Male reproductive ageing: a radical road to ruin.

In modern post-transition societies, we are reproducing later and living longer. While the impact of age on female reproductive function has been well studied, much less is known about the intersection of age and male reproduction. Our current understanding is that advancing age brings forth a progressive decline in male fertility accompanied by a reduction in circulating testosterone levels and the appearance of age-dependent reproductive pathologies including benign prostatic hypertrophy and erectile dysfunction. Paternal ageing is also associated with a profound increase in sperm DNA damage, the appearance of multiple epigenetic changes in the germ line and an elevated mutational load in the offspring. The net result of such changes is an increase in the disease burden carried by the progeny of ageing males, including dominant genetic diseases such as Apert syndrome and achondroplasia, as well as neuropsychiatric conditions including autism and spontaneous schizophrenia. The genetic basis of these age-related effects appears to involve two fundamental mechanisms. The first is a positive selection mechanism whereby stem cells containing mutations in a mitogen-activated protein kinase pathway gain a selective advantage over their non-mutant counterparts and exhibit significant clonal expansion with the passage of time. The second is dependent on an age-dependent increase in oxidative stress which impairs the steroidogenic capacity of the Leydig cells, disrupts the ability of Sertoli cells to support the normal differentiation of germ cells, and disrupts the functional and genetic integrity of spermatozoa. Given the central importance of oxidative stress in defining the impact of chronological age on male reproduction, there may be a role for antioxidants in the clinical management of this process. While animal studies are supportive of this strategy, carefully designed clinical trials are now needed if we are to realize the therapeutic potential of this approach in a clinical context.

Serum testosterone and sex hormone-binding globulin are inversely associated with leucocyte telomere length in men: a cross-sectional analysis of the UK Biobank study.

OBJECTIVE: Older men on an average have lower testosterone concentrations, compared with younger men, and more age-related comorbidities. Whether lower testosterone concentrations contribute to biological ageing remains unclear. Shorter telomeres are a marker for biological age. We tested the hypothesis that testosterone concentrations are associated with leucocyte telomere length (LTL), in middle- to older-aged men. DESIGN: Cross-sectional analysis of the UK Biobank study, involving community-dwelling men aged 40-69 years. METHODS: Serum testosterone and sex hormone-binding globulin (SHBG) were assayed. Free testosterone was calculated (cFT). Leucocyte telomere length was measured using polymerase chain reaction. Multivariable models were used to assess associations of hormones with standardised LTL. RESULTS: In 167 706 men, median age 58 years, adjusting for sociodemographic, lifestyle, and medical factors, total testosterone was inversely associated with standardised LTL, which was 0.09 longer (95% confidence interval [CI], 0.08-0.10, P < .001) in men with total testosterone at median of lowest quintile [Q1] vs highest [Q5]. This relationship was attenuated after additional adjustment for SHBG (0.03 longer, CI = 0.02-0.05, P = .003). The association between cFT and LTL was similar in direction but lower in magnitude. In multivariable analysis, SHBG was inversely associated with standardised LTL, which was 0.12 longer (CI = 0.10-0.13, P < .001) for SHBG at median Q1 vs Q5. Results were similar with testosterone included in the model (0.10 longer, CI = 0.08-0.12, P < .001). CONCLUSIONS: Total testosterone and SHBG were independently and inversely associated with LTL. Men with higher testosterone or SHBG had shorter telomeres, arguing against a role for testosterone to slow biological ageing in men.

Reproductive axis ageing and fertility in men.

Compared to women, increasing male age is not accompanied by such marked changes in reproductive function but changes certainly do happen. These include alterations to the hypothalamo-pituitary-testicular axis, with resultant implications for testosterone production and bioavailability as well as spermatogenesis. There is a decline in sexual function as men age, with a dramatic increase in the prevalence of erectile dysfunction after the age of 40, which is a marker for both clinically evident as well as covert coronary artery disease. Despite a quantitative decline in spermatogenesis and reduced fecundability, the male potential for fertility persists throughout adult life, however there are also increasingly recognised alterations in sperm quality and function with significant implications for offspring health. These changes are relevant to both natural and medically assisted conception.

Testosterone, cognitive decline and dementia in ageing men.

