Follistatin, an activin-binding protein, plays a key role in the modulation of activin-dependent functions. In the anterior pituitary, activin stimulates the synthesis and secretion of FSH. In the current study, we assessed the roles of locally produced activin and follistatin in the control of FSH gene expression and secretion. The anterior pituitary gland follistatin content was measured at frequent intervals during the rat estrous cycle. Follistatin protein levels were high before the primary gonadotropin surges, decreased by 50% on proestrous evening, and rebounded to a peak at midnight on proestrus before returning to presurge levels on estrus morning. Changes in pituitary follistatin protein content were preceded by parallel changes in pituitary follistatin messenger RNA (mRNA). The trough in follistatin protein content on proestrus coincided with a peak in circulating levels of free activin A (not bound to follistatin) and a sharp rise in FSHbeta mRNA levels, suggesting that decreased pituitary follistatin leads to increased available activin. To quantitate the contribution of pituitary free activin to pituitary expression of FSHbeta mRNA and the primary and secondary serum FSH surges, rats were infused through carotid catheters with saline or recombinant human follistatin (288-amino acid isoform; rhFS-288) at different times during the estrous cycle. Infusion of rhFS-288 on diestrus did not affect FSH production. In contrast, infusion of rhFS-288 during the secondary FSH surge decreased the peaks in FSHbeta mRNA and serum FSH by 63% and 47%, respectively, relative to those in saline-infused control animals. Infusion of rhFS-288 during the primary FSH surge decreased serum FSH to a lesser degree (24%). These data indicate a physiological role for pituitary follistatin in the control of activin-mediated FSH synthesis and secretion during the rat estrous cycle.

OBJECTIVE

Are there any correlations between the phenotypes of polycystic ovary syndrome (PCOS) and the genotypes of the PCOS susceptibility single nucleotide polymorphisms (SNPs) in THADA, DENND1A and LHCGR?

CONCLUSIONS

The PCOS susceptibility genes, THADA and DENND1A, carry risk alleles that are associated with endocrine and metabolic disturbances in patients with PCOS.

BACKGROUND

PCOS is a heterogeneous endocrinopathy characterized by oligo-anovulation, hyperandrogenism and polycystic ovaries. In a previous genome-wide association study, the SNP variants rs13429458, rs12478601, rs2479106, rs10818854 and rs13405728 in the THADA, DENND1A and LHCGR genes were identified as being independently associated with PCOS. The aim of this study was to identify any additional correlations between the phenotypes of PCOS and genotypes of the five SNPs described in the previous study.

METHODS

In the present cross-sectional study, a total of 1731 PCOS patients and 4964 controls were enrolled.

METHODS

Patients were diagnosed according to Rotterdam criteria. Clinical information was collected from the patients and controls. Endocrine and metabolic parameters were evaluated for phenotype-genotype correlation analyses.

RESULTS

Using a recessive model, the AA group for rs13429458 in THADA was associated with increased luteinizing hormone (LH) (P < 0.01) and testosterone (T) (P = 0.02) levels in subjects with PCOS; the LH/follicle-stimulating hormone ratio was also higher in the AA group (P < 0.01). Also using a recessive model, the CC genotype of rs12478601, also in THADA, was associated with increased levels of low-density lipoprotein (P = 0.02). Using a dominant model, the GG + AG group for rs2479106 in DENND1A was associated with elevated serum insulin levels 2 h after a glucose load in the patients with PCOS (P = 0.02). All of the comparisons were adjusted for age and BMI.

CONCLUSIONS

The relatively younger age of the participants may represent a considerable bias when evaluating metabolic alterations as a function of different genotypes, as significant metabolic disturbances may emerge later in life. Furthermore, the sample sizes of several sub-genotype groups were relatively small; to some extent this limited the statistical power of the analysis.

CONCLUSIONS

The PCOS susceptibility genes, THADA and DENND1A, carry risk alleles that are associated with endocrine and metabolic disturbances in PCOS patients of Han Chinese descent. The findings have shown genuine heterogeneity, stratified on the basis of both clinical findings and genotypes. Replication of these results is expected in other ethnic groups.

