (WT) and estrogen receptor alpha knockout (ERalphaKO) mice of both sexes were gonadectomized and implanted with a Silastic capsule containing either estradiol (E2), dihydrotestosterone (DHT), testosterone, or a blank capsule. Ten days later, plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were measured. Pituitary mRNA levels of gonadotropin subunit (alpha, LHbeta, FSHbeta) and prolactin (PRL) were quantified. LH levels in gonad-intact ERalphaKO females were elevated, similar to values seen following gonadectomy. By contrast, serum LH concentrations in gonad-intact ERalphaKO males were low and rose following gonadectomy, suggesting androgen feedback. Estradiol treatment significantly decreased plasma LH in WT animals, but not in ERalphaKOs. In fact, in female ERalphaKOs, our dose of E2 increased plasma levels of LH as compared with untreated, ovariectomized ERalphaKOs. All the steroid treatments suppressed LH in WT animals whereas only DHT consistently suppressed LH concentrations in ERalphaKO mice. The postgonadectomy rise in plasma FSH was prevented by steroid treatments in WT females, but not in any of the other groups. Gonadotropin subunit and PRL mRNA responses to E2 treatment (both inhibitory and stimulatory) were absent in ERalphaKO mice, suggesting a critical role for ERalpha. Although E2 can exert negative feedback effects on LH release in both males and females by actions at the ERalpha, the androgen receptor plays the primary physiological role in the male mouse.

Galanin, a 29-aminoacid neuropeptide, was infused for 60 min into healthy volunteers at 7.8 pmol/kg/min (n = 4) or 33.2 pmol/kg/min (n = 6). During the infusion there was no change in heart rate or blood pressure and the only symptoms were a transitory bitter taste and slight hypersalivation. Plasma growth hormone levels rose during the high-dose galanin infusion from 2.8 +/- 0.8 mU/l to a mean peak of 48.5 +/- 19.8 mU/l; prolactin levels rose from 176 +/- 33 mU/l to 274 +/- 33 mU/l. A significant rise in growth hormone also occurred with the low-dose infusion (2.5 +/- 1.1 mU/l to a mean peak of 23.5 +/- 6.6 mU/l). There was no change in cortisol, thyroid-stimulating hormone, follicle-stimulating hormone, or luteinising hormone at either dose. 20 min after the start of the infusion a 25 g glucose bolus was given intravenously. Galanin reduced glucose clearance without significantly affecting plasma insulin concentrations. Pancreatic polypeptide levels were suppressed by the galanin infusion but levels of glucagon and gastric inhibitory peptide were unchanged.

To determine the timing of pubertal development and the frequency of gonadal dysfunction in children who survive acute lymphoblastic leukemia, we assessed pubertal status and the plasma levels of sex steroids, gonadotropin, and inhibin in 45 children (20 girls and 25 boys) who had received combination chemotherapy along with 24 Gy of irradiation to the cranium (modified LSA2L2 protocol). We also reexamined testicular biopsy specimens, obtained at the time of the cessation of chemotherapy, for the presence of germ cells. Germ-cell damage, indicated by marked elevations in the plasma level of follicle-stimulating hormone (P less than 0.001 for the comparison with normal children), was evident in both sexes and was confirmed in the boys by the absence of germ cells in the testicular biopsy specimens and by the small size of the testes for pubic-hair stage. Only 44 percent of the pubertal girls had measurable plasma inhibin levels, as compared with more than 93 percent of normal pubertal girls. Although plasma sex-steroid levels were normal, the secretion of luteinizing hormone in response to stimulation with gonadotropin-releasing hormone was elevated in the pubertal children (P less than 0.01 for the comparison with normal controls)--a finding that suggests compensation for decreased gonadal function. Despite clear evidence of gonadal damage, girls had early menarche at a mean age (+/- SD) of 11.95 +/- 0.91 years, as compared with the Australian standard of 12.98 +/- 1.11 years (P less than 0.01). Thus, in girls, puberty was early despite primary gonadal damage. Thirteen of 23 boys reached puberty at a mean age of 12.36 +/- 0.73 years. We conclude that treatment for acute lymphoblastic leukemia may lead to primary gonadal damage in both sexes, regardless of the age at treatment, but that the secondary characteristics of puberty develop at a normal age or, in girls, relatively early.

