Decrease In Inhibin Research Articles

Inflammation and Ovarian Function in Reproductive-Aged Women.

Inflammation is a marker of immune activation. Inflammation may have an effect on both ovarian function and luteal function, both essential to pregnancy. High inflammation may also signal dysregulated processes within the ovary, which could be in part measured through Anti-Müllerian hormone, follicle-stimulating hormone, and inhibin B levels. To determine the relationship between inflammation, measured by C-reactive protein, and three biomarkers of ovarian function during the early follicular phase: Anti-Müllerian hormone, follicle-stimulating hormone, and inhibin B. Secondary cross-sectional analysis of data and serum obtained in Time to Conceive, a prospective cohort study sample of 843 women attempting pregnancy in central North Carolina from 2008 to 2016. Participants were aged 30 and 44 years, had no history of infertility, endometriosis, or polycystic ovarian syndrome, and were not currently breastfeeding. Serum samples were obtained on days 2, 3, or 4 of the menstrual cycle. C-reactive protein (natural-log transformed), Anti-Müllerian hormone (natural-log transformed), follicle-stimulating hormone (natural-log transformed), and inhibin B (untransformed) were measured in serum. Diminished ovarian reserve was examined dichotomously and defined as an Anti-Müllerian hormone level below 0.7 ng/mL. The analysis included 703 participants with C-reactive protein measured. In an adjusted linear regression model, a 20% increase in C-reactive protein was associated with a 0.57 pg/mL decrease in inhibin B (95% CI: -0.84 to -0.29 pg/mL) and a 0.535% decrease in follicle-stimulating hormone (95% CI: -1.01 to -0.06). Although there was not a significant relationship between Anti-Müllerian hormone and C-reactive protein, a 20% increase in C-reactive protein was associated with a 0.87% increase in Anti-Müllerian hormone (95% CI: -0.27 to 2.01). C-reactive protein was not associated with the odds of diminished ovarian reserve in an adjusted logistic regression model (OR: 0.97, 95% CI: 0.77-1.20). Inflammation, as measured by C-reactive protein, is associated with early follicular phase follicle-stimulating hormone and inhibin B, although this is not true of AMH. Inflammation may exert an effect on ovarian function.

The Effect of Marigold Leaf Ethanol Extract on Inhibin B Mice Exposed to Cigarette Smoke

Cigarette smoke can cause oxidative damage because the amount of free radicals (oxidants) generated is far greater than the endogenous antioxidant capacity of cells. Inhibin B is used as an indicator of reproductive function in men. The content of antioxidants present in marigold leaves (Tagetes erecta), can maintain reproductive function. This study aims to analyze differences in levels of inhibin B resulting from the administration of marigold leaf ethanol extract (EDM) to mice (Mus musculus) exposed to cigarette smoke. This investigation is a laboratory experimental study with a randomized posttest-only control group design. There were 40 mice divided into 5 groups (8 mice/group). K- was only given a placebo, K+ was given a placebo and exposed to cigarette smoke 1 cigarette per day, P1 was exposed to cigarette smoke 1 cigarette per day + EDM 0.25g/kg-BW, P2 was exposed to cigarette smoke 1 cigarette per day + EDM 0.5 g/kg-BW, P3 was exposed to cigarette smoke 1 cigarette per day + EDM 1.0 g/kg-BW. The results showed that there was a significant difference between groups in the inhibin B variable with a p-value of 0.000. The results of this study showed that there was a significant difference in inhibin B levels between the K+ group with P1, P2, and P3, and the K- group with P1, P2, and P3. The average levels of inhibin B K- 0.672 ng/L; K+ 0.615 ng/L; P1 0.340ng/L; P2 0.299 ng/L; P3 0.284ng/L. The findings of this research indicate that administering an ethanol extract derived from marigold leaves to mice subjected to cigarette smoke leads to a decrease in inhibin B levels in spermatogenesis.

Sexual dysfunction in female and male people with multiple sclerosis: disability, depression and hormonal status matter.

