Androgens in Health and Disease.pdf - E Library

Chapter 21/Androgens and Male Contraception 409
of gonadotropins well when cetrorelix was discontinued (20). A derivative of 19-NT,
7α-methyl-19-nortestosterone (MENT; see Fig. 2D) is of considerable interest. The 7methylation
of this compound prevents 5α-reduction, effectively preventing the compound
from exhibiting any dihydrotestosterone (DHT)-like effects (21). DHT is thought
to stimulate prostate enlargement and blocking DHT production by the exogenous
administration of MENT could reduce the long-term risk of symptomatic prostate disease
and possibly prostate cancer. In addition, DHT is the T metabolite most closely
associated with acne and male-pattern baldness, so a contraceptive containing MENT
might have appeal to men for reasons other than contraception. Such noncontraceptive
health benefits have been well established with the estrogen/progesterone combined oral
contraceptive for women (a reduction in the risk of endometrial and ovarian cancer, acne,
and dysmennorhea) (22) and could significantly approve the appeal of a male hormonal
contraceptive to men.
In one recent study in castrated monkeys, MENT showed a 10-fold greater potency
(vs T) in terms of LH inhibition, but only a twofold greater potency at stimulating
prostate growth (23). Preliminary work on the pharmacokinetics of MENT has been
undertaken. Single injections of 2, 4, and 8 mg of micronized MENT injected intramuscularly
in healthy men have a short half-life, probably because that MENT does not
appear to bind to sex hormone-binding globulin (SHBG) (24). Subsequent studies with
MENT implants seem to have overcome this hurdle. In healthy men, MENT-acetate
implants suppressed serum T, DHT, and gonadotropins by 80–90% throughout a 1-mo
test period (25). A contraceptive study using MENT implants has been published in
abstract form and demonstrates that MENT is as effective as T in inducing azoospermia
(26). Combinations of MENT with a progestin may be promising.
Transdermal T patches for the treatment of male hypogonadism have been in use for
the last several years, but they have only recently been tested for male contraception. A
study combining 5.4 mg of T daily delivered via transdermal patch with the progestin
levonorgestrel was recently described (27). This combination, however, resulted in
azoospermia in only 2 of 11 men, and counts below 3 million sperm/mL in three others.
This low success rate was probably the result of the insufficient doses of T delivered by
the patch. Transdermal delivery of T is also hampered by the skin irritation caused by
the patches. In another study combining T patches with the progestin desogestrel (28),
24% of participants withdrew from the study because of skin irritation. The only reported
use of an androgen gel combined a DHT gel with the progestin levonorgestrel (29).
Contraceptive efficacy was poor with no individuals reaching azoospermia. In addition,
the DHT gel was found to be uncomfortable by the majority of subjects.
Recently, nonsteroidal androgenic compounds have been described (30,31). These
compounds can safely be administered orally to rats, and if safe in humans, they could
easily be incorporated into a contraceptive regimen. Further animal testing, however,
will be required before these compounds can be studied in humans.
GNRH ANALOGS AND TESTOSTERONE COMBINATIONS
The failure to achieve uniform azoospermia with T alone has led to the study of T
combined with second agents, such as GnRH analogs or progestins, to improve contraceptive
efficacy. The combination of T with the widely available GnRH agonists has
proven disappointing, but the use of GnRH antagonists remains promising. These GnRH