Lifestyle, metabolic disorders and male hypogonadism - A one-way ticket?

Hypogonadism is more frequent among men with common metabolic diseases, notably obesity and type 2 diabetes. Indeed, endocrine disruption caused by metabolic diseases can trigger the onset of hypogonadism, although the underlying molecular mechanisms are not entirely understood. Metabolic diseases are closely related to unhealthy lifestyle choices, such as dietary habits and sedentarism. Therefore, hypogonadism is part of a pathological triad gathering unhealthy lifestyle, metabolic disease and genetic background. Additionally, hypogonadism harbors the potential to aggravate underlying metabolic disorders, further sustaining the mechanisms leading to disease. To what extent does lifestyle intervention in men suffering from these metabolic disorders can prevent, improve or reverse hypogonadism, is still controversial. Moreover, recent evidence suggests that the metabolic status of the father is related to the risk of inter and transgenerational inheritance of hypogonadism. In this review, we will address the proposed mechanisms of disease, as well as currently available interventions for hypogonadism.

Clinical and biochemical correlates of male hypogonadism in type 2 diabetes.

The origin of hypogonadism, a condition including both symptoms and biochemical criteria of androgen deficiency, in type 2 diabetes is poorly known. In a cross-sectional study of 267 unselected patients, we analyzed the potential correlation of several clinical and biochemical variables as well as chronic micro- and macrovascular diabetic complications with hypogonadism. Hypogonadism was present in 46 patients (17.2%) using a cutoff of total testosterone 10.4 nmol/L and in 31 (11.6%) with a cutoff of 8 nmol/L. Among these patients, hypogonadotropic hypogonadism was the most prevalent form (82.6%). Compared to eugonadal subjects, hypogonadal men had significantly lower glomerular filtration rate (67.1 ± 23.4 vs. 78.4 ± 24.6 mL/min/1.73 m2 , p = 0.005) and higher prevalence of chronic kidney disease (43.5% vs. 20.4%, p = 0.002), abnormal liver function tests (26.7% vs. 12%, p = 0.019), and psychiatric treatment (23.9% vs. 10.4%, p = 0.025). Total testosterone levels correlated inversely with age (R = -0.164, p = 0.007), fasting blood glucose (R = -0.127, p = 0.037), and triglycerides (R = -0.134, p = 0.029) and directly with glomerular filtration rate (R = 0.148, p = 0.015). Calculated free testosterone and bioavailable testosterone correlated directly with hemoglobin (R = 0.171, p = 0.015 and R = 0.234, p = 0.001, respectively). Multivariate logistic regression analysis, after adjusting for relevant confounding variables, showed that age >60 years (OR = 3.58, CI 95% = 1.48-8.69, p = 0.005), body mass index >27 kg/m2 (OR = 2.85, CI 95% = 1.14-7.11, p = 0.025), hypertriglyceridemia (OR = 2.16, CI 95% = 1.05-4.41, p = 0.035), glomerular filtration rate <60 mL/min/1.73 m2 (OR = 2.51, CI 95% = 1.19-5.29, p = 0.015), and abnormal liver function tests (OR = 3.57, CI 95% = 1.48-8.60, p = 0.005) were independently associated with male hypogonadism. Although older age, body mass index, and hypertriglyceridemia have been previously related to hypogonadism, our results describe that chronic kidney disease and abnormal liver function tests are independently correlated with hypogonadism in type 2 diabetic men.

The presence of symptoms of testosterone deficiency in the exercise-hypogonadal male condition and the role of nutrition.

