Activity Of Gonadal Axis Research Articles

Total osteocalcin levels are independently associated with worse testicular function and a higher degree of hypothalamic–pituitary–gonadal axis activation in Klinefelter syndrome

PurposeThe role of osteocalcin (OCN) in pubertal development, male hypogonadism, and the effect of testosterone (Te) replacement therapy (TRT) remains unclear. We aimed to investigate the total OCN (tOCN) concentrations in male patients with Klinefelter syndrome (KS), a model of adult hypergonadotropic hypogonadism.MethodsThis retrospective longitudinal study investigated 254 male patients with KS (47,XXY) between 2007 and 2021 at an academic referral center, categorized as (1) prepubertal, (2) pubertal, and (3) adults. All prepubertal patients were Te-naïve. Adult patients were subcategorized as (1) eugonadal, (2) hypogonadal, and (3) receiving TRT. We also analyzed 18 adult patients with available tOCN levels before and 3 months after TRT commencement.ResultsThe tOCN levels varied throughout the lifespan according to pubertal status, were highest in eugonadal and significantly lower in TRT subjects, correlated with both LH (p = 0.017) and FSH levels (p = 0.004) in adults, and significantly declined after 3 months of TRT (p = 0.006) in the adult KS cohort. HPG-axis hormones levels demonstrated no correlation in prepubertal boys. Adjustment for age and body mass index confirmed previous results and revealed significant inverse correlations with total Te (p = 0.004), calculated free Te (p = 0.016), the Te/LH (p = 0.010), and calculated free Te/LH ratios (p = 0.031).ConclusionIn KS, a model of male hypergonadotropic hypogonadism, tOCN levels were not associated with gonadal function during normal prepuberty and pubertal development but were associated with worse testicular function and a higher degree of HPG stimulation in adults. TRT acutely reduced tOCN levels in adults.

LBMON175 Nadir Growth Hormone Concentrations In Patients With Acromegaly Relate To Disease Activity, Glucose Metabolism, BMI And Sex

Abstract Background In healthy subjects, nadir growth hormone (GH) concentrations following an oral glucose load are related to BMI, gender and estrogen use. To date, very few data exist on factors influencing nadir GH in patients with acromegaly. Methods Glucose suppression tests (2h-75g) were performed in 166 patients with acromegaly not receiving any acromegaly-specific medical therapy: 132 OGTTs were performed at the initial disease diagnosis and 126 after at least one pituitary surgery. Glucose, insulin and C-peptide were measured every 30 minutes and the metabolic response was evaluated by minimal model analysis. Uni- and multivariate regression analysis was performed to test the relationship between nadir GH concentrations, patient characteristics and parameters of disease activity, lipid and glucose metabolism. Results In patients with active acromegaly (46% males), nadir glucose concentrations positively correlated to fasting IGF-1 (expressed as fold-ULN; p<0. 001), fasting insulin and C-peptide (both p=0. 004), HOMA-insulin resistance index (p=0. 016), and prehepatic beta-cell function (p=0. 002), but not to BMI and gender. In multivariate analysis, fasting C-peptide and IGF-1 were both independent predictors of nadir GH levels in patients with newly diagnosed acromegaly (p<0. 001). When testing for sex-specific predictors of nadir GH, we found a negative relationship between nadir GH and age in male patients, but not in females. After surgery, IGF-1 decreased from 805.5 (3.2 xULN, IQR 437.8) to 277.5 ng/ml (1.1 xULN, IQR 234. 0) and nadir GH after glucose suppression decreased from 8.8 (IQR 16.2) to 0.5 ng/ml (IQR 1.9). The decrease in biomarkers of disease activity following surgery leads to changes in predictors of nadir GH: postoperatively nadir GH relates to IGF-1 (p<0. 001), prehepatic beta-cell function (p=0. 02), weight (p=0. 031) and BMI (p=0. 044), with beta-cell-function being the only independent predictor in multivariate analysis (p=0. 003). When postoperative OGTTs performed in men and women were separately analyzed, nadir GH remained in a positive relationship to GH and IGF-1 in both sexes, but the relationship with beta-cell-function and other parameters of glucose metabolism remained significant only in male patients. In addition, postoperative nadir GH in male patients positively relates to LDL-cholesterol and triglycerides, and negatively to gonadal axis activity. Conclusion Here we describe that nadir GH concentrations in patients with acromegaly are mainly determined by parameters of disease activity and beta-cell function, but not by BMI and sex. A positive relationship between nadir GH and weight/BMI is only observed following improvement of disease activity after surgery, but appears mainly influenced by morphologic gender differences, as it disappears when male and female cohorts are analyzed separately. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Inverse age-related changes between hypothalamic NPY and KISS1 gene expression during pubertal initiation in male rhesus monkey