A putative FSH receptor (FSH-R) cDNA was cloned from African catfish testis. Alignment of the deduced amino acid sequence with other (putative) glycoprotein hormone receptors and analysis of the African catfish gene indicated that the cloned receptor belonged to the FSH receptor subfamily. Catfish FSH-R (cfFSH-R) mRNA expression was observed in testis and ovary; abundant mRNA expression was also detected in seminal vesicles. The isolated cDNA encoded a functional receptor since its transient expression in human embryonic kidney (HEK-T) 293 cells resulted in ligand-dependent cAMP production. Remarkably, African catfish LH (cfLH; the catfish FSH-like gonadotropin has not been purified yet) had the highest potency in this system. From the other ligands tested, only human recombinant FSH (hrFSH) was active, showing a fourfold lower potency than cfLH, while hCG and human TSH (hTSH) were inactive. Human CG (as well as cfLH, hrFSH, eCG, but not hTSH) stimulated testicular androgen secretion in vitro but seemed to be unable to bind to the cfFSH-R. However, it was known that hCG is biologically active in African catfish (e.g., induction of ovulation). This indicated that an LH receptor is also expressed in African catfish testis. We conclude that we have cloned a cDNA encoding a functional FSH-R from African catfish testis. The cfFSH-R appears to be less discriminatory for its species-specific LH than its avian and mammalian counterparts.

This 1 year study examined the effect of high impact and low impact activities on bone mineral density (BMD) at the lumbar vertebrae (L2-L4) in healthy, sedentary, early postmenopausal women. Fifteen subjects whose postmenopausal status was verified by the blood levels of follicle stimulating hormone (FSH) and estradiol were chosen. These subjects were tested on the following variables: BMD via dual photon absorptiometry, heart rate response to the Balke treadmill test, percent fat via skinfolds, and a 3-d dietary analysis. Subjects were matched and then assigned randomly to one of three groups: (a) a control nonexercising group, (b) a low impact exercise group, and (c) a high impact exercise group. The control nonexercising group experienced a significant linear decrease in BMD during the study (F = 12.63, P = 0.002). Both the low and high impact exercise groups maintained BMD during the study (F = 0.04, P = 0.85; F = 1.08, P = 0.31, respectively). The difference in BMD between the low impact and the high impact exercise groups was not significant (F = 0.36, P = 0.55). In conclusion, 20 min of moderate intensity low impact or high impact exercise 3 d.wk-1 for 1 yr is effective in maintaining BMD in early postmenopausal women.

Although gonadotropin-releasing hormone (GnRH) is believed to mediate the hypothalamic control of pituitary gonadotropin secretion, continuous or repeated administration of GnRH or its agonist analogues has been shown to cause paradoxical antifertility effects in several species, including primates. GnRH-induced interruption of reproductive cycles and pregnancy is associated with diminished progesterone production, implying defective function of the corpus luteum. These luteolytic effects have been attributed to the well recognized desensitising actions of elevated luteinising hormone (LH) levels on ovarian LH receptors and steroidogenesis, subsequent to GnRH-induced gonadotropin release from the anterior pituitary. However, treatment with high doses of exogenous LH did not cause suppression of serum progesterone levels during early pregnancy in rats, whereas a highly active GnRH analogue was effective in this regard. These observations suggested that GnRH and its agonist analogues, given in high or sustained doses, can exert a direct action on the ovary that is independent of the pituitary. This hypothesis was further supported by the ability of GnRH and its agonists to inhibit human chorionic gonadotropin (HCG)-induced ovarian and uterine weight gain in hypophysectomised rats and to delay the onset of puberty in intact female rats. Also, GnRH and its agonist analogues have recently been shown to inhibit steroidogenesis induced by follicle-stimulating hormone (FSH) in cultured granulosa cells, confirming the direct action of such peptides on the ovarian follicle. The marked inhibitory effects of GnRH and its agonists on corpus luteum function suggest that these compounds could exert direct actions by binding to specific receptors on luteal cells. The present experiments, which examine the effects of GnRH agonists on luteal steroidogenesis, demonstrate the existence of such actions and their mediation by specific high-affinity receptor sites present in luteal cell membranes.