There is evidence to suggest that follicle-stimulating hormone (FSH) can facilitate the neovascularization of ovarian cancers by increasing vascular endothelial growth factor (VEGF) expression in cancer cells, although the underlying molecular mechanism of this process is not well known. Therefore, we investigated the effect of FSH on VEGF expression in the ovarian cancer cell lines SKOV-3 and ES-2. Treatment with FSH significantly increased VEGF expression in a dose- and time-dependent manner. In addition, FSH treatment enhanced the expression of survivin and hypoxia-inducible factor-1 (HIF-1alpha). Knockdown of survivin or HIF-1alpha suppressed VEGF expression, but only knockdown of survivin inhibited FSH-stimulated VEGF expression. Pretreatment with LY294002, a phosphoinositide 3-kinase (PI3K)/AKT inhibitor, neutralized the enhanced expression of survivin induced by FSH, but treatment with U0126, a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, had no such effect. We further showed that ovarian serous cystadenocarcinoma samples had much higher incidence of positive AKT and phosphorylated AKT (pAKT) protein staining than did benign ovarian cystadenoma samples (p < 0.01). The 5-year survival rate was only about 15% in patients with ovarian serous cystadenocarcinoma who had AKT and pAKT expression, whereas it was about 80% in those who did not have AKT or pAKT expression. Taken together, these results indicate that FSH increases the expression of VEGF by upregulating the expression of survivin, which is activated by the PI3K/AKT signaling pathway. Understanding the role of the PI3K/AKT pathway in FSH-stimulated expression of survivin and VEGF will be beneficial for evaluating the prognosis for patients with ovarian serous cystadenocarcinoma and for pursuing effective treatment against this disease.

Vitamin D levels have been linked to various health outcomes including reproductive disorders. The purpose of this study was to explore the association between serum vitamin D level (25-hydroxy-vitamin D, or 25OHD) and semen and hormonal parameters. This is a cross-sectional study that included 170 healthy men recruited for the study of spermatogenesis from the general population. Men completed general and reproductive health questionnaires, and donated blood and semen samples. The main measures were hormonal (total and free testosterone, sex hormone-binding globulin, estradiol, follicle-stimulating hormone and luteinizing hormone) and semen parameters, adjusted (n=147) for age, body mass index (BMI), season, alcohol intake and smoking, in relation to categories of vitamin D levels, determined a priori. The mean age of the study population was 29.0±8.5 years and mean BMI was 24.3±3.2 kg m(-2). The mean 25OHD was 34.1±15.06 ng ml(-1). BMI showed a negative association with 25OHD. Sperm concentration, sperm progressive motility, sperm morphology, and total progressively motile sperm count were lower in men with '25OHD≥50 ng ml(-1)' when compared to men with '20 ng ml(-1)≤25OHD<50 ng ml(-1)'. Total sperm count and total progressive motile sperm count were lower in men with '25OHD<20 ng ml(-1)' when compared to men with '20 ng ml(-1)≤25OHD<50 ng ml(-1)'. The adjusted means of various hormonal parameters did not show statistical difference in the different categories of 25OHD. In conclusion, serum vitamin D levels at high and low levels can be negatively associated with semen parameters.

OBJECTIVE

The aim of this prospective study was to investigate whether occupational pesticide exposure during pregnancy causes adverse effects on the reproductive development in the male infants.

METHODS

Pregnant women employed in greenhouses in Denmark were consecutively recruited, and 113 mother-son pairs were included. The mothers were categorized as occupationally exposed (91 sons) or unexposed (22 sons) to pesticides during pregnancy. Testicular position and volume, penile length, and position of urethral opening were determined at 3 months of age using standardized techniques. Concentrations of reproductive hormones in serum from the boys were analyzed.

RESULTS

The prevalence of cryptorchidism at 3 months of age was 6.2% [95% confidence interval (CI), 3.0-12.4]. This prevalence was considerably higher than among Danish boys born in the Copenhagen area (1.9%; 95% CI, 1.2-3.0) examined by the same procedure. Boys of pesticide-exposed mothers showed decreased penile length, testicular volume, serum concentrations of testosterone, and inhibin B. Serum concentrations of sex hormone-binding globulin, follicle-stimulating hormone, and the luteinizing hormone:testosterone ratio were increased compared with boys of nonexposed mothers. For individual parameters, only the decreased penile length was statistically significant (p = 0.04). However, all observed effects were in the anticipated direction, and a joint multivariate test showed that this finding had a p-value of 0.012.

CONCLUSIONS

Our findings suggest an adverse effect of maternal occupational pesticide exposure on reproductive development in the sons despite current greenhouse safeguards and special measures to protect pregnant women.

OBJECTIVE

Using basal specimens from original gonadotropin radioimmunoassays, it was not possible to differentiate prepuberty from puberty hence gonadotropin-releasing hormone or gonadotropin-releasing hormone analog (GnRHa) testing was required to make this distinction. Third-generation gonadotropin assays have far greater specificity and sensitivity. Using a group of patients who had the diagnosis of central precocious puberty (CPP) verified or excluded by using GnRHa and traditional diagnostic criteria, the objective of this study was to determine if a single basal gonadotropin measurement was adequate to verify the diagnosis of CPP by using 2 third-generation gonadotropin assays.

