To test the hypothesis that dimeric inhibin A and/or inhibin B concentrations represent improved markers of in-vitro fertilization (IVF) outcome over follicle stimulating hormone (FSH), 78 women who ...achieved pregnancy within three assisted reproduction treatment cycles were matched to 78 women who underwent at least three assisted reproductive treatment cycles and failed to achieve pregnancy. Baseline serum inhibin B and FSH were obtained between days 1 and 4 in a cycle prior to ovarian stimulation, and inhibin A and B were measured immediately before the ovulatory stimulus and in follicular fluid from the lead follicle. Comparing pregnant and non-pregnant subjects at baseline, younger age (34.0 ± 0.5 versus 36.0 ± 0.5 years; P < 0.003) and a combination of FSH lower than the median value (11.2 IU/l) and inhibin B higher than the median value (76.5 pg/ml) were associated with pregnancy (P < 0.03), but FSH (11.7 ± 0.5 versus 12.9 ± 0.9 IU/ml) and inhibin B (89.0 ± 10.2 versus 79.7 ± 7.7 pg/ml) were not independently associated. At the time of the ovulatory stimulus, serum inhibin A (52.8 ± 3.8 versus 40.0 ± 2.7 IU/ml; P < 0.004), inhibin B (1623.8 ± 165.1 versus 859.2 ± 94.8 pg/ml; P < 0.0009) and the number of oocytes retrieved (14.6 ± 0.8 versus 10.1 ± 0.6; P < 0.0001) were predictive of pregnancy when controlled for age. Inhibin A was correlated with the number of embryos (r = 0.4; P < 0.0001). However, neither inhibin A nor inhibin B provided additional information in predicting successful outcome over age and number of oocytes. We conclude that: (i) in patients undergoing assisted reproductive technology, age and number of oocytes retrieved are the strongest predictors of success; (ii) of the parameters available prior to cycle initiation, a combination of lower FSH and higher inhibin B was associated with a greater chance for a successful outcome but an absolute cut-off could not be defined; and (iii) during ovarian stimulation, higher concentrations of inhibin A and inhibin B in serum are associated with successful IVF and mark ovarian reserve as a measure of oocyte number and quality.
To test the hypothesis that estradiol, inhibin A, and inhibin B contribute differentially to FSH negative feedback in specific phases of the menstrual cycle, daily blood samples were obtained across ...a control cycle and after selective estrogen blockade with tamoxifen. To examine the site of estradiol-negative feedback in control and tamoxifen treatment cycles, early follicular phase GnRH (free α-subunit) pulse frequency was assessed in normal women, and FSH levels were examined in GnRH-deficient women in whom hypothalamic output was fixed with GnRH administration. FSH was higher in the early follicular phase in the presence of estrogen receptor blockade (15.7 ± 3.1 vs. 13.2 ± 1.9 IU/liter; P < 0.05) but was not increased in the late follicular phase. In the luteal phase, FSH was elevated (10.1 ± 0.7 vs. 7.3 ± 0.6 IU/liter; P < 0.01). In normal women, free α-subunit pulse frequency increased (7.3 ± 0.4 vs. 4.8 ± 0.4 pulses per 8 h; P < 0.003), but in GnRH-deficient women, there was no FSH increase (11.1 ± 1.6 vs. 12.5 ± 3.6 IU/liter) in the early follicular phase in the presence of estrogen blockade. In conclusion, estradiol exerts a greater role over inhibin in FSH-negative feedback regulation during the luteal phase and the luteal-follicular transition. In contrast, inhibin A and/or B plays a more critical role as the follicular phase progresses. In addition, these studies support a primary if not exclusive hypothalamic site of estrogen-negative feedback in the early follicular phase.
The development of assays specific for dimeric inhibin A and inhibin B defined the distinct physiology of these two hormones in the normal menstrual cycle. Inhibin A and inhibin B expression and ...secretion along with their differential regulation by gonadotropins explain their unique serum patterns and their potential endocrine and ovarian autocrine-paracrine functions. There is evidence that inhibin A and inhibin B play an endocrine role in the negative regulation of follicle-stimulating hormone (FSH) in nonhuman primates and humans. However, some studies suggest that estradiol is a more important, if not the only, negative feedback regulator of FSH in women. There is also evidence from animal models that inhibins and activins play a critical role in follicle development. Future work will be necessary to define further the relative role of the inhibins, estradiol, and other autocrine-paracrine factors in these important reproductive functions.
Context: Previous studies suggest that inhibin subunit expression is decreased in granulosa cells of women with polycystic ovary syndrome (PCOS).
Objective: The objective of this study was to test ...the hypothesis that inhibin A and inhibin B protein concentrations are also decreased in PCOS follicles.
Design: The design was a parallel study.
Setting: The study was performed at an in vitro fertilization suite.
Participants: We studied women with regular cycles (n = 36) and women with PCOS (n = 8).
Interventions: Follicular fluid was aspirated from the follicles of women with PCOS (n = 14 follicles) and from women with regular cycles at various times during the follicular phase (n = 50 follicles).
Main Outcome Measure: Inhibin A and B concentrations from PCOS follicles were compared with those in size-matched follicles, dominant follicles (≥10 mm), and subordinate follicles from regularly cycling women.
