Genome-wide studies have demonstrated regulatory roles for diverse non-coding elements, but their precise and interrelated functions have often remained enigmatic. Addressing the need for mechanistic insight, we studied their roles in expression of Lhb which encodes the pituitary gonadotropic hormone that controls reproduction. We identified a bi-directional enhancer in gonadotrope-specific open chromatin, whose functional eRNA (eRNA2) supports permissive chromatin at the Lhb locus. The central untranscribed region of the enhancer contains an iMotif (iM), and is bound by Hmgb2 which stabilizes the iM and directs transcription specifically towards the functional eRNA2. A distinct downstream lncRNA, associated with an inducible G-quadruplex (G4) and iM, also facilitates Lhb expression, following its splicing in situ. GnRH activates Lhb transcription and increased levels of all three RNAs, eRNA2 showing the highest response, while estradiol, which inhibits Lhb, repressed levels of eRNA2 and the lncRNA. The levels of these regulatory RNAs and Lhb mRNA correlate highly in female mice, though strikingly not in males, suggesting a female-specific function. Our findings, which shed new light on the workings of non-coding elements and non-canonical DNA structures, reveal novel mechanisms regulating transcription which have implications not only in the central control of reproduction but also for other inducible genes.

In mammals, secretion of tonic (pulsatile) gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) is often suppressed during lactation. Suppression of GnRH/LH pulses in lactating dams is assumed to be caused by suckling stimuli and a chronic negative energy balance due to milk production. The present study aimed to investigate whether the central enkephalin-δ opioid receptor (DOR) signaling mediated the suppression of LH secretion by acute suckling stimuli and/or chronic negative energy balance due to milk production in rats during late lactation when dams were under a heavy energy demand. On postpartum day 16, the number of Penk (enkephalin mRNA)-expressing cells in the arcuate nucleus was significantly higher in lactating rats than in non-lactating control rats. Pulsatile LH secretion was suppressed in rats with chronic suckling or acute 1-h suckling stimuli 6 h after pup removal on day 16 of lactation. Central DOR antagonism significantly increased the mean LH concentrations and the baseline of LH pulses in rats with chronic suckling but not with acute suckling stimuli on day 16 of lactation. Besides, central κ opioid receptor (KOR) antagonism increased the amplitude of LH pulses in rats with the acute suckling stimuli on day 16 of lactation. These results suggest that central DOR signaling mediates the suppression of LH secretion caused by a negative energy balance in rats receiving chronic suckling during late lactation. On the other hand, central KOR signaling likely mediates acute suckling stimuli-induced suppression of LH secretion in rats during late lactation.

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UNASSIGNED: The study aimed to investigate the correlation between the change of sex hormone levels and ocular surface parameters in girls with idiopathic central precocious puberty(ICPP).
UNASSIGNED: Eighteen girls with ICPP and 18 age-matched normal girls participated in this study, all of the participants had undergone physical measurements, laboratory tests, imaging examination and ocular surface assessments.
UNASSIGNED: The Objective Scatter Index (OSI) in the ICPP group was significantly higher than in the control group (P = 0.031), girls with ICPP showed slightly lower MNITBUT compared to the normal control group, although this difference was not statistically significant. Bivariate analysis revealed a positive association between estradiol and OSI (r=0.383, P=0.021), Additionally, in the study population, both Luteinizing hormone (LH) and Follicle-stimulating hormone (FSH) were negatively correlated with Mean noninvasive tear breakup time (MNITBUT) (r=-0.359, P=0.031)(r=-0.357, P=0.032).
UNASSIGNED: In comparison with the normal control group, alterations in the OSI were observed in girls with ICPP. This alteration may be associated with an elevation in estrogen levels. Although there was a slight non-significant decrease in NITBUT in ICPP girls, the negative correlation between LH and FSH with MNITBUT suggests new perspective for further investigation.