As men grow older, circulating testosterone concentrations decline, while prevalence of cognitive impairment and dementia increase. Epidemiological studies of middle-aged and older men have demonstrated associations of lower testosterone concentrations with higher prevalence and incidence of cognitive decline and dementia, including Alzheimer's disease. In observational studies, men with prostate cancer treated by androgen deprivation therapy had a higher risk of dementia. Small intervention studies of testosterone using different measures of cognitive function have provided inconsistent results, with some suggesting improvement. A randomised placebo-controlled trial of one year's testosterone treatment conducted in 788 men aged ≥ 65 years, baseline testosterone < 9.54 nmol/L, showed an improvement in sexual function, but no improvement in cognitive function. There is a known association between diabetes and dementia risk. A randomised placebo-controlled trial of two year's testosterone treatment in 1,007 men aged 50-74 years, waist circumference ≥ 95 cm, baseline testosterone ≤ 14 nmol/L, showed an effect of testosterone in reducing type 2 diabetes risk. There were no cognitive endpoints in that trial. Additional research is warranted but at this stage lower testosterone concentrations in ageing men should be regarded as a biomarker rather than a proven therapeutic target for risk reduction of cognitive decline and dementia, including Alzheimer's disease.

Longitudinal changes in serum testosterone and sex hormone-binding globulin in men aged 40-69 years from the UK Biobank.

OBJECTIVE: Testosterone and sex hormone-binding globulin (SHBG) concentrations are reported to decline during male ageing, but whether these changes reflect physiological ageing or age-related comorbidities remains uncertain. We examined longitudinal changes in serum testosterone and SHBG concentrations in middle-aged to older men, concordance between baseline and follow-up values and relationships with concomitant changes in lifestyle and medical factors. DESIGN: Population-based longitudinal cohort study. PARTICIPANTS: Community-dwelling men aged 40-69 years. MEASUREMENTS: Immunoassay serum total testosterone (n = 7812) and SHBG (n = 6491) at baseline (2006-2010) and follow-up (2012-2013). Free testosterone (cFT) was calculated. Bland-Altman analyses and concordance correlation of repeated measurements were conducted. Associations of changes in hormone concentrations with lifestyle and medical factors were explored using Spearman's rank correlation. RESULTS: Over 4.3 years follow-up, there was a negligible mean change (±SE) in serum total testosterone concentration (+0.06 ± 0.03 nmol/L), whereas mean SHBG concentration increased (+3.69 ± 0.12 nmol/L) and cFT decreased (-10.7 ± 0.7 pmol/L). Concordance estimates were 0.67 (95% confidence interval [CI]: 0.66-0.69) for total testosterone, 0.83 (CI = 0.82-0.84) for SHBG and 0.56 (CI = 0.54-0.58) for cFT. Changes in serum total testosterone correlated with changes in SHBG (Spearman's rank ρ = 0.33, CI = 0.30-0.35), and inversely with changes in body mass index (BMI) (ρ = -0.18, CI = -0.20 to -0.16) and waist circumference (ρ = -0.13, CI = -0.15 to -0.11) and in SHBG with changes in BMI (ρ = -0.34, CI = -0.36 to -0.32) and waist circumference (ρ = -0.21, CI = -0.24 to -0.19). CONCLUSION: In relatively healthy middle-aged to older men, mean serum total testosterone concentration is stable with ageing, while mean SHBG concentration increases. Both total testosterone and SHBG concentrations were highly concordant over time.

D-Chiro-Inositol improves testosterone levels in older hypogonadal men with low-normal testosterone: a pilot study.

BACKGROUND: Several recent journal articles report that D-chiro-inositol (DCI), primarily known as insulin second messenger, influences steroidogenesis. In particular, new evidence is arising on DCI ability to regulate aromatase expression and testosterone biosynthesis. In this regard, DCI administration could represent a good therapeutic opportunity in case of reduced levels of testosterone. Older men generally have lower testosterone concentrations than younger men, and recent randomized controlled trials have examined whether testosterone treatment might improve health outcomes in this age group. There is limited information about the safety of testosterone replacement therapy in these men, hence DCI could represent an interesting alternative for future trials. Therefore, this study aims to evaluate the effect of DCI treatment on testosterone levels in older male patient. RESULTS: Ten older men with basal low testosterone levels were enrolled in this study. Patients took 600 mg of DCI, two-times per day, for 30 days. We evaluated hormonal and glycaemic parameters, weight, waist circumference, and Body-Mass Index at baseline (T0) and after 30 days (T1). Finally, all patients also filled in the standardized International Index of Erectile Function questionnaire and performed the Handgrip test at T0 and T1. Men receiving DCI showed increased androgen and reduced oestrogen concentrations, and improved glycaemic profiles. DCI was also associated with reduced weight, Body-Mass Index, waist circumference, and improved grip strength and self-reported sexual function. All these effects led to the improvement of sexual function and physical strength. CONCLUSIONS: In this pilot study, DCI treatment improved the levels of testosterone and androstenedione at the expense of oestrogens in elder men with low basal levels of these hormones without adverse effects. TRIAL REGISTRATION: Clinicaltrials.gov: D-chiroinositol Administration in Hypogonadal Males, NCT04708249.

