Hypothalamic Gliosis by MRI and Visceral Fat Mass Negatively Correlate with Plasma Testosterone Concentrations in Healthy Men.

OBJECTIVE: This study aimed to determine whether a relationship was evident between gliosis in the mediobasal hypothalamus (MBH) and plasma testosterone concentrations in men. METHODS: A total of 41 adult men (aged 18-50 years) from 23 twin pairs underwent fasting morning blood draw and brain magnetic resonance imaging. T2 relaxation time was used to quantify gliosis in the MBH and control areas in the putamen and amygdala. Plasma concentrations of testosterone and 17ß-estradiol were measured by liquid chromatography-tandem mass spectrometry. Body composition including visceral adiposity was measured by dual x-ray absorptiometry. RESULTS: A negative association was found between MBH T2 relaxation time and plasma concentrations of both free and total testosterone (r = -0.29, P < 0.05 and r = -0.37, P < 0.01, respectively). Visceral adiposity exhibited a negative correlation with plasma total testosterone concentration (r = -0.45, P = 0.001) but a positive correlation with MBH T2 relaxation time (r = 0.24, P = 0.03). The negative correlation between plasma total testosterone and MBH T2 relaxation time remained significant after adjustment for visceral adiposity, age, BMI, and insulin resistance. CONCLUSIONS: In healthy men across a range of BMIs, MBH gliosis was associated with higher visceral adiposity but lower endogenous testosterone. These findings suggest that MBH gliosis could provide novel mechanistic insights into gonadal dysfunction in men with obesity.

A Perspective on Middle-Aged and Older Men With Functional Hypogonadism: Focus on Holistic Management.

Context: Middle-aged and older men (≥50 years), especially those who are obese and suffer from comorbidities, not uncommonly present with clinical features consistent with androgen deficiency and modestly reduced testosterone levels. Commonly, such men do not demonstrate anatomical hypothalamic-pituitary-testicular axis pathology but have functional hypogonadism that is potentially reversible. Evidence Acquisition: Literature review from 1970 to October 2016. Evidence Synthesis: Although definitive randomized controlled trials are lacking, evidence suggests that in such men, lifestyle measures to achieve weight loss and optimization of comorbidities, including discontinuation of offending medications, lead to clinical improvement and a modest increase in testosterone. Also, androgen deficiency-like symptoms and end-organ deficits respond to targeted treatments (such as phosphodiesterase-5 inhibitors for erectile dysfunction) without evidence that hypogonadal men are refractory. Unfortunately, lifestyle interventions remain difficult and may be insufficient even if successful. Testosterone therapy should be considered primarily for men who have significant clinical features of androgen deficiency and unequivocally low testosterone levels. Testosterone should be initiated either concomitantly with a trial of lifestyle measures, or after such a trial fails, after a tailored diagnostic work-up, exclusion of contraindications, and appropriate counseling. Conclusions: There is modest evidence that functional hypogonadism responds to lifestyle measures and optimization of comorbidities. If achievable, these interventions may have demonstrable health benefits beyond the potential for increasing testosterone levels. Therefore, treatment of underlying causes of functional hypogonadism and of symptoms should be used either as an initial or adjunctive approach to testosterone therapy.

Testosterone administration in older men.

The only indication for testosterone administration in older men is testosterone replacement therapy for male hypogonadism. Compared with young hypogonadal men, the diagnosis and management of male hypogonadism in older men is more challenging. Both the clinical manifestations of androgen deficiency and low testosterone levels may be caused or modified by comorbid illnesses that occur and medications taken more frequently by older men, resulting in a greater likelihood for overdiagnosis of hypogonadism and subsequent inappropriate use of and inadequate response to testosterone treatment. It is important to use a systematic, holistic approach to the diagnosis and management of older men with hypogonadism.

Blunted hypothalamic neuropeptide gene expression in response to fasting, but preservation of feeding responses to AgRP in aging male Brown Norway rats.

