Multifactorial basis for age-associated hypoandrogenemia in men

The Institute of Medicine recommended in 2004 that mechanistic studies be pursued to elucidate why testosterone (Te) availability declines with age, noting that neither the long-term safety nor the therapeutic benefit of androgen supplementation in healthy older men is established.

The World Health Organization has projected that both the absolute number and the proportion of men aged 60 years or older will increase substantially during the next 50 years in certain countries, such as the United States.

Johannes D. Veldhuis, M.D., Endocrinology, Mayo Clinic in Rochester, Minn., says: "Investigations of the causes of aging-associated hypogonadism have been stymied by major technical and paradigmatic hurdles." Technical challenges include the facts that:

  • Neuroendocrine adaptations unfold gradually and subtly as individuals age.
  • Unobservable changes in the hypothalamic release of gonadotropin-releasing hormone (Gn-RH) influence pituitary luteinizing hormone (LH) secretion, which in turn affects testicular Te synthesis.
  • Concentrations of Te and estradiol (E2) feed back negatively on both Gn-RH and LH signaling, thus creating a dynamic system. However, Gn-RH outflow and Te and E2 feedback are not directly observable, thus necessitating validated analytical tools to quantify the interlinked dynamics of the Gn-RH-LH-Te axis.

One successful approach comprises biomathematical constructs. Dr. Veldhuis explains: "Such models predict concomitant reductions in all three — Gn-RH secretion, LH-induced Te secretion, and Te negative feedback. Together, these factors may explicate the tetrad of low-amplitude and high-frequency LH pulses, irregular LH secretion patterns, and hypoandrogenemia in older men."

More particularly, clinical investigations at Mayo Clinic and elsewhere now suggest that advanced age results in:

  • Diminished amount of hypothalamic Gn-RH secreted in each pulse
  • Reduced stimulatory efficacy (maximal effect) of endogenous LH pulses and exogenous recombinant human LH pulses in driving Te secretion
  • Impairment of estrogen's feedback at the pituitary level while accentuating androgenic feedback on the hypothalamus

Low Te availability typically accompanies acute illness and chronic disease, which are further associated with increased cortisol and reduced insulinlike growth factor I (IGF-I) concentrations. Thus, changes in all three axes may confound interpretation of aging effects.

Dr. Veldhuis notes: "An unstudied possibility is that metabolic, inflammatory and lifestyle (sleep-deprivation) stressors inhibit Gn-RH-LH-Te secretion to a greater extent in older than young men. This unifying concept would link age-related failure of stress adaptations of the LH-Te, growth hormone IGF-I and corticotropin-cortisol axes."

Implications of testosterone deficiency in aging men

Impoverished Te production in older men has been documented by:

  • Direct sampling of the spermatic vein
  • Meta-analysis of cross-sectional data
  • Longitudinal investigations in healthy cohorts

Dr. Veldhuis highlights: "Cross-sectional data collected in healthy men in Olmsted County, Minn., verify the age-associated decrements in Te concentrations measured by tandem mass spectrometry.

"Interest is motivated by epidemiological associations among hypoandrogenemia and muscle weakness, sarcopenia, osteopenia, diminished physical stamina, erectile dysfunction, systolic hypertension, carotid artery thickness, increased abdominal visceral-fat mass, insulin resistance, reduced high-density lipoprotein cholesterol concentrations, postprandial somnolence, impaired quality of life, depressive mood, diminished working memory and decreased executive-cognitive function."

Dr. Veldhuis continues: "Among such postulated relationships, low Te availability correlates best with reduced grip strength, decreased lean-body mass, and increased visceral adiposity in meta-analyses. Moreover, these three pathophysiological features are markedly reversed by Te supplementation.

"Of note, certain medications, stress, diabetes mellitus, inflammation, sleep deprivation, acute illness, systemic disease and other comorbidities exacerbate androgen deficiency in aging populations. What is unknown is how such factors repress the Gn-RH-LH-Te axis in older men."

Dr. Veldhuis concludes: "Decreased Te and E2 concentrations accompany long-term institutionalization, critical illness, trauma, cardiovascular disease, human immunodeficiency virus and other infections, rheumatoid arthritis, systemic lupus erythematosus, lymphoproliferative disorders, surgery, burns, stroke, myocardial infarction, and sepsis.

"They also accompany chronic alcoholism, systemic inflammation, diabetes mellitus, the metabolic syndrome, malignancy, acute hypoglycemia, sleep deprivation, and aging. An emerging thesis is that aging disrupts joint neuroendocrine adaptations among Gn-RH, LH and Te and that multiple systemic illnesses exacerbate ensemble disruption."