Chapter 26: Androgens & Estrogens Flashcards
ESTROGENS
Estradiol USED IN MANY COMBINATIONS
Estrone MENEST
Ethinyl estradiol USED IN MANY COMBINATIONS
Mestranol (w/norethindrone) NECON
1/50, NORINYL 1+50
SELECTIVE ESTROGEN-RECEPTOR
MODULATORS (SERMs)
Clomiphene CLOMID, SEROPHENE
Raloxifene EVISTA
Tamoxifen TAMOXIFEN, NOLVADEX
Toremifene FARESTON
PROGESTOGENS
Desogestrel USED IN MANY COMBINATIONS
Drospirenone (w/ethinyl estradiol)
BEYAZ, YAZ, YASMIN
Levonorgestrel MIRENA, NEXT CHOICE,
PLAN B ONE-STEP
Medroxyprogesterone PROVERA
Norelgestromin (w/ethinyl estradiol)
ORTHO EVRA
Norethindrone NOR-QD, ORTHO MICRONOR
Norethindrone acetate AYGESTIN
Norgestimate USED IN MANY COMBINATIONS
Norgestrel (w/ethinyl estradiol) LO/
OVRAL
Progesterone USED IN MANY COMBINATIONS
Ospemifene OSPHENA
Toremifene FARESTON
Dienogest (w/estradiol valerate)
NATAZIA
Etonogestrel (w/ethinyl estradiol)
Etonogestrel (subdermal)
Levonorgestrel MIRENA, NEXT CHOICE,
PLAN B ONE-STEP
Medroxyprogesterone PROVERA
Norelgestromin (w/ethinyl estradiol)
ORTHO EVRA
Norethindrone NOR-QD, ORTHO MICRONOR
Norethindrone acetate AYGESTIN
Norgestimate USED IN MANY COMBINATIONS
Norgestrel (w/ethinyl estradiol) LO/
OVRAL
Progesterone USED IN MANY COMBINATIONS
PROGESTERONE AGONIST/ANTAGONIST
Ulipristal acetate ELLA
PROGESTERONE ANTAGONIST
Mifepristone MIFEPREX
ANDROGENS
Danazol DANOCRINE
Fluoxymesterone ANDROXY
Oxymetholone ANADROL
Testosterone ANDRODERM, ANDROGEL,
AXIRON, FORTESTA, STRIANT, TESTIM, TESTOPEL
Testosterone enanthate DELATESTRYL
Methyltestosterone ANDROID, TESTRED,
Oxandrolone OXANDRIN
METHITEST
Testosterone cypionate
DEPO-TESTOSTERONE
Testosterone enanthate DELATESTRYL
ANTIANDROGENS
Bicalutamide CASODEX
EnzalutamideXTANDI
Finasteride PROPECIA, PROSCAR
Flutamide EULEXIN
Nilutamide NILANDRON
Dutasteride AVODART
ESTROGENS
Estradiol [ess-tra-DYE-ole], also known as 17β-estradiol, is the most
potent estrogen produced and secreted by the ovary. It is the principal
estrogen in premenopausal women. Estrone [ESS-trone] is a metabolite
of estradiol that has approximately one-third the estrogenic potency of
estradiol. Estrone is the primary circulating estrogen after menopause,
and it is generated mainly from conversion of androstenedione in peripheral
tissues. Estriol [ess-TRI-ole], another metabolite of estradiol, is significantly
less potent than is estradiol. It is present in significant amounts
during pregnancy, because it is the principal estrogen produced by the
placenta. A preparation of conjugated estrogens containing sulfate esters
of estrone and equilin (obtained from urine of pregnant mares) is an oral
preparation used for hormone replacement therapy. Plant-derived conjugated
estrogen products are also available. Synthetic estrogens, such
as ethinyl estradiol [ETH-ih-nil ess-tra-DYE-ole], undergo less first-pass
metabolism than do naturally occurring steroids and, thus, are effective
when administered orally at lower doses. Nonsteroidal compounds that
bind to estrogen receptors and exert either estrogenic or antiestrogenic
effects on target tissues are called selective estrogen receptor modulators
(SERMs). These include tamoxifen and raloxifene, among others.
A. Mechanism of action
After dissociation from their binding sites on sex hormone–binding
globulin or albumin in the plasma, steroid hormones diffuse across
the cell membrane and bind with high affinity to specific nuclear receptor proteins (Figure 26.2). The activated steroid–receptor complex
interacts with nuclear chromatin to initiate hormone-specific RNA
synthesis. This results in the synthesis of specific proteins that mediate
a number of physiologic functions. [Note: The steroid hormones
may elicit the synthesis of different RNA species in diverse target
tissues and, therefore, are both receptor and tissue specific.] Other
pathways that require these hormones have been identified that lead
to more rapid actions. For example, activation of an estrogen receptor
in the membranes of hypothalamic cells has been shown to couple to
a G protein, thereby initiating a second-messenger cascade. In addition,
estrogen-mediated dilation of coronary arteries occurs by the
increased formation and release of nitric oxide and prostacyclin in
endothelial cells.
