Release Of Reproductive Hormones Research Articles

Apigenin as a Promising Agent for Enhancing Female Reproductive Function and Treating Associated Disorders.

Apigenin is an organic flavonoid abundant in some plants such as parsley, chamomile, or celery. Recently, it has been investigated for several of its pharmacological characteristics, such as its ability to act as an antioxidant, reduce inflammation, and inhibit the growth of cancer cells. The purpose of this review is to provide a summary of the existing knowledge regarding the effects of apigenin on female reproductive systems and its dysfunctions. Apigenin can influence reproductive processes by regulating multiple biological events, including oxidative processes, cell proliferation, apoptosis, cell renewal and viability, ovarian blood supply, and the release of reproductive hormones. It could stimulate ovarian folliculogenesis, as well as ovarian and embryonal cell proliferation and viability, which can lead to an increase in fertility and influence the release of reproductive hormones, which may exert its effects on female reproductive health. Furthermore, apigenin could inhibit the activities of ovarian cancer cells and alleviate the pathological changes in the female reproductive system caused by environmental pollutants, harmful medications, cancer, polycystic ovarian syndrome, ischemia, as well as endometriosis. Therefore, apigenin may have potential as a biostimulator for female reproductive processes and as a therapeutic agent for certain reproductive diseases.

Honghua Xiaoyao tablet combined with estradiol improves ovarian function in D-galactose-induced aging mice by reducing apoptosis and affecting the release of reproductive hormones: an in vivo study.

Context: It is very necessary to delay ovarian aging and prevent age-related health problems. The active ingredient in Honghua Xiaoyao tablet (HHXYT) has the effects of anti-oxidation, anti-inflammation, immune regulation and so on. Objective: To explore the effect and mechanism of Honghua Xiaoyao tablet on aging model mice. Materials and methods: The aging model was established by intraperitoneal injection of D-galactose in model mice. The mice in the HHXYT-L,M,H group were given 0.3g/kg, 0.6g/kg and 1.2g/kg Honghua Xiaoyao tablet suspension respectively, and the HHXYT-M + E2 group was given 0.6g/kg HHXYT +0.13mg/kg estradiol valerate for 30days. In this study, ELISA, HE, Western blot, IH and TUNEL were used. Results: HHXYT + E2 can improve the gonadal index, estrous cycle of aging mice. In HHXYT-M + E2 group, the level of FSH and LH decreased, while E2 and AMH increased significantly. The number of growing follicles in HHXYT-M + E2 group increased, which was better than that of HHXYT alone. Western blot results showed that HHXYT-M + E2 group decreased the expression of Bax, cleaved-Parp, cleaved-Casp-3 and CytC molecules and increased the expression of Bcl-2 in ovarian tissue. FSHR expression decreased in model group and increased in HHXYT group. TUNEL staining showed that the number of apoptotic cells in HHXYT group was reduced, and the HHXYT-M + E2 group was the most significantly. Discussion and conclusion: HHXYT can improve the level of sex hormones and increase the number of growing follicles in aging mice. HHXYT-M + E2 group has the best effect, and its mechanism may be related to reducing ovarian granulosa cell apoptosis.

OR17-06 Clinical And Mechanistic Insight For The Therapeutic Potential Of Intranasal Kisspeptin Administration To Treat Reproductive Disorders In Humans

