Role Of Follicle-stimulating Hormone Research Articles

Roles of follicle stimulating hormone and sphingosine 1-phosphate co-administered in the process in mouse ovarian vitrification and transplantation

Some major challenges of ovarian tissue vitrification and transplantation include follicle apoptosis induced by cryopreservation and ischemia-reperfusion injury, as well as ovarian follicle loss during post-transplantation. This research aimed to investigate the protective effects and underlying mechanisms of follicle-stimulating hormone (FSH) and Sphingosine-1-phosphate (S1P) on vitrified and post-transplantation ovaries. Ovaries from 21-day-old mice were cryopreservation by vitrification with 0.3 IU/mL FSH, 2 µM S1P, and 0.3 IU/mL FSH + 2 µM S1P, respectively, for follicle counting and detection of apoptosis-related indicators. The results demonstrated that FSH and S1P co-intervention during the vitrification process could preserve the primordial follicle pool and inhibit follicular atresia by suppressing cell apoptosis. The thawed ovaries were transplanted under the renal capsule of 6–8 week-old ovariectomized mice and removed 24 h or 7 days after transplantation. The results indicated that FSH and S1P co-intervention can inhibit apoptosis and autophagy in ovaries at 24 h after transplantation, and promote follicle survival by up-regulating Cx37 and Cx43 expression, enhanced angiogenesis in transplanted ovaries by promoting VEGF expression, as well as increased the E2 levels to restore ovarian endocrine function at 7 days after transplantation. The hypoxia and ischemia cell model was established by CoCl2 treatment for hypoxia in human granulosa-like tumor cell line (KGN), as well as serum-free culture system was used for ischemia. The results confirmed that ischemia-hypoxia-induced apoptosis in ovarian granulosa cells was reduced by FSH and S1P co-intervention, and granulosa cell autophagy was inhibited by up-regulating the AKT/mTOR signaling pathway. In summary, co-administration of FSH and S1P can maintain ovarian survival during ovarian vitrification and increase follicle survival and angiogenesis after transplantation.

Extra-Gonadal and Non-Canonical Effects of FSH in Males.

Recombinant follicle-stimulating hormone (FSH) is commonly used for the treatment of female infertility and is increasingly being used in males as well, as recommended by notable guidelines. FSH is composed of an α subunit, shared with other hormones, and a β subunit, which confers specificity of biological action by interacting with its surface receptor (FSHR), predominantly located in granulosa and Sertoli cells. However, FSHRs also exist in extra-gonadal tissues, indicating potential effects beyond male fertility. Emerging evidence suggests that FSH may have extra-gonadal effects, including on bone metabolism, where it appears to stimulate bone resorption by binding to specific receptors on osteoclasts. Additionally, higher FSH levels have been associated with worse metabolic and cardiovascular outcomes, suggesting a possible impact on the cardiovascular system. FSH has also been implicated in immune response modulation, as FSHRs are expressed on immune cells and may influence inflammatory response. Furthermore, there is growing interest in the role of FSH in prostate cancer progression. This paper aims to provide a comprehensive analysis of the literature on the extra-gonadal effects of FSH in men, with a focus on the often-conflicting results reported in this field. Despite the contradictory findings, the potential for future development in this area is substantial, and further research is needed to elucidate the mechanisms underlying these effects and their clinical implications.

Review: Roles of follicle-stimulating hormone in preantral folliculogenesis of domestic animals: what can we learn from model species and where do we go from here?

