Follicle-stimulating Hormone Secretion Research Articles

Neuroendocrine Defects in Polycystic Ovary Syndrome (PCOS): Different Phenotypes based on the Levels of Gonadotropins (FSH and LH), and Body Mass Index

Introduction: Polycystic ovary syndrome (PCOS) is a genetically complex disorder associated with abnormal follicular growth, hyperandrogenism and subfertility or infertility. There are untimely high levels of luteinizing hormone (LH) and expression of the LH receptor in PCOS women; however, these defects are not part of the criteria for the diagnosis of PCOS. Young women with PCOS require advanced IVF procedures to conceive, but they have a low rate of successful pregnancies. Aims: To understand the variations in gonadotropin levels in women with PCOS. Methods: We hypothesized that PCOS women may have differences in the neuroendocrine defects that may ultimately lead to PCOS symptoms. Here, we report different PCOS phenotypes where both follicle stimulating hormone (FSH) and LH levels were elevated, or just LH secretion was higher than normal. In this cohort of PCOS women, 71% had high LH levels. Result: However, high insulin levels were not associated with either high LH or obesity. Obese PCOS women with high FSH had high insulin levels; however, that could be associated with obesity and not FSH. Conclusion: The defect in the secretion of FSH, LH, or both leads to the reproductive abnormalities in women with PCOS. With the emerging connection between FSH, LH, and insulin receptor substrates, there may be an increase in the susceptibility of women with PCOS to metabolic disorders due to imbalance in FSH and LH secretion.

Increased luminescence of the GloSensor cAMP assay in LβT2 cells does not correlate with cAMP accumulation under low pH conditions

Cyclic adenosine monophosphate (cAMP) plays a pivotal role in gonadotrope responses in the pituitary. Gonadotropin-releasing hormone (GnRH) mediated synthesis and secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are regulated by both the Gs/cAMP and Gq/Ca2+ signaling pathways. Pituitary adenylate cyclase-activating polypeptide (PACAP) also regulates GnRH responsiveness in gonadotropes through the PACAP receptor, which activates the Gs/cAMP signaling pathway. Therefore, measuring intracellular cAMP levels is important for elucidating the molecular mechanisms of FSH and LH synthesis and secretion in gonadotropes. The GloSensor cAMP assay is useful for detecting cAMP levels in intact, living cells. In this study, we found that increased GloSensor luminescence intensity did not correlate with cAMP accumulation in LβT2 cells under low pH conditions. This result indicates that cell type and condition must be considered when using GloSensor cAMP.

Investigating the genetic determination of clutch traits in laying hens

Clutch traits were proposed as a more detailed description of egg-laying patterns than simple total egg production. In this study, egg production of 23,809 Rhode Island Red (RIR) and 22,210 White Leghorn (WL) hens was described in terms of number of clutches, average and maximum clutch size, age at first egg, total saleable egg production, and percentage of egg defects. Genetic parameters were estimated using a six-trait animal model. Of the phenotyped birds, 1433 RIR hens and 1515 WL hens were genotyped with line specific 50K Affymetrix Axiom single nucleotide polymorphism chips to perform genome-wide association analyses. Moderate heritabilities were estimated for clutch traits of 0.20 to 0.42 in the RIR line and 0.29 to 0.41 in the WL line. Average and maximum clutch size was positively genetically correlated with total saleable egg number in both lines. Genome-wide association analysis identified seven regions that were associated with egg production in the RIR line and 12 regions in the WL line. The regions identified were line and trait specific, except for one region on chromosome 6 from 28 to 29 Mb that influenced number of clutches and maximum and average clutch size in WL hens. Regions associated with egg production identified here overlapped with 260 genes, with some strong positional candidates based on gene ontology including WASH1, which is involved in oocyte maturation, NPVF, involved in regulation of follicle-stimulating hormone secretion, and FOXO3, involved in oocyte maturation and ovulation from the ovarian follicle. Confirmation of the role of these genes in regulation of egg production pattern will require further studies.

