Age-related Decline In Testosterone Research Articles

Low testosterone levels relate to poorer cognitive function in women in an APOE-ε4-dependant manner

BackgroundPast research suggests that low testosterone levels relate to poorer cognitive function and higher Alzheimer’s disease (AD) risk; however, these findings are inconsistent and are mostly derived from male samples, despite similar age-related testosterone decline in females. Both animal and human studies demonstrate that testosterone’s effects on brain health may be moderated by apolipoprotein E ε4 allele (APOE-ε4) carrier status, which may explain some previous inconsistencies. We examined how testosterone relates to cognitive function in older women versus men across healthy aging and the AD continuum and the moderating role of APOE-ε4 genotype.MethodsFive hundred and sixty one participants aged 55–90 (155 cognitively normal (CN), 294 mild cognitive impairment (MCI), 112 AD dementia) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), who had baseline cognitive and plasma testosterone data, as measured by the Rules Based Medicine Human DiscoveryMAP Panel were included. There were 213 females and 348 males (self-reported sex assigned at birth), and 52% of the overall sample were APOE-ε4 carriers. We tested the relationship of plasma testosterone levels and its interaction with APOE-ε4 status on clinical diagnostic group (CN vs. MCI vs. AD), global, and domain-specific cognitive performance using ANOVAs and linear regression models in sex-stratified samples. Cognitive domains included verbal memory, executive function, processing speed, and language.ResultsWe did not observe a significant difference in testosterone levels between clinical diagnostic groups in either sex, regrardless of APOE-ε4 status. Across clinical diagnostic group, we found a significant testosterone by APOE-ε4 interaction in females, such that lower testosterone levels related to worse global cognition, processing speed, and verbal memory in APOE-ε4 carriers only. We did not find that testosterone, nor its interaction with APOE-ε4, related to cognitive outcomes in males.ConclusionsFindings suggest that low testosterone levels in older female APOE-ε4 carriers across the aging-MCI-AD continuum may have deleterious, domain-specific effects on cognitive performance. Although future studies including additional sex hormones and longitudinal cognitive trajectories are needed, our results highlight the importance of including both sexes and considering APOE-ε4 carrier status when examining testosterone’s role in cognitive health.

Exogenous Nucleotides Ameliorate Age-Related Decline in Testosterone in Male Senescence-Accelerated Mouse Prone-8 (SAMP8) Mice by Modulating the Local Renin-Angiotensin System Antioxidant Pathway.

In older men, an age-related decline in testosterone is closely associated with various adverse health outcomes. With the progression of aging, hyperactivation of the local renin-angiotensin system (RAS) and oxidative stress increase in the testis. The regulation of RAS antioxidants may be a target to delay testicular aging and maintain testosterone levels. Exogenous nucleotides (NTs) have anti-aging potential in several systems, but there are no studies of their effects on the reproductive system. In our study, we examined the effects of exogenous NTs on testosterone synthesis and explored possible mechanisms of action. Therefore, senescence-accelerated mouse prone-8 (SAMP8) mice and senescence-accelerated mouse resistant 1 (SAMR1) were used in the experiment, and they were randomly divided into an NTs free group (NTs-F), a normal control group (control), a low-dose NTs group (NTs-L), a middle-dose NTs (NTs-M), a high-dose NTs group (NTs-H) and SAMR1 groups, and the testis of the mice were collected for testing after 9 months of intervention. The results showed that exogenous NTs could increase the testicular organ index in mice during aging, and delayed the age-associated decline in testosterone levels in SAMP8 male mice, possibly by modulating the local RAS antioxidant pathway and reducing oxidative stress to protect the testis. The present study provides new research clues for the development of preventive and therapeutic strategies for related diseases.

Involvement of p38 MAPK in Leydig cell aging and age-related decline in testosterone.