METHODS

Girls referred for assessment of early puberty had previously been evaluated for central precocious puberty including gonadotropin-releasing hormone analog stimulation testing with gonadotropin measurements by 2 different chemiluminescent third-generation immunoassays. Diagnosis of central precocious puberty was made on the basis of the response to the gonadotropin-releasing hormone analog, and clinical criteria. Girls with central precocious puberty had luteinizing hormone responses ranging from 9.1 to 67.6 U/L, the prepubertal luteinizing hormone response range was 0.2 to 5.0 U/L. Basal serum luteinizing hormone and follicle-stimulating hormone concentrations from these girls have been assessed to determine the utility of using such a single sample to diagnose central precocious puberty.

RESULTS

Basal luteinizing hormone levels using the 2 third-generation gonadotropin assays were sufficient to diagnose central precocious puberty in >90% of the girls. Luteinizing hormone values were undetectable in both assays with different lower limits of detection (<0.15 and <0.20 U/L) in 29 of 34 prepubertal girls; the detectible values in 5 girls ranged from 0.20 to 0.66 U/L. All girls with central precocious puberty had values of >0.83 U/L, except a single value of 0.46 U/L. The basal follicle-stimulating hormone failed to differentiate prepubertal girls from those with central precocious puberty, whereas luteinizing hormone/follicle-stimulating hormone ratios would seem to have limited discernment.

CONCLUSIONS

A single basal luteinizing hormone measurement is adequate to document a pubertal hypothalamic-pituitary-ovarian axis in most but not all girls with central precocious puberty.

OBJECTIVE

To investigate the involvement of autophagy in folliculogenesis and its correlation with apoptosis.

METHODS

Animal model-based study.

METHODS

University medical center.

METHODS

Twenty-one day-old female Sprague-Dawley rats.

METHODS

Ovaries obtained from established immature rat models primed with pregnant mare serum gonadotropin (PMSG) were used for the induction of follicular development and atresia. Granulosa cells isolated from developing follicles were cultured in serum-free condition with or without follicle-stimulating hormone.

METHODS

Microtubule-associated light-chain protein 3 (LC3) and autophagic vacuoles were used as autophagic markers, and cleaved caspase-3 was used as an apoptotic marker in ovaries and/or granulosa cells.

RESULTS

The LC3 protein was expressed mainly in granulosa cells during all developmental stages. In granulosa cells isolated from PMSG-primed immature rat ovaries, LC3-II expression showed a similar expression pattern to cleaved caspase-3. In addition, granulosa cells of atretic follicles that showed intense cleaved caspase-3 staining also showed intense LC3 immunoreactivity. An in vitro culture experiment revealed that the levels of LC3-II and cleaved caspase-3 proteins were gonadotropin-dependent. The induction and the gonadotropin dependency of granulosa cell autophagy were confirmed by the observation of autophagic vacuoles under transmission electron microscopy.

CONCLUSIONS

These preliminary results suggest that autophagy is induced mainly in granulosa cells during folliculogenesis and shows good correlation with apoptosis.

OBJECTIVE

To evaluate testicular function in men after treatment with cytotoxic chemotherapy.

METHODS

We measured testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels in 209 men after treatment with mechlorethamine, vinblastine, procarbazine, and prednisone, hybrid chemotherapy, or high-dose chemotherapy and in 54 healthy age-matched controls.

RESULTS

The mean age of the patients was 38 years (range, 19 to 68 years), and all patients had received chemotherapy between 1 and 22 years previously. Patients had significantly higher mean LH (7.9 v 4.1 IU/L; P < .0001) and FSH levels (18.8 v 3.1 IU/L; P < .0001) than controls. There was no significant difference in mean total testosterone level between the patients and controls, but there was a trend toward a lower mean testosterone/SHBG ratio in the patients (0.63 v 0.7; P = .08). Analysis of the hormonal parameters using a model that allowed for the effects of increasing age on testicular function showed evidence of significant recovery of gonadal function in the first 10 years after treatment. Fifty-two percent of patients had LH levels at or above the upper limit of normal, and 32% of patients had increased LH with testosterone levels in the lower half of the normal range, suggesting a degree of Leydig cell impairment.

CONCLUSIONS

In a significant proportion of men, there is good evidence of Leydig cell dysfunction after cytotoxic chemotherapy. The clinical significance of this Leydig cell dysfunction is not clear, but some of these men may benefit from testosterone replacement. Further studies are warranted.