RéSUMé: CONTEXTE: Plusieurs articles de revues récents rapportent que le D-chiro-inositol (DCI), principalement connu sous le nom de second messager de l'insuline, influence la stéroïdogenèse. En particulier, de nouvelles preuves apparaissent sur la capacité du DCI à réguler l'expression de l'aromatase et la biosynthèse de la testostérone. À cet égard, l'administration de DCI pourrait représenter une bonne opportunité thérapeutique en cas de réduction des taux de testostérone. Les hommes d'âge avancé ont généralement des concentrations de testostérone plus faibles que celles d'hommes plus jeunes, et de récents essais contrôlés randomisés ont examiné, si le traitement par testostérone pourrait améliorer dans ce groupe d'âge les résultats en matière de santé. Il existe peu d'informations sur l'innocuité de cette thérapie de remplacement de la testostérone chez ces hommes ; le DCI pourrait ainsi constituer une intéressante alternative pour de futurs essais. Par conséquent, la présente étude vise à évaluer l'effet du traitement par DCI sur les taux de testostérone chez les hommes d'âge avancé. RéSULTATS: Dix hommes d'âge avancé ayant un faible taux basal de testostérone ont été recrutés dans la présente étude. Les patients ont pris 600 mg de DCI, deux fois par jour, pendant 30 jours. Nous avons évalué les paramètres hormonaux et glycémiques, le poids, le tour de taille et l'indice de masse corporelle au départ (T0) et après 30 jours (T1). Enfin, tous les patients ont également rempli le questionnaire normalisé de l'indice international de la fonction érectile et ont effectué le test de force de préhension (handgrip test) à T0 et T1. Les hommes prenant le DCI ont présenté des concentrations augmentées d'androgènes et réduites d'œstrogènes, ainsi qu'une amélioration des profils glycémiques. La prise de DCI était également associée à une réduction du poids, de l'indice de masse corporelle, du tour de taille, et à une amélioration de la force de préhension et de la fonction sexuelle autodéclarée. Tous ces effets ont conduit à une amélioration de la fonction sexuelle et de la force physique. CONCLUSIONS: Dans cette étude pilote, le traitement par DCI a amélioré les taux de testostérone et d'androstènedione au détriment des œstrogènes chez des hommes d'âge avancé ayant de faibles taux de base de ces hormones, sans effets indésirables.

Effects of testosterone treatment, with and without exercise training, on ambulatory blood pressure in middle-aged and older men.

CONTEXT: With age, testosterone (T) and physical activity levels often decline in parallel. The effect of combining T treatment and exercise training on ambulatory blood pressure (ABP) is unclear. OBJECTIVE: To assess T and exercise effects, alone and in combination, on ABP in men aged 50-70 years, waist circumference ≥ 95 cm and low-normal serum T (6-14 nmol/L), without organic hypogonadism. DESIGN: A 2 × 2 factorial randomised, placebo-controlled study. INTERVENTION: Randomization to daily transdermal AndroForte5® (Testosterone 5.0%w/v, 100 mg in 2 ml) cream (T), or matching placebo (P) (double-blind), and to supervised exercise (Ex) or no additional exercise (NEx), for 12 weeks. RESULTS: Average 24-h systolic blood pressure (SBP) increased with T treatment (testosterone*time, p = .035). Average 24-h SBP increased in T+Ex (T+Ex:+3.0 vs. P+NEx: -3.0 mmHg, p = .026) driven by day-time changes (T+Ex:+3.5 vs. P+NEx: -3.0 mmHg, p = .026). There was an effect of T for 24-h average diastolic blood pressure (DBP, testosterone*time, p = .044) driven by the decrease in P+Ex (P+Ex: -3.9 vs. T+NEx: -0.5 mmHg, p = .015). Night-time DBP was lower with exercise (P+Ex: -4.0 vs. P+NEx: +0.7 mmHg, p = .032). The effect of exercise to lower night-time DBP was not apparent in the presence of T (T+Ex: -0.4 vs. P+NEx: +0.7 mmHg, p > .05). Ex increased average 24-h pulse pressure (PP, exercise*time, p = .022), largely during daytime hours (exercise*time, p = .013). CONCLUSIONS: There was a main effect of T to increase 24-h SBP, primarily seen when T was combined with Ex. Exercise alone decreased 24-h and night-time DBP; an effect attenuated by T. BP should be carefully assessed and monitored, when prescribing T treatment to middle-aged and older men, especially when combined with exercise training.