CONTRACEPTIVE EFFECT OF NEEM SEED OIL AND ITS ACTIVE FRACTIONS ON FEMALE ALBINO RABBITS

Objective: In the present investigation, contraceptive efficacy of neem seed oil and its fractions have been examined in female albino rabbits to find out their contraceptive potential.Methods: The experimental protocol was designed for intact control, Neem seed oil alone and its six active fractions in eight groups for 30 days. The estimation of serum biochemistry, histometry of reproductive organs, and hematological parameters were done.Results: Oral administration of Neem seed oil alone and its Fraction IV and V causes significant reduction in weight of ovary and uterus which reflects antiestrogenic function of plant material. Significant increase in serum cholesterol and phospholipid in Neem seed oil alone and its Fraction IV and V-treated groups reflects that they may affect the intraovarian estrogen level either by inhibiting the ovarian cell function or by inhibiting follicle-stimulating hormone and luteinizing hormone secretion through hypothalamus-hypophysis axis and impaired estrogen synthesis.Conclusion: From the ongoing work, it can be concluded that Neem seed oil alone and its Fraction IV and V cause functional sterility in female albino rabbits without causing any side effect on general metabolism.

Clomiphene Citrate for the Treatment of Hypogonadism.

Clomiphene citrate (CC) is a selective estrogen receptor modulator that has been used for the treatment of hypogonadism in men since the 1970s. It acts centrally to increase secretion of luteinizing hormone and follicle-stimulating hormone, thereby increasing testosterone production and serum levels. Unlike testosterone replacement therapy, CC does not suppress the hypothalamic-pituitary-gonadal axis, preserving intratesticular testosterone production and spermatogenesis. This is especially useful in treating hypogonadal men who are interested in fertility. To review the literature regarding the use of CC in the setting of hypogonadism. A review of the relevant literature through September 2018 was performed via PubMed. The data regarding the efficacy and safety of CC when used in the setting of hypogonadism is summarized. Although results are mixed, many studies show CC reduces symptoms in hypogonadal men. Studies have also shown improvement in erectile function and bone mineral density, as well as a reduction in body mass index. There have been few studies investigating fertility rates in hypogonadal men treated with CC, but a metaanalysis of these shows significant improvement in fertility rates. Several studies show improvement in semen parameters. Few studies have investigated adverse effects of the drug. Reports include headache, dizziness, gynecomastia, and exacerbation of psychiatric illnesses. Despite these reports, CC is generally considered to be safe and well tolerated. CC is safe and effective and should remain in the armament of urologists treating hypogonadal men, especially men interested in preservation of fertility. Wheeler KM, Sharma D, Kavoussi PK, etal. Clomiphene citrate for the treatment of hypogonadism. Sex Med Rev 2019;7:272-276.

Computational and biological approach for studying structure-function of inhibin chimeric peptide antibodies in Clarias batrachus

Inhibins are heterodimeric glycoproteins that belong to transforming growth factor-β superfamily. The present study was aimed at structural elucidation of immunogenic inhibin chimeric peptide (ICP) using immunoinformatics tools, to develop anti-ICP antibodies and to understand the mechanism of interaction between HPG-axis and anti-ICP antibodies in adult female Clarias batrachus. Homology modelling predicted that the ICP adopts a turn and random coil, which was further confirmed by circular dichroism (CD). Competitive binding ELISA with ICP and different unrelated peptides confirmed that the developed anti-ICP antiserum is highly specific and critical for the direct interaction to the inhibin-α subunit. The anti-ICP antibodies increased the mRNA transcript levels of follicle stimulating hormone receptor (FSHr), luteinizing hormone receptor (LHr), activin receptor type I (Act RI) and activin receptor type II (Act RII). Further, the serum concentrations of follicle stimulating hormone (FSH), 17β-estradiol (E2) and progesterone increased significantly in anti-ICP antisera treated groups compared to control. Modelled inhibin-α and ICP exhibits better interaction with each other through two salt bridge formations. Also, ICP showed better interaction with betaglycan through positive and polar-based interactions. The results of the present study suggest that immunoneutralization of inhibin bioactivity, confirms the physiological role of inhibin as a component of ovarian feedback mechanism regulating FSH secretion through augmentation of gonadotropin and activin receptor signalling pathways that could affect the reproductive success in fishes.