Abstract Disclosure: E.G. Mills: None. M. Swedrowska: None. V. Delli: None. K. Chachlaki: None. M. Silva: None. L. Decoster: None. G. Ternier: None. L. Thurston: None. M. Phylactou: None. B. Patel: None. L. Yang: None. S.A. Clarke: None. B. Muzi: None. E.C. Alexander: None. M. Choudhury: None. P. Bech: None. A. Abbara: None. B. Forbes: None. P. Giacobini: None. V. Prevot: None. A.N. Comninos: None. W.S. Dhillo: None. Background: Kisspeptin is a key regulator of hypothalamic GnRH neurons with emerging potential to treat reproductive, psychosexual and bone disorders. However, current therapeutic application is limited to the subcutaneous or intravenous routes, which presents significant barriers to further development. Alternative delivery routes could overcome this and capitalise on the clinical utility of kisspeptin-based therapeutics. Herein, we comprehensively examine the translational potential of intranasal kisspeptin administration for the first time using a series of human, rodent and pharmaceutical studies. Methods:Human studies: Healthy men (n=12) and a patient group of women with Hypothalamic Amenorrhoea (HA) (n=5) completed a randomised, double-blind, crossover, placebo-controlled study investigating the acute effects of intranasal kisspeptin-54 administration (doses 3.2-25.6nmol/kg [healthy men] and 12.8nmol/kg [women with HA] vs 0.9% saline placebo). Plasma kisspeptin and serum reproductive hormones were measured every 15mins for 4hrs. Thereafter, we conducted rodent studies in adult C57BL/6J male mice to elucidate the possible mechanism by which intranasal kisspeptin induces reproductive hormone release, using intranasal administration of fluorescently-tagged kisspeptin-54 and a series of c-Fos experiments. From a medicines development perspective, we undertook pharmaceutical studies to evaluate the chemical stability of kisspeptin-54 in solution for nasal delivery in real-time. Results:Human studies: in healthy men, intranasal kisspeptin dose-dependently increased plasma kisspeptin at doses 6.4-25.6nmol/kg (p<0.01 for all doses vs placebo), with the maximal rises achieved within 15-30 minutes. Correspondingly, intranasal kisspeptin acutely and potently increased serum LH at doses 6.4-25.6nmol/kg (p<0.01 all doses vs placebo) with maximal rises at 30 minutes. Likewise, in women with HA, intranasal kisspeptin acutely increased plasma kisspeptin (p=0.004 vs placebo) and serum LH (p=0.004 vs placebo). Animal studies: To provide mechanistic insight, we demonstrate in male mice that GnRH neurons located in the olfactory bulb express kisspeptin receptors and that intranasal administration of fluorescently-tagged kisspeptin-54 binds to the olfactory epithelium. Pharmaceutical studies: Kisspeptin-54 in 0.9% saline remained within pharmaceutically accepted limits for stability for up to 60 days at 4°C demonstrating realistic pharmaceutical potential. Conclusion: We identify robust clinical effects and provide mechanistic and pharmaceutical data for intranasal delivery as a novel, non-invasive, safe and effective kisspeptin administration route for the management of common reproductive disorders that would be far preferable to patients and clinicians and so transform the ongoing rapid development of kisspeptin-based therapeutics. Presentation: Saturday, June 17, 2023

The role of GnRH in Tibetan male sheep and goat reproduction.

The hypothalamic-pituitary-gonadal (HPG) axis connects the hypothalamus, pituitary gland, and gonads. The regulation of reproductive processes includes integrating various factors from structural functions and environmental conditions in the HPG axis, with the outcome indication of these processes being the pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus. These factors include feed consumption and nutritional condition, sex steroids, season/photoperiod, pheromones, age, and stress. GnRH pulsatile secretion affects the pattern of gonadotropin secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which then regulates both endocrine function and gamete maturation in the gonads. This regulates gonadotropins and testosterone (T) production. There is evidence that in males, GnRH participates in a variety of host behavioural and physiological processes such as the release of reproductive hormones, progression of spermatogenesis and sperm function, aggressive behaviour, and physiological metabolism. GnRH activates receptors expressed on Leydig cells and Sertoli cells, respectively to stimulate T secretion and spermatogenesis in the testis. Photoperiod affects the reproductive system of the hypothalamic-pituitary axis via rhythmic diurnal melatonin secretion. Increased release of melatonin promotes sexual activity, GnRH production, LH stimulation, and T production. This induces testicular functions, spermatogenesis, and puberty. GnRH reduces the release of LH by the pituitary through the cascade effect and decreases plasma concentration of T. Gut microbiota maintain sex steroid homeostasis and may induce reduction in reproduction productivity. Recently, findings of kisspeptin-neurokinin-dynorphin neuronal network in the brain have resulted in fast advances in how GnRH secretion is controlled. Emerging studies have also indicated that other neuropeptide analogues could be used in control reproduction procedures in various goat and sheep breeds. The Tibetan male sheep and goats reproduce on a seasonal basis and have high reproductive performance. This is a review for the role of GnRH in Tibetan male sheep and goats reproduction. This is intended to enhance reproductive knowledge for understanding the key roles of GnRH relating to male reproductive efficiency of Tibetan sheep or goats.

RF34 | PMON222 Reproductive Hormone Secretion is Increased by Intranasal Kisspeptin in Humans

