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Late-onset hypogonadism: Clinical evidence, biological aspects and evolutionary considerations.

ABSTRACT: The growing life expectancy in modern societies has raised scientific interest in identifying medical interventions to alleviate age-associated pathologies such as vascular calcification, cognitive decline, sarcopenia, osteoporosis and sexual dysfunction. Although no such single treatment has thus far been established in humans, some clinicians and patients have set their hopes on testosterone replacement therapy (TRT) as a potential "fountain of youth" for aging men. While TRT has proven effective in ameliorating distinct symptoms of late-onset hypogonadism (LOH), its safety remains to be demonstrated. Besides humans, multiple other species exhibit age-related reductions in circulating testosterone levels, raising the question whether such changes are an inherent, pathological feature of growing organismal age or rather reflect an adaptive response. In this manuscript, we apply key principles of evolutionary medicine to testosterone biology and LOH to provide a novel perspective on these two fields. Additionally, we discuss insightful data derived from the animal kingdom to illustrate the plasticity of individual testosterone trajectories across the lifespan, outline cost-benefit-considerations of TRT in LOH and highlight potential caveats of such therapies.

SUBMITTER: Jaschke N

PROVIDER: S-EPMC8043243 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Late-onset hypogonadism: Clinical evidence, biological aspects and evolutionary considerations.

Jaschke Nikolai N Wang Andrew A Hofbauer Lorenz C LC Rauner Martina M Rachner Tilman D TD

Ageing research reviews 20210218

The growing life expectancy in modern societies has raised scientific interest in identifying medical interventions to alleviate age-associated pathologies such as vascular calcification, cognitive decline, sarcopenia, osteoporosis and sexual dysfunction. Although no such single treatment has thus far been established in humans, some clinicians and patients have set their hopes on testosterone replacement therapy (TRT) as a potential "fountain of youth" for aging men. While TRT has proven effect ...[more]

PMID: 33610812

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Project description:BackgroundWhile immunocastration has been studied in male pre-pubertal pigs, data on older, sexually mature animals are limited. To understand the physiological effects of androgen deprivation in the late sexual development phase, we compared mature immunocastrated boars (n = 19; average age = 480 days) to young male immunocastrated pigs (n = 6; average age = 183 days) and young entire males (n = 6; average age = 186 days) as positive and negative controls, respectively.ObjectivesWe hypothesized that the timing of gonadotropin-releasing hormone suppression (early or late sexual development phases) influences the extent of reproductive function inhibition, histological structure of testicular tissue, and expression levels of selected genes related to steroid metabolism.Materials and methodsAntibody titer, hormonal status, and histomorphometric analysis of testicular tissue were subjected to principal component analysis followed by hierarchical clustering to evaluate the immunocastration effectiveness in mature boars.ResultsHierarchical clustering differentiated mature immunocastrated boars clustered with young immunocastrated pigs from those clustered with entire males. Although all mature immunocastrated boars responded to vaccination, as evidenced by the increased gonadotropin-releasing hormone antibody titers (p < 0.001), decreased serum luteinizing hormone concentrations (p = 0.002), and changes in testicular tissue vascularization (lighter and less red testicular parenchyma; p ≤ 0.001), the responses were variable. Sharp decreases in testes index (p < 0.001), Leydig cell volume density (p < 0.001), Leydig cell nucleus-to-cytoplasm ratio (p < 0.001), and testosterone concentration (p < 0.001) were observed in mature immunocastrated boars clustered with young immunocastrated pigs compared with those that clustered with entire males. Additionally, mature immunocastrated boars clustered with young immunocastrated pigs showed lower hydroxysteroid 17-beta dehydrogenase 7 expression than entire males (p < 0.05). The young immunocastrated pigs group showed higher follicle-stimulating hormone receptors than the entire males and mature immunocastrated boars, lower steroidogenic acute regulatory protein expression levels compared with entire males, and mature immunocastrated boars clustered with entire males (p < 0.01).ConclusionThe two-dose vaccination regime resulted in progressive but variable regression of testicular function in adult (post-pubertal) pigs; however, it was insufficient to induce a complete immunocastration response in all animals.