The neuroendocrine mechanism underlying the sinusoidal wave nature of gonadotropin–releasing hormone pulse generator activity from infantile to adult age still needs to be meticulously defined. Direct inhibition of kisspeptin neurons by neuropeptide Y (NPY) and close intimacy between the two rekindle the importance of these two neuropeptides controlling reproductive axis activity. Thus, the present study was undertaken to decipher simultaneous fluctuations and to profile correlative changes in the relative expression of KISS1, NPY, and their receptor genes from the mediobasal hypothalamus of infant (n = 3), juvenile, pre-pubertal, and adult (n = 4 in each stage) male rhesus monkey (Macaca mulatta) by RT-qPCR. Significant elevation (p < 0.05−0.01) in KISS1 and KISS1R and low (p < 0.05) expression in NPY and NPY1R mRNA in the adult group as compared to the pre-pubertal group was observed. Moreover, significantly high (p < 0.05) expression of NPY and NPY1R mRNA with non-significant (p> 0.05) decline in KISS1 and KISS1R in pre-pubertal animals in comparison to infants describe inverse correlative age-associated changes during pubertal development. Current findings imply that NPY may contribute as a neurobiological brake for the dormancy of kisspeptin neurons before pubertal onset, while dwindling of this brake is likely to occasion kisspeptin dependent hypothalamic–pituitary–gonadal axis activation at puberty. These findings may help in the development of clinical and therapeutic strategies to regulate fertility in humans.

Pathophysiology of Peripheral Precocious Puberty in girls: an overview

Precocious puberty can be distinguished in central, or peripheral, based on the presence or absence of the Hypothalamic- Pituitary- Gonadal axis activation. The pathogenesis of peripheral precocious puberty (PPP) is based mainly on excessive estrogenic exposure, either endogenous or exogenous. The congenital causes of PPP include McCune- Albright syndrome (MAS) and Congenital Adrenal Hyperplasia (CAH). The main causes of acquired PPP are oestrogen producing tumours, which are mainly of ovarian or adrenal origin, hypothyroidism and environmental oestrogens or substances with estrogenic function.

Obstructive Sleep Apnea Is Associated With Low Testosterone Levels in Severely Obese Men.

BackgroundDisrupted sleep affects cardio-metabolic and reproductive health. Obstructive sleep apnea syndrome represents a major complication of obesity and has been associated with gonadal axis activity changes and lower serum testosterone concentration in men. However, there is no consistent opinion on the effect of obstructive sleep apnea on testosterone levels in men.ObjectiveThe aim of this study was to determine the influence of obstructive sleep apnea on total and free testosterone levels in severely obese men.Materials and methodsThe study included 104 severely obese (Body Mass Index (BMI) ≥ 35 kg/m2) men, aged 20 to 60, who underwent anthropometric, blood pressure, fasting plasma glucose, lipid profile, and sex hormone measurements. All participants were subjected to polysomnography. According to apnea-hypopnea index (AHI) patients were divided into 3 groups: <15 (n = 20), 15 - 29.9 (n = 17) and ≥ 30 (n = 67).ResultsThere was a significant difference between AHI groups in age (29.1 ± 7.2, 43.2 ± 13.2, 45.2 ± 10.2 years; p < 0.001), BMI (42.8 ± 5.9, 43.2 ± 5.9, 47.1 ± 7.8 kg/m2; p = 0.023), the prevalence of metabolic syndrome (MetS) (55%, 82.4%, 83.6%, p = 0.017), continuous metabolic syndrome score (siMS) (4.01 ± 1.21, 3.42 ± 0.80, 3.94 ± 1.81, 4.20 ± 1.07; p = 0.038), total testosterone (TT) (16.6 ± 6.1, 15.2 ± 5.3, 11.3 ± 4.44 nmol/l; p < 0.001) and free testosterone (FT) levels (440.4 ± 160.8, 389.6 ± 162.5, 294.5 ± 107.0 pmol/l; p < 0.001). TT level was in a significant negative correlation with AHI, oxygen desaturation index (ODI), BMI, MetS and siMS. Also, FT was in a significant negative correlation with AHI, ODI, BMI, age, MetS and siMS. The multiple regression analysis revealed that both AHI and ODI were in significant correlation with TT and FT after adjustment for age, BMI, siMS score and MetS components.ConclusionObstructive sleep apnea is associated with low TT and FT levels in severely obese men.

