Luteinizing Hormone Production Research Articles

Low concentrations of the food contaminant Deoxynivalenol trigger apoptosis and impair GnRH-induced LH secretion in pituitary gonadotrope-like cells.

AbstractTheFusariummycotoxin deoxynivalenol (DON) is one of the most frequently occurring food contaminants. Nearly all individuals are exposed to DON, due to it widespread presence in grains and grain-based products. Chronic DON poisoning is associated with growth retardation, immunotoxicity as well as impaired reproduction and fetal development. At the molecular level, DON alters intracellular signaling by activating mitogen-activated protein kinases (MAPKs) that modulate cell growth, differentiation, and apoptosis. Of note, these MAPKs are also critical mediators of gonadotrophin-releasing hormone (GnRH)-induced synthesis and secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by pituitary gonadotrope cells. So far, no research has explored the potential endocrine-disrupting effects of DON on pituitary gonadotropins production. Herein, we show the first evidence that DON affects LH production by the immortalized gonadotrope-like cell line LβT2 in a concentration-dependent manner. Taken together, our experiments demonstrated that low concentrations of DON affect GnRH-induced signaling through a mechanism that, at least in part, involves apoptosis and inhibition of GnRH-induced phosphorylation of ERK-MAPK. Consequently, DON also affects the GnRH-induced expression ofCgaandLhb, two critical genes for LH synthesis and secretion by gonadotrope cells in mammals. This research broadens our knowledge of the toxicity of DON and brings a new depth to the potential neuroendocrine implications for reproduction.Graphical abstract

ZEB1 Inhibits LHβ Subunit Transcription When Overexpressed, but Is Dispensable for LH Synthesis in Mice.

Luteinizing hormone (LH), a heterodimeric glycoprotein produced by pituitary gonadotrope cells, regulates gonadal function. Hypothalamic gonadotropin-releasing hormone (GnRH) stimulates LH synthesis and secretion. GnRH induces LHβ subunit (Lhb) expression via the transcription factor, early growth response 1 (EGR1), acting on the Lhb promoter. In contrast, overexpression of zinc finger E-box binding homeobox 1 (ZEB1) represses LH production in mice, but the underlying mechanism was not previously elucidated. Here, we observed that ZEB1 inhibited GnRH-stimulated but not basal Lhb mRNA expression in homologous murine LβT2 cells. Moreover, ZEB1 blocked GnRH and/or EGR1 induction of murine Lhb but not human LHB promoter-reporter activity in these cells. Using chimeric reporters, we mapped the species-specific ZEB1 sensitivity to sequence differences, including in Z- and E-boxes, in the proximal Lhb/LHB promoters, immediately upstream of the transcription start sites. ZEB1 bound to the murine Lhb promoter with higher affinity than to the human LHB promoter in this region. To examine ZEB1's physiological role in LH synthesis, we characterized gonadotrope-specific Zeb1 knockout mice. Loss of ZEB1 in gonadotropes did not affect LH production or secretion. Collectively, the data suggest that ZEB1, when overexpressed, can inhibit GnRH/EGR1 induction of murine Lhb transcription but does not play a necessary role in LH synthesis in mice.

EFFECT OF HYPOXIC SECRETOME MESENCHYMAL STEM CELLS ON TGF-β EXPRESSION, ESTROGEN HORMONE LEVELS, AND NUMBER OF FOLLICLES (IN-VIVO EXPERIMENTAL STUDY ON FEMALE WISTAR RATS POLYCYSTIC OVARY SYNDROME-LIKE MODELS)