Sexual dysfunction (SD) in people with multiple sclerosis (pwMS) is common and an often underestimated issue in the care of pwMS. The objective of the study was to evaluate risk factors for SD in pwMS, correlate its prevalence with patient-reported measures (quality of life and physical activity) and analyse its association with hormonal status. Sexual dysfunction was determined in 152 pwMS using the Multiple Sclerosis Intimacy and Sexuality Questionnaire 19. A logistical regression model was used to identify independent risk factors for SD. The prevalence of SD in pwMS was 47%. Independent risk factors for the development of SD were ever-smoking (odds ratio [OR] 3.4, p=0.023), disability as measured by the Expanded Disability Status Scale (OR 2.0, p < 0.001), depression (OR 4.3, p=0.047) and bladder and bowel dysfunction (OR 8.8, p < 0.001); the use of disease-modifying treatment was associated with a lower risk for SD (OR 0.32, p=0.043). SD was associated with worse quality of life (Multiple Sclerosis Impact Scale 29: physical score 6.3 vs. 40.0; psychological score 8.3 vs. 33.3; both p < 0.001) and lower physical activity (Baecke questionnaire, p < 0.001). Laboratory analysis revealed significantly higher luteinizing hormone and follicle-stimulating hormone levels and lower 17-beta oestradiol, androstenedione, dehydroepiandrosterone sulfate, oestrone and anti-Mullerian hormone levels in female pwMS with SD. In male pwMS and SD, there was a significant decrease in inhibin B levels. Our findings highlight the requirement of a holistic approach to SD in MS including physical, neurourological and psychosocial factors. Active screening for SD, especially in patients with disability, depression or bladder and bowel dysfunction, is recommended.

Evalution of Inhibin B and some Sexual Hormones Levels in men with Atherosclerosis Kirkuk city

The study designed to evaluate the inhibin B and sexual hormones levels with atherosclerosis. One hundred volunteers resecived at private laboratory between 4/2017 to 7/2017in Kirkuk city (eighty volunteers with atherosclerosis and twenty apparently healthy subjects) were used. Then, volunteers divided to two groups. The first group was including apparently healthy and the second group was including patients (Wt:70-90 kg and age average 50-65 years). Laboratory diagnosis showed a decrease in inhibin B, Testosterone, Lutenizing hormone (LH) follicle stimulating hormone (FSH) in patient group. Moreover, all parameter levels showed significant (P&lt;0.05) decrease in all patients compare with all healthy subject group. It was concluded from this study that the atherosclerosis may led to decrease in an inhibin B and sexual hormones levels.

Protein palmitoylation-mediated palmitic acid sensing causes blood-testis barrier damage via inducing ER stress

Blood-testis barrier (BTB) damage promotes spermatogenesis dysfunction, which is a critical cause of male infertility. Dyslipidemia has been correlated with male infertility, but the major hazardous lipid and the underlying mechanism remains unclear. In this study, we firstly discovered an elevation of palmitic acid (PA) and a decrease of inhibin B in patients with severe dyszoospermia, which leaded us to explore the effects of PA on Sertoli cells. We observed a damage of BTB by PA. PA penetration to endoplasmic reticulum (ER) and its damage to ER structures were exhibited by microimaging and dynamic observation, and consequent ER stress was proved to mediate PA-induced Sertoli cell barrier disruption. Remarkably, we demonstrated a critical role of aberrant protein palmitoylation in PA-induced Sertoli cell barrier dysfunction. An ER protein, Calnexin, was screened out and was demonstrated to participate in this process, and suppression of its palmitoylation showed an ameliorating effect. We also found that ω-3 poly-unsaturated fatty acids down-regulated Calnexin palmitoylation, and alleviated BTB dysfunction. Our results indicate that dysregulated palmitoylation induced by PA plays a pivotal role in BTB disruption and subsequent spermatogenesis dysfunction, suggesting that protein palmitoylation might be therapeutically targetable in male infertility.

Features of reproductive function in infertile women with hyperthyroidism

Objective. The aim was to study the characteristics of reproductive function in women of fertile age with infertility and hyperfunction of the thyroid gland.&#x0D; Materials and methods. The object of the study was 148 women of fertile age. To compare the indicators obtained by special methods, the control group included the indicators of laboratory and instrumental examination of 30 non-pregnant women of reproductive age. Reproductive function was evaluated in 118 women with hyperthyroidism: 58 retrospectively (group I) and 60 prospectively (group II); the control group consisted of 30 healthy women of reproductive age. Hormonal studies were performed by radioimmune and enzyme immunoassay methods using the automatic analyzer "Cobb" ("Hoffmann La Roche", Switzerland), as well as DPS test systems the analyzer Immulite (USA). Ultrasound of the thyroid gland was performed by a linear sensor with a frequency of 7.5 MHz. The volume of the thyroid gland was calculated according to the Bruno formula.&#x0D; Results. For women of fertile age with hyperthyroidism, a decrease in ovarian reserve is characteristic that is manifested by a significant increase in FSH level (14.1 3.1 IU / L, p 0.05), and a decrease in inhibin B level (35.9 12,7 pg / ml, p 0.05). In 47.7 % of women of fertile age with hyperthyroidism, there is a decrease in ovarian volume and a significant reduction in the average number of antral follicles of normal size (4.34 1.56, p 0.05).&#x0D; Conclusions. Based on the results obtained, it can be assumed that in diffuse toxic goiter there are not only functional disorders (metabolism of hormones of the reproductive system), but also deep organic changes in the structure of the ovaries that leads to a rapid suppression of their functions. In cases of thyroid diseases, the clinical manifestation of these changes is premature and early menopause.

