OnLine First 2013

[Michael Scally MD]

Migliaccio S, Francomano D, Bruzziches R, et al. Trunk fat negatively influences skeletal and testicular functions in obese men: clinical implications for the aging male. Int J Endocrinol. 2013:182753. Trunk Fat Negatively Influences Skeletal and Testicular Functions in Obese Men: Clinical Implications for the Aging Male

Osteocalcin (OSCA) seems to act as a negative regulator of energy metabolism and insulin sensitivity. Evidence from male rodents suggests that OSCA may also regulate testosterone (T) synthesis.

Using a cross-sectional design, we evaluated OSCA, 25(OH) vitamin D, T, 17 beta -estradiol (E2), homeostasis model assessment of insulin resistance (HOMA-IR), and body composition in 86 obese (mean BMI = 34) male subjects (18-69 yr old).

Independently from BMI, an inverse relationship between trunk fat percentage and plasma T (r (2) = -0.26, P < 0.01) and between HOMA-IR and OSCA levels (r (2) = -0.22, P < 0.005) was found. OSCA levels, as well as vitamin D, decreased significantly for higher BMI with significant differences above 35 (P < 0.01). A direct correlation between T and bone mineral density at lumbar (BMDL) and neck (BMDH) (P < 0.001, r (2) = -0.20; P < 0.001, r (2) = -0.24) was found, independently from age. An inverse correlation between E2 levels, BMDL, and BMDH (P < 0.001, r (2) = -0.20; P < 0.001, r (2) = -0.19) was observed.

These data provide new evidences that a relationship between trunk fat mass, insulin sensitivity, OSCA and T synthesis occurs. This new relationship with skeletal health has relevant implications for the aging male, suggesting OSCA as a novel marker of metabolic and gonadal health status.

 

[Michael Scally MD]

Celik O, Yucel S. Testosterone Replacement Therapy: Should It Be Performed in Erectile Dysfunction? Nephrourol Mon 2013;5(4):858-61. Testosterone Replacement Therapy: Should It Be Performed in Erectile Dysfunction?

The classical etiology of erectile dysfunction (ED) comprises aging and vascular, neurogenic, psychological and hormonal components. Recent studies have shown that ED can be the forerunner of serious cardiovascular disturbances. It has also been reported that peripheral neuropathy and microvascular injuries caused by pathophysiological changes in patients with diabetes and obesity lead to ED in a significant number of such cases.

These patients develop clinically significant ED and comprise a significant portion of the patient group which do not respond to PDE-5 inhibitors. Testosterone has been shown to increase the expression of PDE-5. This function of testosterone supports its effect on the regulation of erection and increasing the sexual libido. In view of the complexity of ED, as well as the effect of testosterone on erection, it is concluded that PDE-5 inhibitors in combination with testosterone replacement would be a better therapy alternative in the management of erectile dysfunction in hypogonadal patients.

 

[Michael Scally MD]

Sheffield-Moore M, Wiktorowicz JE, Soman KV, et al. Sildenafil increases muscle protein synthesis and reduces muscle fatigue. Clin Transl Sci 2013;6(6):463-8. Sildenafil Increases Muscle Protein Synthesis and Reduces Muscle Fatigue - Sheffield-Moore - 2013 - Clinical and Translational Science - Wiley Online Library

Reductions in skeletal muscle function occur during the course of healthy aging as well as with bed rest or diverse diseases such as cancer, muscular dystrophy, and heart failure. However, there are no accepted pharmacologic therapies to improve impaired skeletal muscle function. Nitric oxide may influence skeletal muscle function through effects on excitation-contraction coupling, myofibrillar function, perfusion, and metabolism. Here we show that augmentation of nitric oxide-cyclic guanosine monophosphate signaling by short-term daily administration of the phosphodiesterase 5 inhibitor sildenafil increases protein synthesis, alters protein expression and nitrosylation, and reduces fatigue in human skeletal muscle. These findings suggest that phosphodiesterase 5 inhibitors represent viable pharmacologic interventions to improve muscle function.