FSH is an important regulator of mammalian gametogenesis and the female reproductive cycle. Although little is known about the transcriptional regulation of the beta-subunit (the rate-limiting subunit of FSH synthesis), sequence analysis of the ovine FSHbeta promoter has revealed a number of potential activating protein-1 (AP-1; Jun/Fos)-binding sites. To determine whether the gene encoding the beta-subunit of ovine FSH (oFSHbeta) is responsive to AP-1 transcriptional complexes, chimeric constructs containing deleted portions of the oFSHbeta promoter fused to a luciferase reporter were transiently transfected along with c-Jun and c-Fos expression constructs into JAR cells. Analysis of these deletion constructs revealed that the proximal promoter of oFSHbeta is highly stimulated by c-Jun and c-Fos proteins (typically 20-fold with a reporter construct containing oFSHbeta sequences from -215 to +759 bp). This stimulation was lost when a similar construct containing sequences from -84 to +759 bp was tested. Transcriptional start site analysis using reverse transcription-PCR verified that the transcriptional initiation of the -215-bp deletion construct, with or without cotransfected c-Jun/c-Fos, was the same as that observed in vivo. Computer analysis of oFSHbeta sequences from -215 to +1 bp identified four putative AP-1-like elements, located at -155, -120, -83, and -10 bp. Gel retardation experiments using oligonucleotides corresponding to the four putative AP-1-like sites revealed that only -120 and -83 sites in oFSHbeta bound AP-1 proteins in vitro. Site-directed mutagenesis of the -120 and -83 sites showed that each element was required for stimulation by c-Jun and c-Fos proteins as well as 12-O-tetradecanoyl phorbol-13-acetate in transient transfection assays. Finally, immunocytochemical dual labeling was used to show that more than 75% of all FSHbeta-containing cells in ovine pituitary sections from cycling ewes contained nuclear c-Jun, JunB, JunD, and Fos proteins. These data, taken together, show that oFSHbeta transcription can be stimulated by c-Jun and c-Fos proteins via two functionally linked AP-1-like sites in the oFSHbeta proximal promoter and that these sites are likely to be important regulators of FSH production in vivo.

OBJECTIVE

To assess the relationships between serum antimüllerian hormone (AMH) and ovarian response and treatment outcomes in good-prognosis patients undergoing controlled ovarian stimulation using a gonadotropin-releasing hormone (GnRH) antagonist protocol.

METHODS

Secondary analysis of data prospectively collected in a randomized, assessor-blind trial comparing two different gonadotropin preparations with respect to ongoing pregnancy rate.

METHODS

Twenty-five centers in seven countries.

METHODS

749 women, aged 21 to 34 years, with primary diagnosis of infertility being unexplained infertility or mild male factor infertility and with serum follicle-stimulating hormone (FSH) level 1-12 IU/L and antral follicle count (AFC) ≥10.

METHODS

Controlled ovarian stimulation with highly purified human menopausal gonadotropin (hphMG) or recombinant FSH in a GnRH antagonist cycle with compulsory single-blastocyst transfer and potential subsequent 1-year cryopreserved blastocyst replacement in natural cycles.

METHODS

Relationships between AMH at start of stimulation and ovarian response and treatment outcome.

RESULTS

Serum AMH concentration was strongly correlated with oocyte yield: AMH accounted for 85%, FSH for 14%, and inhibin B and AFC for <1% each of the explained variation in oocyte yield. Also, AMH showed a high accuracy for the prediction of poor (≤3 oocytes) and high response (≥15 oocytes), which was statistically significantly better than basal FSH, AFC, or inhibin B. AMH was statistically significantly positively associated with ongoing pregnancy rate in the fresh cycle as well as with the 1-year cumulative ongoing pregnancy and live-birth rates.

CONCLUSIONS

There is a positive relationship between AMH and oocyte yield in GnRH antagonist cycles, and AMH is the best predictor for identifying patients with poor and high ovarian response. The positive association between AMH and cumulative live-birth rates after fresh and cryopreserved cycles reflects the availability of more oocytes/blastocysts, not higher quality.

BACKGROUND

NCT00884221.

Luteinizing hormone receptor and follicle stimulating hormone receptor play a crucial role in female and male reproduction. Significant new information has emerged about the structure, mechanism of activation, and regulation of expression of these receptors. Here we provide an overview of the current information on those aspects with an in-depth discussion of the recent developments in the post-transcriptional mechanism of LH receptor expression mediated by a specific LH receptor mRNA binding protein, designated as LRBP. LRBP was identified by electrophoretic gel mobility shift assay using cytosolic fractions from ovaries in the down regulated state. LRBP was purified, its binding site on LH receptor mRNA was identified and characterized. During ligand-induced down regulation, LRBP expression is increased through the cAMP/PKA and ERK signaling pathway, is translocated to translating ribosomes, binds LH receptor mRNA and forms an untranslatable ribonucleoprotein complex. This complex is then routed to the mRNA degradation machinery resulting in diminished levels of both LHR mRNA and cell surface expression of LH receptor. The studies leading to these conclusions are presented.

