Male Gonadal Axis Research Articles

Kisspeptin treatment reverses high prolactin levels and improves gonadal function in hypothyroid male rats

We evaluated whether the administration of kisspeptin-10 (Kp10) is capable of restoring gonadal function in hypothyroid male rats. Hypothyroidism was induced with 6-propyl-2-thiouracil (PTU) for three months. In the last month, half of the hypothyroid animals were treated with Kp10. Hypothyroidism reduced testicular and sex gland mass, decreased the proliferation of the seminiferous epithelium, and compromised sperm morphology, motility, and vigor. A decrease in plasma LH and testosterone levels and an increase in prolactin secretion were observed in the hypothyroid rats. Hypothyroidism reduced Kiss1 and Kiss1r protein and gene expression and Star and Cyp11a1 mRNA levels in the testis. Furthermore, it reduced Lhb, Prl, and Drd2 and increased Tshb and Gnrhr expression in the pituitary. In the hypothalamus, hypothyroidism increased Pdyn and Kiss1r while reducing Gnrh1. Kp10 treatment in hypothyroid rats restored testicular and seminal vesicle morphology, improved sperm morphology and motility, reversed high prolactin levels, and increased LH and testosterone levels. In addition, Kp10 increased testicular expression of Kiss1, Kiss1r, Fshr, and Nr5a1 and pituitary Kiss1 expression. Our findings describe the inhibitory effects of hypothyroidism on the male gonadal axis and sperm quality and demonstrate that Kp10 treatment reverses high prolactin levels and improves gonadal function and sperm quality in hypothyroid rats.

Short term effects of intraarticular triamcinolone acetonide injection on serum testosterone, luteinizing hormone, and follicle stimulating hormone levels in male veterans: A prospective pilot study.

Despite the common practice of intraarticular corticosteroid injections (ICSIs) for peripheral joint disease, little is known about their systemic effects on the hypothalamic-pituitary-gonadal axis. To assess the short-term effects of ICSIs on serum testosterone (T), luteinizing hormone (LH), and follicle stimulating hormone (FSH) levels together with changes in Shoulder Pain and Disability Index (SPADI) scores in a veteran population. Prospective pilot study. Outpatient musculoskeletal clinic. Thirty male veterans, median age 50 (range 30-69) years. Ultrasound-guided glenohumeral joint injection using 3 mL of 1% lidocaine HCl and 1 mL of 40 mg triamcinolone acetonide (Kenalog). Serum T, FSH, and LH levels, Quantitative Androgen Deficiency in the Aging Male (qADAM), and SPADI questionnaires at baseline, 1, and 4 week(s) post procedure. At 1 week post injection, serum T levels decreased by 56.8 ng/dL (95% confidence interval (CI): 91.8, 21.7, p = .002) compared with baseline. Between 1 and 4 weeks post injection, serum T levels increased by 63.9 ng/dL (95% CI: 26.5, 101.2, p = .001), recovering to near baseline levels. SPADI scores were reduced at 1 week (-18.3, 95% CI: -24.4, -12.1, p < .001) and 4 weeks (-14.5, 95% CI -21.1, -7.9, p < .001). A single ICSI can temporarily suppress the male gonadal axis. Future studies are needed to evaluate for long-term effects of multiple injections at a single setting and/or higher corticosteroid doses on male reproductive axis function.

The impact of diabetes mellitus type 1 on male fertility: Systematic review and meta-analysis.