Effects of environmental heat stress on reproduction and its management in chickens

The effects of environmental heat stress on reproduction in chickens were reviewed to find out the associated physiological changes and the interplay of the physiological events, after which the role of certain measures in the management of heat stress were identified. The normal rectal temperature for chicken is 40.6 - 43.0 oC with 45 oC as the upper limit of safety. The rectal temperature begins to increase when the ambient temperature increases, but this is prevented by panting to increase heat loss by respiratory evaporation of water. Chickens are said to be heat stressed when their body heat builds up during high ambient temperature. The physiological responses associated with it include respiratory alkalosis from panting, reduced feed intake and efficiency, reduced absorption of calcium, decrease in secretion of thyroid hormones, estrogen, progesterone and testosterone, and increased secretion of glucocorticoids, luteinising hormone and follicle stimulating hormone. Consequently, heat stress produces decrease in anabolism, increase in catabolism and insulin resistance, loss in body weight, delayed sexual maturity, reduction in number and quality of eggs, infertility in male and female chickens and reduced hatchability of fertile eggs with the greatest effect being on the number and quality of eggs produced. The impact of environmental heat stress remains a challenge as it affects reproduction in chickens and researches in this area are necessary to support increased productivity of chickens in hot semi-arid regions.Keywords: Chickens, eggs, heat stress, management, reproduction

Effects of intracerebroventricular administration of irisin on the hypothalamus-pituitary-gonadal axis in male rats.

Irisin is a product of fibronectin type III domain-containing protein 5 (FNDC5) and plays an important role in energy homeostasis. In this study, we aimed to determine effects of intracerebroventricular administration of irisin on the hypothalamus-pituitary-gonadal axis by molecular, biochemical, and morphological findings. Fourty male Wistar-Albino rats were used and divided into four groups including control, sham (vehicle), 10, and 100 nM irisin infused groups (n = 10). Hypothalamic gonadotropin releasing hormone (GnRH) level and serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels were determined. Testicular tissue histology and spermiogram analysis were also performed. Both irisin concentrations significantly reduced hypothalamic GnRH messenger RNA (mRNA) and protein levels (p < 0.05). It was found that serum LH, FSH, and testosterone levels and Sertoli and Leydig cell numbers were decreased by irisin administration (p < 0.05). In addition, irisin administration reduced sperm density and mobility (p < 0.05). However, it did not cause any change in testicular and epididymis weights and tubular diameter. Our results reveal that irisin can play a role in the central regulation of reproductive behavior and also reduces testosterone levels by suppressing LH and FSH secretion. These results suggest that the discovery of irisin receptor antagonists may be beneficial in the treatment of infertility.

Subplasmalemmal hydrogen peroxide triggers calcium influx in gonadotropes

Gonadotropin-releasing hormone (GnRH) stimulation of its eponymous receptor on the surface of endocrine anterior pituitary gonadotrope cells (gonadotropes) initiates multiple signaling cascades that culminate in the secretion of luteinizing and follicle-stimulating hormones, which have critical roles in fertility and reproduction. Enhanced luteinizing hormone biosynthesis, a necessary event for ovulation, requires a signaling pathway characterized by calcium influx through L-type calcium channels and subsequent activation of the mitogen-activated protein kinase extracellular signal-regulated kinase (ERK). We previously reported that highly localized subplasmalemmal calcium microdomains produced by L-type calcium channels (calcium sparklets) play an essential part in GnRH-dependent ERK activation. Similar to calcium, reactive oxygen species (ROS) are ubiquitous intracellular signaling molecules whose subcellular localization determines their specificity. To investigate the potential influence of oxidant signaling in gonadotropes, here we examined the impact of ROS generation on L-type calcium channel function. Total internal reflection fluorescence (TIRF) microscopy revealed that GnRH induces spatially restricted sites of ROS generation in gonadotrope-derived αT3-1 cells. Furthermore, GnRH-dependent stimulation of L-type calcium channels required intracellular hydrogen peroxide signaling in these cells and in primary mouse gonadotropes. NADPH oxidase and mitochondrial ROS generation were each necessary for GnRH-mediated stimulation of L-type calcium channels. Congruently, GnRH increased oxidation within subplasmalemmal mitochondria, and L-type calcium channel activity correlated strongly with the presence of adjacent mitochondria. Collectively, our results provide compelling evidence that NADPH oxidase activity and mitochondria-derived hydrogen peroxide signaling play a fundamental role in GnRH-dependent stimulation of L-type calcium channels in anterior pituitary gonadotropes.