Interactions between serum FSH, inhibin B and antral follicle count in the decline of serum AMH during the menstrual cycle in late reproductive age.

ObjectiveTo investigate the hormonal interrelationships during the menstrual cycle in women of late reproductive age with suppressed serum AMH and antral follicle count (AFC).MethodsSerum hormones (AMH, FSH, LH, estradiol, progesterone, inhibin A, inhibin B), AFC (2‐10 mm) and AMH/AFC ratio (an estimate of AMH/follicle) were assessed every 2‐3 days across the menstrual cycle in 26 healthy ovulatory women aged 18‐50 years.ResultsAn 11‐fold fall in AMH/AFC was observed in women aged ≥45 years compared to those 18‐45 years (P < .001). Although women ≥45 years exhibited normal menstrual cycle patterns of serum estradiol, progesterone, LH and inhibin A, FSH was elevated (P < .001) and inhibin B suppressed (P < .001) compared to the younger group. Overall FSH was inversely correlated (r = .55, P < .05) and AMH directly correlated (r = .88, P < .01) with AFC; however, these relationships were curvilinear and more pronounced when AFC was low. Inhibin B was directly linearly correlated (r = .70, P < .01) with AFC across both high and low AMH/follicle groups.ConclusionsIt is hypothesized that the marked fall in AMH/follicle in late reproductive age is attributed to the change in the hormonal interplay between the pituitary and ovary. The fall in AFC leads to a decrease in inhibin B and a concomitant increase in FSH by a recognized feedback mechanism. It is postulated the elevated FSH suppresses AMH either directly or indirectly through oocyte‐specific growth factors leading to a marked fall in AMH/follicle. We propose that pituitary‐ovarian and intra‐ovarian regulatory systems underpin the accelerated fall in AMH/follicle during the transition to menopause.

Ethanolic extract of Moringa oleifera leaves alleviate cyclophosphamide-induced testicular toxicity by improving endocrine function and modulating cell specific gene expression in mouse testis

Ethnopharmacological relevanceMoringa oleifera Lam. is known for its nutritional and ethno medicinal values due to the presence of wide array of phytochemicals with multiple biological activities. We have previously reported that ethanolic extract of Moringa oleifera leaves (MOE) ameliorated cyclophosphamide (CP)-induced testicular toxicity and improved functional integrity of spermatozoa as well as spermatogenic cells. Aim of the studyThe present study was planned to investigate whether the mitigation of CP-induced testicular toxicity by MOE is mediated via modulation of endocrine profile, genes associated with function of different cell types and enhancement of DNA repair response in spermatogonial cells. Materials and methodsAdult Swiss albino mice (8 week) were injected with CP (100 mg/kg, one dose in a week for 3 weeks) and MOE (100 mg/kg, 5 doses in a week for 4 weeks) either alone or in combination intraperitoneally. At 35 day post CP injection (first dose), the functional characteristics such as count, motility, head morphology and DNA integrity were assessed in epididymal spermatozoa. Key reproductive hormones like testosterone, follicle stimulating hormone (FSH) and Inhibin B concentration were analyzed in serum and testis. In addition, mRNA expression of genes pertaining to the function of Leydig, Sertoli and spermatogonial cells as well as antioxidant enzymes were evaluated in the testis. To understand the DNA damage and repair process in germ cells, prepubertal (2 week) mice were administered with single dose of CP (200 mg/kg) and/or MOE (100 mg/kg) and analyzed for expression of DNA damage (γ-H2AX, P53 and Caspase3) and repair genes (Rad51 and Ku80) in isolated spermatogonial cells at various time points after treatment. ResultsCP administration resulted in decrease in count, motility and increase in morphological defects and DNA damage in spermatozoa. Testosterone level was marginally decreased while there was a significant increase in FSH (p < 0.001) and decrease in inhibin B (p < 0.05) observed in CP treated mice. Administration of MOE prior to CP, improved sperm functional characteristics, decreased FSH and increased inhibin B levels. Expression of Abp was down-regulated while Transferrin, Fshr and Gata4 (Sertoli cell specific genes) were up-regulated in testis treated with CP. Administration of CP down-regulated the expression of Oct4 and Ddx4 (Spermatogonia specific genes). MOE administration was shown to ameliorate CP-induced damage by modulating the expression of genes specific to Sertoli and spermatogenic cells. Furthermore, MOE treatment reduced CP-induced DNA damage as evident from lower percentage of γ-H2AX positive spermatogonial cells. ConclusionAdministration of MOE mitigated CP-induced testicular damage by improving blood and, intra-testicular hormonal milieu as well as modulating the expression of genes pertaining to Sertoli and spermatogonial cells.