Some evidence suggests that diabetes mellitus type 1 (DM1) could affect male fertility, gonadal axis, semen parameters, and spermatogenesis because of effects of hyperglycemia and insulin deficiency. Anyhow, the exact impact of DM1 on male fertility is unclear. To review the studies evaluating paternity rate, male gonadal axis, and semen parameters in men with DM1. A review of relevant literature from January 1980 to December 2020 was performed. Only studies published in English reporting data on fatherhood (rate of children by natural fertility), hormonal and seminal parameters were included. Out of 14 retrieved articles, the eight studies evaluating semen parameters were meta-analyzed. The rate of children (four studies) was lower than controls among men affected by DM1, especially in men with a longer duration of disease. The data of gonadal hormonal profile in DM1 men (six studies) are very heterogeneous and a neutral effect of DM1 or a condition of subclinical hypogonadism could not be concluded. Meta-analysis showed that men with DM1 (n=380), compared with controls (n=434), have significantly lower normal sperm morphology [-0.36% (-0.66; -0.06), p<0.05, six studies] and sperm progressive motility [33.62% (-39.13; -28.11), p<0.001, two studies] and a trend toward a lower seminal volume [-0.51 (-1.03; 0.02), p=0.06, eight studies], without difference in total sperm count and concentration. Data on scrotal ultrasound and sperm DNA fragmentation are too few. No study evaluated other factors of male infertility, such as transrectal ultrasound, semen infections, sperm auto-antibodies, and retrograde ejaculation. DM1 might impair male fertility and testis functions (endocrine, spermatogenesis), but definition of its actual impact needs further studies. Men with DM1 should be evaluated with a complete hormonal, seminal, and ultrasound workup to better define their fertility potential and need for follow up of testis functions.

Dysregulation of the Hypothalamic-Pituitary-Testicular Axis due to Energy Deficit.

Although gonadal axis dysregulation from energy deficit is well recognized in women, the effects of energy deficit on the male gonadal axis have received much less attention. To identify relevant articles, we conducted PubMed searches from inception to May 2021. Case series and mechanistic studies demonstrate that energy deficit (both acutely over days or chronically over months) either from inadequate energy intake and/or excessive energy expenditure can lower serum testosterone concentration as a result of hypothalamic-pituitary-testicular (HPT) axis dysregulation in men. The extent to which this has clinical consequences that can be disentangled from the effects of nutritional insufficiency, concomitant endocrine dysregulation (eg, adrenal and thyroid axis), and coexisting comorbidities (eg, depression and substance abuse) is uncertain. HPT axis dysfunction is primarily the result of loss of GnRH pulsatility resulting from a failure of leptin to induce kisspeptin signaling. The roles of neuroendocrine consequences of depression, hypothalamic-pituitary-adrenal axis activation, proinflammatory cytokines, Ghrelin, and genetic susceptibility remain unclear. In contrast to hypogonadism from organic pathology of the HPT axis, energy deficit-associated HPT dysregulation is functional, and generally reversible by restoring energy balance. The clinical management of such men should aim to restore adequate nutrition and achieve and maintain a healthy body weight. Psychosocial comorbidities must be identified and addressed. There is no evidence that testosterone treatment is beneficial. Many knowledge gaps regarding epidemiology, pathophysiology, and treatment remain and we highlight several areas that require future research.

