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The present study was conducted to investigate the effects of dietary DHA and EPA on gonadal steroidogenesis in mature females and males, with a feeding trial on tongue sole, a typical marine teleost with sexual dimorphism. Three experimental diets differing basically in DHA:EPA ratio, that is, 0·68 (diet D:E-0·68), 1·09 (D:E-1·09) and 2·05 (D:E-2·05), were randomly assigned to nine tanks of 3-year-old tongue sole (ten females and fifteen males in each tank). The feeding trail lasted for 90 d before and during the spawning season. Fish were reared in a flowing seawater system and fed to apparent satiation twice daily. Compared with diet D:E-0·68, diet D:E-1·09 significantly enhanced the oestradiol production in females, whereas diet D:E-2·05 significantly enhanced the testosterone production in males. In ovaries, diet D:E-1·09 induced highest mRNA expression of follicle-stimulating hormone receptor (FSHR), steroidogenic acute regulatory protein, 17α-hydroxylase (P450c17) and 3β-hydroxysteroid dehydrogenase (3β-HSD). In testes, diet 2·05 resulted in highest mRNA expression of FSHR, cholesterol side-chain cleavage enzyme, P450c17 and 3β-HSD. Fatty acid profiles in fish tissues reflected closely those of diets. Female fish had more gonadal EPA content but less DHA content than male fish, whereas there was a reverse observation in liver. In conclusion, the dietary DHA:EPA ratio, possibly combined with the dietary EPA:arachidonic acid ratio, differentially regulated sex steroid hormone synthesis in mature female and male tongue soles. Females seemed to require more EPA but less DHA for the gonadal steroidogenesis than males. The results are beneficial to sex-specific nutritive strategies in domestic teleost.

Infertility due to Gonadotropin-Resistant Ovary Syndrome (GROS) is a rare type of hypergonadotropic hypogonadism. Here, we report an original case of GROS, associated with compound heterozygous follicle-stimulating hormone receptor (FSHR) variants, in a woman who achieved a live birth by in vitro maturation (IVM) of her oocytes. This 31-year-old woman consulted our assisted reproduction center for a second opinion after having been advised, because of pervasive high serum follicle-stimulating hormone (FSH) levels, to pursue in vitro fertilization (IVF) with donor oocytes. She presented with primary infertility and progressively prolonged menstrual cycles. Her serum FSH levels were indeed found to be high, but in discordance with a normal anti-Müllerian hormone (AMH) level and antral follicle count. Genetic investigation found the patient to be compound heterozygous for two FSHR variants: I160T, a known pathologic variant, and N558H, which has never been previously reported. As there was no ovarian response to high daily doses of exogenous gonadotropins, IVM was proposed to the patient with success and she finally delivered at term a healthy boy. Effects of the receptor variants were analyzed in heterologous cells. Whereas the I160T mutation blocked FSHR membrane trafficking and FSH-stimulated cAMP-dependent signaling in transfected CHO cells, the novel variant, N558H, functioned equivalently to wild-type FSHR in the assays employed. In conclusion, IVM should always be offered as a first-line therapy to infertile women presenting with GROS. The N558H variant discovered in FSHR is novel, but its functional significance, if any, is unresolved and merits further investigation as it may be associated with a recessive FSHR-related disorder.

Background Diminished ovarian reserve(DOR) is associated with female infertility and poor response to ovarian stimulation. Our objective was to assess the effect of dehydroepiandrosterone(DHEA) on DOR women and to explore whether the improvement of ovarian response after DHEA supplementation was dependent on the expression levels of androgen receptor(AR). Methods A prospective cohort study was performed in the Department of Human Reproductive Medicine, Beijing Obstetrics and Gynecology Hospital during August 2014 to August 2016. 103 DOR women who completed the study were divided into the DHEA group ( n  = 53), which received DHEA supplementation (25 mg three times a day) for 8 weeks, and the control group ( n  = 50), which did not receive DHEA, before the IVF cycles. Serum hormone levels(FSH, LH, E 2 , T, DHEAs, AMH, INHB), antral follicle count(AFC) and the expression of AR and FSH receptor(FSHR) in granulosa cells(GCs) were measured, meanwhile ovarian response parameters and IVF outcomes were compared. The GCs from another 36 DOR women were cultured with different concentrations of DHEA in vitro. Then, we compared the expression of AR and FSHR in GCs according to the different numbers of oocytes retrieved both in DHEA and control group. Results In the present study, DHEA supplementation resulted in significantly higher levels of serum T( P  = 0.047), DHEAs( P  = 0.019) and AR mRNA expression in GCs( P  = 0.049). In vitro experiment, the protein and mRNA expression of AR and FSHR in the preovulatory GCs were significantly increased in response to DHEA supplementation( P  <0.05). No significant differences were found in ovarian reserve, ovarian response, or IVF outcomes between the two groups. Subgroup analyses showed the levels of AR and FSHR mRNA in GCs were significantly increased in DHEA group with ≥5 oocytes retrieved( P  <0.05). Conclusion DHEA supplementation can increase the expression of AR in preovulatory GCs both in vivo and in vitro. The selective beneficial effects of DHEA supplementation on ovarian response in DOR women may depend on the increasing expression of AR and FSHR in GCs. Trial registration The Chinese Clinical Trial Registry ( ChiCTR-IPR-15006126 ). Retrospectively Registered 19 March 2015.