The pituitary gonadotropin FSH is a glycoprotein critical for the development of ovarian follicles. Upon binding to its G protein-coupled membrane receptor located on the granulosa cells of ovarian follicles, FSH elicits a cascade of downstream intracellular responses to promote follicle growth, maturation and steroidogenic activity, leading to the acquisition of meiotic and developmental competence of the enclosed oocyte. The essential role of FSH for proper antral follicle development and fertility is indisputable; over the decades, increasing evidence has also pointed toward survival and growth-promoting effects elicited by FSH in earlier-stage preantral follicles, deeming these follicles FSH-responsive as opposed to the FSH-dependent antral follicles. Transgenic mouse models lacking GnRH1, Fshβ or Fshr clearly demonstrate this difference by showing that, morphologically, preantral follicles develop to the secondary stage without FSH signaling; however, exogenous expression or administration of FSH to hormone-deficient mice promotes preantral follicle development, with more pronounced effects seen in earlier stages (i.e., primary follicles). In hypophysectomized sheep, FSH administration also promotes the growth of primary-stage preantral follicles. However, in vivo studies in this area are more challenging to perform in domestic animals compared to rodents, and therefore most of the research to date has been done in vitro. Here, we present the existing evidence for a role of FSH in regulating the growth and survival of preantral follicles from data generated in rodents and domestic animals. We provide an overview of the process of folliculogenesis, FSH synthesis and cellular signaling, and the response to FSH by preantral follicles in vivo and in vitro, as well as interactions between FSH and other molecules to regulate preantral folliculogenesis. The widespread use of FSH in ovarian stimulation programs for assisted reproduction creates a real need for a better understanding of the effects of FSH beyond stimulation of antral follicle growth, and more research in this area could lead to the development of more effective fertility programs. In addition to its importance as an agricultural species, the cow provides a desirable model for humans regarding ovarian stimulation due to similar timing of folliculogenesis and follicle size, as well as similar ovarian architecture. The refinement of minimally invasive methods to allow the study of preantral folliculogenesis in live animals will be critical to understand the short- and long-term effects of FSH in ovarian folliculogenesis.

FSH-inhibited autophagy protects against oxidative stress in goat Sertoli cells through p62-Nrf2 pathway

Oxidative stress is a common cause of male infertility. Sertoli cells are one of the target cells of oxidative injury, which leads to impaired testicular function. Follicle-stimulating hormone (FSH) is critical in Sertoli cell function. However, the role of FSH in the response of goat Sertoli cells to H2O2-induced oxidative stress has not been studied yet. To investigate this response, we established an oxidative stress model using goat Sertoli cells. FSH pretreatment significantly enhanced the decreased cell viability (p < 0.05) caused by oxidative injury and inhibited autophagic flux. FSH significantly increased p62 mRNA and protein levels (p < 0.01). Further investigations revealed that FSH also increased the expression level and nuclear translocation of Nrf2 in Sertoli cells (p < 0.01), which resulted in increased antioxidant enzyme activity (p < 0.05). In contrast, treatment with siNrf2 and sip62 abolished this protective effect of FSH. These findings suggest that FSH protects Sertoli cells against oxidative stress via the p62-Nrf2 pathway, and that p62 accumulation maintains persistent activation of Nrf2. Thus, p62 and Nrf2 are required for FSH-mediated protective role in H2O2-induced Sertoli cell injury. The findings reveal new mechanisms by which FSH protects against oxidative injury in goat Sertoli cells.

A novel role of follicle-stimulating hormone (FSH) in various regeneration-related functions of endometrial stem cells

Follicle-stimulating hormone (FSH) promotes the production and secretion of estrogen, which in turn stimulates the growth and maturation of ovarian follicles. Therefore, consecutive FSH treatment to induce ovarian hyperstimulation (superovulation) is still considered the most cost-effective option for the majority of assisted reproductive technologies (ARTs). However, a relatively high cancellation rate and subsequent low pregnancy outcomes (approximately 15%) are the most challenging aspects of this FSH-based ART. Currently, the main cause for this low implantation rate of FSH-based ART has not yet been revealed. Therefore, we hypothesized that these high cancellation rates with FSH-based superovulation protocols might be associated with the harmful effects of consecutive FSH treatment. Importantly, several recent studies have revealed that tissue-resident stem cell deficiency can significantly reduce cyclic endometrial regeneration and subsequently decrease the pregnancy outcome. In this context, we investigated whether FSH treatment could directly inhibit endometrial stem cell functions and consequently suppress endometrial regeneration. Consistent with our hypothesis, our results revealed for the first time that FSH could inhibit various regeneration-associated functions of endometrial stem cells, such as self-renewal, migration, and multilineage differentiation capacities, via the PI3K/Akt and ERK1/2 signaling pathways both in vitro and in vivo.