NCOG-53. PREDICTORS OF ENDOCRINE OUTCOME AFTER ENDOSCOPIC TRANSSPHENOIDAL SURGERY FOR NON-FUNCTIONING PITUITARY ADENOMAS

Abstract BACKGROUND Although endoscopic transsphenoidal surgery (ETSS) is an established treatment for patients with nonfunctioning pituitary adenomas (NFPAs), data are limited regarding the rates and predictors of pituitary dysfunction and recovery in a large cohort of NFPA patients undergoing ETSS. OBJECTIVE To analyze the comprehensive changes in hormonal function and identify factors that predict recovery or worsening of hormonal axes following ETSS for NFPA. METHODS Among a cohort of 601 consecutive patients who underwent ETSS for NFPA between 2010 and 2018 at Washington University in Saint Louis, recovery or development of new hypopituitarism was retrospectively analyzed in 209 patients. RESULTS Preoperative endocrine deficits were observed in 59.8% of patients (125/209), and the deficit rates were 76.8% for male gonadal axis (86/112), 42.5% for thyroid axis, 25.8% for growth hormone axis, and 15.8% for cortisol axis. Recovery of preoperative pituitary deficit was noted in all four axes, with highest recovery in the cortisol axis with a 1-year cumulative recovery rate of 44.3%. New-onset postoperative hypopituitarism occurred most frequently in the thyroid axis (24.3%, 27/111) and least frequently in the cortisol axis (9.7%, 16/165). Multivariate analyses revealed axis-specific predictors of postoperative recovery and de novo deficiency. Older age was a negative predictor for recovery of both male hypogonadism (P= 0.04) and adrenal insufficiency (P=0.046), and a larger tumor volume was a negative predictor for recovery of hypothyroidism (P=0.043). Although higher body mass index was generally associated with any new postoperative pituitary deficit (P=0.03), most predictors of new onset deficits also differed by hormone axis. CONCLUSIONS Dynamic changes in pituitary hormonal levels were observed in a significant fraction of patients following ETSS in NFPA patients. The specific hormonal axis dictated postoperative endocrine vulnerability, recovery, and predictors of recovery or loss of endocrine function.

Effects of Bariatric Surgery in Male Obesity-Associated Hypogonadism.

The prevalence of obesity has grown exponentially over the last several decades. Research has linked male obesity to changes in the gonadal axis, which can induce functional hypogonadism. Bariatric surgery provides sustained weight loss and metabolic improvement. This was a retrospective cohort study to evaluate the male gonadal axis and metabolic profiles of obese individuals during the bariatric pre- and post-operative periods while comparing them to a normal body mass index (BMI) group. Twenty-nine obese men, who underwent bariatric surgery between 2012 and 2016 at the Federal University of Santa Catarina Hospital and a control group (CG) of 29 age-matched men with normal BMI, were analyzed. Bariatric pre- and 6-month post-operative data were compared with the CG. The study group (G1) presented an average age, weight, and BMI of 42.8 ± 9.5years, 155.2 ± 25.8kg, and 50.6 ± 7.1kg/m2, respectively. The pre-operative total testosterone (TT) G1 values were different from the CG (229.5 ± 96.4 versus 461.5 ± 170.8ng/dL, p < 0.01). Bariatric surgery promoted a statistically significant improvement in weight, TT, and metabolic profiles in surgical patients. Functional hypogonadism is prevalent in obese men, and we must be aware of this diagnosis. Although studies defining the best diagnostic parameters and indication of adequate hormone replacement therapy are lacking, an increase in TT levels during the first 6months after bariatric surgery was identified in our study. Previous studies have shown that gonadal function can normalize after metabolic improvement.

Reversible male hypogonadotropic hypogonadism due to energy deficit.

Calorie restriction and overtraining are increasingly seen in young men who suffer from increasing societal pressure to attain a perceived ideal male body image. The resulting energy deficit can lead to multiple endocrine consequences, including suppression of the male gonadal axis. We reviewed the literature, including two unpublished cases. We identified 23 cases, aged median (range) 20years (16-33), with a body mass index of 15.9kg/m2 (12.5-20.5). Total testosterone was 3.0nmol/L (0.6-21.3), and luteinizing hormone (LH) 1.2mIU/L (<0.2-7.5), with 91% of cases demonstrating hypogonadotropic hypogonadism. Associated findings included evidence of growth hormone resistance (increased growth hormone in 57% and low insulin-like growth factor-1 in 71%), hypercortisolaemia (50%) and a nonthyroidal illness picture (67%). In cases with longitudinal measurements following weight regain, serum testosterone (n=14) increased from median [interquartile range] 3.2nmol/L [1.9-5.1] to 14.3nmol/L [9.3-21.2] (P<0.001), and LH (n=8) from 1.2IU/L [0.8-1.8] to 3.5IU/L [3.3-4.3] (P=0.008). Hypogonadotropic hypogonadism can occur in the context of energy deprivation in young otherwise healthy men and may be underrecognized. The evidence suggests that gonadal axis suppression and associated hormonal abnormalities represent an adaptive response to increased physiological stress and total body energy deficit. The pathophysiology likely involves hypothalamic suppression due to dysregulation of leptin, ghrelin and pro-inflammatory cytokines. The gonadal axis suppression is functional, because it can be reversible with weight gain. Treatment should focus on reversing the existing energy deficit to achieve a healthy body weight, including psychiatric input where required.