Aging mammals lose the ability to maintain energy balance, exhibiting decreased appetite (anorexia) and impaired ability to maintain body weight. To determine the contribution of hypothalamic neuropeptides, two experiments were performed in male Brown Norway rats. To assess the hypothalamic neuropeptide response to food deprivation, young (Y; 4 mo old), middle-aged (M; 13 mo), and old (O; 25 mo) rats were either ad libitum fed or fasted for 72 h (n = 10/group) and killed. Hypothalamic levels of agouti-related peptide (AgRP), proopiomelanocortin (POMC), and cocaine-amphetamine-regulated transcript (CART) mRNA were assessed by in situ hybridization. With aging, arcuate AgRP gene expression decreased and CART mRNA increased, but POMC mRNA did not change. Fasting-induced changes in gene expression of all neuropeptides studied were attenuated with aging. To test the food intake response to appetite-stimulating neuropeptides, Y, M, O, and very old (VO; 33 mo) rats (n = 4-8/group) received one intracerebroventricular injection of each of three treatments: 0.1 nmol AgRP, 2.34 nmol NPY, and saline control. AgRP increased food intake of all groups by 10-20%, compared with saline, and this effect persisted up to 7 days after injection. VO animals were more sensitive to the effects of AgRP than younger animals. In contrast, NPY increased food intake more in Y than in older animals and its effects did not last >24 h. We conclude that the mechanisms by which arcuate nucleus neurons influence appetite are differentially affected by age and speculate that the melanocortin system may be a useful target for treatment of the anorexia of aging.

Suppression of hypothalamic pro-opiomelanocortin (POMC) gene expression by daily melatonin supplementation in aging rats.

Both plasma melatonin levels and hypothalamic arcuate nucleus pro-opiomelanocortin (POMC) (biosynthetic precursor to the endogenous opioid ss-endorphin and other opiomelanocortins) mRNA content decrease with aging. To test whether the decline in melatonin is responsible for the decline in POMC mRNA, we investigated the effects of daily melatonin treatment on hypothalamic POMC mRNA content in middle-aged and older Sprague-Dawley rats. Daily nocturnal melatonin treatment (50 microg kg bw(-1) night(-1), in the night-time drinking water) for 7 months, starting at 13 months of age, did not significantly alter female arcuate nucleus POMC mRNA content determined at the end of the light period (i.e., before nightly melatonin administration), but suppressed (24%, P < 0.05) POMC mRNA content at the end of the dark period (i.e., following melatonin administration). Likewise, nocturnal administration of 50 or 500 microg melatonin kg bw(-1) night(-1) to male rats for 7 months suppressed (31 or 28%, respectively; P < 0.05) POMC mRNA content at the middle of the dark period at 20 months of age. Finally, 10 wk administration of 30 microg melatonin kg bw(-1) day(-1) suppressed (31%, P < 0.01) POMC mRNA content in middle-aged male rats killed at the end of the dark period. Melatonin treatments did not significantly alter estradiol or testosterone levels. Thus, moderate-dosage nocturnal melatonin supplementation suppressed nocturnal hypothalamic POMC gene expression in both middle-aged males and females, suggesting that melatonin supplementation during aging decreases, rather than increases, forebrain opiomelanocortinergic activity. These POMC responses were apparently not dependent on gonadal steroid responses and did not become refractory to melatonin treatment maintained until old age.

Testosterone supplementation therapy for older men: potential benefits and risks.

Serum testosterone levels decline gradually and progressively with aging in men. Many manifestations associated with aging in men, including muscle atrophy and weakness, osteoporosis, reduced sexual functioning, and increased fat mass, are similar to changes associated with testosterone deficiency in young men. These similarities suggest that testosterone supplementation may prevent or reverse the effects of aging. A MEDLINE search was performed to identify studies of testosterone supplementation therapy in older men. A structured, qualitative review was performed of placebo-controlled trials that included men aged 60 and older and evaluated one or more physical, cognitive, affective, functional, or quality-of-life outcomes. Studies focusing on patients with severe systemic diseases and hormone deficiencies related to specific diseases were excluded. In healthy older men with low-normal to mildly decreased testosterone levels, testosterone supplementation increased lean body mass and decreased fat mass. Upper and lower body strength, functional performance, sexual functioning, and mood were improved or unchanged with testosterone replacement. Variable effects on cognitive function were reported, with improvements in some cognitive domains (e.g., spatial, working, and verbal memory). Testosterone supplementation improved exercise-induced coronary ischemia in men with coronary heart disease, whereas angina pectoris was improved or unchanged. In a few studies, men with low testosterone levels were more likely to experience improvements in lumbar bone mineral density, self-perceived functional status, libido, erectile function, and exercise-induced coronary ischemia with testosterone replacement than men with less marked testosterone deficiency. No major unfavorable effects on lipids were reported, but hematocrit and prostate specific antigen levels often increased. Based on these results, testosterone supplementation cannot be recommended at this time for older men with normal or low-normal testosterone levels and no clinical manifestations of hypogonadism. However, testosterone replacement may be warranted in older men with markedly decreased testosterone levels, regardless of symptoms, and in men with mildly decreased testosterone levels and symptoms or signs suggesting hypogonadism. The long-term safety and efficacy of testosterone supplementation remain uncertain. Establishment of evidence-based indications will depend on further demonstrations of favorable clinical outcomes and symptomatic, functional, and quality-of-life benefits in carefully performed, long-term, randomized, placebo-controlled clinical trials.