 

[Michael Scally MD]

Trabado Sv, Maione L, Bry-Gauillard Hln, et al. Insulin-like Peptide 3 (INSL3) in Men With Congenital Hypogonadotropic Hypogonadism/Kallmann Syndrome and Effects of Different Modalities of Hormonal Treatment: A Single-Center Study of 281 Patients. The Journal of Clinical Endocrinology & Metabolism. 2013-288. http://press.endocrine.org/doi/abs/10.1210/jc.2013-2288

Context: Insulin-like factor 3 (INSL3) is a testicular hormone secreted during fetal life, the neonatal period, and after puberty.

Objective: To measure INSL3 levels in a large series of men with congenital hypogonadotropic hypogonadism (CHH)/ Kallmann syndrome (KS), in order to assess its diagnostic value and to investigate its regulation.

Patients: We studied 281 CHH/KS patients (91 untreated, 96 receiving T, and 94 receiving combined gonadotropin therapy [human chorionic gonadotropin, hCG, and FSH]) and 72 age-matched healthy men.

Methods: Serum INSL3 was immunoassayed with a validated RIA.

Results: Mean (±SD) INSL3 levels (pg/mL) were 659 ± 279 in controls and lower (60 ± 43; P < .001) in untreated CHH/KS patients, with no overlap between the two groups, when the threshold of 250 pg/mL was used. Basal INSL3 levels were lower in both untreated CHH/KS men with cryptorchidism than in those with intrascrotal testes and in patients with testicular volumes below 4 mL. Significant positive correlations between INSL3 and both serum total T and LH levels were observed in untreated CHH/KS. Mean INSL3 levels remained low in T-treated CHH/KS patients and were significantly higher in men receiving combined hCG-FSH therapy (P < .001), but the increase was lower cryptorchid patients. FSH-hCG combination therapy or hCG monotherapy, contrary to T and FSH monotherapies, significantly increased INSL3 levels in CHH/KS.

Conclusions: INSL3 is as sensitive a marker as T for the evaluation of altered Leydig cell function in CHH/KS patients. INSL3 levels correlate with LH levels in CHH/KS men showing, together with the rise in INSL3 levels during hCG therapy, that INSL3 secretion seems not constitutively secreted during adulthood but is dependence on pituitary LH.

 

[Michael Scally MD]

Sidhoum VF, Chan Y-M, Lippincott MF, et al. Reversal and Relapse of Hypogonadotropic Hypogonadism: Resilience and Fragility of the Reproductive Neuroendocrine System. The Journal of Clinical Endocrinology & Metabolism. 2013-809. http://press.endocrine.org/doi/abs/10.1210/jc.2013-2809

Context: A subset of patients diagnosed with idiopathic hypogonadotropic hypogonadism (IHH) later achieve activation of their hypothalamic-pituitary-gonadal axis with normalization of steroidogenesis and/or gametogenesis, a phenomenon termed reversal.

Objective: To determine the natural history of reversal and to identify associated phenotypes and genotypes.

Design, Setting, and Subjects: Retrospective review of clinical, biochemical, and genetic features of patients with IHH evaluated at an academic medical center.

Main Outcome Measures: History of spontaneous fertility, regular menses, testicular growth, or normalization of serum sex steroids, LH secretory profiles, brain imaging findings, and sequences of 14 genes associated with IHH.

Results: Of 308 patients with IHH, 44 underwent reversal. Time-to-event analysis estimated a lifetime incidence of reversal of 22%. There were no differences in the rates of cryptorchidism, micropenis, or partial pubertal development in patients with reversal vs. IHH patients without reversal. Fifteen patients with reversal (30%) had Kallmann syndrome (IHH and anosmia); one had undetectable olfactory bulbs on a brain MRI. Subjects with reversal were enriched for mutations affecting neurokinin B signaling compared to a cohort of IHH patients without reversal (10% vs. 3%, p = 0.048); had comparable frequencies of mutations in FGFR1, PROKR2, and GNRHR; and had no mutations in KAL1. Five men did not sustain their reversal and again developed hypogonadotropism.