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.

Proinflammatory Cytokine Infusion Attenuates LH's Feedforward on Testosterone Secretion: Modulation by Age.

In the experimental animal, inflammatory signals quench LH's feedforward drive of testosterone (T) secretion and appear to impair GnRH-LH output. The degree to which such suppressive effects operate in the human is not known. To test the hypothesis that IL-2 impairs LH's feedforward drive on T and T's feedback inhibition of LH secretion in healthy men. Mayo Center for Translational Science Activities. A total of 35 healthy men, 17 young and 18 older. Randomized prospective double-blind saline-controlled study of IL-2 infusion in 2 doses with concurrent 10-minute blood sampling for 24 hours. Deconvolution analysis of LH and T secretion. After saline injection, older compared with young men exhibited reduced LH feedforward drive on T secretion (P < .001), and decreased T feedback inhibition of LH secretion (P < .01). After IL-2 injection, LH's feedforward onto T secretion declined markedly especially in young subjects (P < .001). Concomitantly, IL-2 potentiated T's proportional feedback on LH secretion especially in older volunteers. This investigation confirms combined feedforward and feedback deficits in older relative to young men given saline and demonstrates 1) joint mechanisms by which IL-2 enforces biochemical hypogonadism, viz, combined feedforward block and feedback amplification; and 2) unequal absolute inhibition of T and LH secretion by IL-2 in young and older men. These outcomes establish that the male gonadal axis is susceptible to dual-site suppression by a prototypic inflammatory mediator. Thus, we postulate that selected ILs might also enforce male hypogonadism in chronic systemic inflammation.

Profertility effects of aqueous leaf extract of Telfairia occidentalis in adult male Wistar rats

Telfairia occidentalis is a leafy vegetable consumed commonly for its nutritional and medicinal effects. However, few studies have been carried out on its fertility effects in males with most of such studies offering conflicting results. The present study evaluated the effects of aqueous extract of the leaves of T. occidentalis on male fertility in adult wistar rats. The thirty rats used for this study were randomized into groups A, B and C. Rats in groups B & C were treated with 500 and 1000mg/kg.bwt of the leaf extract respectively by gavage for 56 days while group A served as control. The sperm characteristics, male hypothalamo-pituitary gonadal axis hormones and histological studies were carried out according to existing laboratory methods. Results from all the parameters studied showed that the aqueous extract of leaves of T. occidentalis exhibited profertility properties in adult male wistar rats. Further research to determine the components of the leaf extract implicated in the outcomes observed and the mechanism of action would be necessary. Keywords: Profertility, Telfairia occidentali s, Wistar rats

Male gonadal axis assessment in bariatric surgery candidates

Results We evaluated 69 subjects, mean age 39±10 yrs. and 87% caucasian. Type 2 Diabetes Mellitus (T2D) was found in 47.8%, hypertension in 72.5%, dyslipidemia in 23.2% and metabolic syndrome according to the IDF in 87%. Mean weight, waist circumference and BMI were respectively: 157.4±31.0 kg, 148.2±14.9 cm and 51.2±8.3 kg/m2. The average fasting glycemia was 111.1±34.7 mg/dL (NR 300), LH 3.1±1.3 mUmL (NR 0.8 to 7.6) and calculated free testosterone (CFT) 5.9±2.7 ng/dL (NR> 6.5). 79.7% of subjects had TT ≤ 300 ng/dL and 56.5% CFT ≤ 6.5 ng/dL. Categorizing patients according to the levels of TT [G1 (≤ 200 ng/dL): 53.8±8.5 kg/m2 x G2 (201-299 ng/dL): 49.3±7.2 kg/m2 x G3 (≥ 300 ng/dL): 48.7±8.7 kg/m2], there was a statistically significant difference only in relation to BMI (p=0.04). There were no statistically significant differences in mean TT and CFT between individuals with and without T2D [TT: 218.8±89.4 x 245.5±102.8 ng/dL (p=0.25); CFT: 5.65±2.7 x 2.6±6.21 ng/dL (p=0.39)].

