Pituitary Gonadotropin Release Research Articles

Effects of growth hormone and sex steroid therapy on brain structure and pituitary function in turner syndrome

Introduction: Turner syndrome (TS) is a chromosomal disorder affecting approximately 1 in 2,500 live female births, characterized by the partial or complete absence of one X chromosome. This genetic anomaly leads to physical, cognitive, and endocrine abnormalities, including short stature, gonadal dysgenesis, and structural brain anomalies. Cognitive deficits in TS involve visuospatial processing, memory, and executive function, often linked to structural brain changes. Magnetic resonance imaging (MRI) has revealed significant alterations in gray and white matter volumes in various brain regions. Growth hormone (GH) and sex steroid therapies, such as estrogen and progesterone, are used to address growth and developmental delays in TS. However, their impact on brain structure and pituitary function remains an area of active research. Aim of the Review: To systematically review and synthesize findings on the effects of GH and sex steroid therapy on brain structure and pituitary function in patients with Turner syndrome. Methods: A comprehensive literature review was conducted to identify studies examining the effects of GH and sex steroid therapy on brain structure and pituitary function in TS. Data from various sources were compiled, focusing on MRI-based structural brain changes. Key parameters analyzed included sample size, findings from MRI and fMRI studies, and clinical associations. Studies were summarized and presented in a structured table format. Results: Estrogen-progesterone treatment was found to suppress pituitary gonadotropin release more effectively than estrogen alone, indicating a feedback interaction between pituitary gonadotropin release and sex steroids. MRI studies showed that TS patients exhibit smaller volumes in the hippocampus, caudate, lenticular, thalamic nuclei, and parieto-occipital brain matter, correlating with cognitive deficits. GH-IGF axis abnormalities are modulated by body composition and physical fitness, with sex hormone replacement normalizing the GH-IGF axis and improving body composition. Although GH therapy alone did not significantly improve cognitive functions, the combination of GH with oxandrolone improved working memory. Estrogen deficiency and TS are associated with slower growth in parieto-occipital regions and enhanced volume growth in basal ganglia and cerebellar areas during adolescence, underscoring the importance of estrogen replacement in brain development. Discussion: GH and sex steroid therapies significantly impact brain structure, pituitary function, and clinical outcomes in TS. GH therapy, often combined with sex steroids, improves growth and cognitive functions, particularly working memory. However, GH alone does not significantly impact overall cognitive function. The timing and combination of these therapies are crucial for optimizing outcomes. Regular monitoring and individualized treatment plans are essential to address the complex needs of TS patients. Further research is needed to explore the long-term impacts of these therapies and develop optimal treatment regimens. Conclusion: GH and sex steroid therapies are vital in managing TS contributing to improved growth, body composition, and cognitive enhancements. A multifaceted therapeutic approach and regular monitoring are crucial for optimizing treatment outcomes and quality of life for TS patients.

Gonadotropin-Releasing Hormone (GnRH) and Its Agonists in Bovine Reproduction I: Structure, Biosynthesis, Physiological Effects, and Its Role in Estrous Synchronization.

GnRH is essential for the regulation of mammalian reproductive processes. It regulates the production and release of pituitary gonadotropins, thereby influencing steroidogenesis and gametogenesis. While primarily produced in the hypothalamus, GnRH is also produced in peripheral organs, such as the gonads and placenta. GnRH analogs, including agonists and antagonists, have been synthesized for the reproductive management of animals and humans. This review focuses on the functions of hypothalamic GnRH in the reproductive processes of cattle. In addition to inducing the surge release of LH, the pulsatile secretion of GnRH stimulates the pituitary gland to release FSH and LH, thereby regulating gonadal function. Various GnRH-based products have been synthesized to increase their potency and efficacy in regulating reproductive functions. This review article describes the chemical structures of GnRH and its agonists. This discussion extends to the gene expression of GnRH in the hypothalamus, highlighting its pivotal role in regulating the reproductive process. Furthermore, GnRH is involved in regulating ovarian follicular development and luteal phase support, and estrus synchronization is involved. A comprehensive understanding of the role of GnRH and its analogs in the modulation of reproductive processes is essential for optimizing animal reproduction.