Abstract Background Kisspeptin is a critical activator of hypothalamic gonadotrophin releasing hormone (GnRH) neurons and has significant potential to treat common reproductive disorders. To date, kisspeptin has solely been administered to humans via the intravenous or subcutaneous routes, however intranasal administration could offer a novel non-invasive delivery route, which is preferred by patients. We therefore sought to determine the effects of intranasal kisspeptin on reproductive hormone release in humans for the first time. Methods Randomised, double-blinded, placebo-controlled, cross-over study in 12 healthy men (mean±SEM age 28.3±1.7 yrs; BMI 24.5±0.7 kg/m2). After monitored self-administration of intranasal kisspeptin-54 (3.2, 6.4, 12.8 and 25.6 nmol/kg) or 0.9% saline, serum reproductive hormone levels were measured every 15 minutes for four hours. Subsequently, four women (mean age 29.8±3.7 yrs; BMI 21.2±1.1 kg/m2) with hypothalamic amenorrhoea (HA) attended for the same protocol comparing intranasal kisspeptin-54 (12.8 nmol/kg) and 0.9% saline. Mean ±SEM was presented unless otherwise stated. Time profiles of hormone levels during the four-hour study were compared using two-way ANOVA with Bonferroni's multiple comparison test. Multiple means were compared using one-way ANOVA with Bonferroni's multiple comparison test. Results In healthy men, intranasal kisspeptin dose-dependently increased mean luteinising hormone (LH) levels at doses between 3.2-12.8 nmol/kg (p=0.008 and <0.0001 for 6.4 and 12.8 nmol/kg vs saline, respectively), with the maximal rises occurring at 30-45 minutes post-administration. Correspondingly, the area under the curve (AUC) for the LH change was significantly elevated following all doses of kisspeptin compared to saline (saline: -25.4±70.5 h.IU/L; 3.2 nmol/kg: 172.2±64.2 h.IU/L [p=0.03]; 6.4 nmol/kg: 300.2±79.2 h.IU/L [p=0.002]; 12.8 nmol/kg: 595.7±98.3 h.IU/L [p=0.001]; 25.6 nmol/kg: 549.0±108.6 h.IU/L [p<0.0001]). Follicle stimulating hormone (FSH) levels followed a similar trajectory to LH in response to intranasal kisspeptin. Moreover, kisspeptin at 12.8 nmol/kg increased serum testosterone from 120 minutes onwards (p=0.02), with a maximal change from baseline of 4.9±0.7 nmol/L (p=0.03). In women with HA, intranasal kisspeptin increased mean LH (p=0.002 vs saline), with the peak levels occurring at 30-45 minutes post-administration. The AUC for the LH change was 508.4±77.5 h.IU/L (p=0.02 vs saline AUC for LH). The maximal LH change from baseline was 4.1±0.9 IU/L compared to 0.2±0.4 IU/L for saline (p=0.03). Intranasal kisspeptin increased mean FSH (p=0.01 vs saline). No significant changes in downstream serum oestradiol or progesterone were observed during the acute four-hour study. Conclusion We report the first investigation of the effects of intranasal kisspeptin delivery on reproductive hormone release in humans. Our results demonstrate that intranasal kisspeptin robustly and dose-dependently stimulates reproductive hormone release in healthy men and crucially in a patient-group of women with hypogonadism. Given the ongoing development of kisspeptin therapeutics, intranasal kisspeptin therefore offers a novel, safe, effective and non-invasive route of administration for the management of reproductive disorders. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:36 p.m. - 12:41 p.m.

Heat Stress during Summer Attenuates Expression of the Hypothalamic Kisspeptin, an Upstream Regulator of the Hypothalamic-Pituitary-Gonadal Axis, in Domestic Sows.

The release of reproductive hormones in the hypothalamic-pituitary-gonadal (HPG) axis is regulated by its upstream regulator, kisspeptin, and influenced by external stresses, including heat stress. Since the effect of heat stress (summer infertility) on hypothalamic kisspeptin expression in domestic sows is not yet understood, the present study attempted to identify changes in kisspeptin expression in different seasons (summer and spring). The high atmospheric temperature in summer decreased the pregnancy rate and litter size and increased stress-related hormones as a chronic stressor to domestic sows. The hypothalamic kisspeptin expression in summer was decreased regardless of the estrus phase and negatively correlated with atmospheric temperature, indicating that high temperature decreased kisspeptin. When the activity of hypothalamic kisspeptin neurons in the follicular phase was assessed using c-Fos staining, a decreased number of kisspeptin neurons coexpressing c-Fos was observed in domestic sows in summer. Accordingly, lower expression of kisspeptin induced decreased levels of HPG axis-related reproductive hormones, such as gonadotropins and estrogen, and fewer large ovarian follicles. In conclusion, the present study demonstrated that reduced kisspeptin expression and its neuronal activity in the hypothalamus under heat stress in summer induced downregulation of the HPG axis and caused summer infertility in domestic sows.

Long-term effect of a GnRH-based immunocontraceptive on feral cattle in Hong Kong.

Increasing human-wildlife conflicts worldwide are driving the need for multiple solutions to reducing “problem” wildlife and their impacts. Fertility control is advocated as a non-lethal tool to manage free-living wildlife and in particular to control iconic species. Injectable immunocontraceptives, such as GonaCon, stimulate the immune system to produce antibodies against the gonadotrophin-releasing hormone (GnRH), which in turn affects the release of reproductive hormones in mammals. Feral cattle (Bos indicus or Bos taurus) in Hong Kong are an iconic species whose numbers and impacts on human activities have increased over the last decade. Previous studies have proven that a primer vaccination and booster dose of GonaCon in female cattle are safe and effective in reducing pregnancy levels one year post-treatment. The aims of this project were 1. to evaluate the longevity of the effect of GonaCon in feral cattle up to four years post-vaccination; and 2. to assess if a second booster dose of GonaCon, administered at either two or four years post-vaccination, extends the contraceptive effect in this species. Vaccination with GonaCon, administered as a primer and booster dose, was effective in causing significant infertility in free-living cattle for at least three years post-vaccination, with the percentage of pregnant animals in the vaccinated group decreasing from 76% at vaccination to 35%, 19% and 7% in years 2, 3 and 4 post-vaccination, compared with 67% at vaccination to 50%, 57% and 14% respectively in the control group. A second booster dose of GonaCon administered either 2 or 4 years after vaccination rendered 100% of the Treated cattle infertile for at least another year. These results suggested that vaccination with GonaCon can reduce feral cattle population growth and that a second booster dose can extend the longevity of the contraceptive effect.