Age-related decline in testosterone is associated with Leydig cell aging with impaired testosterone synthesis in aging. Obesity accelerates the age-related decline in testosterone. However, the mechanisms underlying the Leydig cell aging and the effects of obesity on Leydig cell aging remain unclear. Natural aging mice and diet-induced obese mice were used to assess the process of testicular Leydig cell senescence with age or obesity. Bioinformatic analysis of the young and aged human testes was used to explore key genes related Leydig cell aging. Leydig cell-specific p38 MAPK knockout (p38LCKO) mice were used to further analyze the roles of p38 MAPK in Leydig cell aging. The levels of testosterone and steroidogenic enzymes, activity of p38 MAPK, aging status of Leydig cells, and oxidative stress and inflammation of testes or Leydig cells were detected by ELISA, immunoblotting, immunofluorescence, and senescence-associated β-galactosidase (SA-β-Gal) staining analysis, respectively. The serum testosterone level was significantly reduced in aged mice compared with young mice. In the testis of aged mice, the reduced mRNA and protein levels of LHCGR, SRB1, StAR, CYP11A1, and CYP17A1 and the elevated oxidative stress and inflammation were observed. KEGG analysis showed that MAPK pathway was changed in aged Leydig cells, and immunoblotting displayed that p38 MAPK was activated in aged Leydig cells. The intensity of SA-β-Gal staining on Leydig cells and the number of p21-postive Leydig cells in aged mice were more than those of young mice. Similar to aged mice, the testosterone-related indexes decreased, and the age-related indexes increased in the testicular Leydig cells of high fat diet (HFD) mice. Aged p38LCKO mice had higher levels of testosterone and steroidogenic enzymes than those of age-matched wild-type (WT) littermates, with reduced the intensity of SA-β-Gal staining and the expression of p21 protein. Our study suggested that obesity was an important risk factor for Leydig cell aging. p38 MAPK was involved in Leydig cell aging induced by age and obesity. The inhibition of p38 MAPK could delay Leydig cell aging and alleviate decline in testosterone.

The impact of testosterone in men's health.

Testosterone plays a key role in the maintenance of physical and mental functions in men. Age-related testosterone decline is closely associated with sarcopenia and muscle deterioration, while testosterone decline is linked with the etiology and prevention of diseases such as angina pectoris, arteriosclerosis, obesity, metabolic syndrome, and dementia. Late-onset hypogonadism (LOH) is defined as a disease characterized by age-related testosterone decline and associated clinical symptoms. Testosterone replacement therapy improves health-related QOL in patients with LOH.

Relationship between Testosterone and Sarcopenia in Older-Adult Men: A Narrative Review.

Age-related decline in testosterone is known to be associated with various clinical symptoms among older men and it is possible that the accompanying decline in muscle mass and strength might lead to a decline in motor and physical functions. Sarcopenia is an important pathophysiological factor associated with frailty in older adults and is diagnosed in older adults as a decrease in muscle strength, muscle mass, and walking speed, which can lead to a significant decline in the quality of life and shortened healthy life expectancy. Testosterone directly interacts with the androgen receptor expressed in myonuclei and satellite cells and is also indirectly associated with muscle metabolism through various cytokines and molecules. Currently, significant correlations between testosterone and frailty in men have been confirmed by numerous cross-sectional studies. Many randomized control studies have also supported the beneficial effect of testosterone replacement therapy (TRT) on muscle volume and strength among men with low to normal testosterone levels. In the world’s aging society, TRT can be a tool for preventing the onset of sarcopenia in older-adult men. This narrative review aims to show the relationship between the decline in testosterone with age, sarcopenia, and frailty, as well as the effects of testosterone replacement therapy on muscle mass and strength.

Associations of Bioavailable Serum Testosterone With Cognitive Function in Older Men: Results From the National Health and Nutrition Examination Survey.

Age-associated cognitive decline may be influenced by testosterone status. However, studies evaluating the impact of bioavailable testosterone, the active, free testosterone, on cognitive function are scarce. Our study determined the relationship between calculated bioavailable testosterone and cognitive performance in older men. We used data from the U.S. National Health and Nutrition Examination Survey (NHANES) between 2013 and 2014. This study consisted of 208 men aged ≥60 years. Bioavailable serum testosterone was calculated based on the total serum testosterone, sex hormone-binding globulin, and albumin levels, whereas cognitive performance was assessed through the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word List Learning Test (WLLT), Word List Recall Test (WLRT), and Intrusion Word Count Test (WLLT-IC and WLRT-IC), the Animal Fluency Test (AFT), and the Digit Symbol Substitution Test (DSST). Multiple linear regression analyses were performed upon adjustment for age, ethnicity, socioeconomic status, education level, medical history, body mass index, energy, alcohol intake, physical activity levels, and sleep duration. A significant positive association between bioavailable testosterone and DSST (β: 0.049, p = .002) score was detected, with no signs of a plateau effect. No significant associations with CERAD WLLT (p = .132), WLRT (p = .643), WLLT-IC (p = .979), and WLRT-IC (p = .387), and AFT (p = .057) were observed. Calculated bioavailable testosterone presented a significant positive association with processing speed, sustained attention, and working memory in older men above 60 years of age. Further research is warranted to elucidate the impact of the inevitable age-related decline in testosterone on cognitive function in older men.