PURPOSE: High volumes of aerobic exercise have been associated with reduced testosterone (T), known as the exercise-hypogonadal male condition (EHMC). Although the presence of low T has been identified, few studies have assessed the presence of androgen-deficient symptoms. The purpose of this investigation is to assess men exhibiting EHMC and evaluate their hypothalamic-pituitary-gonadal axis, the presence of hypogonadal symptoms, and also investigate a possible contribution of inadequate nutrition to the condition. METHODS: A cross-sectional design compared 9 long-distance runners exhibiting EHMC to 8 non-active controls. Comparisons included serum T, luteinizing hormone (LH), follicle-stimulating hormone, and cortisol, the Aging Male Symptoms (AMS) questionnaire score, bone mineral density (BMD), and a food frequency questionnaire. RESULTS: Mean T was significantly reduced in the EHMC group (EHMC 9.2 nmol L-1 vs. CONT 16.2 nmol L-1). The EHMC group demonstrated significantly higher AMS scores (EHMC 27.1 ± 7.3 vs. CONT 19.7 ± 2.5). There were no differences in bone density, although 3 cases of osteopenia were noted for EHMC in the lumbar spine, 1 in the right femur, and 1 in the radius. Energy availability was significantly reduced in EHMC (EHMC 27.2 ± 12.7 vs. CONT 45.4 ± 18.2 kcal d FFM-1). CONCLUSIONS: Men exhibiting EHMC do appear to present with symptoms associated with androgen deficiency. For the most part, these symptoms are limited to those reported on the AMS questionnaire, although there are also some cases of clinically low BMD. It is possible that inadequate energy intake is contributing to this condition.

RigiScan data under long-term testosterone therapy: improving long-term blood circulation of penile arteries, penile length and girth, erectile function, and nocturnal penile tumescence and duration.

BACKGROUND: Late-onset hypogonadism (LOH) presents with low serum testosterone (TT) levels and sexual and nonsexual symptoms. Erectile dysfunction affects a man's self-esteem and as a result partner relationship and quality of life. OBJECTIVES: To investigate the andrological clinical profile outcomes of testosterone therapy (TTh) in men (n = 88) with symptomatic LOH complaints and symptoms. MAIN OUTCOME MEASURES: Erectile function was assessed using the International Index of Erectile Function-5 questionnaire at baseline and at 6 and 12 months of TTh. In addition, penile length was measured at baseline and 12 months. We also evaluated nocturnal penile tumescence (NPT, using RigiScan) and blood flow of cavernous arteries (penile Doppler ultrasonography) at baseline and 12 months of TT. MATERIALS AND METHODS: Eighty-eight LOH men (Mage 51.1 years) with erectile dysfunction, all with serum TT <10.4 nmol/L before TTh. Patients received intramuscular long-acting testosterone undecanoate for 12 months. RESULTS: Following TTh, in all patients, serum TT levels were restored within 3 months to normal levels. Compared with baseline values, erectile function significantly improved at 6 (mean score increase 1.95) and 12 months (mean score increase 2.16). No significant changes in penile length were observed. NPT significantly improved at 12 months in terms of both the frequency (mean increase 1.27 times) and duration of rigidity (mean increase 5.12 min). As regards the blood flow of the cavernous arteries, we observed a significant improvement (decrease of 1.16 cm/s) and end diastolic velocity of the penile arteries. CONCLUSION: TTh in men with LOH resulted in improvement of the erectile function, NPT, and to some extent the blood flow of the cavernous arteries.

Trabecular bone characterization on the continuum of plates and rods using in vivo MR imaging and volumetric topological analysis.

Osteoporosis is associated with increased risk of fractures, which is clinically defined by low bone mineral density. Increasing evidence suggests that trabecular bone (TB) micro-architecture is an important determinant of bone strength and fracture risk. We present an improved volumetric topological analysis algorithm based on fuzzy skeletonization, results of its application on in vivo MR imaging, and compare its performance with digital topological analysis. The new VTA method eliminates data loss in the binarization step and yields accurate and robust measures of local plate-width for individual trabeculae, which allows classification of TB structures on the continuum between perfect plates and rods. The repeat-scan reproducibility of the method was evaluated on in vivo MRI of distal femur and distal radius, and high intra-class correlation coefficients between 0.93 and 0.97 were observed. The method's ability to detect treatment effects on TB micro-architecture was examined in a 2 years testosterone study on hypogonadal men. It was observed from experimental results that average plate-width and plate-to-rod ratio significantly improved after 6 months and the improvement was found to continue at 12 and 24 months. The bone density of plate-like trabeculae was found to increase by 6.5% (p = 0.06), 7.2% (p = 0.07) and 16.2% (p = 0.003) at 6, 12, 24 months, respectively. While the density of rod-like trabeculae did not change significantly, even at 24 months. A comparative study showed that VTA has enhanced ability to detect treatment effects in TB micro-architecture as compared to conventional method of digital topological analysis for plate/rod characterization in terms of both percent change and effect-size.

