Modulation of pulsatile GnRH dynamics across the ovarian cycle via changes in the network excitability and basal activity of the arcuate kisspeptin network

Pulsatile GnRH release is essential for normal reproductive function. Kisspeptin secreting neurons found in the arcuate nucleus, known as KNDy neurons for co-expressing neurokinin B, and dynorphin, drive pulsatile GnRH release. Furthermore, gonadal steroids regulate GnRH pulsatile dynamics across the ovarian cycle by altering KNDy neurons' signalling properties. However, the precise mechanism of regulation remains mostly unknown. To better understand these mechanisms we start by perturbing the KNDy system at different stages of the estrous cycle using optogenetics. We find that optogenetic stimulation of KNDy neurons stimulates pulsatile GnRH/LH secretion in estrous mice but inhibits it in diestrous mice. These in-vivo results in combination with mathematical modelling suggest that the transition between estrus and diestrus is underpinned by well-orchestrated changes in neuropeptide signalling and in the excitability of the KNDy population controlled via glutamate signalling. Guided by model predictions, we show that blocking glutamate signalling in diestrous animals inhibits LH pulses, and that optic stimulation of the KNDy population mitigates this inhibition. In estrous mice, disruption of glutamate signalling inhibits pulses generated via sustained low-frequency optic stimulation of the KNDy population, supporting the idea that the level of network excitability is critical for pulse generation. Our results reconcile previous puzzling findings regarding the estradiol-dependent effect that several neuromodulators have on the GnRH pulse generator dynamics. Therefore, we anticipate our model to be a cornerstone for a more quantitative understanding of the pathways via which gonadal steroids regulate GnRH pulse generator dynamics. Finally, our results could inform useful repurposing of drugs targeting the glutamate system in reproductive therapy.

Toxoplasma gondii Infection Causes an Atypical Abundance of Oxytocin and Its Receptor in the Female Rat Brain

Infection with the protozoan Toxoplasma gondii causes loss of innate fear of cat odors in both male and female rats. This behavioral change is presumed to reflect a parasitic manipulation that increases transmission of the parasite from its intermediate to definitive host. The host behavioral change in male rats is dependent on gonadal steroids. In contrast, the loss of fear in female rats is not accompanied by greater gonadal steroids and cannot be rescued by gonadectomy. This disparity suggests that proximate mechanisms of the post infection host behavioral change in rats are sexually dimorphic. Here, we report that female rats infected with Toxoplasma gondii exhibit greater abundance of messenger RNA for oxytocin and oxytocin receptors in the paraventricular nucleus of the hypothalamus and posterodorsal medial amygdala, respectively. Brain oxytocin is critical for sex-typical social and sexual behaviors in female rodents. The change in oxytocin and its receptor could potentially alter activity in the social salience circuits, leading to a reduction in defensive behaviors and an increase in approach to ambivalent environmental cues. Our results argue that sexually dimorphic neural substrates underpin sexually monomorphic host behavioral change in this host–parasite association.

Recent Update on the Molecular Mechanisms of Gonadal Steroids Action in Adipose Tissue

The gonadal steroids, including androgens, estrogens and progestogens, are involved in the control of body fat distribution in humans. Nevertheless, not only the size and localization of the fat depots depend on the sex steroids levels, but they can also highly affect the functioning of adipose tissue. Namely, the gonadocorticoids can directly influence insulin signaling, lipid metabolism, fatty acid uptake and adipokine production. They may also alter energy balance and glucose homeostasis in adipocytes in an indirect way, e.g., by changing the expression level of aquaglyceroporins. This work presents the recent advances in understanding the molecular mechanism of how the gonadal steroids influence the functioning of adipose tissue leading to a set of detrimental metabolic consequences. Special attention is given here to highlighting the sexual dimorphism of adipocyte functioning in terms of health and disease. Particularly, we discuss the molecular background of metabolic disturbances occurring in consequence of hormonal imbalance which is characteristic of some common endocrinopathies such as the polycystic ovary syndrome. From this perspective, we highlight the potential drug targets and the active substances which can be used in personalized sex-specific management of metabolic diseases, in accord with the patient’s hormonal status.

Male fertility in relapsing-remitting multiple sclerosis patients treated with natalizumab and ocrelizumab: A prospective case-control study

Scarce data are available about the impact of natalizumab (NTZ) and ocrelizumab (OCR) on male fertility in relapsing-remitting multiple sclerosis (RRMS). In this case–control prospective study, the gonadal steroids and the sperm parameters have been analysed at the time of the RRMS diagnosis and after 12 months from the beginning of the investigated therapies. Sixteen men with RRMS and sixteen matched healthy controls were included. At enrolment and after 12 months on therapy, the gonadal steroids and the sperm parameters of men with RRMS did not differ from the healthy controls. In conclusion, therapy with NTZ and OCR had no impact on fertility status in our cohort of men with RRMS. Further randomized and prospective studies are needed.