Results: Inhibin A (220 ± 38 vs. 400 ± 72 IU/ml; P < 0.05) and inhibin B (75.4 ± 10.4 vs. 139 ± 26 ng/ml; P < 0.05) concentrations were lower in the follicular fluid of PCOS follicles compared with those of size-matched follicles from regularly cycling women. Inhibin A was also lower in the follicular fluid of PCOS compared with subordinate follicles from normal women (577 ± 166 IU/ml; P < 0.05). Inhibin A concentrations increased with increasing follicle size, resulting in significantly higher follicular fluid concentrations in dominant follicles from normal women compared with PCOS follicles (2298 ± 228 IU/ml; P < 0.05).
Conclusions: These data demonstrate that inhibin A and inhibin B concentrations are significantly reduced in the follicular fluid of women with PCOS compared with those in the follicular fluid of size-matched follicles from normal women, consistent with the decreased inhibin subunit mRNA expression in previous studies. These findings point to the potential importance of inhibins in normal follicle development and suggest that inhibin deficiency may play a role in the follicle arrest associated with PCOS.
Previous studies examining reproductive parameters in men with galactosemia have inconsistently demonstrated abnormalities. We hypothesized that men with galactosemia may demonstrate evidence of ...reproductive dysfunction. Pubertal history, physical examination, hormone levels and semen analyses were examined in 26 males with galactosemia and compared to those in 46 controls. The prevalence of cryptorchidism was higher in men with galactosemia than in the general population 11.6 % vs. 1.0 % (95%CI: 0.75–1.26; p < 0.001). Testosterone (461 ± 125 vs. 532 ± 133 ng%; p = 0.04), inhibin B (144 ± 66 vs. 183 ± 52 pg/mL; p = 0.002) and sperm concentration (46 ± 36 vs. 112 ± 75 × 10
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spermatozoa/mL; p = 0.01) were lower and SHBG was higher (40.7 ± 21.5 vs 26.7 ± 14.6; p = 0.002) in men with galactosemia compared to controls. Semen volume was below normal in seven out of 12 men with galactosemia. Men with galactosemia have a higher than expected prevalence of cryptorchidism and low semen volumes. The subtle decrease in testosterone and inhibin B levels and sperm count may indicate mild defects in Sertoli and Leydig cell function, but does not point towards severe infertility causing reproductive impairment. Follow-up studies are needed to further determine the clinical consequences of these abnormalities.
Recent studies have demonstrated the presence of ovarian follicular development in up to 78% of women with premature ovarian failure (POF). The purpose of this study was to examine the control of FSH ...by estradiol and inhibin secretion from these follicles. Weekly blood samples were collected in conjunction with assessment of ovarian follicle development by ultrasound for at least 12 wk in 49 subjects with POF. Results were compared with those of 44 normal cycling women. Ovulatory cycles occurred in 24 subjects (49%) with POF. These ovulatory cycles were characterized by higher FSH and lower inhibin B and inhibin A levels, whereas estradiol levels were higher compared with those in normal women. Follicles developed in the absence of ovulation in 18 women (37%) with POF, whereas the ovaries were inactive in seven women (14%). FSH levels were lower in POF women with ovulatory or anovulatory follicle development compared with levels in women with inactive ovaries. These findings demonstrate that ovulatory cycles in women with POF are characterized by a persistent elevation in FSH compared with levels in normal cycling women. The association of increased FSH with lower levels of inhibin B and inhibin A, but higher estradiol levels provides additional evidence for an important physiological role of the inhibins in the negative feedback control of FSH. These data also demonstrate the variability in FSH levels as a function of underlying follicular development in women with POF.
In the last 2 years, major advances have been made in the understanding of inhibin physiology. Discovery of an inhibin receptor and binding protein has expanded our knowledge of the mechanism whereby ...inhibin antagonizes activin action. Controlled experimental studies have clarified the regulation and physiology of inhibin A and inhibin B, providing evidence for their use as markers of ovarian function. Clinical studies continue to uphold the use of inhibin as a marker for ovarian cancer, but have not generally supported its use over standard prognostic markers in assisted reproductive technologies. Finally, ongoing work suggests alterations in inhibin and follistatin that may be linked to the pathophysiology of polycystic ovary syndrome. Thus, the mechanism of inhibin action and its role in normal and abnormal ovarian function continues to emerge.
We describe the clinical course of three women with presumptive autoimmune oophoritis who developed multiple follicles but very low to undetectable estradiol levels. Multiple follicles developed ...spontaneously in all subjects and during pulsatile GnRH treatment for ovulation induction in subject 1. The development of multiple dominant follicles was accompanied by LH levels in the postmenopausal range and FSH levels at the upper limit for premenopausal women. Serum inhibin B levels were elevated appropriately in the setting of multifollicular development, but estradiol levels remained low. Measurement of estradiol precursors demonstrated androstenedione and estrone levels below the 95th percentile in normal women. Adrenal cortical antibodies, and antibodies to 21-hydroxylase and P450 side chain cleavage enzymes were identified in all subjects. All subjects met the criteria for premature ovarian failure during follow-up. Subject 1 later developed adrenal failure, whereas subject 3 had adrenal failure at the time of the study.These subjects elucidate the hormonal pattern in autoimmune oophoritis, before the full criteria for premature ovarian failure are met. The elevated inhibin A and B levels, which accompany the development of multiple small and dominant follicles in these women, suppress FSH relative to LH levels, virtually independent of estradiol. These data provide further evidence for an important role of inhibin B and inhibin A in the negative feedback control of FSH. In addition, the normal inhibin A and inhibin B production in the absence of estradiol precursors and estradiol provide insight into the selective dysfunction of the theca cells in autoimmune oophoritis.
Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances ...including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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