The effect of testosterone treatment on prostate histology and apoptosis in men with late-onset hypogonadism.

OBJECTIVES: To investigate the effect of testosterone replacement therapy (TRT) on prostate histology and apoptosis in men with late-onset hypogonadism (LOH). METHODS: The study included 25 men, having LOH with prostate-specific antigen (PSA) level of 4 ng/ml or less. All patients underwent transrectal ultrasound guided prostate biopsy at baseline, and received testosterone undecanoate treatment for 1 year. Prostate biopsy was repeated at the end of 1 year of testosterone therapy. In addition to clinical and biochemical parameters, prostate histology and apoptotic index (AI) were compared before and after the TRT. RESULTS: The mean serum total testosterone significantly increased from 178.04 ± 51.92 to 496.28 ± 103.73 ng/dl (p = 0.001). No significant differences were observed in serum total and free PSA level, prostate volume and maximal urinary flow rate. There were also no significant differences in AI, stroma/epithelial cells ratio, Ki-67 positive cells and atrophy score of prostate tissue before and after the TRT. CONCLUSIONS: This study demonstrated that TRT did not affect serum PSA level, prostate volume and maximal urinary flow rate. This study also suggests that TRT does not cause the risk for prostate cancer development, because of no significant differences in prostate histology after TRT.

Outcomes of Prostate Biopsy in Men with Hypogonadism Prior or During Testosterone Replacement Therapy

Introduction: The relationship between Testosterone Replacement Therapy (TRT) and prostate cancer remains controversial. Most TRT studies show no change in prostate specific antigen (PSA) but some men do have PSA rise or develop an abnormal digital rectal exam (aDRE). Our objective was to examine the biopsy results of men with symptomatic hypogonadism before or during therapy. Materials and Methods: Data was extracted from our medical record on men with hypogonadism who had a prostate biopsy within the past 4 years done by 3 Urologists with guideline driven practice patterns. Results: 96 men were identified. Mean age at biopsy was 63 (range 40–85) and median PSA was 3.78ng/dL (0.5–662). Of the 61 men not on TRT, median PSA was 4.34 (0.5 to 662) and mean total testosterone 254 (191–341). There were 29 (47.5%) prostate cancers found (6 Gleason score 6, 13 Gleason score 7, 10 Gleason score 8 or 9). Of the 35 men on TRT, median PSA was 3.27 (0.5 to 13.7). The %PSA increase ranged from 2 to 251% (mean 93.5%). Mean total testosterone was 383 (146–792). Of the 14 men treated < 2 years, none had cancer. Of the 21 men treated 2 or more years 5 had cancer (2 Gleason score 6, 3 Gleason score 7). Conclusions: Men with hypogonadism and a clinical indication for biopsy often have prostate cancer, many high grade. No men with an initial PSA rise on TRT had cancer. Men on long term TRT should be monitored with PSA and DRE per guidelines.

[My Back is Still Hurting!]. / Der Rücken tut aber noch immer weh!

We present the case of a 39-year-old man who reported to the primary care physician for low back pain. Pain persisted despite extensive assessment and therapy. During the course, bilateral femoral neck fractures occurred and due to multiple enrichments in scintigraphy chronic multifocal (sterile) osteomyelitis was suspected. In the further follow-up the appropriate diagnosis of osteomalacia was established in bone biopsy and adequate treatment with Vitamin D was initiated. During therapy, the patient was free of pain or discomfort.

Outcomes of Prostate Biopsy in Men with Hypogonadism Prior or During Testosterone Replacement Therapy.