Roles of Follicle-Stimulating Hormone on Bone Metabolism in Late Postmenopausal Women.

BackgroundThe effects of elevated follicle-stimulating hormone (FSH) levels on physiological changes in the bone remain unclear. This study aimed to clarify the association between FSH concentrations and bone mineral density (BMD) and bone turnover markers (BTM) in late postmenopausal women.MethodsA total of 169 Korean women were enrolled. The participants’ ages ranged from 60 to 84 years (mean age, 69.0±5.1) and reported a mean duration of 19.4±6.6 years since menopause (YSM). The participants showed an average body mass index (BMI) of 24.4±2.8 kg/m2. Age, YSM, estradiol, testosterone, and BMI were confounders in the Pearson’s partial correlation. A test for trends across the quartiles of FSH levels was performed for each variable.ResultsThe mean FSH and estradiol concentrations were 61.5 IU/L and 2.9 pg/mL, respectively. Serum FSH concentration was not significantly associated with BMD (lumbar, r=0.09, P=0.30; total hip, r=0.00, P=0.96; and femoral neck, r=0.05, P=0.62). BTM across the FSH quartiles did not show any trend association (bone-specific alkaline phosphate, P=0.31; cross-linked C-terminal telopeptide of type I collagen, P=0.90). Instead, FSH levels were negatively correlated with BMI (r=−0.34, P=0.00). In the multivariate regression model adjusted for age, testosterone, and estradiol, only BMI showed a negative value across the FSH quartiles (β coefficient −0.11, P=0.00).ConclusionsThis study identified that high FSH concentrations were not associated with bone loss or high bone turnover in women in the late postmenopausal period.

Comparison of Triggering Final Oocyte Maturation with Follicle Stimulating Hormone Plus Human Chorionic Gonadotropin, versus Human Chorionic Gonadotropin Alonein Normoresponder Women Undergoing Intracytoplasmic Sperm Injection: A Randomized Clinical Trial.

Few studies have so far been done about the role of follicle stimulating hormone (FSH) in final oocyte<br />maturation. However, none of these studies have been performed solely on normoresponder patients. This study aimed<br />to determine whether oocyte maturation, as well as fertilization and pregnancy rates, could be improved in normoresponder women with concomitant FSH and human chorionic gonadotropin (hCG) trigger compared to those with the hCG trigger alone.<br />Materials and Methods: In this prospective randomized clinical trial, 117 normoresponder women, aged 19-40 years<br />who were candidates for the gonadotropin-releasing hormone (GnRH) antagonist protocol at Avicenna Infertility<br />treatment Center, were enrolled and claasified in two groups. Final oocyte maturation was triggered using 10000 IU of<br />hCG plus 450 IU of FSH in the first group (59 subjects) and 10000 IU of hCG alone in the second group (58 subjects).<br />The primary outcome was clinical pregnancy rate.<br />Results: Mean age of the patients was 33.21 ± 4.41 years. There was no difference in clinical pregnancy among the<br />two groups (30.9% vs. 25.5%, P=0.525). There was no statistically significant difference in fertilization rate (80.0%<br />vs. 74.1%, P=0.106), implantation rates (18.9% vs. 16.7%, P=0.352), and chemical pregnancy rates (38.2% vs. 32.7%,<br />P=0.550). Oocyte maturation rate (84.2% vs. 73.6%, P<0.001), 2 pronuclei (2PNs) (6.53 ± 2.54 vs. 5.36 ± 2.85,<br />P=0.021) and total embryos (5.85 ± 2.43 vs. 4.91 ± 2.58, P=0.046) were significantly higher in the first group.<br />Conclusion: Adding FSH to hCG for oocyte triggering, significantly improved oocyte maturation rates and total embryos.<br />While there was no significant difference in the clinical and chemical pregnancy rates, between these two groups<br />(registration number: IRCT20190108042285N1).