PCOS develops when the ovaries are stimulated to produce more androgen hormones so that the development of follicle count is disrupted. Elevated insulin levels contribute directly to abnormalities in the pituitary hypothalamus of the ovaries which have a direct impact on the occurrence of PCOS by hyperinsulinemia mechanism that increases the frequency of GnRH (Gonadotropin Releasing Hormone) secretion, LH (Luteinizing Hormone) production exceeds FSH, increased ovarian androgen production, decreased follicle count maturation, and increased TGF-β (transforming growth factor β) expression. This study aimed to determine the effect of SH-MSCs administration on TGF-β expression, estrogen hormone levels, and follicle count in female Wistar strain rats with PCOS-like. This study is an in vivo experimental study using a post-test-only control group design. The subjects of this study were female Wistar strain rats divided into 4 treatments consisting of 1 group of healthy mice, 2 negative control groups, 3 treatment groups 1, and treatment group 2 with each different dose. Then the data was analyzed using the One Way Annova Test to determine the influence of each group.One Way ANOVA test showed the results of TGF-β expression (p = 0.000), then the results of estrogen hormone levels (p = 0.000), then the Kruskall Wallis test showed the number of cystic follicles (p = 0.045) in all groups there was a significant difference (p < 0.05) except cystic follicle.There is an effect of SH-MSCs secretome administration on decreasing TGF-β expression and caustic follicle count. There is an effect of SH-MSC administration on increasing estrogen hormone levels and corpus luteum count.

Effects of intracerebroventricular administration of calcitonin gene-related peptide (CGRP) on sex hormones and sperm quality in rats.

Therapeutic strategies with calcitonin gene-related peptide (CGRP) or its receptor have been investigated, but there are few studies regarding the possible harmful effects of CGRP in other body organs. This study aimed to investigate the effect of intracerebroventricular (ICV) injection of CGRP on sex hormones and sperm quality in rats. Twelve male rats were divided into two groups (n=6 per group). The first group (control) rats were injected with 5µl artificial cerebrospinal fluid intra-ICV; the second group rats, 5µl (1.5nmol) CGRP. The levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone were measured. Epididymal sperms were used to determine the sperm parameters. The levels of testosterone, LH and FSH in CGRP group was significantly lower than in artificial cerebrospinal fluid (ACSF) group (P<0.05). The concentration and motility of sperm in CGRP group was significantly lower than in ACSF group (P<0.05). In CGRP group live spermatozoa and intact acrosome significantly reduced compared to the ACSF group (P<0.05). In addition, in CGRP group dead spermatozoa and lose acrosome significantly increased compared to the ACSF group (P<0.05). ICV injection of CGRP may reduce sperm quality, probably through induction of an imbalance in FSH and LH production as well as testosterone.

FRI287 Pituitary Gene Signatures Link Chronic Systemic Inflammation To Female Reproductive Physiology

Abstract Disclosure: C. Garcia: None. L. Velez: None. C. Fox: None. A. Mark: None. K.M. Fisch: None. M.A. Lawson: None. A. Duleba: None. M.M. Seldin: None. D. Nicholas: None. Female reproductive function depends on a perfectly choreographed sequence of hormonal secretion and action, where specific stresses such as inflammation exert profound disruptions. Specifically, LPS-induced inflammation inhibits luteinizing hormone production and secretion from the pituitary, thereby inhibiting downstream production of sex hormones. However, this outcome has only been observed in acute inflammatory stress and little is known about the mechanisms by which chronic inflammation affects reproduction. In this study we seek to understand the chronic effects of LPS on luteinizing hormone secretion and consequent pituitary function. An inflammatory state was induced in female mice using biweekly doses of LPS injections. Surprisingly, luteinizing hormone was not inhibited and instead we found it was increased dose-dependently with LPS treatments. This is consistent with the features of the reproductive disorder polycystic ovary syndrome (PCOS). Here, analysis of bulk RNA-sequencing of mouse pituitary and integration with genetic variation of human pituitary expression profiles revealed pathways that are highly conserved between species. These results provide insights into the impacts of LPS-induced chronic inflammation on reproductive physiology. Presentation: Friday, June 16, 2023

α-Lipoic acid eliminates dioxin-induced offspring sexual immaturity by improving abnormalities in folic acid metabolism

Maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes developmental and reproductive disorders in pups due to the attenuated luteinizing hormone (LH) production during the perinatal stage; however, the administration of α-lipoic acid (LA) to TCDD-exposed pregnant rats reversed the attenuated LH production. Therefore, reproductive disorders in pups are expected to be ameliorated with LA supplementation. To address this issue, pregnant rats orally received low dose TCDD at gestational day 15 (GD15) and proceeded to parturition. The control received a corn oil vehicle. To examine the preventive effects of LA, supplementation with LA was provided until postnatal day 21. In this study, we demonstrated that maternal administration of LA restored the sexually dimorphic behavior of male and female offspring. TCDD-induced LA insufficiency is likely a direct cause of TCDD reproductive toxicity. In the analysis to clarify the mechanism of the decrease in LA, we found evidence suggesting that TCDD inhibits the synthesis and increases the utilization of S-adenosylmethionine (SAM), a cofactor for LA synthesis, resulting in a decrease in the SAM level. Furthermore, folate metabolism, which is involved in SAM synthesis, is disrupted by TCDD, which may adversely affect infant growth. Maternal supplementation of LA restored SAM to its original level in the fetal hypothalamus; in turn, SAM ameliorated abnormal folate consumption and suppressed aryl hydrocarbon receptor activation induced by TCDD. The study demonstrates that the application of LA could prevent and recover next-generation dioxin reproductive toxicity, which provides the potential to establish effective protective measures against dioxin toxicity.

Association of age, hormonal, and lifestyle factors with the Leydig cell biomarker INSL3 in aging men from the European Male Aging Study cohort.

BackgroundAging in men is accompanied by a broad range of symptoms, including sexual dysfunction, cognitive and musculoskeletal decline, obesity, type 2 diabetes, cardiovascular disease and hypertension, organ degeneration/failure, and increasing neoplasia, some of which are associated with declining levels of Leydig cell‐produced testosterone. High natural biological variance, together with multiple factors that can modulate circulating testosterone concentration, may influence its interpretation and clinical implications. Insulin‐like peptide 3 is a biomarker of Leydig cell function that might provide complementary information on testicular health and its downstream outcomes.ObjectivesTo characterize insulin‐like peptide 3 as a biomarker to assess gonadal status in aging men.Methods and materialsA large European multicenter (European Male Aging Study) cohort of community‐dwelling men was analyzed to determine how insulin‐like peptide 3 relates to a range of hormonal, anthropometric, and lifestyle parameters.Results and discussionInsulin‐like peptide 3 declines cross‐sectionally and longitudinally within individuals at approximately 15% per decade from age 40 years, unlike testosterone (1.9% per decade), which is partly compensated by increasing pituitary luteinizing hormone production. Importantly, lower insulin‐like peptide 3 in younger men appears to persist with aging. Multiple regression analysis shows that, unlike testosterone, insulin‐like peptide 3 is negatively dependent on luteinizing hormone and sex hormone‐binding globulin and positively dependent on follicle‐stimulating hormone, suggesting a different mechanism of gonadotropic regulation. Circulating insulin‐like peptide 3 is negatively associated with increased body mass index or waist circumference and with smoking, and unlike testosterone, it is not affected by weight loss in obese individuals. Geographic variation in mean insulin‐like peptide 3 within Europe appears to be largely explained by differences in these parameters. The results allowed the establishment of a European‐wide reference range for insulin‐like peptide 3 (95% confidence interval) adjusted for increasing age.ConclusionInsulin‐like peptide 3 is a constitutive biomarker of Leydig cell functional capacity and is a robust, reliably measurable peptide not subject to gonadotropin‐dependent short‐term regulation and within‐individual variation in testosterone.

Resistance training reduced luteinising hormone levels in postmenopausal women in a substudy of a randomised controlled clinical trial: A clue to how resistance training reduced vasomotor symptoms.