Is Men's Health Just a Single Letter?

For several years, a marketing campaign to peddle T prescriptions has cleverly centered on the question: “Is it low T? Have an honest conversation with your doctor about all of the symptoms you are experiencing.” “Low T” has become a part of the popular vernacular to describe all sorts of symptoms that might (or might not) be associated with a low serum T level in men. T sales have surged in many countries (1). With the advent of the increased sales of T formulations to treat aging men, questions about the potential adverse effects of T therapy including cardiovascular disease and prostate cancer have emerged. There have been concerns that T might increase adverse cardiovascular events since at least the 1960s. The Coronary Drug Project was designed in 1965 to test the hypothesis that estrogen therapy might decrease recurrent cardiovascular ischemic events in men by raising highdensity lipoprotein cholesterol and lowering serum T levels (2). A high dosage of conjugated estrogen (enough to suppress the male gonadal axis) was associated with increased cardiovascular events (3). Later, a number of epidemiological studies demonstrating an association between cardiovascular disease and low serum T levels in men generated the opposing hypotheses that low T levels might increase the risk of cardiovascular events in men or that normal T might even be protective against cardiovascular events (4). Three recent epidemiological studies have fueled the debate on the effects of T on all-cause mortality and cardiovascular disease. Shores et al (5) reported in a retrospective database study of veterans with low serum T levels that T therapy was not associated with increased mortality or cardiovascular disease. Shores et al (5) reported lower mortality in the subset of men treated with T therapy than men who were not treated; this effect remained after adjustment for age, diabetes mellitus, and prevalent cardiovascular disease. In another retrospective database study of veterans, Vigen et al (6) reported an association between T therapy and an increase in the combined incidence of myocardial infarction, stroke, and overall mortality in men who underwent coronary angiography for evaluation of chest pain and were subsequently found to have low serum total T levels. In the Vigen et al (6) study of veterans, the unadjusted absolute rate of the combined endpoint (myocardial infarction, stroke, and death) was 21% for the untreated men and 10% for the T-treated men. After analysis with a sophisticated adjustment model, this pattern reversed with a lower rate of the combined endpoint (19.9%) in the untreated group compared to the T-treated group (25.7%). A third important epidemiological study on the association between T, cardiovascular disease, and overall mortality appears in this issue of the JCEM. Yeap et al (7) suggest that there is a U-shaped association between serum total or calculated free serum T levels and all-cause mortality, with a similar trend between T levels and cardiovascular mortality. In the Yeap et al study (7), over 4000 Western Australian older men ( 70 years of age) who were a subset of a larger cohort study had total T, dihydrotestosterone, and estradiol levels measured on an early morning blood sample with a highly accurate liquid chromatography-tandem mass spectrometry assay. Free T levels were calculated using a validated empiric formula. The men were followed for an average of 7 years. The primary outcomes were death of any cause and death due to ischemic heart disease as reported to the Western Australia Database Linkage System (WADLS), an intricate, publicly funded database that captures health outcomes including deaths of citizens of Western Australia. Because all residents of Western

Glucose ingestion acutely lowers pulsatile LH and basal testosterone secretion in men