U-Shaped Relationship of Leukocyte Telomere Length With All-Cause and Cancer-Related Mortality in Older Men.

BACKGROUND: Telomeres are essential DNA-protein complexes whose attrition results in cellular dysfunction and senescence. Leukocyte telomere length (LTL) correlates with tissue telomere length, representing a biomarker for biological age. However, its predictive value for mortality risk, and for cardiovascular versus cancer deaths, in older adults remains uncertain. METHOD: We studied 3608 community-dwelling men aged 77.0 ± 3.6 years. Leukocyte telomere length was measured using multiplex quantitative PCR, expressed as amount of telomeric DNA relative to single-copy control gene (T/S ratio). Deaths from any cause, cardiovascular disease (CVD), and cancer were ascertained using data linkage. Curve fitting used restricted cubic splines and Cox regression analyses adjusted for age, cardiometabolic risk factors, and prevalent disease. RESULTS: There was a U-shaped association of LTL with all-cause mortality. Men with T/S ratio in the middle quartiles had lower mortality (quartiles, Q2 vs Q1, hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.77-0.97, p = .012; Q3 vs Q1 HR = 0.88, CI 0.79-0.99, p = .032). There was no association of LTL with CVD mortality. There was a U-shaped association of LTL with cancer mortality. Men with LTL in the middle quartiles had lower risk of cancer death (Q2 vs Q1, HR = 0.73, CI 0.59-0.90, p = .004; Q3 vs Q1, HR = 0.75, CI 0.61-0.92, p = .007). CONCLUSIONS: In older men, both shorter and longer LTL are associated with all-cause mortality. A similar U-shaped association was seen with cancer deaths, with no association found for cardiovascular deaths. Further research is warranted to explore the prognostic utility of LTL in ageing.

[Male age in assisted reproductive technologies: Is there a limit?] / Âge du père en assistance médicale à la procréation : faut-il une limite ?

In France, there does exist any age limit for infertile men management neither in the law nor for the coverage by the "French Assurance Maladie". French law specifies only that both partners of the couple have to be "of childbearing age", but there is no definition for men of childbearing age. Does legislation have to determine a limit on man management in function of his age? Could ART practitioners decide (themselves) whether they take care of infertile men or not? Should male age be a criteria to decide this management? Would ART practitioners "need" a legislation to help them to decide? In 2016, the "French Assurance Maladie" covers all costs for infertile couple if woman is less than 43 years old, whatever male age. If an age-threshold should be establish for the coverage of infertile men management by the "French Assurance Maladie", then what should be this threshold? In order to try to answer these questions, we asked them to French ART practitioners (gynecologists and embryologists) and gynecologists. The first questionnaire included 13 questions and was filled by 244 ART specialists; the second was filled by 138 gynecologists. Most of them agree to limit the male management and the coverage by the "French Assurance Maladie" at 60 for men in ART. Gynecologists who does not practice ART wish a limit for insurance (80% of them but are only 57% to wish a legal limit).

Aging male symptoms: the relationship between physical activity and quality of life

OBJECTIVE: To examine the relationship between physical activity (PA) and the aging male symptoms of middle-aged men in the quality of life (QOL). METHODOLOGY: Cross-sectional study with a probabilistic samples of 416 men (40-59 years old), all residents in two cities in southern of Brazil. A questionnaire was used. The studied population was divided into two groups: with and without symptoms. The analyses were carried out in a descriptive and inferential approaches. RESULTS: Aging male symptoms were related to QOL. Men who perceive their overall QOL as good presented a13% lower probability of (95%CI = 0.77-0.98) being insufficiently active. For those with symptoms, QOL scores were higher in social and environmental domain in PA between 30-60 min/day, and the physical domain for more than 60min/day. CONCLUSION: Our findings show the importance of PA to achieve significant benefits in QOL and health of men in middle age with aging male symptoms

Female access and diet affect insemination success, senescence, and the cost of reproduction in male Mexican fruit flies Anastrepha ludens.