Vaginal pH as a diagnostic tool for menopause: A preliminary analysis

Introduction:Menopause is defined as the permanent cessation of menstruation, as a result of decrease in ovarian follicles and the loss of ovarian activity. There is decrease in inhibin B level which causes decrease in negative feedback on the serum follicle-stimulating hormone (FSH), which in turn increases the level of serum FSH. Serum FSH is routinely used as a marker of menopause. Decline in the estrogen level causes thinning of vaginal epithelium, resulting in less exfoliation of the vaginal epithelial cells, lesser available glycogen, and decreased substrate for acid production, leading to increase in vaginal pH.Aims:The aim of this study is to compare the sensitivity of vaginal pH versus serum FSH level to diagnose menopause.Settings and Design:This is a cross-sectional study, performed in obstetrics and gynecology outpatient department of a teaching hospital of central Gujarat.Subjects and Methods:A total of 120 women who had their last menstrual period >1 year back (menopause) were included in the study. Vaginal pH was measured and serum sample was taken to measure FSH level. Sensitivity of both vaginal pH and serum FSH to diagnose menopause was compared. McNemar test was used to analyze the convergence of the two methods for the diagnosis of menopause.Results:In the absence of vaginal infection, sensitivity of vaginal pH to diagnose menopause was 90%, while sensitivity of the serum FSH was 85%.Conclusions:Sensitivity of the vaginal pH is similar to the serum FSH for diagnosis of menopause.

Inhibin B level changes during the follicular phase in rats with unilateral ovarian torsion

Objective: To investigate the association between duration of ovarian torsion and levels of serum inhibin B in an animal model. Materials and Methods: An animal model prospective study was conducted in a tertiary referral hospital and chemical pathology institute. Nineteen female Lewis rats were divided to four groups. In the first group, the control group, laparotomies alone were performed. In groups 2-4 laparotomies and right ovarian torsion for 720 degrees with fixation of the adnexa to the parietal peritoneum were performed. Blood samples were taken from the rat groups at 12, 24, and 36 hours after laparotomy. Inhibin B levels were measured by ELISA. Results: Serum mean ± SD inhibin B level in the control rats during the beginning of the metesterus, 12, 24, and 36 hours later were 108.4 ± 43.6, 129.5 ± 49.3, 99.07 ± 60.50, and 91.58 ± 27.74 pg/ml, respectively. Inhibin B levels in the control group increased 12 hours after the beginning of the metesterus, whereas in the study group, a decline in inhibin B levels was found at the same time. This difference was significant (p = 0.05). Inhibin B levels at 24 and 36 hours from the beginning of the metestrus did not show statistical difference. Conclusions: Unilateral ovarian torsion in rats changed the pattern of inhibin B secretion at the beginning of the metesterus and was associated with a significant decrease in inhibin B serum levels. This observation, following acute ovarian vascular occlusion, is probably due the effects of ischemia on hormonal regulation during the early follicular phase.

Changes in Anti-Müllerian Hormone and Inhibin B in Children Treated for Cancer.