Conclusions: Reversal of IHH may be more widespread than previously appreciated and occurs across a broad range of genotypes and phenotypes. Enrichment for mutations that disrupt neurokinin B in patients who reversed indicates that, despite the importance of this signaling pathway for normal pubertal timing, its function is dispensable later in life. The occurrence of reversal in a patient with no olfactory bulbs demonstrates that these structures are not essential for normal reproductive function. Patients with IHH require lifelong monitoring for reversal and, if reversal occurs, subsequent relapse.

 

[Michael Scally MD]

Novaira HJ, Sonko ML, Hoffman G, et al. Disrupted kisspeptin signaling in GnRH neurons leads to reproductive abnormalities and HH. Molecular Endocrinology. 2013-1319. http://press.endocrine.org/doi/abs/10.1210/me.2013-1319

Landmark studies have shown that mutations in kisspeptin and the kisspeptin receptor (Kiss1r) result in reproductive dysfunction in humans and genetically altered mouse models. However, since kisspeptin and its receptor are present in target cells of the central and peripheral reproductive axis, the precise location(s) for the pathogenic signal is unknown.

The herein described study shows that the kisspeptin-kiss1r signaling pathway in the GnRH neuron is singularly critical for both the onset of puberty as well as the attainment of normal reproductive function.

In this study, we directly test the hypothesis that kisspeptin neurons regulate GnRH secretion through the activation of Kiss1r on the plasma membrane of GnRH neurons. A GnRH neuron-specific Kiss1r knockout mouse model (GKirKO) was generated and reproductive development and phenotype were assessed.

Both female and male GKirKO mice were infertile having low serum LH and FSH levels. External abnormalities such as microphallus and decreased anogenital distance associated with failure of preputial gland separation were present in GKirKO males. A delay in pubertal onset and abnormal estrous cyclicity were observed in female GKirKO mice.

Taken together, these data provide in vivo evidence that Kiss1r in GnRH neurons is critical for reproductive development and fertility.

 

[Michael Scally MD]

Cai X, Tian Y, Wu T, Cao CX, Li H, Wang KJ. Metabolic effects of testosterone replacement therapy on hypogonadal men with type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials. Asian J Androl 2014;16(1):146-52. Metabolic effects of testosterone rep... [Asian J Androl. 2014 Jan-Feb] - PubMed - NCBI

This systematic review was aimed at assessing the metabolic effects of testosterone replacement therapy (TRT) on hypogonadal men with type 2 diabetes mellitus (T2DM). A literature search was performed using the Cochrane Library, EMBASE and PubMed. Only randomized controlled trials (RCTs) were included in the meta-analysis. Two reviewers retrieved articles and evaluated the study quality using an appropriate scoring method. Outcomes including glucose metabolism, lipid parameters, body fat and blood pressure were pooled using a random effects model and tested for heterogeneity. We used the Cochrane Collaboration's Review Manager 5.2 software for statistical analysis. Five RCTs including 351 participants with a mean follow-up time of 6.5-months were identified that strictly met our eligibility criteria. A meta-analysis of the extractable data showed that testosterone reduced fasting plasma glucose levels (mean difference (MD): -1.10; 95% confidence interval (CI) (-1.88, -0.31)), fasting serum insulin levels (MD: -2.73; 95% CI (-3.62, -1.84)), HbA1c % (MD: -0.87; 95% CI (-1.32, -0.42)) and triglyceride levels (MD: -0.35; 95% CI (-0.62, -0.07)). The testosterone and control groups demonstrated no significant difference for other outcomes. In conclusion, we found that TRT can improve glycemic control and decrease triglyceride levels of hypogonadal men with T2DM. Considering the limited number of participants and the confounding factors in our systematic review; additional large, well-designed RCTs are needed to address the metabolic effects of TRT and its long-term influence on hypogonadal men with T2DM.