Hypotheses exploring the influence of dietary conditions on the life history trade-off between survival and reproductive success are extensively tested in female insects, but are rarely explored in males. Here, the impact of dietary quality and female access on age-specific reproduction and survival of male Mexican fruit flies, Anastrepha ludens Loew (Diptera: Tephritidae), are examined. There is a clear cost of female access for males with access to dietary protein, measurable as a decrease in life expectancy, which is further influenced by the age when females are introduced. A protein deficient diet reduces the lifespan benefit of virginity and masks the detrimental effect of female access on male life expectancy. Dietary protein is not necessary for reproductive success, but access to protein at eclosion improves the lifetime reproductive success of males compared to when it is delayed. Overall, reproductive success diminishes as the male flies age, regardless of the dietary conditions, providing evidence for reproductive senescence in males. Delaying the males' access to a protein source fails to influence the negative effect of age on reproductive ability. Because age specific reproductive rates decline with age, regardless of diet, male fitness does not benefit from lifespan extension. Therefore, males can be expected to allocate available resources towards reproductive effort in favour of extended lifespan, regardless of mate and protein availability.

Hormonal changes and their impact on cognition and mental health of ageing men.

Demographic changes resulting in ageing of the world's population have major implications for health. As men grow older, circulating levels of the principal androgen or male sex hormone testosterone (T) decline, while the prevalence of ill-health increases. Observational studies in middle-aged and older men have shown associations between lower levels of T and poorer mental health in older men, including worse cognitive performance, dementia and presence of depressive symptoms. The role of T metabolites, the more potent androgen dihydrotestosterone (DHT) and the oestrogen receptor ligand estradiol (E2) in the pathophysiology of cognitive decline are unclear. Studies of men undergoing androgen deprivation therapy in the setting of prostate cancer have shown subtle detrimental effects of reduced T levels on cognitive performance. Randomised trials of T supplementation in older men have been limited in size and produced variable results, with some studies showing improvement in specific tests of cognitive function. Interventional data from trials of T therapy in men with dementia are limited. Lower levels of T have also been associated with depressive symptoms in older men. Some studies have reported an effect of T therapy to improve mood and depressive symptoms in men with low or low-normal T levels. T supplementation should be considered in men with a diagnosis of androgen deficiency. Beyond this clinical indication, further research is needed to establish the benefits of T supplementation in older men at risk of deteriorating cognition and mental health.

Late-onset hypogonadism in men with systolic heart failure: prevalence, clinical associates, and impact on long-term survival.

BACKGROUND: Male ageing is characterized by diminished circulating androgens with several adverse psychosomatic consequences and can be aggravated by concomitant chronic diseases. According to the European Male Aging Study (EMAS) Group, late-onset hypogonadism (LOH) refers to testosterone deficiency accompanied by sexual complaints. AIM: We investigated the prevalence of LOH in men with systolic heart failure (HF), and its clinical determinants and prognostic consequences. METHODS: Among 201 men with systolic HF (age: 60 ± 11 years), serum total testosterone (TT) was assessed using an immunoassay, and estimated free testosterone (eFT) was calculated using Vermeulen's formula. LOH was diagnosed when TT < 3.2 ng/mL and eFT < 64 pg/mL were accompanied by three sexual symptoms (decrease in the number of morning erections, reduced potency, and low libido) of at least moderate severity assessed using the Aging Males' Symptoms Scale. RESULTS: Decreased frequency of morning erections, reduced potency, and low libido were experienced by 56%, 62%, and 55% of men with HF, respectively; whereas 67%, 61%, and 44% of subjects complained of at least one, two, and three symptoms, respectively. Hypogonadal TT and eFT were observed in 34% and 47% of patients, respectively; and in 33% subjects, both TT and eFT were reduced. Finally, 30 men with HF (15%) were diagnosed with LOH as compared with 2% in a European male population (EMAS). In a multivariable model, older age and higher serum uric acid were independently associated with greater LOH prevalence (both P < 0.05). Among men aged ≤60 years (but not in those aged >60 years), LOH increased 5-year all-cause mortality in the univariable model; however, when adjusted for HF severity, the association lost its statistical significance. CONCLUSIONS: Men with systolic HF commonly report sexual complaints. LOH-the combination of sexual dysfunction and testosterone deficiency-occurs more frequently than in a general male population. LOH does not affect long-term mortality, when adjusted for HF severity.

Testosterone and growth hormone in older men: for better or for worse?

Evaluation of: Sattler FR, Castaneda-Sceppa C, Binder EF et al. Testosterone and growth hormone improve body composition and muscle performance in older men. J. Clin. Endocrinol. Metab. 94(6), 1991-2001 (2009). In men, testosterone and IGF1 levels decline with increasing age, and lower levels of these hormones are associated with poorer health. A recent, randomized clinical trial demonstrates the additive effects of testosterone and growth hormone supplementation to increase lean body mass, reduce fat mass and improve muscle strength in older men. These findings highlight the interaction between these two hormones and provide a model for further evaluation of combined therapy to explore other end points, such as cardiovascular risk.