Chronic hyperglycemia inhibits the male gonadal axis. The present analyses test the hypothesis that acute glucose ingestion also suppresses LH and testosterone (T) secretion and blunts the LH-T dose-response function. The design comprised a prospectively randomized crossover comparison of LH and T secretion after glucose vs. water ingestion in a Clinical Translational Research Center. The participants were healthy men (n = 57) aged 19-78 yr with body mass index (BMI) of 20-39 kg/m(2). The main outcome measurements were deconvolution and LH-T dose-response analyses of 10-min data. LH-T responses were regressed on glucose, insulin, leptin, adiponectin, age, BMI, and CT-estimated abdominal visceral fat. During the first 120 min after glucose ingestion, for each unit decrease in LH concentrations, T concentrations decreased by 86 (27-144) ng/dl (r = 0.853, P < 0.001). Based upon deconvolution analysis, glucose compared with water ingestion reduced 1) basal (nonpulsatile; P < 0.001) and total (P < 0.001) T secretion without affecting pulsatile T output and 2) pulsatile (P = 0.043) but not basal LH secretion. By multivariate analysis, pulsatile LH secretion positively predicted basal T secretion after glucose ingestion (r = 0.374, P = 0.0042). In addition, the glucose-induced fall in pulsatile LH secretion was exacerbated by higher fasting insulin concentrations (P = 0.054) and attenuated by higher adiponectin levels (P = 0.0037). There were no detectable changes in the analytically estimated LH-T dose-response curves (P > 0.30). In conclusion, glucose ingestion suppresses pulsatile LH and basal T secretion acutely in healthy men. Suppression is influenced by age, glucose, adiponectin, and insulin concentrations.

Noninvasive Analytical Estimation of Endogenous GnRH Drive: Analysis Using Graded Competitive GnRH-Receptor Antagonism and a Calibrating Pulse of Exogenous GnRH

Homeostatic control of endocrine systems proceeds via feedforward (agonistic, stimulatory) and feedback (antagonistic, inhibitory) interactions mediated via implicit dose-response functions. However, neither the feedback/feedforward pathways nor the dose-response interfaces are directly observed in vivo. Thus, the goal was to formulate and estimate an ensemble construct of time-varying feedback/feedforward interactions among GnRH, LH, and testosterone (T) in the male gonadal axis. The new analytical model revises and extends an earlier construct by: 1) allowing systemic T concentrations to inhibit hypothalamic GnRH output; 2) estimating GnRH outflow after injection of a calibrating pulse of biosynthetic GnRH; 3) framing the pituitary response to GnRH as a secretory burst, rather than continuous LH release; and 4) regressing feedback and feedforward ensemble parameters on age, rather than evaluating age dichotomously. Application of this methodology in 21 men aged 23-72 yr unveiled age-related 1) diminution of GnRH efficacy normalized for the decline in free T with age (P = 0.016), 2) potentiation of maximal T feedback onto (inhibition of) GnRH secretion (P = 0.006), and 3) accentuation of hypothalamic GnRH's sensitivity to T repression (P = 0.003). Outcomes were specific, because injected GnRH agonist and antagonist concentrations were invariant of age. We conclude that combining experimental and analytical strategies may provide a noninvasive means to investigate and decipher feedback determinants of unobserved endocrine signal(s).

A Comparison of Two Repeated Restraint Stress Paradigms on Hypothalamic‐Pituitary‐Adrenal Axis Habituation, Gonadal Status and Central Neuropeptide Expression in Adult Male Rats