Project description:Although suppressed serum testosterone (T) is common in ageing men, only a small proportion of them develop the genuine syndrome of low T associated with diffuse sexual (e.g., erectile dysfunction), physical (e.g. loss of vigor and frailty) and psychological (e.g., depression) symptoms. This syndrome carries many names, including male menopause or climacterium, andropause and partial androgen deficiency of the ageing male (PADAM). Late-onset hypogonadism (LOH) describes it best and is therefore generally preferred. The decrease of T in LOH is often marginal, and hypogonadism can be either due to primary testicular failure (low T, high luteinizing hormone (LH)) or secondary to a hypothalamic-pituitary failure (low T, low or inappropriately normal LH). The latter form is more common and it is usually associated with overweight/obesity or chronic diseases (e.g., type 2 diabetes mellitus, the metabolic syndrome, cardiovascular and chronic obstructive pulmonary disease, and frailty). A problem with the diagnosis of LOH is that often the symptoms (in 20%-40% of unselected men) and low circulating T (in 20% of men >70 years of age) do not coincide in the same individual. The European Male Ageing Study (EMAS) has recently defined the strict diagnostic criteria for LOH to include the simultaneous presence of reproducibly low serum T (total T <11 nmol l-1 and free T <220 pmol l-1 ) and three sexual symptoms (erectile dysfunction, and reduced frequency of sexual thoughts and morning erections). By these criteria, only 2% of 40- to 80-year-old men have LOH. In particular obesity, but also impaired general health, are more common causes of low T than chronological age per se. Evidence-based information whether, and how, LOH should be treated is sparse. The most logical approach is lifestyle modification, weight reduction and good treatment of comorbid diseases. T replacement is widely used for the treatment, but evidence-based information about its real benefi ts and short- and long-term risks, is not yet available. In this review, we will summarize the current concepts and controversies in the pathogenesis, diagnosis and treatment of LOH.

Project description:BackgroundMultiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid oxidation due to deficiency of the mitochondrial electron transfer chain. The late-onset form is characterized by exercise intolerance, muscle weakness, and lipid storage in myofibers. Most MADD patients greatly benefit from riboflavin supplementation.Patients and methodsA retrospective study was conducted on patients with a diagnosis of vacuolar myopathy with lipid storage followed in our neuromuscular unit in the last 20 years. We selected 10 unrelated patients with the diagnosis of MADD according to clinical, morphological, and biochemical aspects. Clinical features, blood tests including serum acylcarnitines, EMG, and ENG were revised. Muscle biopsy was performed in all, and one individual underwent also a sural nerve biopsy. Gene sequencing of ETFA, ETFB, and ETFDH was performed as a first-tier genetic analysis followed by next-generation sequencing of an hyperCKemia gene panel in patients with undefined genotypes.ResultsClinical evaluation at onset in all our patients showed fatigue and muscle weakness; four patients showed difficulties in chewing, three patients complained of dysphagia, two patients had a dropped head, and a patient had an unexpected ataxia with numbness and dysesthesia. Laboratory blood tests revealed a variable increase in serum CK (266-6,500) and LDH levels (500-2,000). Plasma acylcarnitine profile evidenced increased levels of different chains intermediates. EMG was either normal or showed myogenic or neurogenic patterns. NCS demonstrated sensory neuropathy in two patients. Muscle biopsies showed a vacuolar myopathy with a variable increase in lipid content. Nerve biopsy evidenced an axonal degeneration with the loss of myelinated fibers. ETFDH genetic analysis identifies 14 pathogenic variants. Patients were treated with high doses of riboflavin (400 mg/die). All of them showed a rapid muscle strength improvement and normalization of abnormal values in laboratory tests. Neuropathic symptoms did not improve.ConclusionOur data confirmed that clinical features in MADD patients are extremely variable in terms of disease onset and symptoms making diagnosis difficult. Laboratory investigations, such as serum acylcarnitine profile and muscle biopsy evaluation, may strongly address to a correct diagnosis. The favorable response to riboflavin supplementation strengthens the importance of an early diagnosis of these disorders among the spectrum of metabolic myopathies.

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Late-onset hypogonadism: Clinical evidence, biological aspects and evolutionary considerations.

Publications

Late-onset hypogonadism: Clinical evidence, biological aspects and evolutionary considerations.

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