Purpose: Diminished reproductive function can be a major late effect of childhood cancer treatment. This study evaluates the changes, and occurrence of possible recovery, in gonadal function markers in children treated for cancer. Methods: Gonadal function markers were measured before (T0), directly after (T1), and 1 year after (T2) end of treatment of childhood cancer. Anti-Müllerian hormone (AMH) was measured in girls and inhibin B in boys and compared to reference populations. Repeated measures analysis of variance and t-tests were employed for data analysis. Results: Baseline gonadal function markers (T0) at diagnosis were available in 129 girls and 150 boys. Paired gonadal function markers were available in 49 girls and 54 boys for T0-T1, and in 27 girls and 32 boys for T1-T2. Gonadal function markers were significantly lower than the reference population at each time point (p < 0.001). Post-menarcheal girls showed a decrease in AMH between T0 and T1 (standard deviation scores [SDS] -0.72 to -1.32, p = 0.007), and in the boys cohort, a decrease in inhibin B (SDS -1.14 to -1.43, p = 0.045) was observed. Impaired gonadal function levels (<5th percentile) at T1 were observed in 15 of 27 (56%) girls and in 15 of 32 (47%) boys. However, gonadal function had recovered at T2 in seven girls and six boys. Conclusion: Our data suggest that gonadal function is already compromised at diagnosis and is further decreased by childhood cancer treatment. Nevertheless, about half of the children with gonadal impairment recovered over time. Evaluation of gonadal function markers before 1 year after end of treatment may therefore be unreliable.

Impact on testicular function of a single ablative activity of 3.7 GBq radioactive iodine for differentiated thyroid carcinoma

What are the consequences of radioactive iodine (RAI) therapy for testicular function? A single activity of 3.7 GBq RAI for differentiated thyroid carcinoma (DTC) treatment in young men transiently altered Sertoli cell function and induced sperm chromosomal abnormalities. Few studies, mainly retrospective, have reported the potential impacts of RAI on endocrine and exocrine testicular function. A longitudinal prospective multi-center study on testicular function performed in DTC patients before a single 131I ablative activity of 3.7 GBq (V0) and at 3 months (V3) and 13 months (V13) after treatment. Forty male patients, aged 18-55 years, with DTC participated. Hormonal analysis included FSH, LH, testosterone and inhibin B serum levels at V0, V3 and V13. Furthermore, sperm parameters, DNA fragmentation and sperm chromosomal abnormalities were evaluated at each time points. The differences in all parameters, between V0-V3, V0-V13 and V3-V13, were analyzed, using a Wilcoxon test. Prior to RAI administration, all patients had normal gonadal function. At V3, a statistically significant increase in FSH levels and a decrease in inhibin B levels were observed and sperm concentration, as well as the percentage of morphologically normal spermatozoa, were significantly decreased (P < 0.0001). These modifications were transient as both sperm concentration and normal morphology rate returned to baseline values at V13. However, at this later time point, FSH and inhibin B levels were still impacted by RAI administration but remained in the normal range. Although no DNA fragmentation was observed at V3 nor V13, our study revealed a statistically significant increase in the number of sperm chromosomal abnormalities both at V3 (P < 0.001) and V13 (P = 0.01). Among the 40 patients included in the study, only 24 had all the parameters available at all visits. Prospective studies with longer term follow up would be helpful to determine whether the chromosome abnormalities persist. These studies would be required before sperm banking should be suggested for all patients. However, sperm preservation for DTC patients who require cumulative radioiodine activities higher than 3.7 GBq should be proposed. This study was supported by the Programme Hospitalier de Recherche Clinique, AP-HP (No. P040419). The authors report no conflict of interest in this work. NCT01150318.

Inhibin B Response to Testicular Toxicants Hexachlorophene, Ethane Dimethane Sulfonate, Di‐(n‐butyl)‐phthalate, Nitrofurazone, DL‐Ethionine, 17‐alpha Ethinylestradiol, 2,5‐Hexanedione, or Carbendazim Following Short‐Term Dosing in Male Rats