KNDy neurones and GnRH/LH pulse generation: Current understanding and future aspects.

Uncovering the central mechanism underlying mammalian reproduction is warranted to develop new therapeutic approaches for reproductive disorders in humans and domestic animals. The present study focused on the role of arcuate kisspeptin neurones (also known as KNDy neurones) as an intrinsic gonadotropin-releasing hormone (GnRH) pulse generator, which plays a fundamental role in mammalian reproduction via the stimulation of pituitary gonadotropin synthesis and release and thereby in gametogenesis and steroidogenesis in the gonads of mammals. We also discuss the mechanism that inhibits pulsatile GnRH/gonadotropin release under a negative energy balance, considering that reproductive disorders often occur during malnutrition in humans and livestock.

The role of gonadotropin-releasing hormone neurons in polycystic ovary syndrome.

Given the critical central role of gonadotropin‐releasing hormone (GnRH) neurons in fertility, it is not surprising that the GnRH neural network is implicated in the pathology of polycystic ovary syndrome (PCOS), the most common cause of anovulatory infertility. Although many symptoms of PCOS relate most proximately to ovarian dysfunction, the central reproductive neuroendocrine system ultimately drives ovarian function through its regulation of anterior pituitary gonadotropin release. The typical cyclical changes in frequency of GnRH release are often absent in women with PCOS, resulting in a persistent high‐frequency drive promoting gonadotropin changes (i.e., relatively high luteinizing hormone and relatively low follicle‐stimulating hormone concentrations) that contribute to ovarian hyperandrogenemia and ovulatory dysfunction. However, the specific mechanisms underpinning GnRH neuron dysfunction in PCOS remain unclear. Here, we summarize several preclinical and clinical studies that explore the causes of aberrant GnRH secretion in PCOS and the role of disordered GnRH secretion in PCOS pathophysiology.

Photoperiodic light pulse induces ovarian development in the catfish, Mystus cavasius: Possible roles of dopamine and melatonin in the brain

In the freshwater catfish, Mystus cavasius, locally known as gulsha, ovarian maturation is triggered by long-day conditions. Using dopaminergic neuronal activity in the brain, the purpose of this study was to identify the brain’s detection of a nocturnal light pulse that induced ovarian development. Since direct inhibition of pituitary gonadotropin release is exerted by dopamine (DA), it may serve as a neuromodulator of photoperiodic stimulation in teleosts. We studied functional effects of photoperiodicity on dopaminergic rhythmicity in gulsha brain. Nocturnal illumination and Nanda-Hamner photocycles revealed that ovarian development is induced by a 1 h light pulse between zeitgeber time (ZT) 12 and 13. Daily fluctuations in DA, 3, 4-dihydroxyphenylacetic acid (DOPAC) and DOPAC/DA were observed under a 12L:12D photoperiod. Fish exhibited increased levels during the daytime and decreased levels at night. Rhythmic patterns of dopaminergic activity also showed clear circadian oscillations under constant light, but not constant dark conditions. After 7 days of exposure to long photoperiod (14L:10D), DA, DOPAC and DOPAC/DA in the brain at ZT12 and ZT16 were significantly higher than during a short photoperiod (10L:14D). Melatonin-containing water inhibited the release of DA and DOPAC 6 h and 24 h after treatment, respectively, and DOPAC/DA 6 h after treatment. This inhibition was blocked by the melatonin receptor antagonist, luzindole. These results suggest that a 1 h nocturnal light pulse induces ovarian development through alteration of dopaminergic neuronal excitability in the brain, via oscillation in melatonin triggered by photic stimuli, which may interfere with the reproductive endocrine axis in gulsha.

The Role of GnIH in Biological Rhythms and Social Behaviors.