Manganese (Mn) is an essential element required for normal development and reproduction. However, little is known about the reproductive toxicity of Mn in birds. To investigate the Mn-induced toxicity on testicular trace element levels and crucial hormonal parameters on male reproduction in birds, 50-day-old male Hyline cocks were fed either a commercial diet or a Mn-supplemented diet. The changes in contents of copper (Cu), iron (Fe), zinc (Zn), and calcium (Ca) in testis were detected. Hormonal parameters were evaluated including the levels of testosterone (T), luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), triiodothyronine (T3), and thyroxine (T4) in the serum. The mRNA levels of luteinizing hormone receptor (LHR) and follicle-stimulating hormone receptor (FSHR) were determined in this study. The results showed that Mn was accumulated in testis, and the content of Cu, Fe, Zn, and Ca decreased. Exposure to Mn significantly lowered the content of T, LH, FSH, and the mRNA expression levels of LHR and FSHR. Levels of T3 and T4 appeared with a decreased tendency, and TSH presented no obvious regularity. It indicated that Mn exposure resulted in the disbalance of testicular trace elements and influenced hormone levels in the molecular level, which may be possible underlying reproductive toxicity mechanism induced by Mn.

Menopause is associated with bone loss and enhanced visceral adiposity. A polyclonal antibody that targets the β-subunit of the pituitary hormone follicle-stimulating hormone (Fsh) increases bone mass in mice. Here, we report that this antibody sharply reduces adipose tissue in wild-type mice, phenocopying genetic haploinsufficiency for the Fsh receptor gene Fshr . The antibody also causes profound beiging, increases cellular mitochondrial density, activates brown adipose tissue and enhances thermogenesis. These actions result from the specific binding of the antibody to the β-subunit of Fsh to block its action. Our studies uncover opportunities for simultaneously treating obesity and osteoporosis. An antibody against the pituitary hormone Fsh reduces adiposity and increases thermogenesis in ovariectomized mice or mice fed a high-fat diet. Fat-reducing antibody Menopause is associated with bone loss and enhanced build-up of abdominal fat. Previously, Mone Zaidi and colleagues showed that an antibody against the pituitary hormone Fsh increases bone mass in mice. In this paper, they show that this antibody also reduces fatty tissue in mice that have had their ovaries removed or mice on a high fat diet. The anti-obesity effect is accompanied by increases in UCP1 expression and thermogenesis in brown and beige fat, increased whole-body oxygen consumption rate and physical activity. The authors suggest that these findings could open up opportunities for combined treatment of obesity and osteoporosis.

Abstract The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved adaptive response that functions to maintain mitochondrial homeostasis following mitochondrial damage. In Caenorhabditis elegans, the nervous system plays a central role in responding to mitochondrial stress by releasing endocrine signals that act upon distal tissues to activate the UPRmt. The mechanisms by which mitochondrial stress is sensed by neurons and transmitted to distal tissues are not fully understood. Here, we identify a role for the conserved follicle-stimulating hormone G protein-coupled receptor, FSHR-1, in promoting UPRmt activation. Genetic deficiency of fshr-1 severely attenuates UPRmt activation and organism-wide survival in response to mitochondrial stress. FSHR-1 functions in a common genetic pathway with SPHK-1/sphingosine kinase to promote UPRmt activation, and FSHR-1 regulates the mitochondrial association of SPHK-1 in the intestine. Through tissue-specific rescue assays, we show that FSHR-1 functions in neurons to activate the UPRmt, to promote mitochondrial association of SPHK-1 in the intestine, and to promote organism-wide survival in response to mitochondrial stress. We propose that FSHR-1 functions cell nonautonomously in neurons to activate UPRmt upstream of SPHK-1 signaling in the intestine.