Inhibin B is a heterodimer glycoprotein that downregulates follicle-stimulating hormone and is produced predominantly by Sertoli cells. The potential correlation between changes in plasma Inhibin B and Sertoli cell toxicity was evaluated in male rats administered testicular toxicants in eight studies. Inhibin B fluctuations over 24 hr were also measured. Adult rats were administered one of eight testicular toxicants for 1 to 29 days. The toxicants were DL-ethionine, dibutyl phthalate, nitrofurazone, 2,5-hexanedione, 17-alpha ethinylestradiol, ethane dimethane sulfonate, hexachlorophene, and carbendazim. In a separate study plasma was collected throughout a 24-hr period via an automatic blood sampler. Histomorphologic testicular findings included seminiferous tubule degeneration, round and elongate spermatid degeneration/necrosis, seminiferous tubule vacuolation, aspermatogenesis, and interstitial cell degeneration. There was a varying response of plasma Inhibin B levels to seminiferous tubule toxicity, with three studies showing high correlation, three studies with a response only at a certain time or dose, and two studies with no Inhibin B changes. In a receiver operating characteristics exclusion model analysis, where treated samples without histopathology were excluded, Inhibin B showed a sensitivity of 70% at 90% specificity in studies targeting seminiferous tubule toxicity. Decreases in Inhibin B correlated with Sertoli cell toxicity in the majority of studies evaluated, demonstrating the value of Inhibin B as a potential biomarker of testicular toxicity. There was no correlation between decreases in Inhibin B and interstitial cell degeneration. In addition, a pattern of Inhibin B secretion could not be identified over 24 hr.

Analytic Evaluation of a Human ELISA Kit for Measurement of Inhibin B in Rat Samples

A cross-laboratory analytic evaluation of a commercially available human inhibin B ELISA for measuring inhibin B in rat serum and plasma has been undertaken. Dilution linearity, spiked recovery, intra- and inter-assay precision, functional sensitivity, matrix effects, and frozen stability were assessed across five laboratories. Reference ranges were generated for male Sprague Dawley and Han Wistar rats. Acceptable performance was defined as an overall assay coefficient of variation ≤ 20% with an intraday LLOQ ≤ 20 pg/ml. Intra- and inter-assay precision and functional sensitivity (≤6.4 pg/ml) generally met these criteria, but with occasional evidence of greater variability, particularly at lower concentrations. Dilution linearity was acceptable with occasional low recovery. Acceptable recovery of kit calibrators from rat serum confirmed the absence of matrix effects. Matched serum and plasma samples gave comparable results. The signal increased on freezing, remained constant for ≥3 freeze-thaw cycles and was generally stable for at least 8 weeks. Mean inhibin B ranged from 33.5 to 140.6 pg/ml in adult rats across laboratories, with some evidence for a decline from 6 to 9 weeks of age. Power calculations using preliminary reference range data indicated 10 animals/group would generally detect a 40% decrease in inhibin B at AstraZeneca, but laboratories with lower control values would require larger groups. The assay meets the analytical performance criteria; however, precision at the low end of the standard curve, biological variability, and low control values observed in some laboratories indicate that the utility of the assay may be limited in some laboratories.

Evaluation of hormonal suppression with two contraceptive regimens using ethinyl estradiol and desogestrel

Because of the lack of data on hormone levels in the hormone-free interval of the contraceptive regimens with desogestrel and ethynil estradiol, the objective of this study was to compare hormonal levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and inhibin B using two contraceptive regimens with those steroids. Prospective and randomized study with 21 patients. Eleven patients received a 21/7 regimen (group 1) and ten patients received a 21/2 placebo/5 ethinyl estradiol 10 μg regimen (group 2). We found a significant increase in FSH and LH levels in both groups. There was a significant reduction of inhibin B in the 21/2/5 regimen. No difference in estradiol levels was found. Steroids withdrawal in the hormone-free interval causes reduced inhibition of the HPO axis. The significant decrease in inhibin B levels of group 2 suggests better suppression of the HPO axis in the 21/2/5 regimen.

What Is the Missing Hormonal Factor Controlling Menopausal Bone Resorption?