Hair Cortisol, Testosterone, Dehydroepiandrosterone Sulfate and Their Ratios in Stallions as a Retrospective Measure of Hypothalamic-Pituitary-Adrenal and Hypothalamic-Pituitary-Gonadal Axes Activity: Exploring the Influence of Seasonality.

Simple SummaryThe monitoring of a horse’s endocrine status can provide valuable information of its welfare and sexual and health conditions. The use of non-invasive matrixes for hormonal monitoring, as alternatives to blood samples, are being increasingly used. Among them, the measurement of hormones deposited in the hair shaft has been widely used as a retrospective hormonal biomarker. In the present study, we aimed to evaluate the seasonal variations in hair C, T and DHEA-S in horses for a whole year, as well as to assess the variations between seasons of C/DHEA-S and T/C ratios as a retrospective measure of the hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axis activity. The results showed how cortisol, testosterone and dehydroepiandrosterone sulphate and their ratios were significantly affected by season. Therefore, as shown in this study, season should be considered when analysing sexual and stress hormones in stallion hair.The monitoring of stress physiology includes studying a wide range of endocrinological mechanisms, which can be assessed using multiple tissue samples. This study aimed to evaluate the seasonal variations of hair C, T and DHEA-S in horses for a whole year, as well as to assess the variations between seasons of C/DHEA-S and T/C ratios as a retrospective measure of the hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axis activity. Ten pure-breed Menorca stallions were included in the study. The hair samples were collected approximately every two months following the shave-reshave method caudally to the sternum. After a methanol-based extraction, samples were analyzed by enzyme immunoassay for cortisol, testosterone, and dehydroepiandrosterone sulphate. Following our findings, we detected that cortisol, testosterone and dehydroepiandrosterone sulphate were significantly affected by seasonality, with the highest values of cortisol during summer and the lowest values of testosterone during spring. Dehydroepiandrosterone sulphate concentrations were increased in autumn compared to the other studied periods. Additionally, the studied hormone ratios showed variations between seasons. To conclude, season should, therefore, be considered when assessing sexual and stress hormones in stallion hair, since this variable can be a potential influencing factor and led to misinterpretations.

Targeted differential monochromatic lighting improves broiler breeder reproductive performance