Gonadotropin-inhibitory hormone (GnIH) was first discovered in the Japanese quail, and peptides with a C-terminal LPXRFamide sequence, the signature protein structure defining GnIH orthologs, are well conserved across vertebrate species, including fish, reptiles, amphibians, avians, and mammals. In the mammalian brain, three RFamide-related proteins (RFRP-1, RFRP-2, RFRP-3 = GnIH) have been identified as orthologs to the avian GnIH. GnIH is found primarily in the hypothalamus of all vertebrate species, while its receptors are distributed throughout the brain including the hypothalamus and the pituitary. The primary role of GnIH as an inhibitor of gonadotropin-releasing hormone (GnRH) and pituitary gonadotropin release is well conserved in mammalian and non-mammalian species. Circadian rhythmicity of GnIH, regulated by light and seasons, can influence reproductive activity, mating behavior, aggressive behavior, and feeding behavior. There is a potential link between circadian rhythms of GnIH, anxiety-like behavior, sleep, stress, and infertility. Therefore, in this review, we highlight the functions of GnIH in biological rhythms, social behaviors, and reproductive and non-reproductive activities across a variety of mammalian and non-mammalian vertebrate species.

Impact of Clomiphene Citrate on the Steroid Profile in Dysmetabolic Men with Low Testosterone Levels.

Clomiphene citrate (CC) in male hypogonadism increases testosterone (T) and estrogen levels by stimulating pituitary gonadotropin release. Our group confirmed these hormonal changes in a randomized, cross-over, double-blind trial of CC versus placebo in addition to metformin, conducted in 21 obese dysmetabolic men with low T levels. However, we hypothesize that based on its mechanism of action, CC may directly or indirectly affect adrenal steroidogenesis. The aim of this sub-study was to better understand the changes in steroid levels and metabolism induced by CC treatment. We assessed 17α-hydroxypregnelone (17αOH-P5), dehydroepiandrosterone (DHEA), progesterone (P4), 17α-hydroxyprogesterone (17αOH-P4), androstenedione (A), T, dihydrotestosterone (DHT), estrone (E1), 17β-estradiol (E2), 11-deoxycortisol (11 S), cortisol (F), and cortisone (E) by LC-MS/MS, and corticosteroid binding globulin (CBG) by ELISA, before and after each treatment. In addition, free-F and steroid product/precursor ratios were calculated. We observed a significant change in serum levels induced by CC compared with placebo for 17αOH-P4, DHT, T, E2, E1, F, E, and CBG, but not free-F. In addition, compared to placebo, CC induced higher 17αOH-P4/P4, E2/E1, 17αOH-P4/17αOH-P5, A/17αOH-P4, T/A, E1/A, F/11 S, and F/E ratios. Therefore, besides the CC stimulating effect on testis steroidogenesis, our study showed increased F, E, but not free-F, levels, indicating changes in steroid metabolism rather than adrenal secretion stimulation. The steroid profiling also revealed the CC stimulation of the Δ5 rather than the Δ4 pathway, thus indicating considerable testicular involvement in the increased androgen secretion.

Kobayashi Award 2019: The neuroendocrine regulation of the mammalian reproduction