BackgroundVasomotor symptoms (VMS) are common around menopause. Menopausal hormone therapy is the most effective treatment for VMS. Physical exercise has been proposed as an alternative treatment since physically active women have previously been found to experience fewer VMS than inactive women. In our randomised controlled trial on resistance training to treat VMS, sympoms were reduced by 50% in the intervention group compared with the control group.ObjectivesTo propose a mechanism to explain how resistance training reduced VMS and to assess if luteinizing hormone (LH) and follicle stimulating hormone (FSH) were affected in accordance with the proposed mechanism.Trial design and methodsA substudy of a randomized controlled trial on 65 postmenopausal women with VMS and low physical activity who were randomised to 15 weeks of resistance training three times per week (n = 33) or to a control group (n = 32). To be regarded compliant to the intervention we predecided a mean of two training sessions per week. The daily number of VMS were registered before and during the 15 weeks. Blood samples were drawn for analysis of LH and FSH at baseline and after 15 weeks.ResultsLH decreased significantly in the compliant intervention group compared with the control group (-4.0±10.6 versus 2.9±9.0, p = 0.028 with Mann-Whitney U test). FSH also decreased in the compliant intervention group compared with the control group, however not enough to reach statistical significance (-3.5±16.3 versus 3.2±18.2, p = 0.063 with Mann-Whitney U test). As previously published the number of hot flushes decreased significantly more in the intervention group than in the control group but there was no association between change in LH or FSH and in number of VMS.ConclusionsWe propose that endogenous opiods such as β-endorphin or dynorphin produced during resistance training decreased VMS by stimulating KNDγ-neurons to release neurokinin B to the hypothalamic thermoregulatory centre. Through effects on KNDγ-neurons, β-endorphin could also inhibit GnRH and thereby decrease the production of LH and FSH. The significanty decreased LH in the compliant intervention group compared with the control group was in accordance with the proposed mechanism.

Ground squirrels initiate sexual maturation during hibernation

Adequate nutrition is essential for normal reproductive function, which is vital for species to survive. In humans and other mammals, starvation and undernutrition deplete fat reserves and cause weight loss, attenuating the function of the reproductive axis and causing hypogonadism.1-4 Thirteen-lined ground squirrels (Ictidomys tridecemlineatus) spend 7months of every year in hibernation without food and water. Hibernating squirrels alternate between periods of torpor and interbout arousal (IBA), when animals temporarily return to an active-like state.5 The physiological significance of IBA is unclear, but it is thought to be essential for hibernation in animals that drop their body temperature to 2°C-4°C during torpor. Here, we report that juvenile male ground squirrels initiate reproductive maturation during their first hibernation season, despite prolonged undernutrition and profound weight loss. We show that the hypothalamic reproductive axis undergoes activation during interbout arousals in the middle of hibernation, triggering production of luteinizing hormone and testosterone, and promoting testicular growth. Initiation of sexual maturation is circannually entrained and is independent of physiological state, ambient temperature, and food availability. Our study suggests a role for interbout arousals during hibernation and uncovers the neurophysiological mechanism of reproductive axis activation during conditions of extreme negative energy balance. VIDEO ABSTRACT.

P140Cap Controls Female Fertility in Mice Acting via Glutamatergic Afference on Hypothalamic Gonadotropin-Releasing Hormone Neurons.

p140Cap, encoded by the gene SRCIN1 (SRC kinase signaling inhibitor 1), is an adaptor/scaffold protein highly expressed in the mouse brain, participating in several pre- and post-synaptic mechanisms. p140Cap knock-out (KO) female mice show severe hypofertility, delayed puberty onset, altered estrus cycle, reduced ovulation, and defective production of luteinizing hormone and estradiol during proestrus. We investigated the role of p140Cap in the development and maturation of the hypothalamic gonadotropic system. During embryonic development, migration of Gonadotropin-Releasing Hormone (GnRH) neurons from the nasal placode to the forebrain in p140Cap KO mice appeared normal, and young p140Cap KO animals showed a normal number of GnRH-immunoreactive (-ir) neurons. In contrast, adult p140Cap KO mice showed a significant loss of GnRH-ir neurons and a decreased density of GnRH-ir projections in the median eminence, accompanied by reduced levels of GnRH and LH mRNAs in the hypothalamus and pituitary gland, respectively. We examined the number of kisspeptin (KP) neurons in the rostral periventricular region of the third ventricle, the number of KP-ir fibers in the arcuate nucleus, and the number of KP-ir punctae on GnRH neurons but we found no significant changes. Consistently, the responsiveness to exogenous KP in vivo was unchanged, excluding a cell-autonomous defect on the GnRH neurons at the level of KP receptor or its signal transduction. Since glutamatergic signaling in the hypothalamus is critical for both puberty onset and modulation of GnRH secretion, we examined the density of glutamatergic synapses in p140Cap KO mice and observed a significant reduction in the density of VGLUT-ir punctae both in the preoptic area and on GnRH neurons. Our data suggest that the glutamatergic circuitry in the hypothalamus is altered in the absence of p140Cap and is required for female fertility.