Copper deposition in Wilson's disease causes male fertility decline by impairing reproductive hormone release through inducing apoptosis and inhibiting ERK signal in hypothalamic-pituitary of mice.

Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism characterized by liver and central nervous system dysfunction. Considerable evidence suggests that infertility is also very common in male patients with WD, but the exact molecular mechanisms involved remain unknown. In order to further investigate the pathological changes in the hypothalamic-pituitary-testicular (HPT) axis and its mechanisms, mice were divided into the normal control group (NC), WD model TX mice group (WD), dimercaptosuccinic acid–treated TX mice group (DMSA), and pregnant horse serum gonadotropin–treated TX mice group (PMSG). The copper content and morphology of hypothalamus and pituitary tissues, the ultrastructure and apoptosis of hypothalamus neurons and pituitary gonadotropin cells, the serum levels of reproductive hormones, and the pregnancy rate and litter size of the female mice were studied. The expression of apoptosis-related proteins and the phosphorylation of extracellular regulatory protein kinase (ERK) 1/2 in the hypothalamus and pituitary were detected. The results showed that the copper content was significantly increased in the WD group, and the histopathological morphology and ultrastructure of the hypothalamus and pituitary were damaged. The levels of the gonadotropin-releasing hormone, the follicle-stimulating hormone, the luteinizing hormone, and testosterone were significantly decreased. The apoptosis rate in the hypothalamus and pituitary was significantly increased. The expressions of proapoptotic proteins Bax and Caspase-3 were significantly increased, the expression of the anti-apoptotic protein Bcl-2 was significantly decreased, and the phosphorylation level of ERK1/2 was significantly decreased. Fertility is significantly reduced. After DMSA intervention, the hypothalamus tissue copper content decreased, the hypothalamus and pituitary tissue morphology and ultrastructure were improved, cell apoptosis was alleviated, the expression of Bax and Caspase-3 was significantly decreased, the expression of Bcl-2 was significantly increased, and the reproductive hormone level, phosphorylation level, and fertility were increased. Fertility was preserved after treatment with PMSG in male TX mice. These results suggest that copper deposition in WD causes male fertility decline by impairing reproductive neuroendocrine hormone release through inducing apoptosis and inhibiting the ERK signal in the hypothalamic–pituitary region. This study can also provide reference for the damage of copper pollution to the male reproductive system.

Gut hormones and reproduction

Reproduction and metabolism are intricately linked. Gut hormones play key roles in the regulation of body weight and glucose homeostasis, factors that influence the functioning of the hypothalamic-pituitary-gonadal axis and reproductive outcomes. Data from rodent models suggest gut hormones may have direct stimulatory effects on reproductive hormone release. However, the effects of gut hormones on reproductive function in humans are more complex, with possible involvement of direct (e.g. via gut hormone receptor agonism) as well as indirect (e.g. via weight reduction in people with obesity) mechanisms. The use of gut hormone receptor agonists has become an integral part of the management of metabolic diseases (including obesity and type 2 diabetes), with additional indications for their use on the horizon. Future work may identify specific roles for gut hormone receptor agonists in the treatment of reproductive co-morbidities that are increasingly being recognised in people with metabolic diseases.

The Transcription Factor Ventral Anterior Homeobox 1 Modulates Circadian Time-Keeping and Fertility Through Direct Regulation of Vasoactive Intestinal Polypeptide Expression in the Suprachiasmatic Nucleus