The available evidence continues to illustrate an inhibitory influence of male gonadal activity on the hypothalamic-pituitary-adrenal (HPA) axis under acute stress. However, far less is known about how these systems interact during repeated stress. Because HPA output consistently declines across studies examining repeated restraint, the potential mechanisms mediating this habituation are often inferred as being equivalent, even though these studies use a spectrum of restraint durations and exposures. To test this generalisation, as well as to emphasise a potential influence of the male gonadal axis on the process of HPA habituation, we compared the effects of two commonly used paradigms of repeated restraint in the rodent: ten daily episodes of 0.5 h of restraint and five daily episodes of 3 h of restraint. Both paradigms produced comparable declines in adrenocorticotrophic hormone and corticosterone between the first and last day of testing. However, marked differences in testosterone levels, as well as corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) expression, occurred between the two stress groups. Plasma testosterone levels remained relatively higher in animals exposed to 0.5 h of restraint compared to 3 h of restraint, whereas forebrain gonadotrophin-releasing hormone (GnRH) cell counts increased in both groups. AVP mRNA was increased after 3 h, but not after 0.5 h of repeated restraint, in the medial parvicellular paraventricular nucleus and in the posterior bed nucleus of the stria terminalis (BST), and increased with 0.5 h of repeated restraint in the medial amygdala. CRH mRNA was increased after 3 h, but not after 0.5 h of repeated restraint, in the central amygdala and anterior BST. The data obtained illustrate that, despite comparable declines in HPA responses, the pathways recruited for stress adaptation appear to be distinct between restraint groups. Given the extreme sensitivity of limbic AVP to testosterone, and conversely CRH to circulating glucocorticoids, whether differences in endocrine profiles might explain these neuropeptide differences remains to be seen. Nonetheless, the present study provides several new entry points for testing gonadal influences on stress-specific HPA habituation.

Seasonal and circadian variation in salivary testosterone in rural Bolivian men

Testosterone (T) plays a key role in the increase and maintenance of muscle mass and bone density in adult men. Life history theory predicts that environmental stress may prompt a reallocation of such investments to those functions critical to survival. We tested this hypothesis in two studies of rural Bolivian adult men by comparing free T levels and circadian rhythms during late winter, which is especially severe, to those in less arduous seasons. For each pair of salivary T(AM)/T(PM) samples (collected in a approximately 12-h period), circadian rhythm was considered classic (C(CLASSIC)) if T(AM) > 110%T(PM), reverse (C(REVERSE)) if T(PM) > 110%T(AM), and flat (C(FLAT)) otherwise. We tested the hypotheses that mean T(AM) > mean T(PM) and that mean T(LW) < mean T(OTHER) (LW = late winter, OTHER = other seasons). In Study A, of 115 T(PM)-T(AM) pairs, 51% = C(CLASSIC), 39% = C(REVERSE), 10% = C(FLAT); in Study B, of 184 T(AM)-T(PM) pairs, 55% = C(CLASSIC), 33% = C(REVERSE), 12% = C(FLAT). Based on fitting linear mixed models, in both studies T(OTHER-AM) > T(OTHER-PM) (A: P = 0.035, B: P = 0.0005) and T(OTHER-AM) > T(LW-AM) (A: P = 0.054, B: P = 0.007); T(PM) did not vary seasonally, and T diurnality was not significant during late winter. T diurnality varied substantially between days within an individual, between individuals and between seasons, but neither T levels nor diurnality varied with age. These patterns may reflect the seasonally varying but unscheduled, life-long, strenuous physical labor that typifies many non-industrialized economies. These results also suggest that single morning samples may substantially underestimate peak circulating T for an individual and, most importantly, that exogenous signals may moderate diurnality and the trajectory of age-related change in the male gonadal axis.

An Ensemble Model of the Male Gonadal Axis: Illustrative Application in Aging Men

Testosterone (Te) production declines in the aging male, albeit for unknown reasons. Plausible mechanisms include reduced secretion of GnRH, less feedforward by LH, and/or altered feedback by systemic Te. The present study tests all three postulates in a cohort of 10 young (20-35 yr old) and eight older (50-72 yr old) men. The experimental paradigm comprised graded blockade of the GnRH receptor to create four distinct strata of LH and Te pulsatility in each subject. A novel analytical formalism was developed to reconstruct implicit dose-response functions linking 1) virtual GnRH outflow positively to LH secretion, 2) LH pulses positively to Te secretion, and 3) Te concentrations negatively to the size and number of LH secretory bursts. Validation was by direct pituitary sampling in the horse and sheep. Statistical comparisons disclosed that age decreased the efficacy of each of 1) virtual GnRH outflow (P < 0.01), 2) LH drive of Te secretion (P < 0.01), and 3) total, bioavailable and free Te feedback on GnRH-driven LH secretion (P = 0.015). In contrast, age increased the potency of virtual GnRH feedforward (P = 0.013) and did not affect Te's inhibition of LH pulse frequency. Unexplained variance was less than 10%. Robustness was shown by resampling techniques. Accordingly, competitive silencing of one locus of control and ensemble-based analyses identified triple regulatory deficits in the aging male gonadal axis. The generality of the present integrative model suggests utility in parsing interlinked adaptations in other physiological networks.