Prenatal testosterone excess leads to neuroendocrine and periovulatory disruptions in the offspring culminating in progressive loss of cyclicity. It is unknown whether the mediary of these disruptions is androgen or estrogen, because testosterone can be aromatized to estrogen. Taking a reproductive life span approach of studying control, prenatal testosterone, and dihydrotestosterone-treated offspring, this study tested the hypothesis that disruptions in estradiol-negative but not -positive feedback effects are programmed by androgenic actions of testosterone and that these disruptions in turn will have an impact on the periovulatory hormonal dynamics. The approach was to test estradiol-negative and -positive feedback responses of all three groups of ovary-intact females during prepubertal age and then compare the periovulatory dynamics of luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone during the first breeding season. The findings show that estradiol-negative but not estradiol-positive feedback disruptions in prenatal testosterone-treated females are programmed by androgenic actions of prenatal testosterone excess and that follicular phase estradiol and gonadotropins surge disruptions during reproductive life are consistent with estrogenic programming. Additional studies carried out testing estradiol-positive feedback response over time found progressive deterioration of estradiol-positive feedback in prenatal testosterone-treated sheep until the time of puberty. Together, these findings provide insight into the mechanisms by which prenatal testosterone disrupts the reproductive axis. The findings may be of translational relevance since daughters of mothers with hyperandrogenism are at risk of increased exposure to androgens.

BACKGROUND

This study examines interrelationships among age, hormones, and cognition for middle-aged and elderly men, and tests whether hormones predict lower cognitive functioning and mediate the age-cognition relationship.

METHODS

We analyzed Time 2 data from the Massachusetts Male Aging Study, a population-based cohort study. Selection criteria included complete information on cognition and hormones (n = 981). Cognitive measures included working memory (Backward Digit Span test), speed/attention (Digit Symbol Substitution test), and spatial ability (Figural Relations test). Hormones included free testosterone, total testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstanediol glucuronide (3 alpha-A-diol-gluc), luteinizing hormone (LH), follicle-stimulating hormone (FSH), sex hormone-binding globulin (alternatively known as a "binding protein") (SHBG), prolactin (PRL), estrone (E1), and cortisol (CRT). Age was measured in years. Adjusted analyses added educational attainment, health conditions and behaviors, body mass index, and depression.

RESULTS

Older age was associated with lower cognitive functioning. In unadjusted models, logged free and total testosterone, DHEA, and DHEAS related to higher functioning in at least one cognitive domain; logged FSH, SHBG, and LH related to lower functioning in at least one cognitive domain; and logged E1, CRT, and PRL were not significant. In adjusted models, logged hormones did not relate to cognitive function except for logged E1 and CRT, which had negative effects. Logged hormones did not mediate the age-cognition relationship.

CONCLUSIONS

The direct effects of hormones on cognition are not significant when salient factors are considered. Further, hormones do not mediate the age-cognition relationship; it is necessary to look to other explanatory pathways.

BACKGROUND

Premenopausal women treated for early stage breast cancer (ESBC) are at risk for chemotherapy-related amenorrhea (CRA). Prospectively-validated, predictive markers of CRA are needed.

