Page 757 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 40 The Gonadal Hormones & Inhibitors 743

effects on maturation of central nervous system centers governing several well-documented applications. The treatment of advanced
sexual development, particularly in the female. Administration of prostatic carcinoma often requires orchiectomy or large doses of estro-
these drugs to pregnant women may lead to masculinization or gens to reduce available endogenous androgen. The psychological
undermasculinization of the external genitalia in the female and effects of the former and gynecomastia produced by the latter make
male fetus, respectively. Although the above-mentioned effects these approaches undesirable. As noted in Chapter 37, the GnRH
may be less marked with the anabolic agents, they do occur. analogs, such as goserelin, nafarelin, buserelin, and leuprolide acetate,
Sodium retention and edema are not common but must be produce effective gonadal suppression when blood levels are continu-
carefully watched for in patients with heart and kidney disease. ous rather than pulsatile (see Chapter 37 and Figure 40–6).
Most of the synthetic androgens and anabolic agents are
17-alkyl-substituted steroids. Administration of drugs with this ANTIANDROGENS
structure is often associated with evidence of hepatic dysfunction.
Hepatic dysfunction usually occurs early in the course of treat-
ment, and the degree is proportionate to the dose. Bilirubin levels The potential usefulness of antiandrogens in the treatment of
may increase until clinical jaundice is apparent. The cholestatic patients producing excessive amounts of testosterone has led to the
jaundice is reversible upon cessation of therapy, and permanent search for effective drugs that can be used for this purpose. Several
changes do not occur. In older males, prostatic hyperplasia may approaches to the problem, especially inhibition of synthesis and
develop, causing urinary retention. receptor antagonism, have met with some success.
Replacement therapy in men may cause acne, sleep apnea,
erythrocytosis, gynecomastia, and azoospermia. Supraphysiologic Steroid Synthesis Inhibitors
doses of androgens produce azoospermia and decrease in testicular Ketoconazole, used primarily in the treatment of fungal dis-
size, both of which may take months to recover after cessation of ease, is an inhibitor of adrenal and gonadal steroid synthesis, as
therapy. The alkylated androgens in high doses can produce pelio- described in Chapter 39. It does not affect ovarian aromatase, but
sis hepatica, cholestasis, and hepatic failure. They lower plasma it reduces human placental aromatase activity. It displaces estra-
HDL and may increase LDL. Hepatic adenomas and carcinomas diol and dihydrotestosterone from sex hormone-binding protein
have also been reported. Behavioral effects include psychological in vitro and increases the estradiol:testosterone ratio in plasma in
dependence, increased aggressiveness, and psychotic symptoms. vivo by a different mechanism. However, it does not appear to be
clinically useful in women with increased androgen levels because
Contraindications & Cautions of the toxicity associated with prolonged use of the 400–800 mg/d
required. The drug has also been used experimentally to treat pros-
The use of androgenic steroids is contraindicated in pregnant women
or women who may become pregnant during the course of therapy. tatic carcinoma, but the results have not been encouraging. Men
Androgens should not be administered to male patients with treated with ketoconazole often develop reversible gynecomastia
carcinoma of the prostate or breast. Until more is known about the during therapy; this may be due to the demonstrated increase in
effects of these hormones on the central nervous system in develop- the estradiol:testosterone ratio.
ing children, they should be avoided in infants and young children.
Special caution is required in giving these drugs to children to Inhibition of Conversion of Steroid
produce a growth spurt. In most patients, the use of somatotropin Precursors to Androgens
is more appropriate (see Chapter 37). Several compounds have been developed that inhibit the
Care should be exercised in the administration of these drugs to 17-hydroxylation of progesterone or pregnenolone, thereby
patients with renal or cardiac disease predisposed to edema. If sodium preventing the action of the side chain-splitting enzyme and
and water retention occurs, it will respond to diuretic therapy. the further transformation of these steroid precursors to active
Methyltestosterone therapy is associated with creatinuria, but androgens. A few of these compounds have been tested clini-
the significance of this finding is not known. cally but have been too toxic for prolonged use. As noted in
Caution: Several cases of hepatocellular carcinoma have been Chapter 39, abiraterone, a newer 17α-hydroxylase inhibitor,
reported in patients with aplastic anemia treated with androgen has been approved for use in metastatic prostate cancer.
anabolic therapy. Erythropoietin and colony-stimulating factors Since dihydrotestosterone—not testosterone—appears to be
(see Chapter 33) should be used instead. the essential androgen in the prostate, androgen effects in this
and similar dihydrotestosterone-dependent tissues can be reduced
ANDROGEN SUPPRESSION & by an inhibitor of 5α-reductase (Figure 40–6). Finasteride, a
ANTIANDROGENS steroid-like inhibitor of this enzyme, is orally active and causes a
reduction in dihydrotestosterone levels that begins within 8 hours
ANDROGEN SUPPRESSION after administration and lasts for about 24 hours. The half-life is
about 8 hours (longer in elderly individuals). About 40–50% of
In contrast to the lack of strong indications for the use of androgen the dose is metabolized; more than half is excreted in the feces.
supplementation (except in the case of hypogonadism), the use of Finasteride has been reported to be moderately effective in reduc-
inhibitors of androgen synthesis and of androgen antagonists has ing prostate size in men with benign prostatic hyperplasia and is