Mammalian reproductive function is a complex system of many players orchestrated by the hypothalamus-pituitary–gonadal (HPG) axis. The hypothalamic gonadotropin-releasing hormone (GnRH) and the consequent pituitary gonadotropin release show two modes of secretory patterns, namely the surge and pulse modes. The surge mode is triggered by the positive feedback action of estrogen secreted from the mature ovarian follicle to induce ovulation in females of most mammalian species. The pulse mode of GnRH release is required for stimulating tonic gonadotropin secretion to drive folliculogenesis, spermatogenesis and steroidogenesis and is negatively fine-tuned by the sex steroids. Accumulating evidence suggests that hypothalamic kisspeptin neurons are the master regulator for animal reproduction to govern the HPG axis. Specifically, kisspeptin neurons located in the anterior hypothalamus, such as the anteroventral periventricular nucleus (AVPV) in rodents and preoptic nucleus (POA) in ruminants, primates and others, and the neurons located in the arcuate nucleus (ARC) in posterior hypothalamus in most mammals are considered to play a key role in generating the surge and pulse modes of GnRH release, respectively. The present article focuses on the role of AVPV (or POA) kisspeptin neurons as a center for GnRH surge generation and of the ARC kisspeptin neurons as a center for GnRH pulse generation to mediate estrogen positive and negative feedback mechanisms, respectively, and discusses how the estrogen epigenetically regulates kisspeptin gene expression in these two populations of neurons. This article also provides the mechanism how malnutrition and lactation suppress GnRH/gonadotropin pulses through an inhibition of the ARC kisspeptin neurons. Further, the article discusses the programming effect of estrogen on kisspeptin neurons in the developmental brain to uncover the mechanism underlying the sex difference in GnRH/gonadotropin release as well as an irreversible infertility induced by supra-physiological estrogen exposure in rodent models.

Nerve Growth Factor (NGF) and Animal Reproduction.

Stimuli that lead to the release of gonadotropin-releasing hormone (GnRH) and pituitary gonadotropins and, consequently, ovulation in mammals fall into two broad categories. In the first, high plasma oestrogen concentrations induce the events that trigger ovulation, a characteristic of spontaneous ovulators. In the second, nerve stimuli occurring during mating reach the hypothalamus and trigger the release of GnRH and ovulation with a neuroendocrine reflex that characterizes induced ovulators.In this review, we will give an overview of the distribution of NGF and its expression in the different tissues of the male accessory sex glands, the main sites of NGF production. Next, we will highlight the role of NGF in sperm function and its potential cryopreserving role in artificial insemination techniques. Finally, we will evaluate the functions of NGF in ovulation, particularly in induced ovulators. Overall, the information obtained so far indicates that NGF is widely distributed in organs that regulate the reproductive activity, in both males and females. In spontaneous ovulators, NGF exerts mainly a luteotrophic action, while, in induced ovulators it is the main ovulation-inducing factor. A better understanding of the role of NGF in reproduction would be of great interest, since it could help finding innovative therapeutic aids to improve mammalian fertility.

Effects of repeated immobilization stress on hypothalamic-pituitary- ovarian axis in female rats

Objective: To explore the effects of repeated immobilization stress on hypothalamic-pituitary-ovarian axis in female rats. Methods: Forty female SD rats were randomly divided into two groups: control group (n=20) and experimental group (n=20). One group was fed normally, the other group was subjected to incremental load restraint stress. Brake stress once a day in the retainer (starting at 9: 00 a.m.), braking for 2 hours on the first day, increasing load by 0.5 hours a day for two weeks. Body weight, estrous cycle, sex hormone, organ coefficient, pathology and expression of related genes were detected to explore the harm of hypothalamic-pituitary-ovarian axis. Results: Repeated immobilization stress caused weight loss, prolonged estrous cycle, and changed the organ coefficient and morphology of ovaries and uterus. QPCR technique was used to detect the related genes. It was found that the expressions of gonadotropin releasing hormone, pituitary gonadotropin releasing hormone receptor, follicle stimulating hormone and luteinizing hormone mRNA were decreased significantly, while the expressions of ovarian follicle stimulating hormone and luteinizing hormone receptor mRNA were increased significantly. The expression of estrogen receptor mRNA in ovary and uterus was decreased significantly. Conclusion: Repeated immobilization stress may disrupt the estrous cycle by interfering with the endocrine regulation of the hypothalamic-pituitary-ovarian axis, thus damaging the gonadal and reproductive endocrine function of female animals.