Comparison of Triggering Final Oocyte Maturation with Follicle Stimulating Hormone Plus Human Chorionic Gonadotropin, versus Human Chorionic Gonadotropin Alonein Normoresponder Women Undergoing Intracytoplasmic Sperm Injection: A Randomized Clinical Trial

Background:Few studies have so far been done about the role of follicle stimulating hormone (FSH) in final oocyte maturation. However, none of these studies have been performed solely on normoresponder patients. This study aimed to determine whether oocyte maturation, as well as fertilization and pregnancy rates, could be improved in normoresponder women with concomitant FSH and human chorionic gonadotropin (hCG) trigger compared to those with the hCG trigger alone.Materials and Methods:In this prospective randomized clinical trial, 117 normoresponder women, aged 19-40 years who were candidates for the gonadotropin-releasing hormone (GnRH) antagonist protocol at Avicenna Infertility treatment Center, were enrolled and claasified in two groups. Final oocyte maturation was triggered using 10000 IU of hCG plus 450 IU of FSH in the first group (59 subjects) and 10000 IU of hCG alone in the second group (58 subjects). The primary outcome was clinical pregnancy rate.Results:Mean age of the patients was 33.21 ± 4.41 years. There was no difference in clinical pregnancy among the two groups (30.9% vs. 25.5%, P=0.525). There was no statistically significant difference in fertilization rate (80.0% vs. 74.1%, P=0.106), implantation rates (18.9% vs. 16.7%, P=0.352), and chemical pregnancy rates (38.2% vs. 32.7%, P=0.550). Oocyte maturation rate (84.2% vs. 73.6%, P<0.001), 2 pronuclei (2PNs) (6.53 ± 2.54 vs. 5.36 ± 2.85, P=0.021) and total embryos (5.85 ± 2.43 vs. 4.91 ± 2.58, P=0.046) were significantly higher in the first group.Conclusion:Adding FSH to hCG for oocyte triggering, significantly improved oocyte maturation rates and total embryos. While there was no significant difference in the clinical and chemical pregnancy rates, between these two groups (registration number: IRCT20190108042285N1).

The Role of Follicle-stimulating Hormone in Vascular Dysfunction Observed in Hematopoietic Cell Transplant Recipients.

Childhood cancer survivors who receive a hematopoietic cell transplantation (HCT) are at increased risk for follicle-stimulating hormone (FSH) abnormalities, which may have a substantial negative impact on vascular function. The purpose of this study was to examine the association of vascular function with FSH in HCT recipients, non-HCT recipients and healthy controls. The study included childhood cancer survivors who were HCT recipients (n=24) and non-HCT recipients (n=308), and a control group of healthy siblings (n=211) all between 9 and 18 years old. Vascular measures of carotid artery structure and function (compliance and distensibility), brachial artery flow-mediated dilation and endothelial-independent dilation were measured using ultrasound imaging. A fasting blood sample was collected to measure hormone levels. FSH was significantly higher in HCT recipients compared with non-HCT recipients and healthy controls (P<0.01). Carotid compliance and distensibility were significantly lower in HCT and non-HCT recipients compared with healthy controls (P<0.05). Higher FSH was associated with decreased carotid compliance (P<0.05). This study's results suggest that higher levels of FSH in HCT recipients may result in significant reductions in vascular function compared with non-HCT recipients and healthy controls. Therefore, gonadotropin endocrine dysfunction, particularly abnormal FSH levels, may be an underlying mechanism of vascular dysfunction.

Actions and Roles of FSH in Germinative Cells.

