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aging in men is associated with decreases in bone mineral density (BMD) (18, 19), lean body and muscle mass

strength (22, 23) and aerobic capacity (24), as well as with increases in total and abdominal body fat, low-density lipoprotein cholesterol, and/or low-density lipoprotein/high-density lipoprotein cholesterol ratios (25, 26, 27, 28), all of which also occur in nonelderly hypogonadal men

Most (1, 5, 6, 7, 8, 9), but not all (10, 11, 12), cross-sectional studies have demonstrated a decrease, with age, in total T in men

total T, but not free T index, tended to decrease with greater BMI is consistent with prior studies showing that obesity is associated with decreases in both SHBG and total T, with an unchanged T-to-SHBG ratio

The decrease in free T index was somewhat steeper than that of total T, owing to a trend for an increase in SHBG with age

both T and free T index (a calculated value related to free or bioavailable T) decreased progressively at a rate that did not vary significantly with age, from the third to the ninth decades.

contrasts with other studies showing diminished free, as well as total, T in with increasing total (48) or abdominal (49) obesity in men.

Our analysis of date-adjusted T and free T index levels, by decade, showed that relatively high numbers of older men in this generally healthy population had at least one hypogonadal value (defined as below the 2.5th percentile for young men)

The issue of how properly to define hypogonadism, or indeed any hormone deficiency, remains problematic

The conventional definition for T levels is statistical (values more than 2 sd below the mean), rather than functional. Such a definition does not reflect clinical realities, such as the existence of characteristic individual set points for circulating hormone levels, below which one, but not another, individual may develop metabolic changes of hormone deficiency; nor does it address the concept of reserve capacity, the possibility that persons with hormone levels 2 sd below the population mean still may have adequate hormone concentrations to meet their metabolic needs.

LH for gonadal function

It would clearly be better to define the lower limit of normal for a hormone as: the blood level at which metabolic and/or clinical sequelae of hormone deficiency begin to appear, or the level below which definite benefits can be demonstrated for hormone supplementation for a significant proportion of the population

an effect of aging to lower both total and bioavailable circulating T levels at a relatively constant rate, independent of obesity, illness, medications, cigarette smoking, or alcohol intake

The Boston Area Community Health Study reported that 5.6% of men aged 30 to 70 were hypogonadal, as defined by total serum T < 300 ng/dL; or, free serum T < 5 ng/dL plus 3 or more symptoms of hypogonadism

In a health screening project among 819 men in Taiwan, the prevalence of hypogonadism (total serum T < 300 ng/dL) ranged from 16.5% for men in their 40s, 23.0% for men in their 50s, 28.9% for men in their 60s, and 37.2% for men older than 70 years of age

The prevalence of hypogonadism among men in Taiwan is higher than the prevalence reported in the Massachusetts Male Aging Study

CAG repeat sequence, within the androgen receptor (AR). Rajender et al[12] reviewed over 30 studies on the AR trinucleotide repeat and infertility

suggestion that CAG repeat length may determine androgen responsiveness, this issue is not clearly settled

reported prevalence of low T in older men range from 5.6% to 50%

Those in the hypogonadal group (n = 4269) had direct health care costs, that exceeded the eugonadal group (n = 4269) by an average of $7100 over the course of the observation window

higher economic burden and presence of co-morbidities for hypogonadism

minor to moderate improvements in lean mass and muscle strength

increased bone mineral density

modest enhancement in sexual function

reduced adiposity

lessening of depressive symptoms

Meta-analyses of clinical TRT trials as of 2010 have identified three major adverse events resulting from TRT: (1) polycythemia; (2) an increase in prostate-related events; and (3) and a slight reduction in serum high-density lipoprotein (HDL) cholesterol

polycythemia (> 3.5-fold increase in risk

TRT produced a 40% prostate enlargement in older hypogonadal male Veterans over 12 mo

no published analysis has reported measurable increases in prostate cancer risk or Gleason score in men undergoing TRT, or in hypogonadal men with a history of prostate cancer undergoing TRT

the prostate which highly expresses the type II 5α-reductase enzyme. Inhibition of this enzyme via finasteride (a type II 5α-reductase inhibitor) or dutasteride (a dual type I and II 5α-reductase inhibitor) reduces circulating DHT 50%-75% and > 90%, respectively[47], and reduces prostate mass[48] and prostate cancer risk

Normally estradiol partially regulates testosterone levels, at the hypothalamus, blunting LH and FSH release from the pituitary. As a selective estrogen receptor modulator, CC interrupts this pathway, and consequently there is a greater stimulation for the production of testosterone in Leydig cells

Bioavailable and free testosterone are known to correlate better than total testosterone with clinical sequelae of androgenization such as bone mineral density and muscle strength

peak levels seen in the morning following sleep, which can be maintained into the seventh decade

Samples should always be taken in the morning before 11 am

The reliable measurement of serum free testosterone requires equilibrium dialysis. This is not appropriate for clinical use as it is very time consuming and therefore expensive.

With increasing age, a greater number of men have total testosterone levels just below the normal range or in the low-normal range. In these patients total testosterone can be an unreliable indicator of hypogonadal status.

It is advised that at least two serum testosterone measurements, taken before 11 am on different mornings, are necessary to confirm the diagnosis.

Patients with serum total testosterone consistently below 8 nmol/l invariably demonstrate the clinical syndrome of hypogonadism and are likely to benefit from treatment. Patients with serum total testosterone in the range 8–12 nmol/l often have symptoms attributable to hypogonadism and it may be decided to offer either a clinical trial of testosterone treatment or to make further efforts to define serum bioavailable or free testosterone and then reconsider treatment. Patients with serum total testosterone persistently above 12 nmol/l do not have hypogonadism and symptoms are likely to be due to other disease states or ageing per se so testosterone treatment is not indicated.

Total testosterone levels fall at an average of 1.6% per year whilst free and bioavailable levels fall by 2%–3% per year.

With advancing age there is also a reduction in androgen receptor concentration in some target tissues and this may contribute to the clinical syndrome of LOH

Metabolic clearance declines with age

Gonadotrophin levels rise during aging (Feldman et al 2002) and testicular secretory responses to recombinant human chorionic gonadotrophin (hCG) are reduced

There are changes in the lutenising hormone (LH) production which consist of decreased LH pulse frequency and amplitude, (Veldhuis et al 1992; Pincus et al 1997) although pituitary production of LH in response to pharmacological stimulation with exogenous GnRH analogues is preserved

the decreases in testosterone levels with aging seem to reflect changes at all levels of the hypothalamic-pituitary-testicular axis