Human INHBB gene variant (c.1079T>C:p.Met360Thr) alters testis germ cell content, but does not impact fertility in mice

Testicular derived inhibin B (α/βB dimers) acts in an endocrine manner to suppress pituitary production of follicle stimulating hormone (FSH), by blocking the actions of activins (βA/B/βA/B dimers). Previously, we identified a homozygous genetic variant (c.1079T>C:p.Met360Thr) arising from uniparental disomy of chromosome 2 in the INHBB gene (βB-subunit of inhibin B and activin B) in a man suffering from infertility (azoospermia). In this study, we aimed to test the causality of the p.Met360Thr variant in INHBB and testis function. Here, we used CRISPR/Cas9 technology to generate Inhbb M364T/M364T mice, where mouse INHBB p.Met364 corresponds with human p.Met360. Surprisingly, we found that the testes of male Inhbb M364T/M364T mutant mice were significantly larger compared with those of aged-matched wildtype littermates at 12 and 24 weeks of age. This was attributed to a significant increase in Sertoli cell and round spermatid number and, consequently, seminiferous tubule area, in Inhbb M364T/M364T males compared to wildtype males. Despite this testis phenotype, male Inhbb M364T/M364T mutant mice retained normal fertility. Serum hormone analyses however, indicated that the Inhbb M364T variant resulted in reduced circulating levels of activin B, but did not affect FSH production. We also examined the effect of this p.Met360Thr, and an additional INHBB variant (c.314C>T: p.Thr105Met) found in another infertile man, on inhibin B and activin B in vitro biosynthesis. It was found that both INHBB variants resulted in a significant disruption to activin B in vitro biosynthesis. Together, this analysis supports that INHBB variants that limit activin B production have consequences for testis composition in males.

Assessment of serum hormone levels in female patients with acne vulgaris

Introduction: Acne is a chronic inflammatory disorder of the pilosebaceous unit with differential pathogenesis. To elucidate the roles of hormones in acne pathogenesis, we conducted a study to evaluate the serum testosterone, estradiol, progesterone levels in women with acne vulgaris. Methods: We conducted a cross-sectional descriptive study, and 175 women with acne vulgaris were examined; their serum estradiol, progesterone, testosterone were analyzed by chemiluminescence technique and compared with the healthy control group. Results: Increased serum hormone levels in women with acne vulgaris were accounted for 29.7%, and hyperandrogenism was accounted for 16.0% of cases. We found significant differences in testosterone levels (mean value, 55.67±25.56 versus 38.37±10.16 ng/dL, p<0.05) respectively in the acne group and the control group. However, the estradiol level of the acne group (323.15±93.31 pmol/L) was lower than the control group (370.94±58.88 pmol/L) with p<0.05). No statistically significant differences were found for progesterone (0.60±0.38 versus 0.50±0.15 ng/mL, p>0.05) levels. Moreover, we did not find the relationship between serum hormone levels and the severity of acne vulgaris. Conclusion: This study showed that the female acne vulgaris patients may have high serum testosterone levels and low serum estradiol levels compared with those of female controls. However, hormone alterations had no correlation with the acne grades.

Menopause modulates the circulating metabolome: evidence from a prospective cohort study

Aims: We studied the changes in the circulating metabolome and their relation to the menopausal hormonal shift in 17β-oestradiol and follicle-stimulating hormone levels among women transitioning from perimenopause to early postmenopause. Methods and Results: We analysed longitudinal data from 218 Finnish women, 35 of whom started menopausal hormone therapy during the study. The menopausal transition was monitored with menstrual diaries and serum hormone measurements. The median follow-up was 14 months (interquartile range: 8–20). Serum metabolites were quantified with targeted nuclear magnetic resonance metabolomics. The model results were adjusted for age, follow-up duration, education, lifestyle, and multiple comparisons. Menopause was associated with 84 metabolite measures. The concentration of apoB (0.17 standard deviation [SD], 99.5% confidence interval [CI] 0.03–0.31), VLDL triglycerides (0.25 SD, CI 0.05–0.45) and particles (0.21 SD, CI 0.05–0.36), LDL cholesterol (0.17 SD, CI 0.01–0.34) and particles (0.17 SD, CI 0.03–0.31), HDL triglycerides (0.24 SD, CI 0.02–0.46), glycerol (0.32 SD, CI 0.07–0.58) and leucine increased (0.25 SD, CI 0.02–0.49). Citrate (-0.36 SD, CI -0.57 to -0.14) and 3-hydroxybutyrate concentrations decreased (-0.46 SD, CI -0.75 to -0.17). Most metabolite changes were associated with the menopausal hormonal shift. This explained 10% and 9% of the LDL cholesterol and particle concentration increase, respectively. Menopausal hormone therapy was associated with increased medium-to-large HDL particle count and decreased small-to-medium LDL particle and glycine concentration. Conclusions: Menopause is associated with proatherogenic circulating metabolome alterations. Female sex hormones levels are connected to the alterations, highlighting their impact on women's cardiovascular health.