Follicle stimulating hormone (FSH) is produced by the pituitary gland in a coordinated hypothalamic–pituitary–gonadal (HPG) axis event, plays important roles in reproduction and germ cell development during different phases of reproductive development (fetal, neonatal, puberty, and adult life), and is consequently essential for fertility. FSH is a heterodimeric glycoprotein hormone of two dissociable subunits, α and β. The FSH β-subunit (FSHβ) function starts upon coupling to its specific receptor: follicle-stimulating hormone receptor (FSHR). FSHRs are localized mainly on the surface of target cells on the testis and ovary (granulosa and Sertoli cells) and have recently been found in testicular stem cells and extra-gonadal tissue. Several reproduction disorders are associated with absent or low FSH secretion, with mutation of the FSH β-subunit or the FSH receptor, and/or its signaling pathways. However, the influence of FSH on germ cells is still poorly understood; some studies have suggested that this hormone also plays a determinant role in the self-renewal of germinative cells and acts to increase undifferentiated spermatogonia proliferation. In addition, in vitro, together with other factors, it assists the process of differentiation of primordial germ cells (PGCLCs) into gametes (oocyte-like and SSCLCs). In this review, we describe relevant research on the influence of FSH on spermatogenesis and folliculogenesis, mainly in the germ cell of humans and other species. The possible roles of FSH in germ cell generation in vitro are also presented.

Follicle-stimulating hormone impairs dental pulp stem cells odontogenic differentiation.

In addition to bone, the dentin‐pulp complex is also influenced by menopause, showing a decreased regenerative capacity. High levels of follicle‐stimulating hormone (FSH) during menopause could directly regulate bone metabolism. Here, the role of FSH in the odontogenic differentiation of the dentin‐pulp complex was investigated. Dental pulp stem cells (DPSCs) were isolated. CCK‐8 assays, cell apoptosis assays, Western blotting (WB), real‐time RT‐PCR, alkaline phosphatase activity assays, and Alizarin Red S staining were used to clarify the effects of FSH on the proliferation, apoptosis and odontogenic differentiation of the DPSCs. MAPK pathway‐related factors were explored by WB assays. FSH and its inhibitor were used in OVX rats combined with a direct pulp‐capping model. HE and immunohistochemistry were used to detect reparative dentin formation and related features. The results indicated that FSH significantly decreased the odontogenic differentiation of the DPSCs without affecting cell proliferation and apoptosis. Moreover, FSH significantly activated the JNK signalling pathway, and JNK inhibitor partly rescued the inhibitory effect of FSH on DPSC differentiation. In vivo, FSH treatment attenuated the dentin bridge formation and mineralization‐related protein expression in the OVX rats. Our findings indicated that FSH reduced the odontogenic capacity of the DPSCs and was involved in reparative dentinogenesis during menopause.

Prospects for FSH Treatment of Male Infertility.

Despite the new opportunities provided by assisted reproductive technology (ART), male infertility treatment is far from being optimized. One possibility, based on pathophysiological evidence, is to stimulate spermatogenesis with gonadotropins. We conducted a comprehensive systematic PubMed literature review, up to January 2020, of studies evaluating the genetic basis of follicle-stimulating hormone (FSH) action, the role of FSH in spermatogenesis, and the effects of its administration in male infertility. Manuscripts evaluating the role of genetic polymorphisms and FSH administration in women undergoing ART were considered whenever relevant. FSH treatment has been successfully used in hypogonadotropic hypogonadism, but with questionable results in idiopathic male infertility. A limitation of this approach is that treatment plans for male infertility have been borrowed from hypogonadism, without daring to overstimulate, as is done in women undergoing ART. FSH effectiveness depends not only on its serum levels, but also on individual genetic variants able to determine hormonal levels, activity, and receptor response. Single-nucleotide polymorphisms in the follicle-stimulating hormone subunit beta (FSHB) and follicle-stimulating hormone receptor (FSHR) genes have been described, with some of them affecting testicular volume and sperm output. The FSHR p.N680S and the FSHB -211G>T variants could be genetic markers to predict FSH response. FSH may be helpful to increase sperm production in infertile men, even if the evidence to recommend the use of FSH in this setting is weak. Placebo-controlled clinical trials, considering the FSHB-FSHR haplotype, are needed to define the most effective dosage, the best treatment length, and the criteria to select candidate responder patients.