A0401 - Obesity impairs hypogonadism compensation leading to age-related testosterone decline

A0401 - Obesity impairs hypogonadism compensation leading to age-related testosterone decline

The Danger within: Covid-19 Affinity for ACE2 Receptors in Adipose Tissue and Testes. The Protective Effects of Estradiol, Fitness, and Weight Management

The imminent danger of the Covid-19 pandemic has accelerated research in pharmaceuticals that either target the viral Spike proteins fusion with ACE2 receptors, or the infectious RNA replication that often overwhelms immune defences. The scope of this review was to elucidate the main human vulnerabilities to Covid-19, including the accumulation of ACE2 receptors in testes, adipose tissue, thyroid, heart and kidneys that escalate viral affinity in males, the aged, and certain medical conditions, including diabetes, CVD, and pulmonary diseases. Pre-existing inflammation inherent in obesity may exacerbate the “cytokine storm,” a rampaging immune reaction during the course of Covid-19 that is deleterious to the host. We examined the molecular dynamics illustrating the action of new therapeutics necessary for Covid-19 patients; the estradiol advantage hypothesis;alternative therapies including hormone replacement procedures and mesenchymal stem cells; plus preventive and protective interventions.The current perspective also explored the primary components of dysregulated health predisposing individuals to Covid-19, including hormonal imbalance, increased lipids and lipoproteins, thyroid dysfunction, degraded fitness, and age-related testosterone decline accompanied by cortisol increase that provokes stress eating behaviours and weight accumulation.Obesity increases the probability of Covid-19 infection due to its abundance of ACE2 receptors; while physical activity may decrease Covid-19 vulnerability, by reducing fat and increasing muscle mass that manifests a relatively inhibited ACE2 expression. Several weight management solutions feature lasers and radiofrequency which diminish subcutaneous adiposity but do not enhance fitness. A data metanalysis of seven recently published clinical studies on 95 obese individuals, 73 males and 22 females with an average BMI of 30.9, demonstrated visceral fat reduction combined with increased skeletal muscle mass. It also revealed a statistically significant decrease in BMI, lipids, lipoproteins, inflammation and toxicity as measured by CRP, Creatinine and Bilirubin respectively, juxtaposed by optimally healthier levels of Cortisol, Testosterone, Free T3,IGF-1, Insulin, and the appetite controlling hormones Leptin and Ghrelin.

Benefits and Risks of Testosterone Treatment in Men with Age-Related Decline in Testosterone.

The substantial increase in life expectancy of men has focused growing attention on quality-of-life issues associated with reproductive aging. Serum total and free testosterone levels in men, after reaching a peak in the second and third decade of life, decline gradually with advancing age. The trajectory of age-related decline is affected by comorbid conditions, adiposity, medications, and genetic factors. Testosterone treatment of older men with low testosterone levels improves overall sexual activity, sexual desire, and erectile function; improves areal and volumetric bone density, as well as estimated bone strength in the spine and the hip; corrects unexplained anemia of aging; increases skeletal muscle mass, strength and power, self-reported mobility, and some measures of physical function; and modestly improves depressive symptoms. The long-term effects of testosterone on major cardiovascular events and prostate cancer risk remain unclear. The Endocrine Society recommends against testosterone therapy of all older men with low testosterone levels but suggests consideration of treatment on an individualized basis in men who have consistently low testosterone levels and symptoms or conditions suggestive of testosterone deficiency.

The Danger Within: Covid-19 Affinity for ACE2 receptors in Adipose Tissue and Testes. The Protective Effects of Estradiol, Fitness and Weight Management

