Androgens in Health and Disease.pdf - E Library

326 Matsumoto
gen receptor and tissue-specific coactivator and corepressor proteins, an approach that
is being used to develop such compounds is to identify nonsteroidal, orally active selective
androgen-receptor modulators (SARMs), analogous to selective estrogen receptor
modulators (SERMs), such as raloxifene (69,70). Although SARMs may have selective
androgen actions on different target organs, they will probably not have intrinsic estrogen
activity. Unless specific SARMs do not suppress endogenous gonadotropin and E 2
secretion, administration of these compounds will probably produce a state of relative
estrogen deficiency, similar to that which occurs with the administration of nonaromatizable
androgens, such as DHT. Therefore, specific clinical indications (e.g.,
muscle-wasting syndromes) that take advantage of a SARMs unique tissue-selective
properties will need to be identified. Carefully performed studies of their clinical benefits
and risks will need to be performed, with attention to effects on target organs (e.g.,
bone) that are normally mediated, in part, by aromatization of T to E 2.
Another approach used to develop a “designer” androgen is to identify an androgen that
undergoes aromatization to an estrogen but, unlike T, not does not undergo 5α-reduction
to a more potent androgen. One such androgen that was synthesized over 20 yr ago is 7αmethyl-19-nortestosterone,
also known as MENT (71). In orchidectomized monkeys,
compared to T, MENT is 10 times more potent in stimulating body weight gain and
suppressing gonadotropins but only twice as potent in stimulating prostate growth (72).
In hypogonadal men, two subcutaneous MENT acetate implants maintain stable MENT
concentrations, sexual function, and mood for 6 wk (73). However, longer-term effects
on body composition (muscle and fat mass and bone mineral density) relative to its effects
on prostate size have not been evaluated fully.
POTENTIAL RISKS OF T TREATMENT AND MONITORING
Androgen treatment is absolutely contraindicated in men with prostate cancer and
breast cancer (16). Because these are androgen-dependent malignancies, T treatment may
stimulate tumor growth. This has been demonstrated most definitively in men with metastatic
prostate cancer in whom rapid growth and expansion of metastatic tumors may
cause worsening of severe bone pain or spinal cord compression. Prior to initiating
T-replacement therapy, a careful breast examination for masses should be performed in
all hypogonadal men, and digital rectal examination (DRE) for a prostate nodule or
induration should be performed in middle-aged and older men with androgen deficiency.
Measurement of serum prostate-specific antigen (PSA) is useful in men at higher risk for
prostate carcinoma (e.g., older men) and those with an abnormal DRE or family history
of prostate cancer.
Relative contraindications to androgen therapy include patients with untreated obstructive
sleep apnea in whom T treatment may worsen sleep-disordered breathing and associated
oxygen desaturation, men with significant erythrocytosois at baseline in whom further
stimulation of erythropoiesis may result in hyperviscosity and vascular complications, and
patients with severe edematous states (e.g., severe congestive heart failure, nephrotic
syndrome, or hepatic cirrhosis) in whom fluid retention associated with T treatment may
worsen edema.
In general, androgen-replacement therapy using either T ester injections or transdermal
T formulations are tolerated very well and serious adverse effects are rare (16).
Acne and increased oiliness of the skin is relatively common in patients receiving T