Hypoxic stress: A risk factor for post-concussive hypopituitarism?

Hypopituitarism diagnosed months or years following concussive injury can cause a variety of endocrine disturbances including insufficient secretion of human growth, luteinizing, follicle stimulating, thyroid stimulating, adrenocorticotrophic, and antidiuretic hormones. Recent evidence suggests that autoimmune reactions against pituitary and/or hypothalamic tissue constitute an etiologic factor for this hypopituitarism. One important trigger for autoimmunity is hypoxic stress. This trigger may be especially important in the post-concussive brain, which is particularly vulnerable to hypoxic stress. The vulnerable vasculature of the hypothalamic infundibulum can be a source of local exacerbation of any systemic hypoxia. Taking the above into account, it seems reasonable to hypothesize that hypoxic stress is a risk factor for post-concussive hypopituitarism. Following a discussion of literature relevant to this hypothesis, we suggest retrospective and prospective research methods for testing the hypothesis. Retrospective methods for hypothesis testing include comparing post-concussion victims with and without evidence of hypopituitarism in terms of their history of respiratory problems such as smoking, exposure to indoor and outdoor air pollution, chronic obstructive pulmonary disease, asthma, obstructive sleep apnea, and opioid use or abuse. Significantly greater incidence of respiratory history among the hypopituitarism patients would support the hypothesis. Prospective methods include performing detailed respiratory history and examination immediately post-injury, then performing periodic endocrine panels to detect hypopituitarism during long-term follow up. The hypothesis will be supported if development of hypopituitarism among patients with positive respiratory history or examination findings post-injury is more frequent than hypopituitarism among concussion victims with negative respiratory history and exam findings. If the hypothesis is supported, effective prevention of post-concussive hypopituitarism should include efforts to support optimal respiratory function. Such efforts may be relevant to treatment as well. These efforts would include respiratory therapy, smoking cessation, treatment of obstructive sleep apnea, prudent stepping down of opioid use, incentive spirometry, aerobic exercise, and other conventional measures as indicated. Non-Western measures such as yoga should be considered as well. In addition, chiropractic care as an intervention that may ameliorate hypoxia at the systemic and local levels is discussed.

Normal Menstrual Cycle

A normal menstrual cycle is the end result of a sequence of purposeful and coordinated events that occur from intact hypothalamic-pituitary-ovarian and uterine axes. The menstrual cycle is under hormonal control in the reproductively active female and is functionally divided into two phases: the proliferative or follicular phase and the secretory or luteal phase. This tight hormonal control is orchestrated by a series of negative and positive endocrine feedback loops that alter the frequency of the pulsatile secretion of gonadotropin-releasing hormone (GnRH), the pituitary response to GnRH, and the relative secretion of luteinizing hormone and follicle-stimulating hormone from the pituitary gonadotrope with subsequent direct effects on the ovary to produce a series of sex steroids and peptides that aid in the generation of a single mature oocyte and the preparation of a receptive endometrium for implantation to ensue. Any derailment along this programmed pathway can lead to an abnormal menstrual cycle with subsequent impact on the ability to conceive and maintain a pregnancy. This review contains 7 figures and 26 references Key words: follicle-stimulating hormone, follicular phase, gonadotropin-releasing hormone, luteal phase, luteinizing hormone, menstrual cycle, ovulation, progesterone, proliferative phase, secretory phase

Nesfatin-1 Ameliorates Testicular Function Changes in Type 2 Diabetic Rats

Nesfatin-1 Ameliorates Testicular Function Changes in Type 2 Diabetic Rats

The role of mitogen-activated protein kinase-extracellular receptor kinase pathway in female fertility outcomes: a focus on pituitary gonadotropins regulation.