The imminent danger of the Covid-19 pandemic has accelerated research in pharmaceuticals designed to interfere with the virus’ entry into the body via ACE2 receptors, or the viral RNA replication that often overwhelms immune defences. The scope of this review was to elucidate the main human vulnerabilities like certain organs’ enrichment in ACE2 receptors increasing viral affinity to males, the aged and certain pre-existing conditions including diabetes, CVD and pulmonary diseases, that deteriorate with increasing obesity, inflammation and toxicity. The current perspective focuses on the primary components of dysregulated health predisposing individuals to Covid-19, including hormonal imbalance,increased lipids and lipoproteins, thyroid dysfunction, degraded fitness, and age-related testosterone decline accompanied by cortisol increase that provokes stress eating behaviours and weight accumulation.We examined the molecular dynamics illustrating the action of new therapeutics necessary for Covid-19 patients; theestradiol advantage hypothesis; alternative therapies including hormone replacement procedures andmesenchymal stem cells; plus preventive and protective interventions. Obesity increases the probability of Covid-19 infection due to its abundance of ACE2 receptors.Physical activitymay decrease Covid-19 vulnerability, due to the diminished ACE-2 expression in the muscle. There are a number the fat managementsolutions featuring lasers and radiofrequency which, however do not enhance fitness. Seven recently published clinical studies with a total of 95 subjects, 73 males and 22 females, demonstrated visceral fat reduction combined with increasedskeletal muscle mass. A metanalysis performed on their data revealeda statistically significant decrease in several variables including BMI, lipids, lipoproteins, toxicityand inflammation as measured by CRP, Creatinine and Bilirubin, andoptimally healthier levels ofCortisol, Testosterone, Free T3,IGF-1, Insulin, and the appetite controlling hormones Leptin and Ghrelin.

How to manage low testosterone level in men: a guide for primary care.

Male hypogonadism is a clinical syndrome characterised by testosterone deficiency and impaired spermatogenesis; due either to diseases of the hypothalamus or pituitary gland, or of the testes themselves.1 The diagnosis requires the presence of clinical features consistent with lack of testosterone plus the finding of persistent and unequivocally low serum testosterone levels. Failure to recognise and treat men with hypogonadism may predispose them to long-term health problems, such as anaemia, osteoporosis, depression, or sexual dysfunction. Over recent years, there has been a surge in testosterone prescriptions for men with sexual dysfunction or putative age-related decline in testosterone,2 possibly reflecting pharmaceutical promotion, or sharing of misleading information on the internet. With growing demands and expectations of men worried about their wellbeing, there is a real risk of overdiagnosis and unnecessary treatment with testosterone. Suboptimal sampling conditions can lead to misinterpretation of serum biochemistry, and the long-term risks of testosterone therapy for men not having verified hypogonadism may be underestimated by ‘enthusiasts’. ### Diagnosis of hypogonadism Routine screening for hypogonadism in asymptomatic men is not recommended, except in certain conditions (Supplementary Figure S1). Clinical features of hypogonadism are not limited to sexual symptoms — reduced libido, erectile dysfunction (ED), and loss of waking erections. Anaemia, osteoporosis, and vasomotor sweating or flushing are frequently present; indeed, older men may not volunteer sexual symptoms, having ascribed them to ageing. ### Sampling conditions Testosterone secretion has diurnal variation and is suppressed post-prandially, so serum testosterone and sex-hormone binding …

The role of bioidentical hormone replacement therapy in anti-aging medicine: a review of the literature.

The changes in skin and overall appearance that occur with increasing age can be partly attributed to declining hormone levels. While hormonal deficiencies are most commonly associated with postmenopausal females, males are also subject to age-related testosterone decline and may benefit from replacement of deficient hormones. However, great disparities exist between the recommendations of scientific societies and actual use of hormone supplements in aging patients. The purpose of this literature review is to discuss the role of hormones in the aging process of the skin, explain the safety profile of hormone replacement therapy, specifically discussing the superiority of bioidentical hormones, and highlight the benefits of hormone replacement in anti-aging of the skin. In summary, this literature review suggests that hormone replacement with bioidentical hormones is a safe and effective way to prevent skin aging.

A Comparison of men’s Life History, Aging, and Testosterone Levels among Datoga Pastoralists, Hadza Foragers, and Qom Transitional Foragers