Effect of acupuncture on menopausal hot flushes and serum hormone levels: a systematic review and meta-analysis

Objective: To evaluate the efficacy/effectiveness and safety of acupuncture for the treatment of hot flushes and its impact on serum hormone levels in menopausal women. Methods: A total of 10 databases were searched from their inception to August 2018. Reference lists of reviews and included articles were also hand-searched. Randomized controlled trials (RCTs) comparing the effect of acupuncture versus sham acupuncture, or acupuncture versus hormone therapy (HT), as treatment for menopausal hot flushes were included. Outcomes included hot flush frequency, hot flush severity and serum hormone levels of estradiol (E2), luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Meta-analyses were performed using Review Manager 5.3 software. Results: Thirteen RCTs including 1784 patients were selected, seven of which were available for meta-analysis. Compared with sham acupuncture, acupuncture significantly decreased hot flush frequency (mean difference (MD) −0.84, 95% confidence interval (CI) [−1.64, −0.05], I2 = 54%) from baseline to the end of study, but did not impact end scores of hot flush frequency (MD 0.19, 95% CI [−0.61, 0.99], I2 = 0%) or severity (MD 0.02, 95% CI [−0.13, 0.17], I2 = 0%). No differences were found between acupuncture and HT in serum levels of E2 (MD 6.56, 95% CI [−3.77, 16.89], I2 = 76%), FSH (MD 1.06, 95% CI [−1.44, 3.56], I2 = 0%) or LH (MD −3.36, 95% CI [−13.37, 6.65], I2 = 89%). Conclusion: Acupuncture may not decrease hot flush frequency, but yet appears to have similar effects on serum hormone levels as HT, that is, increased E2 and decreased FSH and LH. Considering that no firm conclusions could be drawn due to the low quality and limited number of included trials included, further high-quality RCTs need to be conducted.

The Potential Protective Effect and Possible Mechanism of Peptides from Oyster (Crassostrea hongkongensis) Hydrolysate on Triptolide-Induced Testis Injury in Male Mice

Peptides from oyster hydrolysate (OPs) have a variety of biological activities. However, its protective effect and exact mechanism on testicular injury remain poorly understood. This study aimed to evaluate the protective effect of OPs on triptolide (TP)-induced testis damage and spermatogenesis dysfunction and investigate its underlying mechanism. In this work, the TP-induced testis injury model was created while OPs were gavaged in mice for 4 weeks. The results showed that OPs significantly improved the sperm count and motility of mice, and alleviated the seminiferous tubule injury. Further study showed that OPs decreased malonaldehyde (MDA) level and increased antioxidant enzyme (SOD and GPH-Px) activities, attenuating oxidative stress and thereby reducing the number of apoptotic cells in the testis. In addition, OPs improved the activities of enzymes (LDH, ALP and ACP) related to energy metabolism in the testis and restored the serum hormone level of mice to normal. Furthermore, OPs promoted the expression of Nrf2 protein, and then increased the expression of antioxidant enzyme regulatory protein (HO-1 and NQO1) in the testis. OPs inhibited JNK phosphorylation and Bcl-2/Bax-mediated apoptosis. In conclusion, OPs have a protective effect on testicular injury and spermatogenesis disorders caused by TP, suggesting the potential protection of OPs on male reproduction.