Polycystic ovary syndrome (PCOS) is the most common cause of anovulation. A key feature of PCOS is arrest of follicles at the small- to medium-sized antral stage. To provide further insight into the mechanism of follicle arrest in PCOS, we profiled (i) gonadotropin receptors; (ii) characteristics of aberrant steroidogenesis; and (iii) expression of anti-Müllerian hormone (AMH) and its receptor in granulosa cells (GCs) from unstimulated, human small antral follicles (hSAFs) and from granulosa lutein cells (GLCs). GCs from hSAFs were collected at the time of cryopreservation of ovarian tissue for fertility preservation and GLCs collected during oocyte aspiration before in vitro fertilization/intracytoplasmic sperm injection. We collected hSAF GCs from 31 women (98 follicles): 10 with polycystic ovaries (PCO) and 21 without. GLCs were collected from 6 women with PCOS and 6 controls undergoing IVF. Expression of the following genes: LHCGR, FSHR, AR, INSR, HSD3B2, CYP11A1, CYP19, STAR, AMH, AMHR2, FST, INHBA, INHBB in GCs and GLCs were compared between women with PCO and controls. GCs in hSAFs from women with PCO showed higher expression of LHCGR in a subset (20%) of follicles. Expression of FSHR (P < 0.05), AR (P < 0.05), and CYP11A1 (P < 0.05) was lower, and expression of CYP19A1 (P < 0.05), STAR (P < 0.05), HSD3B2 (P = NS), and INHBA (P < 0.05) was higher in PCO GCs. Gene expression in GL cells differed between women with and without PCOS but also differed from that in GCs. Follicle arrest in PCO is characterized in GCs by differential regulation of key genes involved in follicle growth and function.

Background Accumulating evidence suggests a strong association between polycystic ovary syndrome (PCOS) and ovarian cancer (OC), but the potential molecular mechanism remains unclear. In this study, we identified previously unrecognized genes that are significantly correlated with PCOS and OC via bioinformatics. Materials and methods Multiple bioinformatic analyses, such as differential expression analysis, univariate Cox analysis, functional and pathway enrichment analysis, protein–protein interaction (PPI) network construction, survival analysis, and immune infiltration analysis, were utilized. We further evaluated the effect of OGN on FSHR expression via immunofluorescence. Results TCGA-OC, GSE140082 (for OC) and GSE34526 (for PCOS) datasets were downloaded. Twelve genes, including RNF144B, LPAR3, CRISPLD2, JCHAIN, OR7E14P, IL27RA, PTPRD, STAT1, NR4A1, OGN, GALNT6 and CXCL11, were identified as signature genes. Drug sensitivity analysis showed that OGN might represent a hub gene in the progression of PCOS and OC. Experimental analysis found that OGN could increase FSHR expression, indicating that OGN could regulate the hormonal response in PCOS and OC. Furthermore, correlation analysis indicated that OGN function might be closely related to m6A and ferroptosis. Conclusions Our study identified a 12-gene signature that might be involved in the prognostic significance of OC. Furthermore, the hub gene OGN represent a significant gene involved in OC and PCOS progression by regulating the hormonal response.

Spermatogenesis is regulated by the 2 pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This process is considered impossible without the absolute requirement of LH-stimulated testicular testosterone (T) production. The role of FSH remains unclear because men and mice with inactivating FSH receptor (FSHR) mutations are fertile. We revisited the role of FSH in spermatogenesis using transgenic mice expressing a constitutively strongly active FSHR mutant in a LH receptor-null (LHR-null) background. The mutant FSHR reversed the azoospermia and partially restored fertility of Lhr-/- mice. The finding was initially ascribed to the residual Leydig cell T production. However, when T action was completely blocked with the potent antiandrogen flutamide, spermatogenesis persisted. Hence, completely T-independent spermatogenesis is possible through strong FSHR activation, and the dogma of T being a sine qua non for spermatogenesis may need modification. The mechanism for the finding appeared to be that FSHR activation maintained the expression of Sertoli cell genes considered androgen dependent. The translational message of our findings is the possibility of developing a new strategy of high-dose FSH treatment for spermatogenic failure. Our findings also provide an explanation of molecular pathogenesis for Pasqualini syndrome (fertile eunuchs; LH/T deficiency with persistent spermatogenesis) and explain how the hormonal regulation of spermatogenesis has shifted from FSH to T dominance during evolution.

Zi-Jiang Chen and colleagues report a genome-wide association analysis for polycystic ovary syndrome (PCOS) in Han Chinese. They identify eight new susceptibility loci for PCOS in this population. Following a previous genome-wide association study (GWAS 1) including 744 cases and 895 controls, we analyzed genome-wide association data from a new cohort of Han Chinese (GWAS 2) with 1,510 polycystic ovary syndrome (PCOS) cases and 2,016 controls. We followed up significantly associated signals identified in the combined results of GWAS 1 and 2 in a total of 8,226 cases and 7,578 controls. In addition to confirming the three loci we previously reported, we identify eight new PCOS association signals at P < 5 × 10 −8 : 9q22.32, 11q22.1, 12q13.2, 12q14.3, 16q12.1, 19p13.3, 20q13.2 and a second independent signal at 2p16.3 (the FSHR gene). These PCOS association signals show evidence of enrichment for candidate genes related to insulin signaling, sexual hormone function and type 2 diabetes (T2D). Other candidate genes were related to calcium signaling and endocytosis. Our findings provide new insight and direction for discovering the biological mechanisms of PCOS.