INTRODUCTION: The relationship between Testosterone Replacement Therapy (TRT) and prostate cancer remains controversial. Most TRT studies show no change in prostate specific antigen (PSA) but some men do have PSA rise or develop an abnormal digital rectal exam (aDRE). Our objective was to examine the biopsy results of men with symptomatic hypogonadism before or during therapy. MATERIALS AND METHODS: Data was extracted from our medical record on men with hypogonadism who had a prostate biopsy within the past 4 years done by 3 Urologists with guideline driven practice patterns. RESULTS: 96 men were identified. Mean age at biopsy was 63 (range 40-85) and median PSA was 3.78ng/dL (0.5-662). Of the 61 men not on TRT, median PSA was 4.34 (0.5 to 662) and mean total testosterone 254 (191-341). There were 29 (47.5%) prostate cancers found (6 Gleason score 6, 13 Gleason score 7, 10 Gleason score 8 or 9). Of the 35 men on TRT, median PSA was 3.27 (0.5 to 13.7). The %PSA increase ranged from 2 to 251% (mean 93.5%). Mean total testosterone was 383 (146-792). Of the 14 men treated < 2 years, none had cancer. Of the 21 men treated 2 or more years 5 had cancer (2 Gleason score 6, 3 Gleason score 7). CONCLUSIONS: Men with hypogonadism and a clinical indication for biopsy often have prostate cancer, many high grade. No men with an initial PSA rise on TRT had cancer. Men on long term TRT should be monitored with PSA and DRE per guidelines.

The impact of obesity on the male reproductive axis.

Obesity, defined as a body mass index (BMI) >30 kg/m2, has seen an important increase in prevalence in the last decades, not only in Europe and the United States, but also in developing countries. It is an established risk factor for numerous pathologic conditions like diabetes mellitus, cardiovascular diseases and cancer, but has also been linked to male hypogonadism. Several studies showed a negative impact of excessive BMI on testosterone levels, sexual function and sperm parameters. Possible mechanisms beyond this phenomenon are reduced hypothalamic and pituitary secretory function, excess estrogen production and reduced circulating sex-hormone binding globulin (SHBG). Peptides produced by the adipocyte may also trigger modifications of the reproductive function. Independently of the method used, non-surgical approach or bariatric techniques, weight reduction and a return to a normal BMI have been associated with improvement in the sexual function and levels of sexual hormones in obese males, showing that obesity related hypogonadism is preventable. Sexual and reproductive health might represent additional motivational factors for men in order to maintain a healthy life-style.

A Tunisian patient with two rare syndromes: triple a syndrome and congenital hypogonadotropic hypogonadism.

BACKGROUND/AIMS: The coexistence of triple A syndrome (AAAS) and congenital hypogonadotropic hypogonadism (CHH) has so far not been reported in the literature. This study aimed to characterize at the clinical and genetic level one patient presenting an association of AAAS and CHH in order to identify causal mutations. METHODS: Clinical and endocrinal investigations were performed and followed by mutational screening of candidate genes. RESULTS: At the age of 18, the patient presented sexual infantilism, a micropenis and gynecomastia. No mutation was revealed in GnRHR, TACR3/TAC3, PROK2/PROKR2 and PROP1 genes, except a homozygous intronic variation (c.244 + 128C>T; dbSNP: rs350129) in the KISS1R gene, which is likely nondeleterious. A homozygous splice-donor site mutation (IVS14 + 1G>A) was found in the AAAS gene. This mutation, responsible for AAAS, is a founder mutation in North Africa. CONCLUSION: This is the first report on a Tunisian patient with the coexistence of AAAS and CHH. The diagnosis of CHH should be taken in consideration in patients with Allgrove syndrome and who carry the IVS14 + 1G>A mutation as this might challenge appropriate genetic counseling.

The effect of androgen-replacement therapy on prostate growth: a systematic review and meta-analysis.