Effects of melatonin on the production of GnRH and LH in luteal cells of pregnant sows.

Effects of melatonin on the release and synthesis of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) at the hypothalamus and pituitary levels have been explored in some species, but a similar study in the corpora lutea (CL) has not yet been conducted. In this study, the immunostaining for GnRH and LH was observed in luteal cells of porcine CL during pregnancy, and a significant effect of pregnant stage on the level of GnRH and LH was found; higher values for GnRH and LH immunostaining and mRNA were detected in the early and mid-stages CL than in the later-stage CL (P < 0.01). Furthermore, the patterns of melatonin membrane receptors (MT1 and MT2) expression were consistent with those of GnRH and LH expression in the CL of pregnant sows; the relative levels of MT1 and MT2 in the early and mid-stages were significantly higher than those in the later-stage (P < 0.01). In luteal cells, melatonin dose-dependently increased in GnRH and LH secretion and mRNA expression. Melatonin also increased the GnRH-induced accumulation of LH and the LH-induced secretion of P4 in luteal cells. Additionally, the effects of melatonin on luteal GnRH and LH production were blocked by luzindole, a non-selective MT1 and MT2 receptor antagonist. Our results demonstrate the stimulatory effects of melatonin on GnRH and LH production in luteal cells of pregnant sows, suggesting a potential role for melatonin in luteal function through regulating the release and synthesis of GnRH and LH in luteal cells.

Clinical considerations for the management of psoriasis in women with disorders of the menstrual cycle

Introduction. Psoriasis in women of reproductive age is one of the most pressing medical and social problems. The consequence of psoriasis disease is a significant decrease in the quality of life, disability of patients, difficulties in creating a family and deterioration of family relations, significant psychological discomfort.&#x0D; Objective of the study: to increase the effectiveness of treatment of women with psoriasis with menstrual irregularities by means of pathogenetically substantiated therapy based on the study of hormonal changes.&#x0D; Materials and research methods. The study included 130 women who were divided into three groups: the main group – 75 women with psoriasis with menstrual irregularities, who were randomized into 3 subgroups: 1a – 25 patients who will receive standard psoriasis therapy; 1b – 25 patients, in addition to the standard treatment of psoriasis, will receive gestagens for 3 months; 1c – 25 patients, in addition to the standard treatment of psoriasis, will receive a preparation of an dry extract of herb of creeping anchors for 3 months. The comparison group consisted of 25 women with psoriasis without hormonal disorders, comparable in age and social status with the study group. The control group – 30 apparently healthy women, comparable in age and social status with the study group.&#x0D; Research results. In patients of the main group who received standard psoriasis therapy (1a); who received progestogens for 3 months in addition to standard psoriasis treatment (1b) and, in addition to the standard treatment of psoriasis, who received the preparation of an dry extract of herb of anchors creeping for 3 months (1c), before the start of the treatment, the ratio of LH / FSH – luteinizing hormone (LH) and follicle-stimulating hormone (FSH) was below normal, which indicates a certain deficit in LH production relative to FSH values. In parallel, in these cohorts, the production of prolactin was increased, which suppresses the formation of FSH and LH in the pituitary gland. Changes in the production of gonadotropic hormones are a reaction to the existing deficiency or excess of sex hormones. In the main 1a, 1b and 1c in groups, estradiol values ​​were within the normal range with progesterone deficiency in the luteal phase. The testosterone value in all study groups did not deviate from the standard values.&#x0D; Conclusions. The obtained results of the survey indicate the need to increase the effectiveness of treatment of women with psoriasis with menstrual irregularities by involving measures aimed at correcting hormonal status in complex therapy.