Light provides the primary timing signal that enables fine-tuned behavioral and hormonal entrainment of circadian rhythms to the environment. Light is transmitted from the eye to the brain through the retinohypothalamic tract, where one target is the hypothalamic suprachiasmatic nucleus (SCN), which generates self-sustained circadian rhythms. The vasoactive intestinal polypeptide (VIP) expressing neurons of the SCN relay light information to peripheral cells and tissues through control of hormonal and nervous signals, allowing synchronization of molecular clocks located in individual cells throughout the body. Non-natural light cycles, ie shiftwork, and weakened SCN function through genetic manipulation, disrupt the body’s circadian rhythms, causing deregulated hormone release, metabolic disorders, and negative effects on reproductive systems such as irregular menstrual cycles and decreased sperm count. To further our understanding of how the SCN translates light information into neuroendocrine control of fertility, we conditionally deleted the SCN enriched transcription factor Ventral anterior homeobox 1 (Vax1) in post-developmental VIP neurons, generating Vax1-flox/flox:Vip-Cre+ (cKO) mice. To determine if the SCN timekeeping function was impacted in cKO mice, we single housed males and females with running wheels to examine activity during both 12-hour light/dark cycles and in constant darkness. Wheel-running behavior in constant darkness revealed a shortening of the endogenous free-running period (Tau) of the SCN. Aside from Tau, wheel running behaviors were comparable to controls. Weakened SCN output can negatively impact fertility. While on 12-hour light/dark cycles, we found a modest, but significant change in follicle stimulating hormone and estrogen in cKO females and a reduced sensitivity of GnRH neurons to kisspeptin in males. The changes in hormone release were associated with a slightly lengthened estrous cycle in cKO females and reduced sperm quality in cKO males. To identify the molecular origin of the shortened SCN period, we used immunohistochemistry and RNAscope to examine expression of Vip. We found that diestrus cKO females had a significant reduction in Vip expression at ZT16 and preliminary data suggest a reduction in the circadian clock gene Bmal1. Together, these studies identify a novel role of VAX1 in VIP neurons where VAX1 is required for VIP expression and circadian timekeeping. Loss of VAX1 in VIP neurons weakens SCN output, deregulating reproductive hormone release and modestly reducing reproductive function in both males and females.

SUN-LB58 Repeated Once-Daily Administration of the Non-Hormonal Neurokinin 1,3 Receptor Antagonist NT-814 Reduces LH, Estradiol and Progesterone in Healthy Women

Introduction: Uterine fibroids (UF) affect up to 25% of women and endometriosis (EM) 10% of women worldwide. An ideal therapy would lower estradiol concentrations to reduce hormonal drive to the endometrium and myometrium, but not to the levels which cause the hot flashes and bone loss associated with current treatments. A target estradiol range of 110-180 pmol/L has been proposed1. GnRH secretion is modulated by neurokinin B (NKB) acting at the NK3 receptor via hypothalamic neurons expressing kisspeptin, NKB & dynorphin (KNDy neurons). In addition, Substance P acting at the NK1 receptor may also stimulate reproductive hormone release. We hypothesised that NT-814, a dual NK1,3 receptor antagonist, would reduce GnRH release and hence LH, estradiol and progesterone levels in women. This preliminary clinical study in healthy pre-menopausal women evaluated this hypothesis. Methods: We undertook a randomized, single-blind, placebo-controlled study. 32 healthy women attended for 2 consecutive menstrual cycles. In each cycle blood samples were taken on days 3/4, 9/10, 15/16 and 21/22 to measure serum sex hormone concentrations. No treatment was given in cycle 1 (baseline). During cycle 2, participants received placebo or one of three doses of NT-814 once per day; 40mg, 80mg or 120mg (n=8 per group) for up to 21 days. Results: Compared to placebo, NT-814 reduced LH, estradiol and progesterone concentrations in a dose-related manner. The median changes in average LH (IU/L) during cycle 2 compared to cycle 1 were: placebo, 0.16; 40mg, -0.13; 80mg, -0.46; 120mg, -0.58. Median change in average estradiol (pmol/L) in cycle 2 was: placebo, -16.5; 40mg, -9.3; 80mg, -92.1; 120mg, -141.4. The median changes in progesterone (nmol/L) on day 21/22 in cycle 2 compared to cycle 1 were: placebo, 3.2; 40mg, 8.0; 80mg, -5.7; 120mg, -19.4. The reductions in estradiol and progesterone with 120 mg NT-814 were significant (p=0.038 & p=0.046, respectively). There were no clear changes in FSH concentrations. Of note, in women treated with 120mg NT-814, the average estradiol level reduced from 310.8 pmol/L in cycle 1 to 179.8 pmol/L in cycle 2. Cycle length was extended by at least 6 days in 5 of 8 women receiving the 120 mg dose. NT-814 was well tolerated; no participant experienced hot flashes during treatment. Conclusions: Once-daily administration of the non-hormonal NK1,3 receptor antagonist NT-814 reduced serum LH, estradiol and progesterone in healthy women in a dose-related manner without causing vasomotor symptoms. The 120 mg dose of NT-814 lowered estradiol levels to potentially ideal levels for UF and EM treatment. These preliminary data support further studies with NT-814 to establish its efficacy and safety in treating patients with these hormone driven disorders.

Acrylamide impairs ovarian function by promoting apoptosis and affecting reproductive hormone release, steroidogenesis and autophagy-related genes: An in vivo study.