Glycoprotein hormone receptors (GPHRs) differ from the other seven transmembrane receptors mainly through a complex activation mechanism that requires the binding of a large hormone toward a large N-terminal ectodomain. The intramolecular mechanism of the signal transduction to the serpentine domain upon hormone binding at the ectodomain is not understood. To identify determinants at the GPHR ectodomain that may be involved in signal transduction, we first searched for homologous structural features. Based on high sequence similarity to the determined structures of the Nogo-receptor ectodomain and the intermolecular complex of the Interleukin-8 ligand (IL8) and the N-terminal peptide of the IL8 receptor (IL8RA), the hypothesis was developed that portions of the intramolecular components, Cysteine-box-2 and Cysteine-box-3, of the GPHR ectodomain interact and localize at the interface between ectodomain and serpentine domain. Indeed, point mutations within the D403EFN406 motif at Cysteine-box-3 of the thyrotropin receptor resulted in increased basal cAMP levels, suggesting that this motif may be important for transduction of the signal from the ectodomain to the transmembrane domain. New indications are provided about the tight spatial cooperation and relative location of the new epitope and other determinants at the thyrotropin receptor ectodomain, such as the leucine-rich repeat motif Ser281 and the cysteine boxes. According to the high sequence conservation, the results are of general relevance for the signal transduction mechanism of other glycoprotein hormone receptors such as choriogonadotrophic/luteinizing hormone receptor and follicle-stimulating hormone receptor.

Despite lack of evidence of their utility, biomarkers of ovarian reserve are being promoted as potential markers of reproductive potential.

To determine the associations between biomarkers of ovarian reserve and reproductive potential among women of late reproductive age.

Prospective time-to-pregnancy cohort study (2008 to date of last follow-up in March 2016) of women (N = 981) aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, recruited from the community in the Raleigh-Durham, North Carolina, area.

Early-follicular-phase serum level of antimüllerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B and urinary level of FSH.

The primary outcomes were the cumulative probability of conception by 6 and 12 cycles of attempt and relative fecundability (probability of conception in a given menstrual cycle). Conception was defined as a positive pregnancy test result.

A total of 750 women (mean age, 33.3 [SD, 3.2] years; 77% white; 36% overweight or obese) provided a blood and urine sample and were included in the analysis. After adjusting for age, body mass index, race, current smoking status, and recent hormonal contraceptive use, women with low AMH values (<0.7 ng/mL [n = 84]) did not have a significantly different predicted probability of conceiving by 6 cycles of attempt (65%; 95% CI, 50%-75%) compared with women (n = 579) with normal values (62%; 95% CI, 57%-66%) or by 12 cycles of attempt (84% [95% CI, 70%-91%] vs 75% [95% CI, 70%-79%], respectively). Women with high serum FSH values (>10 mIU/mL [n = 83]) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (63%; 95% CI, 50%-73%) compared with women (n = 654) with normal values (62%; 95% CI, 57%-66%) or after 12 cycles of attempt (82% [95% CI, 70%-89%] vs 75% [95% CI, 70%-78%], respectively). Women with high urinary FSH values (>11.5 mIU/mg creatinine [n = 69]) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (61%; 95% CI, 46%-74%) compared with women (n = 660) with normal values (62%; 95% CI, 58%-66%) or after 12 cycles of attempt (70% [95% CI, 54%-80%] vs 76% [95% CI, 72%-80%], respectively). Inhibin B levels (n = 737) were not associated with the probability of conceiving in a given cycle (hazard ratio per 1-pg/mL increase, 0.999; 95% CI, 0.997-1.001).

Among women aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, biomarkers indicating diminished ovarian reserve compared with normal ovarian reserve were not associated with reduced fertility. These findings do not support the use of urinary or blood follicle-stimulating hormone tests or antimüllerian hormone levels to assess natural fertility for women with these characteristics.

OBJECTIVE

To evaluate the association between FSH efficacy and FSHR alleles.

METHODS

Retrospective study.

METHODS

University-based fertility unit and a private center for biomedical research.

METHODS

One hundred two women with ovarian function who were undergoing controlled ovarian stimulation (COS). Women were categorized as poor responders (< or =3 ovarian follicles at the end of the cycle) or normal responders (>3 follicles).

METHODS

Daily administration of exogenous FSH.

METHODS

Number of good or poor responders.

RESULTS

The allele frequency and genotype distribution of the Ser680Asn marker differed significantly between groups. Cycle cancellations were increased (21%) among women who were homozygous for Ser680 compared with Ser/Asn and Asn/Asn patients, and 36% of poor-responders were homozygous for Ser680.

CONCLUSIONS

The results support a role for FSHR gene in COS outcome. However, the weight of this factor is probably low. The Ser680 allele may act in concert with other environmental and genetic factors that contribute to FSH efficacy.