Relative to industrialized populations, men from subsistence groups exhibit lower testosterone values and more modest declines with age. Limited energy availability has been hypothesized to suppress testosterone production, particularly during young adulthood when testosterone levels are highest, resulting in a flatter trajectory of age-decline. Energetic constraint, however, is not unique to the evolutionary ecology of humans, and yet significant age-related testosterone decline is observed in numerous species of wild primates. Conversely, human life history is distinguished by extensive bi-parental care and male provisioning. Because fathers show decreased testosterone with parenting effort, we argue that within more naturalistic and evolutionarily relevant ecologies, natural fertility and earlier reproduction suppresses testosterone in emerging adulthood such that a lower relative baseline dictates less age-decline across the remaining lifespan. We examine men’s testosterone levels as contrasting functions of energetic status and paternal involvement across three traditional populations with substantial variability in men’s nutritional condition and parental investment. Anthropometric and demographic data along with saliva samples were collected from 70 Datoga, 29 Hadza, and 43 Qom men, ages 20–72 years. Population variation in salivary testosterone was greatest at younger ages and patterned so paternal involvement associated with lower morning and evening testosterone, along with diminished age-decline in both measures. Men’s energetic status as indicated by body mass index was not associated with testosterone values or age-related decline. Within socioecological contexts of smaller scale society, these data suggest that blunted age-decline in men’s testosterone levels is primarily due to population variation in parental investment rather than energetic constraint.

MON-399 Congenital Adrenal Hyperplasia Newly Diagnosed in an Octogenarian

Relevance: The most common form of congenital adrenal hyperplasia (CAH) is 21-hydroxylase deficiency, in which a block in cortisol biosynthesis shifts precursors to pathways that make excess adrenal-derived androgens. We report a rare case in which a new diagnosis of CAH due to 21-hydroxylase deficiency occurred in an octogenarian. Clinical case: An 82 year old man presented for evaluation of persistent headache, anorexia, and unintentional weight loss. He was found to have acute worsening of chronic hyponatremia and hyperkalemia with presenting sodium and potassium levels of 121 and 5.8 mEq/L, respectively. He had increased skin pigmentation, but no hypotension or orthostasis. These findings prompted evaluation of his HPA axis. His AM cortisol was 11.9 mcg/dL (6.7-22.6) and ACTH was 1,036 pg/dL (7.2-63.3). After cosyntropin stimulation, his cortisol remained 10.8 at 30 minutes and 10.5 at 60 minutes. DHEA-S was 34.1 mcg/dL (20.8 - 226.4), Renin was 11.5 ng/mL/hr (0.2-5.4) and Aldosterone was < 1.0 ng/dL (0-30). Further hormonal testing showed an AM testosterone 788 ng/dL (264-916), which was higher than expected given the normal age related decline in testosterone. LH was 3.9 mIU/mL (1.2-8.6), FSH was 4.9 mIU/mL (1.3-19.3) and prolactin was 15.4 ng/mL (4.0-15.2). Oral hydrocortisone was initiated: 10mg in the morning and 5mg in the afternoon, in addition to florinef 0.1mg daily. By hospital day 4, his hyperkalemia and hyponatremia had normalized, his headaches resolved, and his appetite improved. Review of a prior CT chest/abdomen/pelvis (done for unintentional weight loss) demonstrated normal adrenal glands with no evidence of malignancy, hemorrhage, enlargement, or atrophy. 21-hydroxylase antibodies were undetectable. On further history, the patient disclosed that adrenarche occurred at age 6. He had short stature in his youth and was treated with growth hormone injections. He and his wife had difficulty conceiving and he was told of low sperm motility but ultimately had three children by natural conception. An insidious presentation of CAH was suspected based on this history and the high normal testosterone levels in this octogenarian. After uninterrupted treatment with hydrocortisone for two weeks, 17-hydroxy progesterone was 800 ng/dL (27-199), his ACTH improved to 660 and his testosterone decreased to 494. A 21-hydroxylase mutational analysis is pending. Conclusions: Classical CAH is typically diagnosed in infancy or youth in the setting of adrenal insufficiency with/without salt wasting, ambiguous genitalia in female infants or virilization. Although atypical to go undiagnosed for decades, non-classic CAH should be considered as a cause of aldosterone and cortisol deficiency, even among elderly patients, who present with signs and symptoms concerning for adrenal insufficiency. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Understanding how Age-Related Decline in Testosterone Affects Male Sexual Behavior: Neurosteroids as the Missing Piece