Ontogeny of OPN4, OPN5, GnRH and GnIH mRNA Expression in the Posthatch Male and Female Pekin Duck (Anas platyrhynchos domesticus) Suggests OPN4 May Have Additional Functions beyond Reproduction

The hypothalamic–pituitary–gonadal axis (HPG) is known to be regulated by daylength through the deep brain photoreceptor (DBP) system. The post-hatch ontogeny is not known for any of the DBPs. We set out to determine the ontogeny of OPN4 and OPN5 gene expression relative to GnRH and GnIH using qRT-PCR. Brains and serum were collected from five drakes and five hens on the day of hatching (Day 0) and again at 2, 4, 6, 10, 14, 19, 25 and 31 weeks of age and analyzed by qRT-PCR. Hen and drake serum was assayed for circulating levels of estradiol and testosterone, respectively. Data were analyzed between sexes over time using a repeated measures two-way ANOVA. Interestingly, the results show that on the day of hatching (Day 0), ducks showed adult-like levels of relative OPN4, but not OPN5, gene expression. During week 10, DBP levels increased, achieving highest relative expression levels at week 19 that maintained through week 31, typically peak fertility in ducks. GnRH mRNA levels increased following the DBP expression at the onset of puberty, and gonadal steroids increased after GnRH at week 14 while estradiol preceded testosterone. GnIH mRNA levels did not appreciably change during the time course of this experiment. These observations suggest that OPN4 may be active during the peri-hatch period and may have physiological roles beyond puberty and fertility.

Modulation of pulsatile GnRH dynamics across the ovarian cycle: the role of excitability within the arcuate kisspeptin network

Pulsatile GnRH release is essential for normal reproductive function. Kisspeptin secreting neurons found in the arcuate nucleus, known as KNDy neurons for co-expressing neurokinin B, and dynorphin, drive pulsatile GnRH release. Furthermore, gonadal steroids regulate GnRH pulsatile dynamics across the ovarian cycle by altering KNDy neurons’ signalling properties. However, the precise mechanism of regulation remains mostly unknown. Here we investigate these mechanisms using a combination of mathematical and in-vivo approaches. We find that optogenetic stimulation of KNDy neurons stimulates pulsatile GnRH/LH secretion in estrous mice but inhibits it in diestrous mice. Our mathematical modelling suggests that this differential effect is due to well-orchestrated changes in neuropeptide signalling and the excitability of the KNDy population controlled via glutamate signalling. Guided by model predictions, we show that blocking glutamate signalling in the arcuate nucleus in diestrous animals inhibits LH pulses, and that optic stimulation of the KNDy population mitigates this inhibition. In estrous mice, disruption of glutamate signalling inhibits pulses generated via sustained low-frequency optic stimulation of the KNDy population, supporting the idea that the level of network excitability is critical for pulse generation. Our results reconcile previous puzzling findings regarding the estradiol-dependent effect that several neuromodulators have on the GnRH pulse generator dynamics. Therefore, we anticipate our model to be a cornerstone for a more quantitative understanding of the pathways via which gonadal steroids regulate GnRH secretion dynamics. Finally, our results could inform useful repurposing of drugs targeting the glutamate system in reproductive therapy.

Beyond GnRH, LH and FSH: the role of kisspeptin on hypothalalmic-pituitary gonadal (HPG) axis pathology and diagnostic consideration

Kisspeptin as a neuropeptide was established initially as regulator GnRH pulse frequency and intensity. Over time it was recognized that the interaction are mediated through a specific receptor GPR54, which has also been found throughout the hypothalamic-pituitary-gonadal (HPG) axis. Further insights into the mechanisms leading to triggering of kisspeptin were identified to be both negative and positive feedbacks from gonadal steroids along with various internal metabolic alterations and environmental triggers in the shape of diet and lifestyle. More so it was identified that these Kisspeptin/GPR54 receptor interaction was also influenced by endocannabinoid (eCB) system, GABA-ergic neuronal outputs (GABA) and other chemical agents. The most influencing neuronal inputs modifying the release of kisspeptin were identified as group of neurons termed “KNDy” in the ARC nuclei. Based upon these discoveries, scientist attempted to evaluate kisspeptin as diagnostic marker for various diseases including precocious puberty, puberty confirmation, hypogonadism, infertility and polycystic ovarian Continuous...

Role of Sex Hormones in Human Body

Gonadal Steroids hormones play an important role in the reproductive and non-reproductive system. Estrogen has important rule in cardiovascular system as it has vasodilator effect and reduces or prevents platelet activation. In addition, it improves the profile of circulating lipoproteins. All of which may explain why women at premenopausal are less likely to have heart disease than menopause women or men. E2 play grate effect on the skeletal system as it is one of the strongest regulators of osteoblast and osteoclast function, and its responsible for the reduction of adipose tissue and regulation of the body weight, and also has dermatological effect,hence it stimulates the proliferation of keratinocytes and prevents their apoptosis, in addition to the progesterone which increases collagen synthesis. Estrogen is necessary for the functioning and integrity of the tissues of the urinary system specially of the lower urinary tract. Sex steroid are crucial for nervous system, as progesterone is important for production of neurosteroid, and estrogen is currently used in Parkinson’s and Alzheimer’s disease because of its effects on mental health. The androgens also have a crucial biological effects on neural, muscle, bone, adipose tissue,prostate, cardiovascular, haemopoietic, and the reproductive systems. The gonadal steroid hormones play an important role in immune system and regulating the immune response against different viral or bacterial infection.