METHODS

Premenopausal women with ESBC and planned chemotherapy >>/= 25% risk of amenorrhea) were evaluated. Follicle stimulating hormone (FSH), estradiol, Inhibin A and B, anti-Müllerian hormone (AMH), and quality of life (QOL) were prospectively evaluated pre-, post-, 6 months and 1 year post-chemotherapy and correlated with age and menstrual status. CRA was defined as absence of menses 1 year post-chemotherapy.

RESULTS

Forty-four women were evaluated at the time of analysis. Median age at diagnosis and FSH 1 year post-chemotherapy were higher among women with CRA (44 yrs [33-51] vs. 40 yrs [31-43]; p = 0.03; 39.8 vs. 5.0 mLU/mL, p = 0.0058, respectively). Median estradiol 1 year post-chemotherapy was higher among women who resumed menses (108.3 vs. 41.3 pg/mL, p = 0.01). Pre-chemotherapy median Inhibin B and AMH were lower among women with CRA (33.2 vs. 108.8 pg/mL; p = 0.03; 0.16 vs. 1.09 ng/mL, p = 0.02, respectively). The risk of CRA was increased among women with lower pre-chemotherapy Inhibin B (RR = 1.67, p = 0.15) and AMH (RR = 1.83, p = 0.05). Amongst women whose pre-chemotherapy Inhibin B and AMH values were below the median, the incidence of CRA was 87.5%.

CONCLUSIONS

RESULTS indicate that pre-chemotherapy Inhibin B and AMH are lower among women experiencing CRA and may be predictive of CRA among premenopausal women facing chemotherapy for ESBC.

Inflammatory and granulomatous diseases of the pituitary are rare causes of sellar masses. Lymphocytic hypophysitis is the most relevant of these disorders, and it is characterised by autoimmune pathogenesis with focal or diffuse inflammatory infiltration and varying degrees of pituitary gland destruction. Endocrine symptoms may include partial or total hypopituitarism, with adrenocorticotropic hormone (ACTH) deficiency being the earliest and most frequent alteration. Pituitary abscess is a rare but potentially life-threatening disease and, in 30-50% of patients, anterior pituitary hormone deficiencies or central diabetes insipidus (DI) at onset may be observed: the earliest manifestation being growth hormone deficiency (GHD), followed by follicle-stimulating hormone (FSH)/luteinising hormone (LH), thyroid-stimulating hormone (TSH) and ACTH deficiencies. Fungal infections of the pituitary are also very rare and include aspergillosis and coccidioidomycosis. Concerning pituitary involvement in systemic diseases, in sarcoidosis endocrine complications are rare, but the hypothalamus and pituitary are the glands most commonly affected. DI is reported in approximately 25-33 % of all neurosarcoidosis cases and is the most frequently observed endocrine disorder. Hyperprolactinaemia and anterior pituitary deficiencies may also occur. Rarely, partial or global anterior pituitary dysfunction may be present also in Wegener's granulomatosis, either at onset or in the course of the disease, resulting in deficiency of one or more of the pituitary axes. Other forms of granulomatous pituitary lesions include idiopathic giant cell granulomatous hypophysitis, Takayasu's disease, Cogan's syndrome and Crohn's disease. The hypotalamic-pituitary system is involved mainly in children with Langerhans' cells histiocytosis who develop DI, which is the most common endocrine manifestation. Anterior pituitary dysfunction is found more rarely and is almost invariably associated with DI. Pituitary involvement may also be observed in another form of systemic hystiocitosis, that is, Erdheim-Chester disease. Tuberculosis is a rare cause of hypophysitis, which may present with features of anterior pituitary dysfunction, such as hypopituitarism with hyperprolactinaemia. In conclusion, in patients with a sellar mass and unusual clinical presentation (DI, neurological symptoms), aggressiveness and onset and in the presence of systemic diseases, inflammatory and granulomatous pituitary lesions should be carefully considered in differential diagnosis.