Central and peripheral actions of melatonin on reproduction in seasonal and continuous breeding mammals

Under field conditions, especially for mammals that inhabit high latitudes, the regulation of seasonal breeding activity to ensure delivery of the young at the time most conducive to their survival is essential. This is most frequently accomplished by the annual reproductive cycle being linked to seasonal photoperiod changes which determine the nocturnal duration of the pineal melatonin signal. Mating can occur during any season that ensures spring/early summer delivery of the offspring. Thus, the season of mating is determined by the duration of pregnancy. The precise hormonal control of the annual cycle of reproduction by melatonin is accomplished at the level of the hypothalamo-pituitary axis which, in turn, determines the physiological state of the gonad and adnexa due to the regulation of pituitary gonadotrophin release. Many species are continuous rather than seasonal breeders. In these species, melatonin has a minor hormonal influence on the central regulation of reproduction but, nevertheless, its antioxidant functions at the level of the gonads support optimal reproductive physiology. Possibly like all cells, those in the ovary, e.g., granulosa cells and oocytes (less is known about melatonin synthesis by the testes or spermatogenic cells), synthesize melatonin which is used locally to combat free radicals and reactive nitrogen species which would otherwise cause oxidative/nitrosative stress to these critically important cells. Oxidative damage to the oocyte, zygote, blastocyst, etc., results in an abnormal fetus which is either sloughed or gives rise to an unhealthy offspring. The importance of the protection of the gametes (both oocytes and sperm) from oxidative molecular mutilation cannot be overstated. Fortunately, as a highly effective free radical scavenger and indirect antioxidant (by upregulating antioxidant enzyme), locally-produced melatonin is in the optimal location to protect the reproductive system from such damage.

Study on the Mechanism of Sarsasapogenin in Treating Precocious Puberty by Regulating the HPG Axis.

The present study aims to investigate the effects and mechanisms of sarsasapogenin resistance to precocious puberty. Female Sprague Dawley rats were divided into a normal (N) group, model (M) group, leuprolide (L) group, and sarsasapogenin (Sar) group. Rats at 5 days of age were given a single subcutaneous injection of 300 micrograms of danazol to establish the precocious puberty model. After 10 days of modeling, drug intervention was started. The development of the uterus and ovary was observed by hematoxylin and eosin (HE) staining. The levels of the serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E2) were determined by radioimmunoassay. Also, the expressions of the hypothalamic gonadotropin releasing hormone (GnRH), Kiss-1, G protein-coupled receptor 54 (GPR54), and pituitary gonadotropin releasing hormone receptor (GnRH-R) were detected by RT-PCR. The results showed that compared with the model group, sarsasapogenin could significantly delay the opening time of vaginal, decreased uterine and ovarian coefficients, and reduced uterine wall thickness. Moreover, it can significantly downregulate the levels of serum hormones and reduce the expression of GnRH, GnRH-R, and kiss-1. In summary, our results indicate that sarsasapogenin can regulate the HPG axis through the kiss-1/GPR54 system for therapeutic precocious puberty.

Relative energy deficiency in sports (RED-S): elucidation of endocrine changes affecting the health of males and females.

The purpose of this review is to present a different perspective of the relative energy deficiency syndrome, to improve understanding of associated endocrine alterations, and to highlight the need for further research in this area. The term "female athlete triad" was coined over 25years ago to describe three interrelated components: disordered eating, menstrual dysfunction, and low bone mass. The syndrome's etiology is attributed to energy intake deficiency relative to energy expenditure required for health, function, and daily living. Recently, it became clear that there was a need to broaden the term, as the disorder is not an issue of only three interrelated problems but of a whole spectrum of insults resulting from low energy availability (LEA; i.e., insufficient energy availability to cover basic physiological demands) that can potentially affect any exerciser, irrespective of gender. The new model, termed relative energy deficiency in sport (RED-S), has received greater scrutiny in sports medicine due to its effects on both health and performance in athletes of both sexes. RED-S results from low-energy diets (intentional or unintentional) and/or excessive exercise. Energy deficiency reduces hypothalamic pulsatile release of gonadotropin-releasing hormone, this impairing anterior pituitary release of gonadotropins. In women, reduced FSH and LH pulsatility produces hypoestrogenism, causing functional hypothalamic amenorrhea and decreased bone mass. In men, it reduces testosterone and negatively affects bone health. Moreover, LEA alters other hormonal pathways, causing physiological consequences, such as alteration of the thyroid hormone signaling pathways, leptin levels, carbohydrate metabolism, the growth hormone/insulin-like growth factor-1 axis, and sympathetic/parasympathetic tone. This review explains and clarifies the effects of RED-S in both sexes.