Light perception in birds is composed of the retina and extraretinal sites, located in the brain. Previous studies indicate that selective photostimulation of the eye decreased reproductive performance, whereas extraretinal photostimulation increases it. Differential photostimulation of the retina and extraretinal sites is based on the retina's sensitivity to green wavelengths and on the red wavelengths' ability to penetrate body tissues.We previously found that short-day exposure to green light within a long-day exposure to red light increases reproductive activity in female turkeys and broiler breeder hens. Furthermore, in a study conducted recently in our laboratory, we found that blue light repressed expression of green light receptor in the retina, which can further enhance reproduction activity in broiler breeders. Here, we examined the “brain activate/eye deactivate” hypothesis on gonadal axis activity and reproductive performance in a broiler breeder flock.Broiler breeder hens and roosters (ROSS 308) were divided into 5 light-treatment groups (controlled rooms with light-emitting diodes [LED] lamps): warm white (control), long-day (14 h) red (630 nm) and short-day (6 h) green (514 nm) (red-green), long-day green and short-day red (green-red), long-day red and short-day blue (456 nm) (red-blue), and long-day blue and short-day red (blue-red). Birds were reared from 20 to 55 wk of age. Eggs were collected daily. Weekly egg production calculated. All eggs were incubated for fertility and hatchability examination. Blood was drawn monthly for plasma analysis. At 35 wk of age (after peak production) and 55 wk of age (end of the experiment), 10 hens from each treatment group were euthanized, and selected tissues and glands were taken for gene expression trials.Providing long-day red light to extraretinal photoreceptors while maintaining retinal photoreceptors on short day with blue or green light significantly improved reproductive activities, manifested by elevated egg production and gonadal axis activity compared with Controls and primary breeder recommendations. Long-day green light reduced reproductive performances. We suggest that targeted photostimulation enhances reproductive and gonadal axis activities in broiler breeders.

The effect of parachlorophenylalanine treatment on the activity of gonadal and lactotrophic axes in native Polish crested chickens stimulated to broodiness

Brooding behavior, a common characteristic of native breeds of the domestic chicken, is marked by elevated prolactin (PRL) levels, which is necessary for incubation and connected with changes in hypothalamic–pituitary–gonadal axis activity. Evidence indicates the serotoninergic system is a potent modulator of PRL secretion. The objective of this study is to investigate whether blocking serotonin synthesis with parachlorophenylalanine (PCPA) prevents incubation behavior in native Polish crested chickens. In addition, we examined the effect of PCPA on the gene expression of the gonadal and lactotrophic axes. Birds were stimulated to broodiness by artificial eggs in nests. At 34 wk of age (April: spring period), the hens were divided into 2 groups (14 hens in each group): control and PCPA-treated (50 mg/kg BW) group. After 5 wk of treatment, the artificial eggs were removed from the nests. Egg production, incubation activity, and levels of plasma ovarian steroids progesterone (P4), testosterone (T), estradiol (E2), and PRL were examined. At the end of the experiment (45 wk of age, June: summer period), ovarian characteristics and mRNA gene expression of gonadal (gonadotropin-releasing hormone [GnRH] I, luteinizing hormone [LH] ß, follicle-stimulating hormone [FSH] ß) and lactotrophic (vasoactive intestinal peptide [VIP], PRL) axes were measured by quantitative real-time PCR. Incubation activity was observed in the hens of both groups but with lower frequency in PCPA-treated birds. Moreover, the PCPA group had a higher cumulative egg production than the controls. During the first six and 8 wk of the experiment, levels of P4 and E2, respectively, were similar in both groups, but all concentrations increased in the PCPA-treated hens after this period. In addition, increased GnRH-I, LHß, and FSHß and decreased VIP mRNA expression was observed in the PCPA group compared with the controls. There were no differences in PRL mRNA expression, the PRL level, and ovarian morphometry between the 2 groups. These results indicate that blockage of serotonin synthesis by PCPA does not effectively prevent incubation in native Polish crested chickens. However, treatment with PCPA increased gonadal axis activity and improved reproductive performance.

Functional hypothalamic and drug-induced amenorrhea: an overview.

Functional hypothalamic amenorrhea (FHA) is a form of chronic anovulation not due to identifiable organic causes and with adverse health consequences. The identification of women with this disorder or the precocious identification of women at risk is based on the knowledge of lifestyle risk factors or behaviors such as stress, weight loss, and excessive physical exercise that are known to negatively impact gonadal axis activity. In this overview, we described the most common forms of FHA, in particular stress-induced amenorrhea and overtraining-induced amenorrhea. In addition, although its mechanisms can differ from those involved in FHA, we reviewed the available literature on drug-induced amenorrhea, highlighting the clear connection between this condition and psychoactive drugs such as antipsychotics, antidepressants and anti-epilectics thus raising concern about the role that the abuse of substances such as opioids or alcohol can possibly have on the growing unexplained infertility of the female population.