Mammalian reproduction systems are largely regulated by the secretion of two gonadotropins, that is, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The main action of LH and FSH on the ovary is to stimulate secretion of estradiol and progesterone, which play an important role in the ovarian function and reproductive cycle control. FSH and LH secretions are strictly controlled by the gonadotropin-releasing hormone (GnRH), which is secreted from the hypothalamus into the pituitary vascular system. Maintaining normal secretion of LH and FSH is dependent on pulsatile secretion of GnRH. Extracellular signal-regulated kinase (ERK) proteins, as the main components of mitogen-activated protein kinase (MAPK) signaling pathways, are involved in the primary regulation of GnRH-stimulated transcription of the gonadotropins' α subunit in the pituitary cells. However, GnRH-stimulated expression of the β subunit has not yet been reported. Furthermore, GnRH-mediated stimulation of ERK1 and ERK2 leads to several important events such as cell proliferation and differentiation. In this review, we briefly introduce the relationship between ERK signaling and gonadotropin secretion, and its importance in female infertility.

Pituitary estrogen receptor alpha is involved in luteinizing hormone pulsatility at mid-gestation in the South American plains vizcacha, Lagostomus maximus (Rodentia, Caviomorpha)

The South American plains vizcacha, Lagostomus maximus, is a caviomorph rodent native from Argentina, Bolivia and Paraguay. It shows peculiar reproductive features like pre-ovulatory follicle recruitment during pregnancy with an ovulatory process at around mid-gestation. We have described the activation of the hypothalamic – pituitary – ovarian (HPO) axis during pregnancy. A progressive decrease of progesterone (P4) at mid-pregnancy elicits the delivery of gonadotropin-releasing hormone (GnRH) with the consequent secretion of follicle stimulating hormone (FSH) and estradiol (E2) followed by luteinizing hormone (LH) release resulting in follicular luteinization and the P4 concentration recover. Pituitary gland is the central regulator of the HPO axis being E2 a key hormone involved in the regulation of its activity. In this work we analyzed the action of E2 on the pituitary response to the GnRH wave as well as its involvement on LH secretion at mid-gestation in L. maximus. The expression of GnRHR at the pituitary pars distalis showed a significant decrease at mid-pregnancy compared to early- and term-gestating females. ERα showed a significant increment from mid-gestation whereas ERβ did not show variations throughout pregnancy; whereas the LH expression in the pituitary pars distalis showed a significant increase at mid-gestation, concordantly with serum LH, which was followed by a decrease at term-gestation with similar values than at early-pregnancy. The number of cells with co-localization of ERα and GnRHR showed a decline at mid-pregnancy related to early- and term-gestation, whereas the cells with co-localization of ERα and LH increased at mid- and term-pregnancy. On the other hand, ex vivo measuring of LH pulsatility showed a significant increment in the total mass of LH delivered at mid-pregnancy followed by a decrease at term-gestation. The stimulation of ERα with the PPT specific agonist induced a significant increment in the total mass of LH released, whereas no changes were determined when ERβ was stimulated with its specific agonist MPP. These results suggest that LH pulsatility rise at mid-pregnancy would be enabled by the increase of E2 acting through ERα.

Analysis of Follicle-Stimulating Hormone Receptor in Infantile Hemangioma.