The Role of FSH in Osteoporosis and Subsequent Oral Disease

Osteoporosis is an age‐related chronic disease in which osteoclasts degrade minerals of the bone faster than osteoblasts can replace them. In addition to increased risk of fracture, osteoporosis patients experience oral, dental and prosthodontic complications due to degradation of the alveolar and jaw bone. Elderly women are disproportionately impacted by this disease. One potential culprit for the gender‐based disparity is the increased levels of follicle stimulating hormone (FSH) during menopause. An isoform of the FSH receptor can be found on osteoclasts; when FSH binds to this receptor, osteoclast activity and differentiation are increased. Murine monocytes were differentiated into osteoclasts using RANK ligand, and FSH dependent signaling was measured through western blotting. Protein phosphorylation was detected in response to FSH in osteoclasts. A better understanding of the osteoclast FSH receptor could allow for pharmaceutical intervention to interrupt the pathway. Negative allosteric modulators (NAMs) that inhibit FSH signalling on granulosa cells could be used for inhibiting FSH signalling on osteoclasts.

FSH for the Treatment of Male Infertility.

Follicle-stimulating hormone (FSH) supports spermatogenesis acting via its receptor (FSHR), which activates trophic effects in gonadal Sertoli cells. These pathways are targeted by hormonal drugs used for clinical treatment of infertile men, mainly belonging to sub-groups defined as hypogonadotropic hypogonadism or idiopathic infertility. While, in the first case, fertility may be efficiently restored by specific treatments, such as pulsatile gonadotropin releasing hormone (GnRH) or choriogonadotropin (hCG) alone or in combination with FSH, less is known about the efficacy of FSH in supporting the treatment of male idiopathic infertility. This review focuses on the role of FSH in the clinical approach to male reproduction, addressing the state-of-the-art from the little data available and discussing the pharmacological evidence. New compounds, such as allosteric ligands, dually active, chimeric gonadotropins and immunoglobulins, may represent interesting avenues for future personalized, pharmacological approaches to male infertility.

125 Transcriptomic changes in bovine ovarian cortex in response to FSH signaling

Preantral follicles serve as a reservoir of female gametes that could be used in assisted reproductive technologies in humans, livestock, and endangered animals. Invitro culture of ovarian cortex is a widely used method to grow preantral follicles. Follicle-stimulating hormone (FSH) is often added to the culture medium as a folliculogenesis-promoting factor. The roles of FSH in antral follicles is well known; however, the effects of FSH in preantral follicles and indirectly in the ovarian cortical cells is largely unknown. The aim of this study was to determine the transcriptomic responses of the ovarian cortex containing preantral follicles to FSH signalling over time. In 3 biological replicates, small strips of bovine ovarian cortex (10×5mm) were dissected from the medulla and evaluated under a stereomicroscope for removal of all visible antral follicles. Resulting cortical strips were cultured in defined medium with human-recombinant FSH or vehicle for 2 or 4 days at 38.5°C and 5% CO2. The RNA was isolated and subjected to cDNA library preparation and 3′-Tag RNA sequencing. Sequencing data analysis was performed using the edgeR and maSigPro packages (Bioconductor-R). Using a time-course analysis, genes up- or downregulated 2-fold or more and associated with an FDR&amp;lt;0.05 were considered differentially expressed (DEG) and were further analysed with NetworkAnalyst software. We found 252 DEG over time in response to FSH. In FSH-treated samples, significantly enriched biological functions from upregulated genes were associated with glycolysis, gluconeogenesis, carbon metabolism, and biosynthesis of amino acids. In contrast, significantly enriched biological functions from downregulated genes found in FSH-treated samples included phagosome and necroptosis. The germ cell markers BMP15, DAZL, DDX4, GDF9, and ZP2/ZP3 were expressed but unchanged by FSH, suggesting the presence of similar numbers of oocytes between samples. The gene B4GALT2, previously reported as a granulosa cell marker, was upregulated in FSH-treated samples at Day 4. The follicular marker RAB23 was expressed in all samples and not changed by FSH. One interesting finding was upregulation of MAPK signalling (represented by the genes MAPKAPK3, ELK4, MKNK2, and TGFB3) in response to FSH signalling, with no change in expression of the cAMP-response element responsive genes CYP19A1 and INHA. Together, these data indicate that FSH stimulates energy metabolism in ovarian cortical cells and represses negative cell function activity. We conclude that these responses are mostly mediated by granulosa cells, because the FSH receptor is not appreciably expressed in the ovarian cortex stroma. Moreover, the data suggest that FSH may utilise alternative signalling pathways, such as MAPK, in early follicles. This information enhances our understanding of FSH signalling pathways in the ovarian cortex, mediated by preantral follicles to create a positive environment for folliculogenesis.