B. Therapeutic uses
Estrogens are most frequently used for contraception and postmenopausal
hormone therapy (HT). Estrogens were previously widely used
for prevention of osteoporosis, but current guidelines recommend use
of other therapies such as alendronate (see Chapter 35) over estrogen.
Estrogens are also used for replacement therapy in premenopausal
patients who are deficient in this hormone. Estrogen deficiency
can be due to inadequate functioning of the ovaries (hypogonadism),
premature menopause, or surgical menopause.
1. Postmenopausal HT: The primary indication for estrogen therapy
in postmenopausal women is menopausal symptoms, such as
vasomotor instability (for example, “hot flashes” or “hot flushes”)
and vaginal atrophy (Figure 26.3). For women who have an intact
uterus, a progestogen is always included with the estrogen therapy,
because the combination reduces the risk of endometrial
carcinoma associated with unopposed estrogen. For women who
have undergone a hysterectomy, unopposed estrogen
therapy is recommended because progestins may unfavorably alter the
beneficial effects of estrogen on lipid parameters. [Note: The
amount of estrogen used in replacement therapy is substantially
less than the doses used in oral contraception. Thus, the adverse
effects of estrogen replacement therapy are usually less pronounced
than those seen in women taking estrogen for contraceptive
purposes.] Delivery of estradiol by transdermal patch or
gel is also effective in treating postmenopausal symptoms. Due
to concerns over the risks of HT (increased risk of cardiovascular
events and breast cancer), HT should be prescribed at the lowest
effective dose for the shortest possible time to relieve menopausal
symptoms. Women who only have urogenital symptoms,
such as vaginal atrophy, should be treated with vaginal rather
than systemic estrogen.
2. Contraception: The combination of an estrogen and progestogen
provides effective contraception via the oral, transdermal, or
vaginal route.
3. Other uses: Estrogen therapy mimicking the natural cyclic pattern,
and usually in combination with a progestogen, is instituted
to stimulate development of secondary sex characteristics in
young women with primary hypogonadism. Continued treatment
is required after growth is completed. Similarly, estrogen and progestogen
replacement therapy is used for women who have premature
menopause or premature ovarian failure.
Types of estrogens , metabolism & AE
- Naturally occurring estrogens: These agents and their esterified
or conjugated derivatives are readily absorbed through the
gastrointestinal tract, skin, and mucous membranes. Taken orally,
estradiol is rapidly metabolized (and partially inactivated) by the
microsomal enzymes of the liver. Micronized estradiol is available
and has better bioavailability. Although there is some first-pass
metabolism, it is not sufficient to lessen the effectiveness when
taken orally. - Synthetic estrogen analogs: These compounds, such as ethinyl
estradiol, mestranol [MES-trah-nole], and estradiol valerate,
are well absorbed after oral administration. Mestranol is quickly
demethylated to ethinyl estradiol, which is metabolized more slowly
than the naturally occurring estrogens by the liver and peripheral
tissues. Estradiol valerate is rapidly cleaved to estradiol and valeric
acid. Being fat soluble, they are stored in adipose tissue, from
which they are slowly released. Therefore, the synthetic estrogen
analogs have a prolonged action and a higher potency compared
to those of natural estrogens. - Metabolism: Estrogens are transported in the blood bound to
serum albumin or sex hormone–binding globulin. As mentioned
above, bioavailability of estrogen taken orally is low due to firstpass
metabolism. To reduce first-pass metabolism, the drugs may
be administered via the transdermal route (patch, topical gel, topical
emulsion, or spray), intravaginally (tablet, cream, or ring), or
by injection. They are hydroxylated in the liver to derivatives that are subsequently glucuronidated or sulfated. The parent drugs and
their metabolites undergo excretion into bile and are then reabsorbed
through the enterohepatic circulation. Inactive products are
excreted in urine.
D. Adverse effects
Nausea and breast tenderness are among the most common adverse
effects of estrogen therapy. In addition, the risk of thromboembolic
events, myocardial infarction, and breast and endometrial cancer is
increased with use of estrogen therapy. [Note: The increased risk of
endometrial cancer can be offset by including a progestogen along
with the estrogen therapy.] Other effects of estrogen therapy are
shown in Figure 26.4.
SERMS
SERMs are a class of estrogen-related compounds that display selective
agonism or antagonism for estrogen receptors depending on the tissue
type. This category includes tamoxifen, toremifene, raloxifene, clomiphene,
and ospemifene.