UNASSIGNED: This study aimed to investigate the association between sex hormones and the risk of pulmonary fibrosis by conducting a meta-analysis of previously published studies.
UNASSIGNED: We executed a comprehensive search of the PubMed, Embase, Cochrane Library, and Web of Science databases to locate pertinent studies published up to April 2024. We included studies that reported the association between sex hormones and the risk of pulmonary fibrosis. Standardized mean difference (SMD) with 95% confidence intervals (CIs) were calculated using a random-effects model.
UNASSIGNED: A total of 10 articles, encompassing 1371 patients, were finally incorporated in this meta-analysis. Based on the evaluation of the included studies, it was observed that the levels of dehydroepiandrosterone sulfate (DHEA-S) (pooled SMD: -0.72, 95% CI: -1.21 to -0.24, p < 0.001), testosterone (pooled SMD: -1.25, CI: -2.39 and -0.11, p < 0.001) and estrogen (pooled SMD: -0.56, 95% CI: -0.96 to -0.15, p < 0.001) were significantly lower in patients with pulmonary fibrosis, whereas the levels of luteinizing hormone (LH) remained unaffected. Publication bias was ruled out through funnel plots.
UNASSIGNED: This meta-analysis indicates that reduced levels of DHEA-S, testosterone, estrogen may serve as potential risk factors for pulmonary fibrosis. There is a pressing need for additional studies to confirm this association and explore the underlying biological mechanisms. Clinicians should recognize the potential influence of sex hormones in the etiology of pulmonary fibrosis and consider this aspect during the patient management process.

17α-estradiol extends healthspan and lifespan in male mice without significant feminization or deleterious effects on reproductive function, making it a candidate for human translation. However, studies in animal models that more accurately replicate human physiology are necessary to establish 17α-estradiol dosing standards for clinical trials. This study evaluated the tolerability of 17α-estradiol treatment in the common marmoset over a short treatment duration. We found that male marmosets tolerated two dosing regimens (0.37-0.47 or 0.62-0.72 mg/kg/day) as evidenced by the absence of gastrointestinal distress, changes in vital signs, or overall health conditions. 17α-estradiol treatment mildly decreased body mass, adiposity, and glycosylated hemoglobin, although these changes were not statistically significant in most instances. However, neither dose of 17α-estradiol elicited feminization in our study, thereby suggesting that optimized dosing regimens may provide health benefits without feminization in primates. Additional studies are needed to determine if longer duration treatments would also be nonfeminizing and elicit significant health benefits, which would aid in developing dosing regimens targeting healthy aging in humans.

BACKGROUND: Leprosy affects various organs in addition to skin, eyes, and peripheral nerves. Testicular involvement in leprosy patients is common and causes disturbance in endocrine function of the testis and results in hypogonadism. Hypogonadism is frequently undiagnosed and underreported.
OBJECTIVE: This study aimed to assess hypogonadism and associated factors among leprosy patients at Alert Comprehensive Specialized Hospital, Ethiopia.
METHODS: A cross-sectional study design was used in which consecutive 146 male leprosy patients aged between 18 to 65 years attending outpatient follow-up at leprosy outpatient clinic were included. Data was gathered both from patient charts and through patients\' interviews. Androgen deficiency symptoms were assessed by androgen deficiency in the aging male questionnaire, and 5ml of blood samples were taken from study participants and serum total testosterone, LH, and FSH were analyzed by Electrochemiluminescence method. Statistical correlation was assessed by Spearman correlation. A multivariable binary logistic regression model was used to identify the independent factors associated with hypogonadism and P-value <0.05 was used to declare statistical significance.
RESULTS: The prevalence of hypogonadism was 39 (26.7%). Out of this, 34 (87.2%) had primary hypogonadism, whereas 5 (12.8%) had secondary hypogonadism. Total testosterone was inversely correlated with Body mass index (r = -0.37, p = 0.002), Luteinizing hormone (r = -0.43, p <0.001), and Follicular stimulating hormone (r = -0.42, p< 0.001). However, Total testosterone was not significantly correlated with age (r = -0.019, p = 0.81). BMI [AOR = 1.32, 95%CI (1.16-1.51)] and grade-II disability [AOR = 3.80, 95%CI (1.23-11.64)] were identified as independent risk factors for hypogonadism.
CONCLUSIONS: Nearly one-fourth of male leprosy patients had hypogonadism. Overweight and grade-II disability were independent risk factors for hypogonadism.

Neurons co-expressing kisspeptin, neurokinin B, and dynorphin A (KNDy neurons), located in the arcuate nucleus (ARC) of the hypothalamus, are indicated to be the gonadotropin-releasing hormone (GnRH) pulse generator. Dynorphin A is reported to suppress GnRH pulse generator activity. Nalfurafine is a selective agonist of the κ-opioid receptor (KOR), a receptor for dynorphin A, clinically used as an anti-pruritic drug. This study aimed to evaluate the effects of nalfurafine on GnRH pulse generator activity and luteinizing hormone (LH) pulses using female goats. Nalfurafine (0, 2, 4, 8, or 16 μg/head) was intravenously injected into ovariectomized Shiba goats. The multiple unit activity (MUA) in the ARC area was recorded, and plasma LH concentrations were measured 2 and 48 h before and after injection, respectively. The MUA volley interval during 0-2 h after injection was significantly increased in the nalfurafine 8 and 16 μg groups compared with the vehicle group. In 0-2 h after injection, the number of LH pulses was significantly decreased in the nalfurafine 8 and 16 μg groups, and the mean and baseline LH were significantly decreased in all nalfurafine-treated groups (2, 4, 8, and 16 μg) compared with the vehicle group. These results suggest that nalfurafine inhibits the activity of the GnRH pulse generator in the ARC, thus suppressing pulsatile LH secretion. Therefore, nalfurafine could be used as a reproductive inhibitor in mammals.

