Male Hypogonadism. Part II: Etiology, Pathophysiology, and Diagnosis

A. Seftel


Int J Impot Res. 2006;18(3):223-228. 

In This Article


Effects of Testosterone on Sexual Function

It has been suggested that normal or low-normal T levels are necessary to maintain normal sexual function, whereas increases in fat-free and lean-tissue mass rise in a dose-dependent manner over the normal range of circulating T.[6,7]

In a recent study of androgen-deficient patients undergoing subdermal T implantation (T pellets), Handelsman's group determined thresholds for T and free T (FT) below which symptoms of androgen deficiency returned as T levels declined.[8] Reduced libido and lack of motivation and/or energy recurred when T reached approximately 280 ng/dl in patients with secondary (hypogonadotropic) hypogonadism and 337 ng/dl in patients with primary (hypergonadotropic) hypogonadism.

Testosterone appears to play a role in maintaining sexual function, especially libido, although androgen deficiency per se is infrequently the sole cause of ED in hypogonadal males, particularly elderly men.[9] Preclinical evidence suggests that T promotes erectile responses via both the central and peripheral nervous systems.[10,11,12] For instance, T modulates α-adrenergic (antierectile) sensitivity of cavernosal smooth muscle.[13]

Preclinical work in DM-prone rats also suggests that decreases in penile nitric oxide synthase (NOS) expression or activity associated with low serum androgens contribute to the pathophysiology of diabetic ED.[14] Other investigations have suggested that androgen deprivation blunts erectile responses via structural changes in the corpora that culminate in decreased blood storage (i.e. veno-occlusive dysfunction) without influencing NOS activity.[15]

In man, it is believed that androgens mediate nocturnal penile tumescence, whereas erectile responses to visual stimuli are androgen independent.[9,16] It has also been suggested that the influence of T on erectile function may be mediated partly via effects on genital sensitivity and that the T metabolite 5α-dihydrotestosterone may also play a role in maintaining erections.[17,18]

T levels in the corpora cavernosa and peripheral blood during transitions from penile flaccidity to tumescence and rigidity, and then detumescence were compared in healthy subjects and ED patients.[19] In healthy volunteers, T levels increased significantly in corporal blood during the transition from flaccidity (2.9 ng/ml) to tumescence (4.3 ng/ml; P<0.001) and rigidity (4.4 ng/ml), followed by a return to 3.5 ng/ml during detumescence. In ED patients, the rise in cavernous T was of lower magnitude: from 2.6 to 3.0 ng/ml during tumescence (P < 0.05). Similar patterns were observed with respect to T concentrations in peripheral blood.

The rise in cavernous T levels from flaccidity to tumescence was also somewhat more marked in patients with psychogenic rather than organic ED.[19] The investigators suggested that the difference between peripheral and cavernous T concentrations during the flaccid phase might serve as a useful marker of bioavailable T (BT) and T receptor density in corporal smooth muscle.[19]

Effects of Testosterone on Cognitive Function and Affect

Cognitive performance, including mental-rotation tasks, is related to androgen levels across the normal range in healthy volunteers.[20,21] In addition, certain studies have shown that androgen replacement enhances cognitive and language functions (but not memory).[22,23,24]

In vivo studies have also suggested that endogenous androgens confer potentially beneficial neuroprotective effects within the hippocampus and limit accumulation of β-amyloid protein—a central pathophysiologic defect in Alzheimer's disease.[25,26] In addition, a study of nondemented patients with Parkinson's disease demonstrated that the degrees of patient- and informant-reported apathy were inversely related to FT levels.[27]

On the other hand, Kenny and co-workers recently determined that intramuscular T (i.m. T) injections did not significantly affect a wide range of cognitive indices in elderly hypogonadal men with early cognitive impairment and BT<128 ng/dl.[28] I.m. T also did not affect activities of daily living or depression ratings.

In the Rancho Bernardo Study, depression rating scales were inversely related to BT levels (P=0.0007) irrespective of age, physical activity, or alterations in body weight.[29] Although certain elderly dysthymic men and patients with treatment-refractory depression have low T levels, there is no strong evidence that reduced T levels play a pivotal pathophysiologic role in major depression.

At the time of writing, there is insufficient evidence to recommend testosterone replacement therapy (TRT) as first-line therapy for major depressive disorder in men with hypogonadism, although adjunctive T treatment may enhance clinical outcomes in patients with treatment-refractory depression.[30,31,32,33] Moreover, certain elderly men report an enhanced sense of well-being on TRT,[34,35] although this may be an indirect effect of other physiologic changes.

Effects of Testosterone on Body Composition

Androgens may promote bone formation. In two recent studies of young healthy men, serum sex hormone binding globulin (SHBG) emerged as an independent positive predictor of bone turnover or BMD.[36,37] The decrease in bone mass with advancing age may be associated with declining insulin-like growth factor (IGF-1) levels as well as T concentrations.[38]

Partly by facilitating commitment of pluripotent mesenchymal cells, androgens may also foster skeletal-muscle hypertrophy and hence promote lean body mass.[39] Exogenous T increases satellite-cell populations within muscles, with attendant rises in numbers of myoblasts and large-myofiber myonuclei, as well as formation of larger motoneurons. On the other hand, data suggesting that reduced muscle strength in elderly men relates to reversible declines in androgen levels are conflicting.[38,40,41,42]

Androgens also attenuate adipogenesis in man. The effects of TRT on adipogenesis may differ in different anatomic regions. In a recent study of men randomized to a GnRH agonist together with i.m. testosterone enanthate (TE) injections at five doses over the range of 25-600 mg weekly,[7] lowering T levels was associated with increases in adipose-tissue stores, with particularly marked rises in subcutaneous depots. However, increasing T levels above baseline via i.m. T injections preferentially mobilized smaller, deeper i.m. adipose-tissue deposits. Overall fat mass was inversely correlated with TE doses across all sites.[7]