CONTEXT: Androgen-replacement therapy (ART) is a widely accepted form of treatment worldwide for aging men with late-onset hypogonadism syndrome. Urologists have been concerned about the possibility of ART causing prostate growth. OBJECTIVE: To assess the relationship between ART and prostate growth. EVIDENCE ACQUISITION: A literature review was performed to identify all published randomized controlled trials (RCTs) of androgen treatment for hypogonadism. The search included the Medline, Embase, and Cochrane Controlled Trials Register databases. The reference lists of the retrieved studies were also investigated. A systematic review and meta-analysis were conducted. EVIDENCE SYNTHESIS: Results of 16 RCTs involving a total of 1030 patients were analyzed. Seven RCTs were short-term (<12 mo) and nine were long-term (12-36 mo) comparisons of ART with a placebo; ART was administered transdermally, orally, or by injection. Respective p values for injection, transdermal administration, and oral administration of short-term ART were as follows: PSA level: 0.07, 0.01, and 0.95; prostate volume: 0.70, 0.79, and 0.32; IPSS: 0.78, 0.98, and no oral; Qmax: 0.92, no transdermal, and 0.10. Respective p values for injection, transdermal administration, and oral administration of long-term ART were as follows: PSA level: 0.42, 0.51, and 0.57; prostate volume: 0.35, 0.59, and 0.47; IPSS: 0.34, 0.32, and 0.97; Qmax: 0.11, 0.63, and no oral. Neither short-term nor long-term ART showed significant changes in the four determinants of prostate growth investigated compared with placebo. CONCLUSIONS: This meta-analysis shows that regardless of the administration method, neither short-term nor long-term ART increases the risk of prostate growth. Further high-quality, prospective studies are required to confirm this observation.

Primary hypogonadism in a case with XLAG syndrome.

Patients with X-linked lissencephaly with ambiguous genitalia (XLAG) syndrome present with lissencephaly, agenesis of the corpus callosum, refractory epilepsy of neonatal onset, microcephaly, and male genotype with ambiguous genitalia. The basis of the ambiguous genitalia in XLAG syndrome is not well-known. We report a case of the fourth child of healthy consanguineous parents who was presented to the hospital because of non-febrile seizures at 2 months of life. On physical examination, microcephaly, some dysmorphic face features, and ambiguous genitalia were determined. The cranial magnetic resonance imaging of the patient showed lissencephaly, agenesis of the corpus callosum, and enlarged ventricles. His karyotype was 46, XY. He had undetectable testosterone levels and elevated gonadotropins. Neither testicular tissue nor any testosterone response to human chorionic gonadotropin stimulation test was observed. These findings suggest that the hypogonadism in this patient with XLAG syndrome is primary hypogonadism due to gonadal agenesis or dysgenesis.

Mutational analysis of steroidogenic factor 1 (NR5a1) in 24 boys with bilateral anorchia: a French collaborative study.

BACKGROUND Steroidogenic factor 1 (SF1/AdBP4/FTZF1, NR5A1) is a nuclear receptor transcription factor that plays a key role in regulating adrenal and gonadal development, steroidogenesis and reproduction. Recently, haploinsufficiency of SF1 has been described in several 46,XY individuals with mild gonadal dysgenesis and impaired androgenization, but normal adrenal function, suggesting that dosage-sensitive or domain-specific effects of SF1 action are important in human testicular development and function. Our objective was to investigate whether partial defects in SF1 function might be associated with milder male reproductive phenotypes, such as bilateral anorchia ('vanishing testis syndrome') and micropenis. METHODS This study involved mutational analysis of NR5A1 in 24 individuals with bilateral anorchia and micropenis from the French Collaborative Anorchia study, as well as in vitro functional studies of SF1-dependent transcriptional activation and computer modeling. RESULTS A novel heterozygous missense mutation (V355M) in SF1 was found in one boy with a micropenis and testicular regression syndrome. This non-synonymous change was found to affect a highly conserved amino acid within helix 7 of the ligand-binding domain of SF1. This V355M mutation did not affect stability or nuclear localization, but did result in an approximately 50% reduction in SF1 activity in several different assay systems. CONCLUSIONS In conclusion, heterozygous partial loss of function mutations in SF1 may be associated with bilateral anorchia ('vanishing testis syndrome') and micropenis in humans.

Bilateral anorchia in infancy: occurence of micropenis and the effect of testosterone treatment.