Induction of Gonadal Development in Protogynous Grouper with Orally Delivered FSH DNA.

The availability of sexually mature fish often dictates the success of its captive breeding. In this study, we induced reproductive development in juvenile protogynous tiger grouper through oral administration of a plasmid (p) containing an engineered follicle-stimulating hormone (FSH). An expression construct (pcDNA3.1) was designed to express a single-chain FSH consisting of giant grouper FSH β-subunit and glycoprotein subunit-α (CGα), linked by the carboxy-terminal peptide (CTP) sequence from the human chorionic gonadotropin (hCG). Single oral delivery of pFSH encapsulated in liposome and chitosan to tiger grouper yielded a significant increase in plasma FSH protein level after 4days. Weekly pFSH feeding of juvenile tiger groupers for 8weeks stimulated ovarian development as indicated by a significant increase in oocyte diameter and progression of oocytes to cortical alveolar stage. As the pFSH treatment progressed from 20 to 38weeks, female to male sex change was initiated, characterized by oocyte regression, proliferation of spermatogonial cells, and occurrence of spermatogenic cysts. It was also associated with significantly lower mRNA expression of steroidogenic genes (cyp11b, cyp19a1a, and foxl2) and basal plasma levels of sex steroid hormones 17β-estradiol (E2), testosterone (T), and 11-ketotestosterone (11KT). Results suggest that pFSH stimulates ovarian development up to cortical alveolar stage and then initiates sex change in tiger grouper. These findings significantly contribute to our knowledge on the role of FSH in the development of protogynous hermaphroditic fish. This study is the first to demonstrate induction of reproductive development in fish through oral delivery of plasmid gonadotropin.

Cell-based evidence regarding the role of FSH in prostate cancer

IntroductionConversion of androgen-responsive prostate cancer (CaP) to castration-resistant CaP is associated with an acceleration of the disease that often requires treatment modalities other than androgen deprivation therapy only. Recently, follicle-stimulating hormone (FSH) has been shown to play a role in CaP growth, and clinical data showed that high serum concentration of FSH in chemically castrated CaP patients was associated with a shorter time of progression to castration-resistant CaP. In this study, we sought to investigate if FSH could have direct effects on CaP cells, possibly through the androgen receptor and androgen receptor regulated genes, such as prostate-specific antigen (PSA). Materials and methodsThe human CaP cell lines PC-3, LNCaP and C4-2, and nonmalignant PNT1A cells, were utilized to investigate the effects of FSH. qPCR, Western blotting analysis, and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymetoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium assays were performed in order to analyze the FSH effects. ResultsThe FSH receptor was present in all cell lines except PNT1A. FSH significantly increased PSA mRNA (P < 0.01) and protein (P < 0.03) levels in C4-2 cells in a dose-dependent manner. In LNCaP cells, FSH also increased PSA protein level, although to a lesser extent than in C4-2 cells, and the expression was reduced by the antiandrogen enzalutamide. In PC-3 cells, FSH was shown to increase their proliferation (P < 0.03) and β-catenin expression. ConclusionThese findings demonstrate that FSH may have a direct effect in CaP in an androgen-depleted environment. However, further research is needed to understand the significance of direct FSH action in the maintenance of CaP growth at the different phases of transition from androgen dependence to androgen independence.