A new class of pentapeptide KISS1 receptor agonists with hypothalamic–pituitary–gonadal axis activation

The kisspeptin (Kp, Kp-54, metastin)/KISS1R system plays crucial roles in regulating the secretion of gonadotropin-releasing hormone. Continuous administration of nonapeptide Kp analogs caused plasma testosterone depletion, whereas bolus administration caused strong plasma testosterone elevation in male rats. To develop a new class of small peptide drugs, we focused on stepwise N-terminal truncation of Kp analogs and discovered potent pentapeptide analogs. Benzoyl-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (16) exhibited high agonist activity for KISS1R and excellent metabolic stability in rat serum. A single injection of a 4-pyridyl analog (19) at the N-terminus of 16 into male Sprague Dawley rats caused a robust increase in plasma luteinizing hormone levels, but unlike continuous administration of nonapeptide Kp analogs, continuous administration of 19 maintained moderate testosterone levels in rats. These results indicated that small peptide drugs can be successfully developed for treating sex hormone deficiency.

Gonadotropin-Inhibitory Hormone Plays Roles in Stress-Induced Reproductive Dysfunction.

Physical and psychological stressors suppress hypothalamic–pituitary–gonadal axis activity and sexual behavior and consequently induce reproductive dysfunction. Recently, it has been shown that gonadotropin-inhibitory hormone (GnIH), also called RFamide-related peptide 3 (RFRP) in mammals, which is a potent inhibitory regulator of gonadotropin-releasing hormone (GnRH) and gonadotropin, is involved in stress-induced reproductive dysfunction. GnIH/Rfrp (the gene coding RFRP-3) expression and activity are increased by psychological and immune stress, and this alteration suppresses GnRH and gonadotropin secretion. Glucocorticoid acts as a mediator that interacts between stress and hypothalamic GnIH/RFRP-3. GnIH/RFRP-3 also plays important roles in stress-induced suppression of sexual behavior and infertility, and genetic silencing of GnIH/Rfrp completely recovers sexual behavior and fertility. This review summarizes what is currently known about the roles of GnIH in stress-induced reproductive dysfunction.

Male gonadal axis function in patients with type 2 diabetes.

Patients with type 2 diabetes have lower serum testosterone levels and a higher prevalence of hypogonadism than non-diabetic patients, independently of the metabolic control of disease. The mechanisms underlying a decrease in testosterone might be related to age, obesity and insulin resistance, often present in patients with type 2 diabetes. The increase in estrogens due to higher aromatase enzyme activity in increased adipose tissue might exert negative-feedback inhibition centrally. Insulin stimulates gonadal axis activity at all three levels and therefore insulin resistance might account for the lower testosterone production. Leptin exerts a central stimulatory effect but inhibits testicular testosterone secretion. Thus, resistance to leptin in obese subjects with type 2 diabetes determines lower central effects of leptin with lower gonadotropin-releasing hormone (GnRH) secretion and, on the other hand, hyperleptinemia secondary to leptin resistance inhibits testosterone secretion at the testicular level. However, lower testosterone levels in patients with diabetes are observed independently of age, weight and body mass index, which leads to the assumption that hyperglycemia per se might play a role in the decrease in testosterone. Several studies have shown that an overload of glucose results in decreased serum testosterone levels. The aim of this review is to assess changes in the male gonadal axis that occur in patients with type 2 diabetes.

Brain thromboxane A2 via arachidonic acid cascade induces the hypothalamic-pituitary-gonadal axis activation in rats.

The current study was designed to determine the effect of centrally administrated arachidonic acid (AA) on plasma gonadotropin hormone-releasing hormone (GnRH), follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone level, and sperm parameters, and to show the mediation of the central cyclooxygenase (COX) to thromboxane A2 (TXA2) signaling pathway in AA-induced hormonal and sperm parameter effects. Studies were performed in male Sprague-Dawley rats. A total of 150 or 300 μl/5 μl doses of AA were injected intracerebroventricularly (icv). AA significantly caused dose- and time-dependent increases in plasma FSH, LH and testosterone levels of animals, but not plasma GnRH level. AA also significantly increased sperm motility of the rats without change sperm number. Pretreated with ibuprofen, a nonselective COX inhibitor (250 μg/5 μl; icv), and furegrelate, a TXA2 synthesis inhibitor (250 μg/5 μl; icv), prevented AA-evoked increase in plasma FSH, LH and testosterone levels, and sperm motility. In conclusion, our findings show that centrally administered AA increases plasma FSH, LH and testosterone levels and sperm motility of conscious male rats. Moreover, according to our findings, central COX-TXA2 signaling pathway mediates these AA-induced effects.