 

[Michael Scally MD]

Bobjer J, Katrinaki M, Tsatsanis C, Lundberg Giwercman Y, Giwercman A. Negative association between testosterone concentration and inflammatory markers in young men: a nested cross-sectional study. PLoS One 2013;8(4):e61466. PLOS ONE: Negative Association between Testosterone Concentration and Inflammatory Markers in Young Men: A Nested Cross-Sectional Study

OBJECTIVE: Low grade systemic inflammation (LGSI) as well as androgen deficiency has in older men been associated with several pathologies, including cardiovascular disease (CVD). We wanted to investigate whether low testosterone levels are linked to biomarkers of LGSI already in young age, before any concurrent manifestations of CVD or other systemic diseases.

DESIGN: Nested cross-sectional study.

METHODS: Forty subfertile biochemically hypogonadal (n = 20) or eugonadal (n = 20) men (mean age 37 years, SD = 4.3) and 20 age-matched controls were randomly selected from an ongoing study on male subfertility. Subjects comprised male partners in infertile couples in whom also subnormal sperm concentration was present. Blood sampling, interviews, and anthropometric measures were undertaken. Serum levels of testosterone, LH, estradiol, SHBG, and 21 LGSI-markers were assessed.

RESULTS: Among 21 inflammatory markers, macrophage inflammatory protein 1-alpha (MIP1a) (ss = -0.025; p = 0.028), 1-beta (MIP1B) (ss = -0.015; p = 0.049) and tumor necrosis factor alpha (TNFa) (ss = -0.015; p = 0.040) showed negative association to total testosterone (TT) levels. MIP1a (ss = -1.95; p = 0.001) and TNFa (ss = -0.95; p = 0.014) showed negative association to calculated free testosterone (cFT) levels. Compared to men with normal TT and cFT levels, TNFa levels were higher in men with subnormal levels of TT (mean ratio 1.61; p = 0.006) and cFT (mean ratio 1.58; p = 0.007). Also, MIP1a levels were higher in men with subnormal levels of TT (mean ratio 1.84; p = 0.030).

CONCLUSIONS: Subnormal testosterone may already in young age associate to LGSI, which might be a part of the mechanism underlying adverse health outcomes of male hypogonadism.

 

[Michael Scally MD]

Highlights
• Basal testosterone is inversely correlated with human father-infant social exchange.
• Oxytocin alters testosterone concentration in fathers, relative to placebo.
• Oxytocin-induced change in fathers' testosterone is associated with parent-infant social behaviors.

Weisman O, Zagoory-Sharon O, Feldman R. Oxytocin administration, salivary testosterone, and father-infant social behavior. Prog Neuropsychopharmacol Biol Psychiatry 2014;49:47-52. Oxytocin administration, salivary testosterone, and father–infant social behavior

The growing involvement of fathers in childcare is followed by an increased interest in the neurobiology of fatherhood; yet, experimental work on the neuroendocrine basis of paternal care in humans is limited. The steroid Testosterone (T) and the neuropeptide Oxytocin (OT) have each been implicated in complex social behavior including parenting. However, no study to date explored the interaction between these two hormones in the context of fathering.

In the current study, we first test the relationship between father's basal salivary T and father and infant's social behaviors during parent-child interaction. Second, we examine the effects of intranasal OT administration on father's T production, and, finally, address the relations between OT-induced change in father's T with father-infant social behavior.

Thirty-five fathers and their infants participated in a double-blind, placebo-controlled, within-subject study. Father-infant interaction was micro-coded for paternal and infant social behavior and synchrony was measured as the coordination between their gaze, affect, and vocalizations. Father's salivary T levels were measured at baseline and three times after administration.

Results indicate that lower baseline T correlated with more optimal father and infant's behaviors. OT administration altered T production in fathers, relative to the pattern of T in the placebo condition. Finally, OT-induced change in T levels correlated with parent-child social behaviors, including positive affect, social gaze, touch, and vocal synchrony.

Findings support the view that neuroendocrine systems in human males evolved to support committed parenting and are the first to describe the dynamic interactions between OT and T within a bio-behavioral synchrony model.