Acrylamide (ACR) toxicity is quite common due to its widespread use in industry and due to the Maillard browning reaction that occurs in foods containing high concentrations of hydrocarbons subjected to high temperatures. This study aimed to elucidate the female reproductive toxicity of ACR in vivo. Fifty-day-old Wistar-Albino female rats were treated with different dosages of ACR (2.5, 10, and 50mg/kg/day). After treatment, the animals were sacrificed, and serum and ovary samples were collected for histological examination, hormone analysis, TUNEL analysis, and RT-PCR studies. We found that ACR acts by significantly reducing ovarian weight and serum progesterone and estradiol concentrations. In addition, ACR treatment led to pyknotic, heterochromatic characteristics and nuclear fragmentation, as evidenced by hematoxylin staining. The TUNEL assay revealed that granulosa cells were affected after the oral administration of ACR, leading to the apoptosis of follicles at different stages of growth. Compared with the control condition, high doses of ACR (50mg/kg/day) significantly induced the overexpression of INSL3, CYP17a, IGF1, ESR1, ESR2, ATG5, ATG12 and LC3 in the ovary. Moreover, LC3 mRNA levels significantly increased with increasing doses of ACR (2.5, 10 and 50mg/kg/day), suggesting that ACR treatment induced autophagy. In conclusion, ACR induced ovarian dysfunction by affecting steroid hormone release, increasing apoptosis and mRNA levels of autophagy-related genes. The eventual correlation between apoptotic granulosa cell death and autophagy needs to be further explored.

Integrated Hypothalamic Transcriptome Profiling Reveals the Reproductive Roles of mRNAs and miRNAs in Sheep.

Early studies have provided a wealth of information on the functions of microRNAs (miRNAs). However, less is known regarding their functions in the hypothalamus involved in sheep reproduction. To explore the potential roles of hypothalamic messenger RNAs (mRNAs) and miRNAs in sheep without FecB mutation, in total, 172 and 235 differentially expressed genes (DEGs) and 42 and 79 differentially expressed miRNAs (DE miRNAs) were identified in polytocous sheep in the follicular phase versus monotocous sheep in the follicular phase (PF vs. MF) and polytocous sheep in the luteal phase versus monotocous sheep in the luteal phase (PL vs. ML), respectively, using RNA sequencing. We also identified several key mRNAs (e.g., POMC, GNRH1, PRL, GH, TRH, and TTR) and mRNA–miRNAs pairs (e.g., TRH co-regulated by oar-miR-379-5p, oar-miR-30b, oar-miR-152, oar-miR-495-3p, oar-miR-143, oar-miR-106b, oar-miR-218a, oar-miR-148a, and PRL regulated by oar-miR-432) through functional enrichment analysis, and the identified mRNAs and miRNAs may function, conceivably, by influencing gonadotropin-releasing hormone (GnRH) activities and nerve cell survival associated with reproductive hormone release via direct and indirect ways. This study represents an integral analysis between mRNAs and miRNAs in sheep hypothalamus and provides a valuable resource for elucidating sheep prolificacy.

Kisspeptin and attributes of infertile males and females: A cross-sectional study in a subset of Pakistani population.

Kisspeptin, a peptide hormone, plays a pivotal role in fertility and neuroendocrine regulation of hypothalamo-pituitary-gonadal axis. Increased kisspeptin and reproductive hormones are responsible for fertility in male and females. This study aimed to explore the role of kisspeptin on hypothalamo-pituitary-gonadal axis by comparing the levels of kisspeptin in fertile and infertile subjects and identifying single nucleotide polymorphisms (SNPs) of KISS1 gene in exon 2 and exon 3 of infertile male and female cohorts. A cross-sectional study was carried out on 80 males (44 infertile and 36 fertile) and 88 females (44 in each group). Significantly high levels of kisspeptin (KP), follicle-stimulating hormone (FSH), luteinizing hormone and testosterone were observed in fertile male and female subjects except low FSH levels in comparison with infertile female subjects. One polymorphism in exon 2 (E1225K [G/A 3673]) and three in exon 3 (P1945A [C/G 5833]; Insertion of T at 6075; G2026G [C/G 6078]) in infertile group were detected, with low KP and hormonal levels. Male subjects had abnormal sperm parameters and unsuccessful attempt of intracytoplasmic sperm injection in females. Expression of SNP in exon 2 and exon 3 of KISS1 could be responsible for alteration in release of reproductive hormones and gonadal functions, hence causing infertility.

Phoenixin and Its Role in Reproductive Hormone Release.

Phoenixin is novel neuropeptide, recently identified following the description of a peptide sequence highly conserved across several animal species, including humans, cows, and pigs. Expressed both centrally in the hypothalamus and arcuate nucleus and peripherally in cardiac and gastrointestinal tissue, it appears to modulate reproductive hormone secretion in a gonadotrophin-releasing hormone-dependent manner and may also influence anxiety and memory. While there remains much to be described regarding its signaling, this review assesses the currently available literature in both animal and human studies to summarize our understanding of the physiological role of this novel neuropeptide, and its function in reproductive hormone release.