Age-related declines in male sexual behavior are often attributed to a well-documented decline in circulating androgens. Yet, several recent studies and metanalyses have suggested a weak relationship between circulating androgen levels and sexual behaviors, indicating that despite decreases in circulating androgens many men maintain moderate levels of sexual behavior. The lack of a strong relationship between circulating androgens and sexual dysfunction may be due to age-related changes in steroid signaling in the brain, which may be independent of circulating androgens. Androgen concentrations, synthesis, and signaling in the aging brain have been understudied. The purpose of this review is to briefly summarize our understanding of how age-related decreases in circulating androgens influence neural circuits that mediate sexual behavior and reward, and to highlight recent findings in our understanding of androgen receptors, neuroandrogens, and sexual function in healthy aged men. Age-related declines in circulating androgens weakly correlate with declines in sexual behavior, but androgen decline does not account for all the variance in sexual behavior observed among subjects. Evidence now suggests that neural nodes of the consummatory and appetitive sexual behavior circuits are capable of synthesizing androgens, independent of circulating levels of androgens. However, there remains a lack of controlled studies on neural markers of androgen signaling in healthy aged men. This ability to locally regulate androgens may compensate for lower circulating androgen levels to maintain proper sexual functioning. To better understand age-related declines in sexual behavior, compensatory androgen synthesis in the brains of aged males should be explored further in humans and animal models. A greater understanding of these mechanisms can inform the development of pharmacotherapies that can be used to ameliorate age-related sexual dysfunction.

Abstract 3227: Getting rid of obesity in middle-to-late adulthood relates to lower prostate cancer risk: Another piece of evidence supporting the “rapid testosterone reduction theory”

Abstract Background: Previously we demonstrated that a smoothed age-related decline in testosterone was associated with decreased risk of prostate cancer (PCa) (“rapid testosterone reduction theory”). Obesity relates to low testosterone, so body weight pattern reflecting smoothed testosterone decline should be related to lower PCa risk. This study aimed to validate the “rapid testosterone reduction theory” from the perspective of body mass index (BMI) pattern and risk of PCa. Methods: We conducted a nested case-control study in a retrospective hospital cohort with median follow-up of 5.0 years from a tertiary-level hospital in the Southeastern US. Electronic medical records of 18168 patients with prostate-related disease diagnosed between November 4, 1995 and January 10, 2016 were screened. The outcome was newly diagnosed PCa. Only patients with BMI measured at ≥3 differing calendar years before PCa diagnosis or the latest follow-up (for non-PCa patients) were included, resulting in a sample of 1571, among which 128 were PCa patients. BMI was analyzed in cross-section value, change, and developmental trajectories in relation to PCa risk. Results: Participant ages spanned a range of 40 to 90 years, with mean age at baseline was 57 years (standard deviation = 9.6). Baseline BMI was inversely associated with PCa risk (adjusted odds ratio [AOR], 0.76; 95% confidence interval [CI], 0.63-0.91 for every 5-unite increase in BMI). When analyzed in change between baseline and the latest follow-up, BMI increment was associated with increased PCa risk (AOR, 1.26; 95% CI, 1.05-1.51 for every 5-unite increase in BMI change). When analyzed in latent-class trajectory, a downward BMI trajectory of being obese in the 4th, 5th, and 6th decade then progressing to be non-obese since the 7th decade of age was associated with decreased PCa risk (AOR, 0.66; 95% CI, 0.45-0.98), compared to those with consistently normal BMI. When analyzed by strata of PCa diagnosis age, the same associations were more evident for PCa diagnosed after age 65. Conclusions: Weight loss and getting rid of obesity during middle-to-late adulthood is related to a decreased PCa risk, supporting the “rapid testosterone reduction theory” in explaining PCa risk. If this finding can be verified with more rigorous study, provision of testosterone replacement therapy as a weight control measure for men in middle-to-later adulthood has potentials in PCa prevention. Citation Format: Kai Wang, Xinguang Chen, Travis A. Gerke, Victoria Y. Bird, Mattia Prosperi. Getting rid of obesity in middle-to-late adulthood relates to lower prostate cancer risk: Another piece of evidence supporting the “rapid testosterone reduction theory” [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3227.

Individual testosterone decline and future mortality risk in men

Male aging is characterized by a decline in testosterone (TS) levels with a substantial variability between subjects. However, it is unclear whether differences in age-related changes in TS are associated with general health. We investigated associations between mortality and intra-individual changes in serum levels of total TS, SHBG, free TS and LH during a ten-year period with up to 18 years of registry follow-up. 1167 men aged 30-60 years participating in the Danish Monitoring Trends and Determinants of Cardiovascular Disease (MONICA1) study and who had a follow-up examination ten years later (MONICA10) were included. From MONICA10, the men were followed up to 18 years (mean: 15.2 years) based on the information from national mortality registries via their unique personal ID numbers. Cox proportional hazard models were used to investigate the association between intra-individual hormone changes and all-cause, CVD and cancer mortalities. A total of 421 men (36.1%) died during the follow-up period. Men with most pronounced decline in total TS (<10th percentile) had a higher all-cause mortality risk compared to men within the 10th to 90th percentile (hazard ratio (HR): 1.60; 95% confidence interval (CI): 1.08-2.36). No consistent associations were seen in cause-specific mortality analyses. Our study showed that higher mortality rates were seen among the men who had the most pronounced age-related decline in TS, independent of their baseline TS levels.