The life cycle of infantile hemangioma (IH) and secretion of follicle-stimulating hormone (FSH) are identical. We previously have shown that IH contains the FSH receptor (FSHR). The purpose of this study was to identify which cell type(s) in IH expresses FSHR. Human proliferating IH tissues obtained during a clinically indicated surgical procedure were used. Paraffin sections and isolated cell populations (endothelial, pericyte, stem cell) were subjected to immunofluorescence for FSHR. Tissues were costained with DAPI, anti-α smooth muscle actin, or biotinylated Ulex Europaeus Agglutinin I to identify nuclei, pericytes, and endothelial cells, respectively. Whole tissue and purified single cell populations underwent polymerase chain reaction (PCR) for FSHR. Positive control specimens (ovary, sertoli cells) and negative control tissues (skin/subcutis, hepatic cells) were included. Immunofluorescence of 9 IHs demonstrated that FSHR was enriched in pericytes compared with endothelial cells. Follicle-stimulating hormone receptor was expressed in 6 of 6 whole tissue IHs along with the positive control via PCR. Follicle-stimulating hormone receptor was not present in the negative control samples. Four of 5 sets of pericytes expressed FSHR by PCR. Neither IH endothelial cells, IH stem cells, nor negative control cells exhibited FSHR by PCR. Because the secretion of FSH correlates with the growth pattern of IH, FSH might be involved in the disease process. Follicle-stimulating hormone receptor is enriched in the pericytes of IH, suggesting that this cell type may be involved in the pathogenesis of the tumor.

Normal Menstrual Cycle

A normal menstrual cycle is the end result of a sequence of purposeful and coordinated events that occur from intact hypothalamic-pituitary-ovarian and uterine axes. The menstrual cycle is under hormonal control in the reproductively active female and is functionally divided into two phases: the proliferative or follicular phase and the secretory or luteal phase. This tight hormonal control is orchestrated by a series of negative and positive endocrine feedback loops that alter the frequency of the pulsatile secretion of gonadotropin-releasing hormone (GnRH), the pituitary response to GnRH, and the relative secretion of luteinizing hormone and follicle-stimulating hormone from the pituitary gonadotrope with subsequent direct effects on the ovary to produce a series of sex steroids and peptides that aid in the generation of a single mature oocyte and the preparation of a receptive endometrium for implantation to ensue. Any derailment along this programmed pathway can lead to an abnormal menstrual cycle with subsequent impact on the ability to conceive and maintain a pregnancy. This review contains 7 figures and 26 references Key words: follicle-stimulating hormone, follicular phase, gonadotropin-releasing hormone, luteal phase, luteinizing hormone, menstrual cycle, ovulation, progesterone, proliferative phase, secretory phase

Low-dose brain estrogen prevents menopausal syndrome while maintaining the diversity of the gut microbiomes in estrogen-deficient rats.

We evaluated the effects of intracerebroventricular administration (ICV) of brain estrogen and progesterone on menopausal symptoms and their effects on the secretion of follicle-stimulating hormone(FSH) and luteinizing hormone (LH) in estrogen-deficient rats. Three weeks after ovariectomy (OVX) or sham operation, OVX rats were given ICV infusions of either 17β-estradiol (4 μg/day; ICV-E), progesterone(0.8 μg/day; ICV-P), or vehicle (control) for 4 wk. OVX rats in the positive-control group were orally provided 150 μg 17β-estradiol·kg body wt-1·day-1. Sham rats had ICV vehicle infusion (normal-control). Serum 17β-estradiol levels of ICV-E and ICV-P groups were higher than the control group but much lower than the normal- and positive-control groups. Tail skin temperature was higher in the control group than the other groups. Serum FSH and LH levels were much higher in the control group than positive- and normal-control groups, but ICV-E and ICV-P lowered the levels similar to the normal-control treatment. ICV-E and ICV-P prevented the decreased energy expenditure in OVX rats. Homeostasis model assessment estimate of insulin resistance was lowered in the descending order of the control, positive-control, ICV-P, ICV-E, and normal-control treatments. The decreased bone mineral density was prevented by the positive-control, ICV-E, and ICV-P treatments. The control group exhibited decreased short-term memory and spatial memory compared with the other groups. Surprisingly, the control group exhibited a decreased richness of the gut microbiome compared with normal-control group, and ICV-E protected against the decrease the most. In conclusion, small amounts of brain estrogen and, to some extent, progesterone improved menopausal symptoms by decreasing serum FSH levels and maintaining the diversity of the gut microbiome in estrogen-deficient rats.