Pituitary P62 deficiency leads to female infertility by impairing luteinizing hormone production

P62 is a protein adaptor for various metabolic processes. Mice that lack p62 develop adult-onset obesity. However, investigations on p62 in reproductive dysfunction are rare. In the present study, we explored the effect of p62 on the reproductive system. P62 deficiency-induced reproductive dysfunction occurred at a young age (8 week old). Young systemic p62 knockout (p62-/-) and pituitary-specific p62 knockout (p62flox/flox αGSUcre) mice both presented a normal metabolic state, whereas they displayed infertility phenotypes (attenuated breeding success rates, impaired folliculogenesis and ovulation, etc.) with decreased luteinizing hormone (LH) expression and production. Consistently, in an infertility model of polycystic ovary syndrome (PCOS), pituitary p62 mRNA was positively correlated with LH levels. Mechanistically, p62-/- pituitary RNA sequencing showed a significant downregulation of the mitochondrial oxidative phosphorylation (OXPHOS) pathway. In vitro experiments using the pituitary gonadotroph cell line LβT2 and siRNA/shRNA/plasmid confirmed that p62 modulated LH synthesis and secretion via mitochondrial OXPHOS function, especially Ndufa2, a component molecule of mitochondrial complex I, as verified by Seahorse and rescue tests. After screening OXPHOS markers, Ndufa2 was found to positively regulate LH production in LβT2 cells. Furthermore, the gonadotropin-releasing hormone (GnRH)-stimulating test in p62flox/flox αGSUcre mice and LβT2 cells illustrated that p62 is a modulator of the GnRH-LH axis, which is dependent on intracellular calcium and ATP. These findings demonstrated that p62 deficiency in the pituitary impaired LH production via mitochondrial OXPHOS signaling and led to female infertility, thus providing the GnRH-p62-OXPHOS(Ndufa2)-Ca2+/ATP-LH pathway in gonadotropic cells as a new theoretical basis for investigating female reproductive dysfunction.

Effects of Maternal Nutrient Restriction During Gestation on LH Production in the Female Bovine Fetus

Abstract Gestational nutrient restriction causes epigenetic and phenotypic changes that affect multiple physiological processes in the offspring. Gonadotropes, the cells in the anterior pituitary that secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH), are particularly sensitive to nutritional changes during fetal development. Our objective herein was to investigate the effects of gestational nutrient restriction on LH protein content and number of gonadotropes in the fetal bovine pituitary. We hypothesized that moderate nutrient restriction during mid to late gestation decreases pituitary LH production, which is associated with a reduced number of gonadotropes. Embryos were produced in vitro with X-bearing semen from a single sire then split to generate monozygotic twins. Each identical twin was transferred to a virgin dam yielding four sets of female twins. At gestational d 158, the dams were randomly assigned into two groups, one fed 100% NRC requirements (control) and the other fed 70% of NRC requirements (restricted) during the last trimester of gestation, ensuring each pair of twins had one twin in each group. At gestational d 265, the fetuses (n = 4/group) were euthanized by barbiturate overdose, and the pituitaries were collected. Western blots were performed using an ovine LH-specific antibody (Dr. A.F. Parlow, NIDDK). The total LH protein content in the pituitary tended to be decreased in the restricted fetuses compared to controls (P &amp;lt; 0.10). However, immunohistochemistry analysis of the pituitary did not reveal any significant changes in the total number of LH-positive cells (control = 460±23 cells/0.5 mm2; restricted = 496±45 cells/0.5 mm2, P = 0.58). In conclusion, while maternal nutrient restriction during gestation resulted in a trend of reduced LH content in the fetal pituitary, immunohistological findings suggest that these changes are likely related to the individual potential of each gonadotrope to produce LH, rather than alterations in cell differentiation during fetal development.