Estrogen is critical for maintaining normal bone remodeling in women and also in men (1). Postmenopausal osteoporosis is characterized by an imbalance between increasedosteoclastactivityanddecreasedosteoblast function, resulting in increased bone remodeling, bone microarchitecturaldeterioration, andskeletal fragility.Estrogendeficiency may be responsible for both the accelerated phase of bone loss at the menopause and the slower phase of age-related bone loss later in life. Recently, this dogma has been challenged by the assertion that the concomitant increase in serum FSH levels at the time of the menopause may be the principal cause of the increase in bone resorption and accelerated bone loss occurring during the menopause transition. The identification of women with rapid perimenopausal bone loss is important to target aggressive early intervention. The diagnosis of osteoporosis based on T-scores alone or through stratification for a high fracture risk by the WHO FractureRiskAssessmentTool (FRAX)orother fracturerisk calculator tools will exclude these women who are rapidly losing bone. Because all antiosteoporosis therapies, in particular the bisphosphonates, reduce bone loss, some experts propose aggressive, short-term therapy with a goal to reduce bone loss, stabilize bone density, and prevent microarchitectural deterioration for these women with rapid perimenopausal bone loss (2). The finding that perimenopausal bone loss begins when serum estradiol concentrations are still in the normal range launched the search for a missing hormonal factor controlling menopausal bone resorption. Several potential endocrine contributors to this perimenopausal bone loss have been proposed over the years. They include alterations to the luteal phase of ovarian function resulting in low progesterone levels (3), reductions in circulating androgen levels (4), and decreases in serum inhibin (A and B) concentrations (5). Inhibin, which is present in ovarian follicular fluid (6), was originally identified because of its ability to suppress pituitary FSH secretion. Two isoforms have subsequently been identified, inhibin B and inhibin A. Inhibin B and inhibin A are heterodimeric proteins in the TGF superfamily comprising B and A subunits, respectively, and decreases in both have been associated with increases in bone turnover markers (5). However, currently more data have been gathered in favor of FSH having a likely role as a mediator of perimenopausal bone turnover. We previously demonstrated a stronger association between FSH levels and bone resorption markers in late premenopausal women than for serum estradiol, the latter of which remained within the normal range (7). Using an older RIA that did not differentiate between inhibin isoforms, we could not detect differences in serum inhibin levels in the same late premenopausal women, but we did demonstrate decreases in inhibin in both postmenopausal women and women on hormone therapy. Subsequently, other investigators have shown that a selective decrease in ovarian secretion of the inhibin B isoform is associated with this early rise in FSH in the late premenopause (8). Similar to our study, longitudinal data from the U.S. Study of Women’s Health Across the Nation (SWAN) showed that bone loss from the spine and hip was related both to the initial FSH concentrations and to changes in FSH levels, but to neither estradiol nor androgens (9). This could, however, be explained by FSH acting as a better integrated measure of ovarian estradiol production than a single measurement of serum estradiol, rather than being due to a direct effect of FSH on bone remodeling.

Mechanisms of FSH synthesis: what we know, what we don't, and why you should care

The pituitary gonadotropin hormones, FSH and LH, are key regulators of reproductive physiology. Though the two hormones are produced by the same cell type, often in response to the same endocrine and paracrine regulators, they sub-serve different biological functions and their synthesis and secretion are differentially regulated. This stems largely from differences in transcriptional, post-transcriptional, and post-translational regulation of their unique beta subunits. That is, both hormones are dimeric glycoproteins and share a common alpha subunit. Their unique beta subunits, however, derive from different genes encoding distinct proteins. Past and recent research indicates synthesis and release of the two hormones are subject to extensive and independent regulation. LH appears to be secreted predominantly via the regulated secretory pathway, whereas FSH release is largely constitutive. As such, investigations of FSH-beta subunit synthesis may lend direct insight into mechanisms underlying patterns of secreted FSH, more so than investigations of the LHbeta subunit. Here, we review recent investigations of transcriptional regulation of the FSH-beta subunit gene from different mammalian species, including humans. The results reveal both conserved and species-specific regulatory mechanisms that might contribute to inter-species variation in FSH release.

The CXCR4 antagonist AMD3100 suppresses hypoxia-mediated growth hormone production in GH3 rat pituitary adenoma cells