Interactions of circulating estradiol and progesterone on changes in endometrial area and pituitary responsiveness to GnRH†.

Changes in circulating progesterone (P4) and estradiol (E2) during proestrus produce dynamic changes in endometrial function and pituitary release of gonadotropins. Independent and combined effects of P4 and E2 on endometrium and pituitary were evaluated. In a preliminary study, an exogenous hormone model of proestrus was created by removal of corpus luteum and follicles ≥5mm followed by gradual removal of intravaginal P4 implants during 18h and treatment with increasing doses of estradiol benzoate during 48h to mimic proestrus using high E2 (n=9) or low E2 (n=9). Decreased P4, increased E2, and increased endometrial area (EA) simulated proestrus in high-E2 cows and this was used subsequently. The main experiment used a 2×2 factorial design with: high E2 and low P4 (n=11); high E2 and high P4 (n=11); low E2 and high P4 (n=11); low E2 and low P4 (n=10). At 48h, gonadotropin-releasing hormone (GnRH)-induced luteinizing hormone (LH) and follicle stimulating hormone (FSH) release was determined. Variables were analyzed using PROCMIXED of Statistical Analysis System. The EA increased dramatically during 48h only in high-E2 and low-P4 cows. For FSH, high-E2 cows had greater area under the curve (AUC) and FSH peak after GnRH than low E2, with mild negative effects of high P4. For LH, concentration at peak and AUC were 2-fold greater in high E2 compared to low-E2 groups, with low P4 also 2-fold greater than high-P4 groups. Thus, maximal changes in uterus and pituitary during proestrus depend on both low P4 and high E2, but different physiologic responses are regulated differently by E2 and P4. Changes in endometrium depend on low P4 and high E2, whereas GnRH-induced FSH secretion primarily depends on high E2, and GnRH-induced LH secretion is independently increased by high E2 or reduced by high P4.

Current understanding of hypothalamic amenorrhoea.

Hypothalamic amenorrhoea (HA) accounts for approximately 30% of cases of secondary amenorrhoea in women of reproductive age. It is caused by deficient secretion of hypothalamic gonadotrophin-releasing hormone, which in turn leads to failure of pituitary gonadotrophin and gonadal steroid release. Functional HA (FHA) is defined as HA occurring in the absence of a structural lesion and is predominantly caused by significant weight loss, intense exercise or stress. Treatment of FHA is crucial in avoiding the long-term health consequences on fertility and bone health, in addition to reducing psychological morbidity. This article summarises our understanding of the mechanisms underlying FHA, the evidence base for its clinical management and emerging therapies.

372 Baseline Gonadotropin Levels do not Predict Testosterone Response in Hypogonadal Men Treated with Clomiphene Citrate

Clomiphene citrate (CC) is commonly used in the treatment of male hypogonadism/infertility and stimulates pituitary gonadotropin release. Patients variably respond to CC treatment, but whether baseline gonadotropin levels can be used to select patients for CC treatment is unknown. To investigate the role of baseline gonadotropins in predicting the biochemical response to CC treatment. Retrospective review of data from hypogonadal men treated with CC in two high-volume fertility centers was performed between 2013 and 2018. Patient age, body mass index (BMI), and baseline hormones (follicle stimulating hormone [FSH], luteinizing hormone [LH], and total testosterone [TT]) were obtained. Men on exogenous testosterone or gonadotropins within 6 months of CC treatment were excluded. CC starting dose varied from 25-50 mg every day to every other day. Response in treatment was measured as changes in continuous TT levels within 6 months of initiating CC treatment. Linear and curvilinear (quadratic fit) correlations were assessed between baseline gonadotropins and changes in TT levels. We defined the optimal slope transition point, fitting a piecewise linear regression at a threshold that maximized the multiple R statistics. Linear regression models adjusted for age, BMI, and time on CC therapy were fitted to assess the associations between baseline LH and FSH levels with treatment response.