Human FSH exists as two major glycoforms designated, tetra-glycosylated and di-glycosylated hFSH. The former possesses both alpha- and beta-subunit carbohydrates while the latter possesses only alpha-subunit carbohydrate. Western blotting differentiated the glycosylated, 24,000 M(r) hFSHbeta band from the non-glycosylated 21,000 M(r) FSHbeta band. Postmenopausal urinary hFSH preparations possessed 75-95% 24,000 M(r) hFSHbeta, while pituitary hFSH immunopurified from 21- to 43-year-old females and 21-43-year-old males possessed only 35-40% 24,000 M(r) hFSHbeta. The pituitary hFSH from a postmenopausal woman on estrogen replacement was 75% 21,000 M(r) hFSHbeta. Other immunopurified postmenopausal pituitary hFSH preparations possessed 50-60% 21,000 M(r) hFSHbeta. Gel filtration removed predominantly 21,000 M(r) free hFSHbeta and reduced its abundance to 13-22% in postmenopausal pituitary hFSH heterodimer preparations. A major regulatory mechanism for FSH glycosylation involves control of beta-subunit N-glycosylation, possibly by inhibition of oligosaccharyl transferase. Two primate species exhibited the same all-or-none pattern of pituitary FSHbeta glycosylation.

OBJECTIVE

To analyze to what extent the parameters of ovarian functional reserve including female age and basal FSH levels will affect the results of ovarian hyperstimulation and IVF outcome.

METHODS

Retrospective cohort study. University hospital infertility center.

METHODS

One thousand forty-five women undergoing their first cycle of IVF with ovarian stimulation after pituitary desensitization.

METHODS

None.

METHODS

Cycle parameters, cancellation rate, implantation rate, and pregnancy rate.

RESULTS

Both increasing age and basal FSH were associated significantly with reduced numbers of oocytes collected, oocytes fertilized, and embryos transferred. The combined use of age and basal FSH significantly improves the predictive power for these parameters. Increasing age, but not basal FSH, was associated significantly with reduced implantation rate and pregnancy rate. Logistic regression analysis revealed that age, but not basal FSH, was an independent predictor of pregnancy rate. Neither age nor basal FSH had significant association with fertilization rate, miscarriage rate, or ectopic pregnancy rate.

CONCLUSIONS

Both basal FSH and age contributed to the prediction of the quantitative ovarian reserve as reflected by the number of oocytes collected. However, age is a better predictor of pregnancy potential for women undergoing IVF.

OBJECTIVE

To discuss recent progress in our understanding of pituitary gonadotroph development and gonadotropin gene regulation, with an emphasis on differential luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion and subunit synthesis, and the implications this may have on female reproductive health.

RESULTS

In the mature gonadotroph, there is an emerging concept that differential synthesis of gonadotropin beta-subunit genes, essential for cyclic reproductive function, is associated with modification of activation and/or stability of important regulatory proteins and transcription factors. Recent studies suggest that cellular events, which affect histone modification, play an essential role in both gonadotroph development and the ontogeny of gonadotropin subunit gene expression. Such dynamic events are under the orchestration of the hypothalamic neuropeptide gonadotropin-releasing hormone (GnRH), potentially through the ability of GnRH to activate several distinct signaling cascades within the gonadotroph.

CONCLUSIONS

Greater insight into the cellular events that are key to gonadotroph physiology will contribute to our understanding of abnormal gonadotropin secretion in disorders such as hypothalamic amenorrhea and polycystic ovarian syndrome (PCOS), and provide a context for the design of novel therapeutic approaches.

In this study, two polymorphisms of follicle stimulating hormone receptor (FSHR) gene were analysed in the case-control sample using 40 premature ovarian failure (POF) patients, 60 polycystic ovary syndrome (PCOS) patients and 92 healthy controls. All subjects were unrelated Han Chinese from Shanghai. No difference was observed on the allelic or genotypic distribution of FSHR gene polymorphisms between the groups. However, the two-marker haplotypes covering components Thr307Ala (rs6165) G and Asn680Ser (rs6166) A were observed to be significantly associated with PCOS (p=0.007, corrected p=0.042). Meanwhile, a meta-analysis including our study (altogether six POF and eight PCOS studies) showed significant association between rs6166 marker and PCOS (p<0.05). The results suggest that FSH receptor might play a role in genetic susceptibility to PCOS. However, confirmatory studies in independent samples are needed.

The interaction between follicle-stimulating hormone (FSH) and the FSH receptor (FSHR) is essential for normal oogenesis and spermatogenesis. Recently, single-nucleotide polymorphisms (SNPs) have been assigned to the FSHR gene. These give rise to different FSHR haplotypes that modify the action of FSH. In women, FSH sensitivities during the menstrual cycle and different cycle lengths are observed, depending on the FSHR haplotype. Thus, SNPs of the FSHR determine the ovarian response and should, therefore, be considered in controlled ovarian hyperstimulation during assisted-reproduction techniques in women with normal ovarian function. In men, the impact of the FSHR SNPs is unclear. The genetic complexity of FSHR should be considered when studying FSH action. These SNPs are one of the first examples in which genetic changes contribute to fine-tuning the endocrine regulation of reproduction. A rational pharmacogenetic approach that combines FSH dose according to the FSHR haplotype is envisaged.