Relative abundance of chemerin mRNA transcript and protein in pituitaries of pigs during the estrous cycle and early pregnancy and associations with LH and FSH secretion during the estrous cycle

Adipokines such as chemerin affect metabolic status and reproductive function in many species. The hypothesis in the present study was that there were chemerin mRNA transcript and protein in the pituitary of pigs and that relative abundances fluctuate during the estrous cycle and early pregnancy. Chemerin is thought to modulate luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion during the estrous cycle. Changes in the relative abundance of chemerin mRNA transcript and protein in anterior (AP) and posterior (PP) pituitaries of pigs were investigated, for the first time in the present study, during four phases of the estrous cycle and four periods of early pregnancy. Chemerin protein was localized in gonadotrophs, thyrotrophs and somatotrophs during the estrous cycle and early gestation. Chemerin treatments affected both basal, GnRH- and/or insulin-induced LH and FSH production, with there being variations with phase of the estrous cycle when tissues were collected. These findings indicate chemerin may be produced locally in the pituitary and may affect female reproductive function by controlling the release of LH and FSH from AP cells.

Functions of Lysosomes in Mammalian Female Reproductive System

The lysosome is the most acidic membrane-bound intracellular organelle. Lysosomal acidity is primarily maintained by vacuolar H+-ATPase (V-ATPase) and counter ion channels. There are >60 hydrolytic enzymes in the lysosome for its fundamental digestive role. Lysosomes also play important roles in endocytosis, exocytosis, autophagy, and cell death. Studies that have implicated roles of lysosomes in the female reproductive system are reviewed here. In the ovary, lysosomes are implicated in the preparation of free cholesterol for steroidogenesis and degradation of regulators of steroidogenesis, regulation of follicular atresia, follicle rupture during ovulation, luteal cell survival, and luteal regression. In the oviduct, lysosomes are involved in endocytosis of both serum and oviductal luminal components. In the uterus during the menstrual/estrous cycle, lysosomes are associated with endometrial secretion, apoptosis, and menstruation. In the uterus during early pregnancy, lysosomes are involved in the temporal and directional changes of endocytosis, uterine epithelial acidification upon embryo implantation initiation, and embryo-maternal mutual communications via extracellular vesicles. In the placenta, lysosomes are implicated in nutrient transport and placental separation from the uterus for parturition. In the mammary gland, lysosomes are important for mammary gland development and involution. These findings suggest/demonstrate functions of lysosomes in multiple processes of female reproduction, from ovulation to ovarian steroidogenesis for pregnancy maintenance, and from essential in utero nurturing of developing embryos/fetuses via embryo/fetal-maternal communications, to optional postpartum nurturing of newborns via lactation. Future studies using genetically or modified animal models and pharmacological approaches will provide novel insights into the functions and mechanisms of lysosomes in the mammalian female reproductive system.

When male seahorses take the female contraceptive pill ...

17α-ethinylestradiol (EE2), the female contraceptive pill, has been detected in mediterranean coasts where seahorse populations, Hippocampus guttulatus, live. Low environmental concentrations have the potential to disrupt growth but also endocrine metabolism, and this imbalance is all the more critical in early life stage. To investigate the impact of EE2 in reared seahorses, we exposed aged 2months and sexually undifferentiated seahorses to an environmental concentration of 21ng/L of EE2 for a period of 30days. EE2 exposure led to a 19% reduction in weight, but also a mortality rate of 27%. This exposure predicted demasculinization of male individuals with a late onset of secondary sexual characteristics. EE2 exposure led to an increase of the free androgen index, but significant reductions of estradiol and testosterone in males were observed. This low estrogen concentration seemed to impact the positive feedback on luteinizing hormone (LH) with a decrease in LH production. Added to this, synthetic estrogen had a negative impact on the production and the release of follicle-stimulating hormone. Contrary to all expectations, females demonstrated a significant decrease in vitellogenin, following exposure to EE2 at 21ng/L, while no changes were detected in males. This first study on the European long-snouted seahorses confirmed the deleterious impact of the female contraceptive pill with a real impact on growth, sexual differentiation, and maturation in young immature seahorses.

Influence of Gonadotropin Hormone Releasing Hormone Agonists on Interhemispheric Functional Connectivity in Girls With Idiopathic Central Precocious Puberty.