RF9: May it be a new therapeutic option for hypogonadotropic hypogonadism?

Hypogonadotropic hypogonadism (secondary hypogonadism), congenital or acquired, is a form of hypogonadism that is due to problems with either the hypothalamus or pituitary gland affecting gonadotropin levels. Pulsatile secretion of gonadotropin-releasing hormone (GnRH) by hypothalamus is a primer step to initiate the release of pituitary gonadotropins. Kisspeptin and gonadotropin-inhibitory hormone (GnIH) are accepted as two major players in the activation and inhibition of GnRH regarding the neuroendocrine functioning of the hypothalamic pituitary gonadal axis. Kisspeptin is known as the most potent activator of GnRH. Regarding the inhibition of GnRH, RF-amide-related peptide-3 (RFRP-3) is accepted as the mammalian orthologue of GnIH in avian species. RF9 (1-adamantane carbonyl-Arg-Phe-NH2) is an antagonist of RFRP-3/GnIH receptor (neuropeptide FF receptor 1 (NPFFR1; also termed as GPR147). In recent years, several studies have indicated that RF9 activates GnRH neurons and gonadotropins in a kisspeptin receptor (Kiss1r, formerly known as GPR54) dependent manner. These results suggest that RF9 may have a bimodal function as both an RFRP-3 antagonist and a kisspeptin agonist or it may be a kiss1r agonist rather than an RFRP-3/GnIH receptor antagonist. These interactions are possible because Kisspeptin and GnIH are members of the RF-amide family, and both possibilities are not far from explaining the potent gonadotropin stimulating effects of RF9. Therefore, we hypothesize that RF9 may be a new therapeutic option for the hypogonadotropic hypogonadism due to its potent GnRH stimulating effects. A constant or repeated administration of RF9 provides a sustained increase in plasma gonadotrophin levels. However, applications in the same way with GnRH analogues and kisspeptin may result in desensitization of the gonadotropic axis. The reasons reported above contribute to our hypothesis that RF9 may be a good option in the GnRH stimulating as a kisspeptin agonist. We suggest that further studies are needed to elucidate the potential effects of RF9 in the treatment of the hypogonadotropic hypogonadism.

Obesity‐Related Stressors Repress Gonadotropin‐releasing Hormone Gene Expression via the Transcription Factor c‐Fos

In obesity, endoplasmic reticulum (ER) stress is a well‐characterized mediator of hormonal dysfunction in multiple tissues, including liver, pancreas, and adipose tissue. In the brain, ER stress induced by excess nutrients and inflammatory cytokines disrupts insulin and leptin sensitivity in hypothalamic neurons controlling food intake. Obesity‐related cellular stressors may also disrupt hypothalamic control of the reproductive system, as obesity is a risk factor for infertility in both men and women. Thus, we sought to determine how ER stress and nutrient excess directly affect production of gonadotropin‐releasing hormone (GnRH) by hypothalamic neurons. GnRH controls pituitary gonadotropin release and subsequent gonadal function, and expression of the Gnrh1 gene is regulated by multiple transcription factors and signaling pathways. Using an immortalized mouse hypothalamic cell line (GT1‐7), we determined that ER stress induced by tunicamycin or thapsigargin repressed expression of the Gnrh1 gene as measured by qRT‐PCR. We also exposed cells to a saturated fatty acid (palmitic acid) to mimic excess nutrients in obesity and observed similar Gnrh1 repression. Both ER stress and palmitic acid promoted inflammation in GT1‐7 cells, as measured by NFκB and JNK activation and IL‐6 production. Repression of Gnrh1 by ER stress was partially rescued by PKC and JNK inhibitors. Because ER stress and palmitic acid upregulated expression of Fos, and because c‐Fos is a known repressor of Gnrh1, we asked whether inhibition of c‐Fos transcriptional activity could rescue Gnrh1 repression. The c‐Fos/AP‐1 inhibitor T5224 was able to completely reverse repression of Gnrh1 by ER stress and palmitic acid, indicating a pivotal role for c‐Fos induction in Gnrh1 repression by obesity‐related stressors. Thus, our work suggests that obesity‐related stressors can directly impact GnRH neurons, and that dysregulation of Gnrh1 expression may contribute to obesity‐related infertility.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Elevated Expression of follistatin Gene in the Pituitaries of Allotriploid Crucian Carp