SUN-LB044 Effects of Glucagon-Like Peptide-1 (GLP-1) on the Hypothalamic-Pituitary-Gonadal Axis in Healthy Men

Introduction: Normal fertility requires the presence of adequate nutritional stores. The hormone glucagon-like peptide-1 (GLP-1) is a satiety hormone, which is released by intestinal L-cells during meal ingestion to act as a physiological signal of nutritional intake. GLP-1 reduces appetite and stimulates insulin release. Peripheral GLP-1 crosses the blood brain barrier and GLP-1 receptors (GLP-1R) are present in the arcuate nucleus of the hypothalamus (a neuroendocrine centre that regulates metabolism and reproduction). Both in vitro and in vivo animal studies have demonstrated stimulatory effects of GLP-1 on reproductive hormone release. Thus, GLP-1 acts as a signal of adequate energy intake and may act as a key mediator between metabolic and reproductive systems in animals. As GLP-1R agonists are widely used to treat obesity and diabetes, we sought to determine the effects of GLP-1 on the reproductive axis in humans. Methods: Using a blinded placebo-controlled protocol, 18 healthy men (age 24.7±1yr; mean BMI 22.1±0.4kg/m2) received an 8-hour infusion of 0.8pmol/kg/min of GLP-1 on one study visit and rate-matched vehicle infusion on a separate study visit, in random order. Blood samples were taken every ten minutes during infusions. Visual analogue scales (VAS: 0-10cm) for hunger and nausea were completed by the volunteers pre-, mid- and end-infusion. An ad libitum meal study was performed following the last VAS assessment, after which the infusion was stopped. Luteinizing hormone (LH) pulsatility was determined using blinded deconvolution analysis. Data is presented as mean±SEM. Results: GLP-1 infusion resulted in 14% lower food intake (GLP-1 937±87kcal vs vehicle 1094±87kcal, p=0.03) without increasing nausea (change from baseline VAS score: GLP-1 0.25±0.35cm vs vehicle 0.25±0.22cm, p=0.74). There was no difference in the number of LH pulses over 8hrs (GLP-1 4.7±0.3 vs vehicle 4.4±0.4, p=0.38), LH pulse mass (GLP-1 4.82±0.38IU/L vs vehicle 4.78±0.42IU/L, p=0.94), mean LH (GLP-1 2.86±0.2IU/L vs vehicle 2.75±0.2IU/L, p=0.50), LH AUC (GLP-1 1524±101IU.min/L vs vehicle 1484±88IU.min/L, p=0.70), FSH AUC (GLP-1 1216±112IU.min/L vs vehicle 1210±112IU.min/L, p=0.86) or testosterone AUC (GLP-1 11088±792nmol.min/L vs vehicle 10893±615nmol.min/L, p=0.77). Conclusions: Our results indicate that GLP-1 administration, at a biologically active dose (which reduces food intake), has neither a detrimental nor stimulatory effect on the reproductive axis. This provides important safety data for GLP-1 based therapeutic agents. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

English

The Brazilian poultry production currently has a substantial impact on the national and international economy. Brazil ranks sixth in the world rankings of the largest egg producers. However, the activity still has barriers related to management and facilities, such as high waste of electrical energy due to the low energy efficiency of the lighting systems. The artificial lighting programs represent an important management tool to accelerate or delay sexual maturity of laying, stimulate the release of reproductive hormones, increase the egg production, besides promoting improvements in the shell quality and the size of the eggs. There is a large number of lamps that are available for use in artificial lighting systems, however, each light source has different characteristics (light intensity, wavelength, color, temperature and fluctuations) which may cause positive or negative effect on hens performance, egg quality and production costs. The LED technology is an innovative alternative that can improve the sustainability of the activity, since it has better energy efficiency, longer lifetime and emits light of different colors. This literature review aims to discuss the beneficial characteristics of the LED and its effects on the production of commercial layers.   Key words: Eggs, electric energy, layer production, layers, lighting program.

Dietary supplementation of yucca (Yucca schidigera) affects ovine ovarian functions