The Selective NMDA Receptor GluN2B Subunit Antagonist CP-101,606 with Antidepressant Properties Modulates Cytochrome P450 Expression in the Liver

Recent research indicates that selective NMDA receptor GluN2B subunit antagonists may become useful for the treatment of major depressive disorders. We aimed to examine in parallel the effect of the selective NMDA receptor GluN2B subunit antagonist CP-101,606 on the pituitary/serum hormone levels and on the regulation of cytochrome P450 in rat liver. CP-101,606 (20 mg/kg ip. for 5 days) decreased the activity of CYP1A, CYP2A, CYP2B, CYP2C11 and CYP3A, but not that of CYP2C6. The alterations in enzymatic activity were accompanied by changes in the CYP protein and mRNA levels. In parallel, a decrease in the pituitary growth hormone-releasing hormone, and in serum growth hormone and corticosterone (but not T3 and T4) concentration was observed. After a 3-week administration period of CP-101,606 less changes were found. A decrease in the CYP3A enzyme activity and protein level was still maintained, though no change in the mRNA level was found. A slight decrease in the serum concentration of corticosterone was also maintained, while GH level returned to the control value. The obtained results imply engagement of the glutamatergic system in the neuroendocrine regulation of cytochrome P450 and potential involvement of drugs acting on NMDA receptors in metabolic drug–drug interactions.

Mice with Whole-Body Disruption of AMPK-Glycogen Binding Have Increased Adiposity, Reduced Fat Oxidation and Altered Tissue Glycogen Dynamics

The AMP-activated protein kinase (AMPK), a central regulator of cellular energy balance and metabolism, binds glycogen via its β subunit. However, the physiological effects of disrupting AMPK-glycogen interactions remain incompletely understood. To chronically disrupt AMPK-glycogen binding, AMPK β double knock-in (DKI) mice were generated with mutations in residues critical for glycogen binding in both the β1 (W100A) and β2 (W98A) subunit isoforms. We examined the effects of this DKI mutation on whole-body substrate utilization, glucose homeostasis, and tissue glycogen dynamics. Body composition, metabolic caging, glucose and insulin tolerance, serum hormone and lipid profiles, and tissue glycogen and protein content were analyzed in chow-fed male DKI and age-matched wild-type (WT) mice. DKI mice displayed increased whole-body fat mass and glucose intolerance associated with reduced fat oxidation relative to WT. DKI mice had reduced liver glycogen content in the fed state concomitant with increased utilization and no repletion of skeletal muscle glycogen in response to fasting and refeeding, respectively, despite similar glycogen-associated protein content relative to WT. DKI liver and skeletal muscle displayed reductions in AMPK protein content versus WT. These findings identify phenotypic effects of the AMPK DKI mutation on whole-body metabolism and tissue AMPK content and glycogen dynamics.

Rhamnocitrin Ameliorates Ovarian Fibrosis Via PPARγ/TGF-β1/Smad Pathway to Repair Ovarian Function in Polycystic Ovary Syndrome Rats Running Title：rhamnocitrin Ameliorates Ovarian Fibrosis in Polycystic Ovary Syndrome Rats

Background: Polycystic ovary syndrome (PCOS) is one of the major endocrine disorders in women, characterized by androgen excess, chronic anovulation and ovarian fibrosis. Rhamnocitrin is an herbal bioactive flavonoid that has anti-inflammation and antioxidant effects. We intended to investigate the impacts of Rhamnocitrin on PCOS-induced ovarian fibrosis and its underlying mechanisms.Methods: Dehydroepiandrosterone (DHEA) induced-PCOS rats were treated with Rhamnocitrin. HE staining was performed to detect ovarian histological features. Ovarian fibrosis was evaluated by Sirius Red and Masson staining. Vaginal smear was examined to exhibit estrus cycle stage and vaginal cornification. The serum hormone levels of FSH, LH, E2 and T were measured with ELISA. The related mRNAs and proteins of fibrosis factors and PPARγ/TGF-β1/Smad2 signaling were detected by RT-qPCR and western blot. The weights of rat bodies and ovaries were recorded. PPARγ inhibitor T0070907 and its agonist GW1929 were employed for the mechanistic investigation.Results: The corpus luteum and follicles were increased and irregular estrous cycle was restored after Rhamnocitrin treatment in PCOS rats. Rhamnocitrin inhibited ovarian fibrosis and down-regulated the expressions of fibrotic factors. Rhamnocitrin reduced the increased levels of LH, E2, and T, and elevated the decreased FSH level in PCOS rats. Besides, Rhamnocitrin elevated the down-regulated PPARγ, and suppressed the up-regulated TGF-β1 and p-Smad2 expressions induced by PCOS. These effects of Rhamnocitrin on PCOS rats could be antagonized by T0070907, whereas GW1929 markedly mimics the functions of Rhamnocitrin. Conclusions: Rhamnocitrin ameliorates ovarian fibrosis in PCOS rats through regulation PPARγ/TGF-β1/Smad2pathway, suggesting it can be a potentially effective therapeutic candidate for PCOS treatment.