OBJECTIVE: To analyze the clinical and histological findings in boys with bilateral anorchia and the response to testosterone treatment on penis length. STUDY DESIGN: Patients were divided into two groups according to the absence (group A, n = 29) or the presence (group B, n = 26) of palpable intrascrotal or inguinal mass at first clinical examination. RESULTS: A micropenis was found in 46% of patients (n = 24) with a similar proportion in both groups. Testosterone treatment induced a mean penis length gain of 1.9 +/- 1.3 SDS (standard deviation score). However, micropenis persisted in six patients. Histological examination (n = 18) confirmed the absence of any testicular structure with deferent ducts being present unilaterally or bilaterally in all but three patients. In these three patients, a hemorrhagic testis, probably as a result of a mechanical torsion, was found. CONCLUSIONS: The presence of isolated micropenis in almost half of patients with bilateral anorchia strongly suggests that the testicular damage frequently occurs during the second half of gestation after male sexual differentiation. In most cases, testosterone treatment stimulates the penile growth. Although the pathogenesis of bilateral anorchia may be heterogeneous, our study suggests that gonads may have been functionally abnormal before they disappeared, and suggests that some patients have an intrinsic endocrine disorder.

Fertile eunuch syndrome with the mutations (Trp8Arg and Ile15Thr) in the beta subunit of luteinizing hormone.

Fertile eunuch syndrome is caused by isolated LH deficiency, but its pathophysiology still remains controversial. We report a case of fertile eunuch syndrome with homozygous Trp8Arg and Ile15Thr mutations in the LH beta subunit gene. An 18-year-old man was admitted to our hospital for hypogonadism. Examination of genitalia revealed Tanner G1PH1, whereas both testes were elastically palpated and developed up to 18 ml. Endocrinological evaluations revealed normogonadotropic hypogonadism and there were normal responses after GnRH and hCG stimulation. Intratesticular testosterone concentration was almost normal (1.34 x 10(3) ng/g). By PCR direct sequencing, homozygous Trp (8) Arg and Ile (15) Thr mutations in exon 2 of LH beta were detected. Normal virilization and improved semen parameters were achieved after hCG supplementation. To our knowledge, this is the first case of fertile eunuch syndrome with homozygous Trp (8) Arg and Ile (15) Thr mutations in beta subunit of LH gene.

Case report: olfactory function in a fertile eunuch with Kallmann syndrome.

The olfactory and gonadal dysfunction in Kallmann syndrome share a common embryologic pathophysiology. To characterize further the linkage between the hypogonadotropic hypogonadism and anosmia, the authors performed a detailed evaluation of olfactory function in a patient with Kallman Syndrome having the rare variant of partial gonadotropin deficiency (fertile eunuch). The subject was seen initially at age 16 years because of delayed puberty. He received testosterone replacement therapy and subsequently completed pubertal development. As an adult, while untreated, he had subnormal levels of serum testosterone, low gonadotropins, and normal response to luteinizing hormone- releasing hormone. He also had impotence that was reversible with testosterone therapy, and a normal sperm count. Despite the mild degree of hypogonadism, olfactory function was completely absent, and the response to nasal trigeminal stimulants was markedly attenuated. Complete anosmia may therefore be associated with gonadotropin deficiency that is only partial; the presence of anosmia does not predict the need for gonadotropin therapy to attain fertility.

The prostate in eunuchs.

In 1960, there were 26 eunuchs from the palace of the Qing Dynasty still living in Beijing. The authors took that unique opportunity of carrying out a general physical examination, including palpation of the prostate, for every one of them. Their average age then was 72 years (59-83 years). They became eunuchs at the age of 10-26 years. The prostate was impalpable in 26 (81%) and 1-2 cm in width rectally in five, with a flat surface. At the time of the examination they had been eunuchs on the average for 54 years (41-65 years). This is probably the largest series of human beings followed for such a long period of time to confirm that testicular hormone is essential for the development and preservation of the prostate. The type of operation, the traditional way of carrying out the operation and the usual complications are presented.