The relationship between follice-stimulating hormone and its receptor in male reproduction

Follicle stimulating hormone (FSH) is the key endocrine hormone regulating the gonadal function of both sexes. FSH stimulates male testicular Sertoli differentiation, promotes testicular development, and mitosis of spermatogonia. FSH maintains adult Sertoli cell metabolism and plays an important role in spermatogenesis, germ cell survival and male fertility. FSH and follicle-stimulating hormone receptor (FSHR) gene mutation or gene polymorphism may affect the role of FSH on target organs. This article reviews the relationship between FSH and FSHR and male reproductive relationship. Key words: Follicle stimulating hormone; Receptors, FSH; Fertility; Men; Review

Serum follicle stimulating hormone is associated with reduced risk of diabetes in postmenopausal women: The Hong Kong osteoporosis study

Menopause is an important transition of reproductive stage in a woman’s life. It is associated with diabetes, but the role of follicle stimulating hormone (FSH), a menopause-related hormone, in the risk of diabetes is largely unknown. We evaluated the relationship between serum FSH and diabetes in 1274 participants from the Hong Kong Osteoporosis Study aged≥55 at baseline. We also searched relevant databases for studies on serum FSH and incident diabetes and conducted a meta-analysis using fixed-effect modeling. Cases of incident diabetes (N = 60) were ascertained during a median follow-up of 10.7 years. Serum FSH was significantly associated with reduced risk of diabetes in both a crude model (hazard ratio [HR] per SD increase: 0.66; 95% CI: 0.48-0.89; P = 0.007) and a full model with adjustment for age, sex, body mass index, factors related to risk of diabetes, and reproductive health (HR per SD increase: 0.70; 95% CI: 0.51-0.97; P = 0.030); a similar result was observed when FSH was analysed in quintiles. In a fixed-effect meta-analysis of two studies, including the current study, serum FSH > 50 IU/L was associated with reduced risk of diabetes (HR = 0.56; 95% CI: 0.36-0.85; P = 0.006; I2 = 0). In conclusion, serum FSH levels were independently associated with diabetes.

Facing the Challenges of Neuropeptide Gene Knockouts: Why Do They Not Inhibit Reproduction in Adult Teleost Fish?

Genetic manipulation of teleost endocrine systems started with transgenic overexpression of pituitary growth hormone. Such strategies enhance growth and reduce fertility, but the fish still breed. Genome editing using transcription activator-like effector nuclease in zebrafish and medaka has established the role of follicle stimulating hormone for gonadal development and luteinizing hormone for ovulation. Attempts to genetically manipulate the hypophysiotropic neuropeptidergic systems have been less successful. Overexpression of a gonadotropin-releasing hormone (gnrh) antisense in common carp delays puberty but does not block reproduction. Knockout of Gnrh in zebrafish does not impact either sex, while in medaka this blocks ovulation in females without affecting males. Spawning success is not reduced by knockout of the kisspeptins and receptors, agouti-related protein, agouti signaling peptide or spexin. Hypotheses for the lack of effect of these genome edits are presented. Over evolutionary time, teleosts have lost the median eminence typical of mammals. There is consequently direct innervation of gonadotrophs, with the possibility of independent regulation by >20 neurohormones. Removal of a few may have minimal impact. Neuropeptide knockout could leave co-expressed stimulators of gonadotropins functionally intact. Genetic compensation in response to loss of protein function may maintain sufficient reproduction. The species differences in hypothalamo-hypophysial anatomy could be an example of compensation over the evolutionary timescale as teleosts diversified and adapted to new ecological niches. The key neuropeptidergic systems controlling teleost reproduction remain to be uncovered. Classical neurotransmitters are also regulators of luteinizing hormone release, but have yet to be targeted by genome editing. Their essentiality for reproduction should also be explored.