Effects of Opium Dependency on Hypothalamic Pituitary Gonadal Axis

The aim of this study was to determine the effect of opium on hypothalamic pituitary gonad function. Fifty-six opium dependent (28 men and 28 women; mean age, 25±5 year) were enrolled for hypothalamic pituitary gonadal axis. The control group considered of 56 non-opium dependent subject (28 men and 28 women; mean age 25±5 year). Decreased libido or impotency was present in 26 of 28 opium dependent men. The serum testosterone level was below 9 nmol L-1 in 24 of 28 men and was significantly lower than that in the control group (p<0.001). The free androgen index was below normal in 16 of 28 men and was significantly lower than that in the control group (p<0.001). The serum LH level was less than 2 U L-1 in 17 of 28 men significantly lower than that in the control group (p<0.001). Serum FSH was normal in both groups. Decreased libido was present in 16 of 28 women opium dependent. Serum LH, estradiol and progesterone levels were lower in opium group. In conclusion, of all opium addicts the large majority of men and all of women developed hypogonadotropic hypogonadism. The results reveal that opium can extract deleterious actions upon male and female hypothalamic pituitary gonadal axis and these findings suggested that further investigations are required to determine the need for endocrine work-up in opium dependent and the important substitutive therapy.

Hypothesis testing of the aging male gonadal axis via a biomathematical construct.

Neuroendocrine axes are feedback- and feedforward-coupled dynamic ensembles. Disruption of selected pathways in such networklike organizations may explicate loss of orderly hormonal output as observed in aging. To test this notion more explicitly, we implemented an earlier computer-assisted biomathematical model of the interlinked male hypothalamo [gonadotropin-releasing hormone (GnRH)]-pituitary [luteinizing hormone, (LH)]-testicular [Leydig cell testosterone (Te)] axis (Am J Physiol Endocrinol Metab Physiol 275: E157--E176, 1988; Keenan D., W. Sun, and J. D. Veldhuis, SIAM J Appl Math 61: 934--965, 2000). Thereby, we appraise mechanistic hypotheses for more disorderly LH and Te secretion in aging men. We compare model predictions with monitored abnormalities in the older male, namely, irregular patterns of individual and synchronous LH and Te release, reduced 24-h rhythmic Te output, and variably elevated LH secretion. Among the mechanisms examined, the most parsimonious aging hypothesis would entail impaired LH feedforward on Te without or with attenuated Te feedback on GnRH/LH secretion. This investigative strategy should aid in exploring new postulates of disrupted feedback networks in pathophysiology.

Effect of obesity and fertility status on sex steroid levels in men

Endocrine studies were performed on fertile and infertile obese men and compared with fertile and infertile nonobese men in order to determine the independent and codependent effects of obesity and fertility status on the male hypothalamic-pituitary gonadal axis. The obese infertile group exhibited significant endocrinologic changes as compared with fertile nonobese control group which was not observed in any of the other three groups. Serum testosterone was significantly lower. The testosterone/estradiol ratio was significantly lower despite a lack of significant change in serum estradiol levels. Serum steroid hormone binding globulin (SHBG) was significantly lower which correlated with elevated bioavailability of both testosterone and estradiol in the obese infertile group. Serum luteinizing hormone levels were no different, suggesting that free testosterone levels were unchanged. Obese infertile men exhibit endocrinologic changes that are not observed in men with either obesity or infertility alone. Reduction of serum SHBG, total testosterone, and testosterone/estradiol ratio appear to be a marker of infertility among obese men.