We investigated a screening method using only serum hormone levels and AI (artificial intelligence) predictive analysis. Among 3662 patients, numbers for NOA (non-obstructive azoospermia), OA (obstructive azoospermia), cryptozoospermia, oligozoospermia and/or asthenozoospermia, normal, and ejaculation disorder were 448, 210, 46, 1619, 1333, and 6, respectively. \"Normal\" was defined as semen findings normal according to the WHO (World Health Organization) Manual for Human Semen Testing of 2021. We extracted age, LH (luteinizing hormone), FSH (follicle stimulating hormone), PRL (prolactin), testosterone, E2 (estradiol), and T (testosterone)/E2 from medical records. A total motility sperm count of 9.408 × 106 (1.4 ml × 16 × 106/ml × 42%) was defined as the lower limit of normal. The Prediction One-based AI model had an AUC (area under the curve) of 74.42%. For the AutoML Tables-based model, AUC ROC (receiver operating characteristic) was 74.2% and AUC PR (precision-recall) 77.2%. In a ranking of feature importance from 1st to 3rd, FSH came a clear 1st. T/E2 and LH ranked 2nd and 3rd for both Prediction One and AutoML Tables. Using data from 2021 and 2022 to verify the Prediction One-based AI model, the predicted and actual results for NOA were 100% matched in both years.

OBJECTIVE: The aim of the study was to explore the optimal timing of gonadotropin initiation and the reasonable interval of luteinizing hormone (LH) levels in the gonadotropin-releasing hormone antagonist (GnRH-A) protocol.
METHODS: A retrospective cohort study was conducted to analyze the data concerning the oocyte retrieval cycles from 1,361 cases with the GnRH-A protocol implemented. The ovarian responses (including AMH, AFC) in these patients were divided into the poor ovarian response group (an antral follicle count [AFC] ≤ 6, n = 394), the normal ovarian response group (an AFC > 6 and < 15, n = 570), and the high ovarian response group (an AFC ≥ 15, n = 397), according to the AFC. The patients were sub-grouped according to LH levels on the protocol initiation day, and the clinical outcomes (including dose of Gn initiation, Gn administration days, GnRH-ant administration days, P levels on the HCG day, E2 levels on the HCG day, LH levels on the HCG day, number of embryos transferred, total fertilization rate, embryo implantation rate(%), proportion of 2PN, proportion of good-quality embryos, endometrial thickness on the hCG injection day(mm), moderate to severe OHSS, AFC on the initiation day, proportion of type A endometrium on the hCG injection day, clinical pregnancy rate, biochemical pregnancy rate, early abortion rate, ectopic pregnancy rate) were compared.
RESULTS: On the GnRH-A protocol initiation day, among all patients with different ovarian responses, the body mass index (BMI) in those with an LH ≥ 5 IU/L was lower. The differences in pregnancy outcomes between the LH < 5 IU/L group and the LH ≥ 5 IU/L group were not statistically significant across the different ovarian response groups, but the LH < 5 IU/L group had a higher proportion of good-quality embryos (80.3±24.9 vs. 74.8±26.9, P =0.035) than the LH≥5IU/Lgroup in those with poor ovarian response. The total fertilization rate (82.2±18.1 vs 85.4±15.1, P =0.021) and proportion of two pronuclei (2PN) (69.0±20.9 vs 72.7±19.9, P =0.035) were higher in the LH ≥ 5 IU/L group than the LH<5 IU/L group for those with normal ovarian responses. The embryo implantation rate (41.4±41.3 vs 52.6±43.4, P =0.012) was higher in the LH ≥ 5 IU/L group than in the LH<5 IU/L group in those with high ovarian response. The results of the multivariate logistic analysis showed that the age of the female partner, number of embryos transferred, proportion of good-quality embryos, endometrial thickness on the hCG injection day, and moderate- to-severe ovarian hyperstimulation syndrome (OHSS) were independent factors correlated with the outcome of live births (P < 0.05).
CONCLUSIONS: The LH levels on the gonadotropins (Gn) initiation day in the GnRH-A protocol will not affect pregnancy outcomes.