AbstractAs a paracrine factor, Follistatin (Fst) plays an important role in regulating biosynthesis and release of pituitary gonadotropin (GTH), gonadal development, and ovulation cycle. In this study, full‐length complementary DNAs (cDNAs) of the follistatin gene in diploid red crucian carp, Carassius auratus red var., allotriploid crucian carp, and allotetraploid hybrids were obtained. Our data showed that the cDNAs of follistatin of all three fish encoded 322 amino acids. Referring to the structural characteristics of Fst in other species, we found that the Fst protein of these three fish had four domains, respectively. Reverse transcriptase polymerase chain reaction (PCR) indicated that the follistatin gene was widely expressed in all tested tissues, except spleens, in these three fish. Real‐time quantitative PCR analysis of different seasonal profiles showed that allotriploids had significantly higher expression of follistatin messenger RNA in pituitaries during both the prespawning and spawning periods. These results suggest that the elevated expression of the follistatin gene in the pituitaries of allotriploids might lead to sterility of allotriploids by blocking the inhibitory effect of activin on luteinizing hormone β subunit. Furthermore, the results may improve our understanding of reproduction characteristics in triploids, which benefits polyploidy breeding.

Using kisspeptin to assess GnRH function in an unusual case of primary amenorrhoea.

SummaryPrimary amenorrhoea is defined as the failure to commence menstruation by the age of 15 years, in the presence of normal secondary sexual development. The potential causes of primary amenorrhoea extend from structural to chromosomal abnormalities. Polycystic ovarian syndrome (PCOS) is a common cause of secondary amenorrhoea but an uncommon cause of primary amenorrhoea. An early and prompt diagnosis of PCOS is important, as up to 30% of these women are predisposed to glucose intolerance and obesity, with the subgroup of women presenting with primary amenorrhoea and PCOS displaying a higher incidence of metabolic dysfunction. We describe a case of an 18-year-old female presenting with primary amenorrhoea of unknown aetiology. Although initial investigations did not demonstrate clinical or biochemical hyperandrogenism or any radiological evidence of polycystic ovaries, a raised luteinising hormone (LH) suggested a diagnosis of PCOS. If PCOS was the correct diagnosis, then one would expect intact hypothalamic GnRH and pituitary gonadotropin release. We used the novel hormone kisspeptin to confirm intact hypothalamic GnRH release and a GnRH stimulation test to confirm intact pituitary gonadotroph function. This case highlights that kisspeptin is a potential unique tool to test GnRH function in patients presenting with reproductive disorders.Learning points:Polycystic ovarian syndrome (PCOS) can present with primary amenorrhoea, and therefore, should be considered in the differential diagnosis.PCOS is a heterogeneous condition that may present in lean women with few or absent signs of hyperandrogenism.GnRH stimulation tests are useful in evaluating pituitary function; however, to date, we do not have a viable test of GnRH function. Kisspeptin has the potential to form a novel diagnostic tool for assessing hypothalamic GnRH function by monitoring gonadotropin response as a surrogate marker of GnRH release.Confirmation of intact GnRH function helps consolidate a diagnosis in primary amenorrhoea and gives an indication of future fertility.