Regulation of FSH expression by differentially expressed miR-186-5p in rat anterior adenohypophyseal cells.

Follicle-stimulating hormone (FSH) has key roles in animal reproduction, including spermatogenesis and ovarian maturation. Many factors influence FSH secretion. However, despite the broad functions of microRNAs (miRNAs) via the regulation of target genes, little is known about their roles in FSH secretion. Our previous results suggested that miR-186-5p targets the 3′ UTR of FSHb; therefore, we examined whether miR-186-5p could regulate FSH secretion in rat anterior adenohypophyseal cells. miR-186-5p was transfected into rat anterior pituitary cells. The expression of FSHb and the secretion of FSH were examined by RT-qPCR and ELISA. A miR-186-5p mimic decreased the expression of FSHb compared with expression in the control group and decreased FSH secretion. In contrast, both the mRNA levels and secretion of FSH increased in response to miR-186-5p inhibitors. Our results demonstrate that miR-186-5p regulates FSH secretion by directly targeting the FSHb 3′ UTR, providing additional functional evidence for the importance of miRNAs in the regulation of animal reproduction.

Molecular regulation of follicle-stimulating hormone synthesis, secretion and action.

Follicle-stimulating hormone (FSH) plays fundamental roles in male and female fertility. FSH is a heterodimeric glycoprotein expressed by gonadotrophs in the anterior pituitary. The hormone-specific FSHβ-subunit is non-covalently associated with the common α-subunit that is also present in the luteinizing hormone (LH), another gonadotrophic hormone secreted by gonadotrophs and thyroid-stimulating hormone (TSH) secreted by thyrotrophs. Several decades of research led to the purification, structural characterization and physiological regulation of FSH in a variety of species including humans. With the advent of molecular tools, availability of immortalized gonadotroph cell lines and genetically modified mouse models, our knowledge on molecular mechanisms of FSH regulation has tremendously expanded. Several key players that regulate FSH synthesis, sorting, secretion and action in gonads and extragonadal tissues have been identified in a physiological setting. Novel post-transcriptional and post-translational regulatory mechanisms have also been identified that provide additional layers of regulation mediating FSH homeostasis. Recombinant human FSH analogs hold promise for a variety of clinical applications, whereas blocking antibodies against FSH may prove efficacious for preventing age-dependent bone loss and adiposity. It is anticipated that several exciting new discoveries uncovering all aspects of FSH biology will soon be forthcoming.

GnRH Receptor Expression and Reproductive Function Depend on JUN in GnRH Receptor‒Expressing Cells.

Gonadotropin-releasing hormone (GnRH) from the hypothalamus regulates synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gonadotropes. LH and FSH are heterodimers composed of a common α-subunit and unique β-subunits, which provide biological specificity and are limiting components of mature hormone synthesis. Gonadotrope cells respond to GnRH via specific expression of the GnRH receptor (Gnrhr). GnRH induces the expression of gonadotropin genes and of the Gnrhr by activation of specific transcription factors. The JUN (c-Jun) transcription factor binds to AP-1 sites in the promoters of target genes and mediates induction of the FSHβ gene and of the Gnrhr in gonadotrope-derived cell lines. To analyze the role of JUN in reproductive function in vivo, we generated a mouse model that lacks JUN specifically in GnRH receptor‒expressing cells (conditional JUN knockout; JUN-cKO). JUN-cKO mice displayed profound reproductive anomalies such as reduced LH levels resulting in lower gonadal steroid levels, longer estrous cycles in females, and diminished sperm numbers in males. Unexpectedly, FSH levels were unchanged in these animals, whereas Gnrhr expression in the pituitary was reduced. Steroidogenic enzyme expression was reduced in the gonads of JUN-cKO mice, likely as a consequence of reduced LH levels. GnRH receptor‒driven Cre activity was detected in the hypothalamus but not in the GnRH neuron. Female, but not male, JUN-cKO mice exhibited reduced GnRH expression. Taken together, our results demonstrate that GnRH receptor‒expression levels depend on JUN and are critical for reproductive function.