Purpose: The pubertal growth suppressive effects of gonadotropin hormone releasing hormone agonists (GnRHa) are well-known, although it remains unclear if long-term GnRHa treatment influences the brain function of treated children. The present study investigated the differences in the homotopic resting-state functional connectivity patterns in girls with idiopathic central precocious puberty (ICPP) with and without GnRHa treatment using voxel-mirrored homotopic connectivity (VMHC).Methods: Eighteen girls with ICPP who underwent 12 months of GnRHa treatment, 40 treatment-naïve girls with ICPP, and 19 age-matched girls with premature thelarche underwent resting-state functional magnetic resonance imaging using a 3T MRI. VMHC method was performed to explore the differences in the resting-state interhemispheric functional connectivity. The levels of serum pubertal hormones, including luteinizing hormone (LH), follicular-stimulating hormone, and estradiol, were assessed. Correlation analyses among the results of clinical laboratory examinations, neuropsychological scales, and VMHC values of different brain regions were performed with the data of the GnRHa treated group.Results: Significant decreases in VMHC of the lingual, calcarine, superior temporal, and middle frontal gyri were identified in the untreated group, compared with the control group. Medicated patients showed decreased VMHC in the superior temporal gyrus, when compared with the controls. Compared to the unmedicated group, the medicated group showed a significant increase in VMHC in the calcarine and middle occipital gyrus. Moreover, a positive correlation was observed between basal LH levels and VMHC of the middle occipital gyrus in medicated patients.Conclusions: These findings indicate that long-term treatment with GnRHa was associated with increased interhemispheric functional connectivity within several areas responsible for memory and visual process in patients with ICPP. Higher interhemispheric functional connectivity in the middle occipital gyrus was related to higher basal LH production in the girls who underwent treatment. The present study adds to the growing body of research associated with the effects of GnRHa on brain function.

Characterization of gene expression in the hypothalamo-pituitary-gonadal axis during the preovulatory surge in the turkey hen

ABSTRACTA preovulatory surge (PS) of luteinizing hormone (LH) and progesterone triggers follicle ovulation, which is the first step of egg production and is orchestrated by the hypothalamo-pituitary-gonadal (HPG) axis. In the HPG axis, hypothalamic peptides, gonadotropin releasing hormone, and gonadotropin inhibitory hormone, control the production of follicle stimulating hormone and LH by the pituitary, which subsequently regulate ovarian production of estradiol and progesterone, respectively. The goal of this study was to characterize the HPG axis function of average egg producing hens by assessing plasma hormone profiles and hypothalamic, pituitary, and follicle gene expression outside and during the PS (n = 3 per group). Results were analyzed by a one-way ANOVA using the mixed models procedure of SAS. Plasma estradiol was not affected by the PS (P > 0.05), but plasma progesterone levels increased 8-fold during the PS when compared to basal progesterone levels (P < 0.05). HPG axis gene expression related to ovulation stimulation (e.g., GNRH, GNRHR, and LHB) was down-regulated during the PS; whereas gene expression related to follicle development (e.g., FSHB) was up-regulated during the PS. Additionally, in the hypothalamus and pituitary, estradiol receptor expression was up-regulated during the PS, whereas progesterone receptor expression was down-regulated during the PS. In the follicle cells, gene expression pertaining to progesterone (e.g., STAR), androgen (e.g., HSD17B1), and estradiol (e.g., CYP19A1) production was up-regulated during the PS. Prior to this study, the HPG axis had yet to be characterized during the PS in the turkey hen. This study showed that the PS significantly impacted gene expression in the hypothalamus, pituitary, and ovarian follicles. These results provide a foundation for further research into the regulation of ovulation and egg production in turkey hens.

Gonadotropin receptors as targetable biomarkers in advanced, high-grade serous ovarian cancer

Objective: Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are probable risk factors for development of high-grade serous epithelial ovarian cancer (HGSOC). Gonadotropin-releasing hormone (GnRH) is released by the anterior pituitary and stimulates the production of FSH and LH. Reports suggest that endogenous production of GnRH by these malignant cells may provide an autostimulatory loop for cell growth. We hypothesized that targeted inhibition of gonadotropin hormone signaling would increase platinum cytotoxicity.