A. Mechanism of action
Tamoxifen [tah-MOKS-ih-fen], toremifene [tore-EM-i-feen], and raloxifene
[rah-LOX-ih-feen] compete with estrogen for binding to the
estrogen receptor in breast tissue. [Note: Normal breast growth is stimulated
by estrogens. Therefore, some breast tumors regress following
treatment with these agents.] In addition, raloxifene acts as an estrogen
agonist in bone, leading to decreased bone resorption, increased
bone density, and decreased vertebral fractures (Figure 26.5). Unlike
estrogen and tamoxifen, raloxifene does not have appreciable estrogen
receptor agonist activity in the endometrium and, therefore, does not
predispose to endometrial cancer. Raloxifene also lowers serum total
cholesterol and low-density lipoprotein (LDL). Clomiphene [KLOE-mifeen]
acts as a partial estrogen agonist and interferes with the negative feedback of estrogens on the hypothalamus. This effect increases the
secretion of gonadotropin-releasing hormone and gonadotropins,
thereby leading to stimulation of ovulation.
B. Therapeutic uses
Tamoxifen is currently used in the treatment of metastatic breast
cancer, or as adjuvant therapy following mastectomy or radiation for
breast cancer. Both tamoxifen and raloxifene can be used as prophylactic
therapy to reduce the risk of breast cancer in high-risk patients.
Raloxifene is also approved for the prevention and treatment of osteoporosis
in postmenopausal women. Clomiphene is useful for the treatment
of infertility associated with anovulatory cycles. Ospemifene is
indicated for the treatment of dyspareunia (painful sexual intercourse)
related to menopause.
C. Pharmacokinetics
The SERMs are rapidly absorbed after oral administration. Tamoxifen
is extensively metabolized by cytochrome P450 isoenzymes, including
formation of active metabolites via the CYP3A4/5 and CYP2D6
isoenzymes. [Note: Patients with a genetic polymorphism in CYP2D6
may produce less active metabolite, resulting in diminished activity of
tamoxifen.] Raloxifene is rapidly converted to glucuronide conjugates
through first-pass metabolism. These agents undergo enterohepatic
cycling, and the primary route of excretion is through the bile into feces.
D. Adverse effects
The most frequent adverse effects of tamoxifen and toremifene are hot
flashes and nausea. Due to its estrogenic activity in the endometrium,
endometrial hyperplasia and malignancies have been reported with
tamoxifen therapy. This has led to recommendations for limiting the
length of time on the drug for some indications. Because it is metabolized
by various CYP450 isoenzymes, tamoxifen is subject to many
drug interactions. [Note: Tamoxifen is also an inhibitor of CYP3A4 and
P-glycoprotein.] Some CYP450 inhibitors may prevent the formation
of active metabolites of tamoxifen and possibly reduce the efficacy
(for example, amiodarone, haloperidol, risperidone). Hot flashes and
leg cramps are common adverse effects with raloxifene. In addition,
there is an increased risk of deep vein thrombosis, pulmonary embolism,
and retinal vein thrombosis. Women who have a past or active
history of venous thromboembolic events should not take the drug.
Cholestyramine can significantly reduce the absorption of raloxifene,
and concurrent use should be avoided. Adverse effects of clomiphene
are dose related and include headache, nausea, vasomotor flushes,
visual disturbances, and ovarian enlargement. Use of clomiphene
increases the risk of multiple births (twins or triplets).
PROGESTOGEN
Progesterone, the natural progestogen, is produced in response to luteinizing
hormone (LH) by both females (secreted by the corpus luteum, primarily
during the second half of the menstrual cycle, and by the placenta) and by males (secreted by the testes). It is also synthesized by the adrenal
cortex in both sexes.
A. Mechanism of action
Progestogens exert their mechanism of action in a manner analogous
to that of the other steroid hormones. In females, progesterone promotes
the development of a secretory endometrium that can accommodate
implantation of a newly forming embryo. The high levels of
progesterone that are released during the second half of the menstrual
cycle (the luteal phase) inhibit the production of gonadotropin
and, therefore, prevent further ovulation. If conception takes place,
progesterone continues to be secreted, maintaining the endometrium
in a favorable state for the continuation of the pregnancy and reducing
uterine contractions. If conception does not take place, the release of
progesterone from the corpus luteum ceases abruptly. This decline
stimulates the onset of menstruation. Figure 26.6 summarizes the
hormones produced during the menstrual cycle.
B. Therapeutic uses of progestogens
The major clinical uses of progestogens are for contraception or
the treatment of hormone deficiency. For contraception, they are
often used in combination with estrogens. Progesterone by itself
is not used widely as a contraceptive therapy because of its rapid
metabolism, resulting in low bioavailability. Synthetic progestogens
(that is, progestins) used in contraception are more stable to firstpass
metabolism, allowing lower doses when administered orally.