Pituitary adenomas produce the chemokine stromal cell-derived factor (SDF-1α/CXCL12) and its receptor, CXCR4. A recent study indicated that CXCL12 and CXCR4 are concomitantly up-regulated in hypoxia. The objective of this study was to analyze the molecular mechanism of hypoxia-mediated CXCR4 up-regulation and assess the effect of pharmacological inhibition of CXCR4 by the receptor blocker, AMD3100, on pituitary function. CXCR4 expression in pituitary adenoma tissues was determined by a tissue microarray analysis of 62 pituitary adenoma samples. CXCR4 expression was significantly elevated and positively correlated with Knosp grade in pituitary adenomas (P < 0.005), and was higher in macroadenoma and growth hormone (GH)-producing adenomas. Pre-operative serum GH levels were significantly correlated with CXCR4 levels in the microarray (P < 0.0001). The relative expression of genes/gene categories that were modulated by up-regulated CXCL12/CXCR4 signaling was determined by a comparative transcriptome analysis of wild-type and CXCR4-knockdown cells in normoxia and hypoxia using the rat GH-producing and prolactin-producing pituitary adenoma cell line, GH3. Real-time reverse transcriptase-polymerase chain reaction analysis (RT-PCR) showed that CXCR4 mRNA expression in GH3 cells was increased by hypoxia (1% oxygen), and a cDNA microarray analysis revealed that inhibin β-C expression was diminished. siRNA-mediated CXCR4 knockdown blocked the hypoxia-induced decrease in inhibin β-C mRNA expression, as did inhibition of CXCR4 activity with AMD3100. An ELISA study demonstrated that GH secretion by wild-type GH3 cells was moderately enhanced by hypoxia and further potentiated by exposure to recombinant SDF-1α/CXCL12 protein. Conversely, hypoxia-induced GH secretion was reduced in CXCR4-silenced cells and in cells treated with the CXCR4 antagonist, AMD3100, notwithstanding the presence of SDF-1α/CXCL12 protein. These latter observations reflect the failure of hypoxia to suppress expression of inhibin β-C in cells deficient in CXCR4 or in which CXCR4 signaling was blocked. Together, these results indicate that the SDF-1α/CXCL12-CXCR4 signaling pathway interfaces with the classical endocrine pathway to up-regulate GH production via suppression of inhibin β-C. Because it blocks CXCR4 and prevents hypoxia-induced down-regulation of inhibin β-C expression, AMD3100 has promise as a molecular-targeting agent in the treatment of GH-producing adenomas.

Gonadal dysfunction in male cancer patients before cytotoxic treatment

Male patients diagnosed with cancer are often referred for semen cryopreservation before gonadotoxic treatment but often have low semen quality. The aim of this study was to evaluate which type of cancer affects gonadal function and proposes a risk factor for low pre-treatment semen quality. Between January 1983 and August 2006, 764 male cancer patients were referred for semen cryopreservation prior to chemotherapy and radiotherapy. We compared semen characteristics and reproductive hormones between different groups of cancer patients. In addition, we evaluated the role of tumour markers in patients with testicular germ-cell tumours (TGCT) on fertility. Abnormal semen parameters were found in 489 men (64%) before cancer treatment. Patients with TGCT and extragonadal germ-cell tumours had significantly lower sperm concentrations and inhibin B levels than all other patient groups. No semen could be banked in 93 patients (12.2%). Eight hundred and thirty-nine of 927 (90%) produced semen samples were adequate for cryopreservation. Inhibin B in all groups showed to be the best predictor of semen quality. Although pre-treatment raised tumour markers were associated with a decrease in inhibin B and increased follicle stimulating hormone, both predictive for low semen quality; no direct linear association could be found between raised beta-HCG, alfa-fetoprotein and semen quality. Only 1/3 of cancer patients had normal semen parameters prior to cancer treatment. Patients with TGCT and extragonadal GCT have the highest risk for impaired semen quality and gonadal dysfunction at the time of semen cryopreservation.

Factors that influence entry into stages of the menopausal transition.

The aim of this study was to estimate the probabilities and identify risk factors for entering the menopausal transition and moving into each subsequent transition stage. Estimations of probabilities of entry into each menopausal transition stage and predictors associated with each transition stage were conducted in a population-based cohort of midlife women. The likelihood of entering the menopausal transition and moving into each subsequent stage was increased for each unit increase in follicle-stimulating hormone (FSH) (P < 0.001) and with each unit decrease in inhibin B (P < 0.001) in the adjusted multivariable model. The largest observed change in average FSH levels was the comparison of women in the late transition (stage 4), with an average of 24.78 mIU/mL, to those in the early transition (stage 3), with 10.38 mIU/mL. Women experiencing this amount of change in FSH had an odds of transitioning from stages 3 to 4 of 1.90 (95% CI, 1.86-1.95). Decreases in inhibin B resulted in odds ratios similar to the magnitude of changes in FSH. Current smoking increased the odds of transition into each stage by approximately 30% (odds ratio, 1.30; 95% CI, 1.28-1.32). Average estradiol levels did not change dramatically between stages. However, higher estradiol significantly increased the odds of entering the transition (P = 0.013). Age and race predicted transitions into some but not all stages. Body mass index, alcohol use, and age at menarche did not predict entrance into any stage of the menopausal transition after adjusting for other study variables. These results show that increased FSH, decreased inhibin B, and smoking strongly predict entry into the earliest stages of the menopausal transition as defined by changes in bleeding patterns. African Americans entered the transition before white women, but race did not predict entry into late transition stages. Higher estradiol levels predict entry into the earliest transition stage but not subsequent stages.