Influence of marital status on testosterone levels–A ten year follow-up of 1113 men

Based on a large population of 1113 men aged 30–60 at baseline (mean: 44.1 years, standard deviation: 10.5), we investigated whether intra-individual changes in testosterone (T) and related reproductive hormones during a ten year period were dependent of marital status at baseline and follow-up. The studied men were part of a health survey in Denmark, conducted between 1982 and 1984 with a follow-up examination approximately ten years later. Data on reproductive hormones, measured in serum, and lifestyle and marital status were obtained at both time points. As expected, an age-related decline in testosterone was observed. However, independent of age and lifestyle, we observed that men who went from unmarried to married (n=81) during the study period experienced an accelerated age-related decline in testosterone (−6.6nmol/L) whereas men who went from married to unmarried (n=67) experienced an attenuated age-related decline (−2.3nmol/L). Men who were either married or unmarried at both time points (n=167, n=798, respectively) had a testosterone decline in between (−3.7nmol/L and −4.6nmol/L, respectively). Changes in T/LH ratio did not differ according to marital status indicating that the lowered T level is not compensated by increasing LH levels. This could suggest a modification of the gonadostat due to an adaptation to changing life circumstances.

Male Hypogonadism and Osteoporosis: The Effects, Clinical Consequences, and Treatment of Testosterone Deficiency in Bone Health.

It is well recognized that bone loss accelerates in hypogonadal states, with female menopause being the classic example of sex hormones affecting the regulation of bone metabolism. Underrepresented is our knowledge of the clinical and metabolic consequences of overt male hypogonadism, as well as the more subtle age-related decline in testosterone on bone quality. While menopause and estrogen deficiency are well-known risk factors for osteoporosis in women, the effects of age-related testosterone decline in men on bone health are less well known. Much of our knowledge comes from observational studies and retrospective analysis on small groups of men with variable causes of primary or secondary hypogonadism and mild to overt testosterone deficiencies. This review aims to present the current knowledge of the consequences of adult male hypogonadism on bone metabolism. The direct and indirect effects of testosterone on bone cells will be explored as well as the important differences in male osteoporosis and assessment as compared to that in females. The clinical consequence of both primary and secondary hypogonadism, as well as testosterone decline in older males, on bone density and fracture risk in men will be summarized. Finally, the therapeutic options and their efficacy in male osteoporosis and hypogonadism will be discussed.

Predicting low testosterone in aging men: a systematic review.

Physicians diagnose and treat suspected hypogonadism in older men by extrapolating from the defined clinical entity of hypogonadism found in younger men. We conducted a systematic review to estimate the accuracy of clinical symptoms and signs for predicting low testosterone among aging men. We searched the MEDLINE and Embase databases (January 1966 to July 2014) for studies that compared clinical features with a measurement of serum testosterone in men. Three of the authors independently reviewed articles for inclusion, assessed quality and extracted data. Among 6053 articles identified, 40 met the inclusion criteria. The prevalence of low testosterone ranged between 2% and 77%. Threshold testosterone levels used for reference standards also varied substantially. The summary likelihood ratio associated with decreased libido was 1.6 (95% confidence interval [CI] 1.3-1.9), and the likelihood ratio for absence of this finding was 0.72 (95% CI 0.58-0.85). The likelihood ratio associated with the presence of erectile dysfunction was 1.5 (95% CI 1.3-1.8) and with absence of erectile dysfunction was 0.83 (95% CI 0.76-0.91). Of the multiple-item instruments, the ANDROTEST showed both the most favourable positive likelihood ratio (range 1.9-2.2) and the most favourable negative likelihood ratio (range 0.37-0.49). We found weak correlation between signs, symptoms and testosterone levels, uncertainty about what threshold testosterone levels should be considered low for aging men and wide variation in estimated prevalence of the condition. It is therefore difficult to extrapolate the method of diagnosing pathologic hypogonadism in younger men to clinical decisions regarding age-related testosterone decline in aging men.