 

[Michael Scally MD]

Skuse DH, Lori A, Cubells JF, et al. Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills. Proc Natl Acad Sci U S A. Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills

The neuropeptides oxytocin and vasopressin are evolutionarily conserved regulators of social perception and behavior. Evidence is building that they are critically involved in the development of social recognition skills within rodent species, primates, and humans. We investigated whether common polymorphisms in the genes encoding the oxytocin and vasopressin 1a receptors influence social memory for faces. Our sample comprised 198 families, from the United Kingdom and Finland, in whom a single child had been diagnosed with high-functioning autism. Previous research has shown that impaired social perception, characteristic of autism, extends to the first-degree relatives of autistic individuals, implying heritable risk. Assessments of face recognition memory, discrimination of facial emotions, and direction of gaze detection were standardized for age (7-60 y) and sex. A common SNP in the oxytocin receptor (rs237887) was strongly associated with recognition memory in combined probands, parents, and siblings after correction for multiple comparisons. Homozygotes for the ancestral A allele had impairments in the range -0.6 to -1.15 SD scores, irrespective of their diagnostic status. Our findings imply that a critical role for the oxytocin system in social recognition has been conserved across perceptual boundaries through evolution, from olfaction in rodents to visual memory in humans.

 

[Michael Scally MD]

IMO, there will be significant advances in understanding the HPTA leading to new and innovative therapies for hypogonadism. For this fact alone, checking for HPTA Functionality/Restoration is of some import.

A pharmacological chaperone (or pharmacoperone, from "protein chaperone") is a small molecule that enters cells and serves as a molecular scaffolding in order to cause otherwise-misfolded mutant proteins to fold and route correctly within the cell.

Mutation of proteins often causes molecular misfolding, which results in protein misrouting within the cell. Accordingly, mutant molecules may retain proper function but end up in parts of the cell where the function is inappropriate, or even deleterious, to cell function. Misfolded proteins are usually recognized by the quality-control system of the cell and retained (and often destroyed or recycled)in the endoplasmic reticulum.

Pharmacoperones correct the folding of misfolded proteins, allowing them to pass through the cell's quality-control system and become correctly routed. Since mutations often cause disease by causing misfolding and misrouting, pharmacoperones are potentially therapeutic agents, since they are able to correct this defect.


Janovick JA, Stewart MD, Jacob D, et al. Restoration of testis function in hypogonadotropic hypogonadal mice harboring a misfolded GnRHR mutant by pharmacoperone drug therapy. Proceedings of the National Academy of Sciences 2013;110(52):21030-5. Restoration of testis function in hypogonadotropic hypogonadal mice harboring a misfolded GnRHR mutant by pharmacoperone drug therapy

Mutations in receptors, ion channels, and enzymes are frequently recognized by the cellular quality control system as misfolded and retained in the endoplasmic reticulum (ER) or otherwise misrouted. Retention results in loss of function at the normal site of biological activity and disease. Pharmacoperones are target-specific small molecules that diffuse into cells and serve as folding templates that enable mutant proteins to pass the criteria of the quality control system and route to their physiologic site of action. Pharmacoperones of the gonadotropin releasing hormone receptor (GnRHR) have efficacy in cell culture systems, and their cellular and biochemical mechanisms of action are known. Here, we show the efficacy of a pharmacoperone drug in a small animal model, a knock-in mouse, expressing a mutant GnRHR. This recessive mutation (GnRHR E90K) causes hypogonadotropic hypogonadism (failed puberty associated with low or apulsatile luteinizing hormone) in both humans and in the mouse model described. We find that pulsatile pharmacoperone therapy restores E90K from ER retention to the plasma membrane, concurrently with responsiveness to the endogenous natural ligand, gonadotropin releasing hormone, and an agonist that is specific for the mutant. Spermatogenesis, proteins associated with steroid transport and steroidogenesis, and androgen levels were restored in mutant male mice following pharmacoperone therapy. These results show the efficacy of pharmacoperone therapy in vivo by using physiological, molecular, genetic, endocrine and biochemical markers and optimization of pulsatile administration. We expect that this newly appreciated approach of protein rescue will benefit other disorders sharing pathologies based on misrouting of misfolded protein mutants.