Troglitazone treatment of aging Brown Norway rats improves food intake and weight gain after fasting without increasing hypothalamic NPY gene expression.

Compared to younger animals, aged male Brown Norway (BN) rats demonstrate increased body fat and serum insulin, and lower prepro-neuropeptide Y (ppNPY) mRNA content in the arcuate nucleus (ARC), and blunted food intake (FI) and body weight (BW) gain in response to a 72 h fast. Since centrally administered insulin decreases FI and weight of young rats and inhibits fasting-induced increases of NPY gene expression, we hypothesized that hyperinsulinemia in old rats contributes to an age-related central dysregulation of energy balance. Young, middle-aged and old BN rats were fed chow with troglitazone (Trog; 200 mg/kg BW/d) or without drug for 75 d (Experiment 1) or 66 d (Experiment 2). Rats were then fasted for 72 h, refed for 2 weeks and sacrificed after an overnight fast (Experiment 1) or fasted for 72 h and sacrificed (Experiment 2). Serum insulin and leptin were measured from trunk blood and brains were analyzed for ppNPY mRNA by in situ hybridization. In Experiment 1, troglitazone treatment resulted in increased post-fast weight gain, rate of gain and FI in old rats. Troglitazone decreased serum insulin by 50% in old rats, while leptin levels decreased 20-30% in all age groups in Experiment 1. No differences in serum insulin or leptin were detectable with troglitazone treatment in Experiment 2, due to the extreme suppression caused by the 72 h fast. Troglitazone treatment did not increase ARC NPY gene expression either after a 72 h fast and re-feeding for 2 weeks (Experiment 1) or immediately after a 72 h fast (Experiment 2). These findings suggest that increased insulin levels may contribute to age-related impairments of FI and BW regulation. However, improvements in these defects in energy regulation induced by troglitazone do not appear to result from changes in NPY gene expression, and may be due to alterations in other hypothalamic neuropeptides that regulate energy balance.

Testosterone (T)-induced changes in arcuate nucleus cocaine-amphetamine-regulated transcript and NPY mRNA are attenuated in old compared to young male brown Norway rats: contribution of T to age-related changes in cocaine-amphetamine-regulated transcript and NPY gene expression.

The age-related decrease in serum T levels is associated with impairments in food intake and weight regulation and alterations in brain peptides that regulate energy balance. To test the hypothesis that reduced T levels contribute to altered hypothalamic cocaine-amphetamine-regulated transcript (CART) and NPY gene expression, the mRNA content of these neuropeptides was measured by in situ hybridization in sham-operated (intact), castrated, and T-replaced castrated young and old male Brown Norway rats. T levels in T-replaced young and old rats were similar to those in intact young animals. Compared with castrated rats, arcuate nucleus CART mRNA was lower and NPY mRNA was higher in both young and old T-replaced castrated animals, suggesting reciprocal regulation of these peptides by T; these T-induced changes were localized primarily in the rostral arcuate and were markedly attenuated in old animals. Compared with intact animals, paraventricular nucleus CART mRNA was lower in castrated animals and similar in T-replaced young and old rats. We conclude that hypothalamic CART and NPY neurons remain responsive to T regulation in old rats, albeit less so than in young animals, suggesting that the age-related reduction of T contributes in part to altered brain neuropeptide gene expression favoring anorexia and wasting with aging.