Yucca (Yucca schidigera) is a popular medicinal plant due to its many positive effects on animal and human physiology, including their reproductive systems. To examine the effect of supplemental yucca feeding on sheep reproduction, including ovarian functions and their hormonal regulators, ewes were fed (or not fed, control) yucca powder (1.5 g/head/day, 30 days). Macromorphometric indexes of the oviduct, ovary, and ovarian folliculogenesis were measured. Reproductive hormone levels in the blood were measured using a radioimmunoassay. Granulosa cells were aspirated from the ovary, and their proliferation and apoptosis were detected using immunocytochemistry. To assess secretory activity and its response to gonadotropin, ovarian fragments of treated and control ewes were cultured with and without follicle-stimulating hormone (FSH; 0, 0.1, 1, 10, or 100 IU/mL), and the release of reproductive hormones into the culture medium was evaluated. Finally, to examine the direct action of yucca on the ovary, ovarian fragments from control ewes were cultured with and without yucca extract (1, 10, or 100 μg/mL), and the release of reproductive hormones was measured. Yucca supplementation significantly decreased the size of small antral follicles (2 to <5 mm in diameter), increased accumulation of the apoptosis marker bax, and decreased serum progesterone (P4) and estradiol (E2) levels. It inhibited the release of P4 (but not other hormones), to prevent the stimulatory action of FSH on P4 output and promoted insulin-like growth factor I (IGF-I) release by fragments cultured with FSH. However, yucca supplementation did not affect the size of larger follicles and number of follicles, volume and weight of ovaries, length and weight of oviducts, caspase 3 accumulation, cell proliferation, testosterone (T) or IGF-I serum levels, or T or E2 release by cultured ovarian fragments and their response to FSH. Yucca addition to culture medium inhibited P4 and IGF-I, but not T or E2 release at the lowest (1 μg/mL) dose, and stimulated P4, but not T, E2, or IGF-I release at the highest (100 μg/mL) dose. These data suggest that yucca supplementation can reduce small antral ovarian follicle development possibly via the stimulation of apoptosis of their granulosa cells, suppression of ovarian P4 and E2 release, and alteration of ovarian IGF-I output and ovarian response to gonadotropin. Thus, yucca can directly affect P4 and IGF-I release by ovine ovarian cells.

Relationships between docility and reproduction in Angus heifers (2014)

Reproductive success is relevant in beef cattle operations because income generated by the sale of calves is often a large portion of an operation's income. Selecting for fertility is difficult because it is influenced by a variety of factors. Temperament could be a factor affecting fertility. Physiological responses associated with temperament can influence the probability of cows becoming pregnant because stress hormones in the bloodstream can negatively affect the release of reproductive hormones. Methods have been developed to assess temperament in cattle. Exit velocity measures the time it takes for an animal to cover a predetermined distance after vacating a chute. Chute scores range from 1 (quiet) to 6 (aggressive) and are based on the animal's behavior when confined in a chute. Positive correlations of chute score and exit velocity with cortisol indicate that both scores are reliable indicators of temperament. Handling of cattle is associated with changes in concentrations of stress hormones. Blood serum collection can provide insight into short-term stressors, and fecal sampling can be reflective of stress experienced 2'3 days before sampling. This study was conducted to investigate the relationship between animal temperament and heifer fertility as indicated by first-service artificial insemination conception rate.

Timeline: kisspeptins

Kisspeptins are peptides encoded by KISS1. The gene was first discovered in 1996, in Hershey, PA, USA, and was subsequently named after Hershey's chocolate kisses. The peptide product of KISS1 is a 145 aminoacid peptide that is cleaved into four shorter peptides: kisspeptin-54, kisspeptin-14, kisspeptin-13, and kisspeptin-10 (the numbers denote how many aminoacids in each). All these isoforms activate the kisspeptin receptor. Kisspeptins produced in the hypothalamus stimulate neurons in the hypothalamus that secrete gonadotropin-releasing hormone (GnRH), which subsequently stimulates release of gonadotropins and sex steroid hormones. Kisspeptin has been shown to have a crucial role in puberty. Inactivating mutations of the kisspeptin receptor or KISS1 gene lead to pubertal failure due to hypogonadotrophic hypogonadism in mice and in people. Conversely, activating mutations of the kisspeptin receptor in people lead to central precocious puberty. Exogenous kisspeptin stimulates gonadotropin release in all animal species studied and in people. This effect is mediated predominantly by stimulating GnRH release (because pretreatment with a GnRH antagonist completely blocks the ability of kisspeptin to stimulate gonadotropin release). Recent evidence also suggests that the kisspeptin system is important in the generation of GnRH pulses, which are crucial for normal fertility. In a subpopulation of neurons in the hypothalamic arcuate nucleus, kisspeptin colocalises with two other hormones known to affect GnRH release, namely neurokinin B (NKB) and dynorphin (DYN). This group of cells is often referred to as the KNDy neurons. Increasing data suggest that KNDy neurons have a key role in mediation of pulsatile GnRH release. Evidence thus far suggests that kisspeptin has exciting therapeutic potential in people—eg, acute use of kisspeptin for infertility could stimulate reproductive hormone release more naturally than by conventional methods. Data for human beings also suggest that kisspeptin might stimulate pulses of luteinising hormone, indicating its therapeutic potential for the treatment of women with anovulatory infertility. Chronic use of high doses of kisspeptin causes desensitisation and reduces secretion of gonadotropins. Hence, longacting forms of kisspeptin are being developed to treat hormone-sensitive cancers, with promising early results in people.