Gonadotropin and Estradiol Levels after Leuprolide Stimulation Tests in Brazilian Girls with Precocious Puberty

Study ObjectiveTo determine the best cutoff value on the leuprolide stimulation test for the diagnosis of central precocious puberty (CPP) in a Brazilian population. Design, Setting, and ParticipantsThis observational study included 60 girls with CPP, as shown on the basis of serum concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) before and 3 hours after subcutaneous administration of 500 μg leuprolide acetate and by measuring serum estradiol concentrations 24 hours later. Six months later, each subject was clinically evaluated to determine whether she had experienced progressive or nonprogressive puberty. Main Outcome MeasuresAnalyzing the best cutoff for LH after subcutaneous administration of 500 μg leuprolide acetate. ResultsThe best cutoff was a 3-hour LH level of greater than 4.0 mIU/mL, providing the highest sensitivity (73%) and specificity (83.1%), whereas a 3-hour LH level greater than 8.4 mIU/mL had a specificity of 100%. A 24-hour E2 concentration greater than 52.9 pg/mL had a sensitivity of 68% and a specificity of 74%. There was no association between pubertal development and disease progression. Signs such as thelarche and pubarche did not determine the evolution of the disease (P = .17). Clinical condition was associated with bone age/chronological age (P = .01), basal LH (P < .01), 3-hour LH (P = .02), baseline LH/FSH indices (P < .01) and after 3 hours (P < .01), and E2 at 24 hours (P = .02). ConclusionThe optimal parameter indicating hypothalamic–pituitary–gonadal axis activation in our sample was a 3-hour LH level greater than 4.0 mIU/mL. A diagnosis of CPP, however, should be based on a set of criteria and not on an isolated measurement, because typical laboratory findings associated with CPP may not be present in all patients.

Depression in premenopausal women: gonadal hormones and serotonergic system assessed by d-fenfluramine challenge test

Purpose: The aim of the study was to compare the activity of gonadal hormones and serotonergic system in premenopausal women with or without depression in relation to clinical and hormonal indices of menopause. Methods: The sample included 60 women with single or recurrent major depressive episode with disease onset after 38 year of age (mean age 43 years) and 30 healthy control women (mean age 41 years). Psychometric assessment was done by means of 17-item Hamilton Depression Rating Scale (HDRS) and the Beck Depression Inventory (BDI). The presence of menopausal symptoms was assessed by Kupperman Menopause Index (KMI). Activity of gonadal axis was measured by estimating estradiol and follicle-stimulating hormone (FSH) levels. For the assessment of central serotonergic activity, the d-fenfluramine test was used. Results: Depressed women had higher intensity of menopausal symptoms, significantly lower concentration of estradiol, and higher of FSH than control women. Severity of depression correlated with both the intensity of menopausal symptoms and the concentration of FSH. Baseline levels of prolactin were not different in both groups. Following d-fenfluramine administration, there was a significant increase in prolactin concentration in healthy women and a transient decrease in depressed ones. Baseline cortisol level was significantly higher in depressed women and correlated with the severity of depression. d-Fenfluramine challenge caused a significant increase of cortisol secretion in healthy women and a significant decrease in depressed ones. A relationship was observed between baseline estradiol, FSH, and cortisol level and the magnitude of prolactin and cortisol response to d-fenfluramine. Conclusions: In premenopausal women, a high degree of interconnections was demonstrated between symptoms of depression and symptoms of menopause on both clinical and hormonal level. The results confirm the association between depressive and menopausal symptoms as well as an involvement of gonadal hormones, cortisol, and serotonin deficiency in this process.