OBJECTIVE

To obtain information about preorchiectomy gonadal function in patients with testicular germ cell cancer to improve the clinical management of fertility and other andrologic aspects in these men.

METHODS

In group 1, a group of 83 consecutive patients with testicular germ cell cancer (TGCC) investigated before orchiectomy, semen analysis was carried out in 63 patients and hormonal investigations, including measurement of follicle-stimulating hormone, luteinizing hormone (LH), testosterone, estradiol, sex hormone-binding globulin (SHBG), inhibin B, and human chorionic gonadotropin (hCG), in 71 patients. Hormone levels in patients with elevated hCG (n = 41) were analyzed separately. To discriminate between general cancer effects and specific effects associated with TGCC, the same analyses were carried out in a group of 45 consecutive male patients with malignant lymphoma (group 2). Group 3 comprised 141 men employed in a Danish company who served as controls in the comparison of semen parameters. As a control group in hormone investigations, 193 men were selected randomly from the Danish National Personal Register to make up group 4.

RESULTS

We found significantly lower sperm concentration (median, 15 x 10(6)/mL; range, 0 to 128 x 10(6)/mL) and total sperm count (median, 29 x 10(6)/mL; range, 0 to 589 x 10(6)) in patients with testicular cancer than in patients with malignant lymphomas (sperm concentration: median, 48 x 10(6)/mL; range, 0.04 to 250 x 10(6)/mL; sperm count: median, 146 x 10(6); range, 0.05 to 418 x 10(6)) (P < .001 and P < .001) and healthy men (sperm concentration: median, 48 x 10(6)/mL; range, 0 to 402 x 10(6)/mL; sperm count: median, 162 x 10(6); range, 0 to 1253 x 10(6)) (P < .001 and P < .001). FSH levels were increased in men with testicular cancer (median, 5.7 IU/L; range, 2.0 to 27 IU/L) compared with both men with malignant lymphomas (median, 3.3 IU/L; range, 1.01 to 12.0 IU/L) and healthy controls (median, 4.1 IU/L; range, 1.04 to 21 IU/L)(P = .001 and P = .007, respectively). Surprisingly, we found significantly lower LH in the group of men with TGCC (median, 3.6 IU/L; range, 1.12 to 11.9 IU/L) than in healthy men (median, 4.7 IU/L; range, 1.3 to 11.9 IU/L) (P = .01). We could not detect any differences between men with testicular cancer and men with malignant lymphomas and healthy men with regard to serum levels of testosterone, SHBG, and estradiol. Men with testicular cancer who had increased hCG levels had significantly lower LH and significantly higher testosterone and estradiol than those without detectable hCG levels.

CONCLUSIONS

Spermatogenesis is already impaired in men with testicular cancer before orchiectomy. Neither local suppression of spermatogenesis by tumor pressure nor a general cancer effect seems to fully explain this impairment. The most likely explanation is preexisting impairment of spermatogenesis in the contralateral testis in men with testicular cancer. The question of whether also a pre-existing Leydig cell dysfunction is present in men with testicular cancer could not be answered in this study because the tumor seems to have a direct effect on the Leydig cells. Men with testicular cancer had low LH values as compared with controls. We speculate that increased intratesticular level of hCG also in men without measurable serum hCG may play a role by exerting LH-like effects on the Leydig cells, causing increased testosterone and estrogen levels and low LH values in the blood.

BACKGROUND

Circulating levels of testosterone and gonadotrophins of patients with chronic obstructive pulmonary disease (COPD) have never been compared with those of elderly men with normal pulmonary function. Moreover, the relationship of hypogonadism with quadriceps muscle weakness and exercise intolerance has been studied scarcely in men with COPD.

OBJECTIVE

To compare circulating levels of hormones of the pituitary-gonadotrophic axis of men with COPD with those of age-matched control subjects. Moreover, to study the relationship of hypogonadism with quadriceps muscle force, 6-min walking distance, and systemic markers of inflammation in the patients.

METHODS

Circulating levels of follicle-stimulating hormone, luteinizing hormone, testosterone, and sex hormone-binding globulin were determined, and free testosterone was calculated in 78 patients (FEV1: 44 +/- 17% of the predicted values) and 21 control subjects. Moreover, quadriceps muscle force, 6-min walking distance, number of pack-yr, and systemic inflammation were determined.

RESULTS

Follicle-stimulating hormone and luteinizing hormone were higher in the patients, whereas testosterone was lower (p < or = 0.05). The latter finding was also present in 48 non-steroid-using patients with normal blood gases. Low androgen status was significantly related to quadriceps muscle weakness (r = 0.48) and C-reactive protein (r = -0.39) in the patients, but not to exercise intolerance, the number of pack-yr, or increased circulating levels of interleukin 8 or soluble receptors of tumor necrosis factor alpha.

CONCLUSIONS

In contrast to exercise intolerance, quadriceps muscle weakness is related to low circulating levels of testosterone in men with COPD.

The process of folliculogenesis requires a tightly regulated series of gene expression that are a pre-requisite to the development of ovarian follicle. Among these genes, follicle-stimulating hormone (FSH) is notable for its dual role in development of follicles as well as proliferation and differentiation of granulosa cells. The post-transcriptional expression of these genes is under the control of microRNAs (miRNAs), a class of small, endogenous RNAs that negatively impact gene expression. This study was carried out to determine the role of several miRNAs including mir-143, let-7a, mir-125b, let-7b, let-7c, mir-21 in follicular development in the mouse. The expression of these RNAs was very low in primordial follicles but these became readily detectable in the granulosa cells of primary, secondary and antral follicles. We show that this expression of some miRNAs (mir-143, let-7a, mir-15b) is under negative control of FSH. Together, these findings suggest that FSH regulates folliculogenesis by a novel pathway of miRNAs.

OBJECTIVE

To determine if ghrelin and adipocytokine (leptin, adiponectin, resistin) levels vary with menopause stage or with estradiol (E2), testosterone (T), follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG) concentrations measured in three stages of the menopause transition.

METHODS

A study of adipocytokines and menopause was nested in a population-based, longitudinal study of Caucasian women [Michigan Bone Health and Metabolism Study (MBHMS)]. Annual serum and urine samples, available from the MBHMS repository, were selected to correspond to the pre-, peri-, and postmenopause stages of the menopause transition. Participants included forty women, stratified into obese versus non-obese groups based upon their baseline body mass index, who had specimens corresponding to the three menopause stages.

RESULTS

Mean resistin levels were approximately two times higher during premenopause compared to peri- or postmenopause. There were significantly lower adiponectin and higher ghrelin levels in the perimenopause stage, compared to either the pre- or postmenopause stage. Increases in FSH concentrations were significantly and positively associated with higher leptin in non-obese women (P<0.01) but not in obese women (P<0.23). Increases in FSH concentrations were also significantly (P<0.005) and positively associated with higher adiponectin concentrations but were negatively associated with ghrelin concentrations (P<0.005). Associations remained following adjustment for waist circumference, waist circumference change, chronological age, and time between measures.

CONCLUSIONS

Menopause stages and underlying FSH changes are associated with notable changes in levels of the metabolically active adipocytokines and ghrelin and these changes may be related to selected health outcomes observed in women at mid-life.

OBJECTIVE

The menopausal transition is characterized by irregular menstrual cycles and unpredictable hormone levels, including dramatic swings in estradiol (E2). An increasing number of studies have found variable high E2 and low luteal phase progesterone occur with progression of Stages of Reproductive Aging Workshop (STRAW)stage, but the cause remains unclear. To explore the causes of the erratic changes in E2, individual within-cycle secretion patterns of E2, progesterone, follicle-stimulating hormone, luteinizing hormone, inhibin A, and inhibin B were explored in detail.

METHODS

Blood samples taken three times per week over 1 1/3 menstrual cycles from 77 women aged 21 to 55 classified as mid-reproductive age (STRAW stages 5 and 4; n = 21), late-reproductive age (STRAW stages 4 and 3; n = 16), early menopausal transition (STRAW stage 2; n = 17), and late menopausal transition (STRAW stage 1; n = 23) were analyzed.

RESULTS

Eleven of the 29 (37%) early and late menstrual transition ovulatory cycles exhibited a specific pattern of E2 secretion that was characterized by a second increase in E2 during the mid- and late luteal phases and that continued to a peak during the subsequent menstrual phase. This second rise and fall in E2 was typical in appearance of a normal follicular phase, except that it was superimposed on an existing ovulatory cycle(specifically during the luteal and menstrual phases). The pattern was therefore referred to as a luteal out-of-phase(LOOP) follicular event. In four of these LOOP cycles, a luteinizing hormone peak and ovulatory episode followed the second E2 peak early in the subsequent cycle. Compared with the typical ovulatory cycles, the cycles with LOOP events exhibited lower luteal phase progesterone, higher early cycle follicle-stimulating hormone, and lower early cycle inhibin B. They were also associated with abnormally short (<21 d) or long (>40 d) cycle length.

CONCLUSIONS

Many of the marked increases in ovulatory cycle E2 and cycle irregularities during the menopausal transition may be due to LOOP events and appear to be triggered by prolonged high follicular phase follicle-stimulating hormone levels.