These agents include desogestrel [des-oh-JES-trel], dienogest [dye-
EN-oh-jest], drospirenone [droe-SPY-re-none], levonorgestrel [leevoe-
nor-JES-trel], norethindrone [nor-ETH-in-drone], norethindrone
acetate, norgestimate [nor-JES-tih-mate], and norgestrel [nor-JEStrel].
Medroxyprogesterone [me-DROK-see-proe-JES-ter-one] acetate
is an injectable contraceptive, and the oral form is a common
progestin component of postmenopausal HT. Progestins are also
used for the control of dysfunctional uterine bleeding, treatment of
dysmenorrhea, and management of endometriosis and infertility.
C. Pharmacokinetics
A micronized preparation of progesterone is rapidly absorbed after
oral administration. It has a short half-life in the plasma and is almost
completely metabolized by the liver. The glucuronidated metabolite
is excreted primarily by the kidney. Synthetic progestins are less rapidly
metabolized. Oral medroxyprogesterone acetate has a half-life of
30 days. When injected intramuscularly or subcutaneously, it has a
half-life of about 40 to 50 days and provides contraceptive activity for
approximately 3 months. The other progestins have half-lives of 1 to
3 days, allowing for once-daily dosing.
D. Adverse effects
The major adverse effects associated with the use of progestins are
headache, depression, weight gain, and changes in libido (Figure
26.7). Progestins that are derived from 19-nortestosterone (for example,
norethindrone, norethindrone acetate, norgestrel, levonorgestrel) possess some androgenic activity because of their structural similarity
to testosterone and can cause acne and hirsutism. Less androgenic
progestins, such as norgestimate and drospirenone, may be preferred
in women with acne. Drospirenone may raise serum potassium
due to antimineralocorticoid effects, and concurrent use with other
drugs that increase potassium (for example, angiotensin-converting
enzyme inhibitors) may increase the risk of hyperkalemia.
E. Antiprogestin
Mifepristone [mih-feh-PRIH-stone] (also designated as RU-486) is a
progesterone antagonist with partial agonist activity. Administration of
this drug to females early in pregnancy usually results in abortion of
the fetus due to interference with the progesterone needed to maintain
pregnancy. Mifepristone is often combined with the prostaglandin
analog misoprostol (administered orally or intravaginally) to induce
uterine contractions. The major adverse effects are significant uterine
bleeding and the possibility of an incomplete abortion.
Contraceptives
A. Major classes of contraceptives
1. Combination oral contraceptives: Products containing a combination
of an estrogen and a progestin are the most common type
of oral contraceptives. Monophasic combination pills contain a
constant dose of estrogen and progestin given over 21 to 24 days.
Triphasic oral contraceptive products attempt to mimic the natural
female cycle and most contain a constant dose of estrogen with
increasing doses of progestin given over three successive 7-day
periods. [Note: The combination of estradiol valerate and dienogest
is available as a four-phasic oral contraceptive.] With most
oral contraceptives, active pills are taken for 21 to 24 days, followed
by 4 to 7 days of placebo, for a total regimen of 28 days.
Withdrawal bleeding occurs during the hormone-free (placebo)
interval. [Note: The most common estrogen in the combination pills
is ethinyl estradiol. The most common progestins are norethindrone,
norethindrone acetate, levonorgestrel, desogestrel, norgestimate,
and drospirenone.] These preparations are highly effective
in achieving contraception (Figure 26.9). Use of extended-cycle
contraception (84 active pills followed by 7 days of placebo) results
in less frequent withdrawal bleeding. A continuous oral contraceptive
product (active pills taken every day) is also available.
2. Transdermal patch: An alternative to combination oral contraceptives
is a transdermal patch containing ethinyl estradiol and
the progestin norelgestromin. One contraceptive patch is applied
each week for 3 weeks to the abdomen, upper torso, or buttock. No
patch is worn during the 4th week, and withdrawal bleeding occurs.
The transdermal patch has efficacy comparable to that of the oral
contraceptives, but it is less effective in women weighing greater
than 90 kg. Contraindications and adverse effects for the patch
are similar to those of oral contraceptives. Total estrogen exposure
with the transdermal patch may be significantly greater than that
seen with oral contraceptives. Increased exposure to estrogen may
increase the risk of adverse events such as thromboembolism.
3. Vaginal ring: An additional contraceptive option is a vaginal ring
containing ethinyl estradiol and etonogestrel. The ring is inserted
into the vagina and is left in place for 3 weeks and then removed.
No ring is used during the fourth week, and withdrawal bleeding
occurs. The contraceptive vaginal ring has efficacy, contraindications,
and adverse effects similar to those of oral contraceptives.
4. Progestin-only pills: Products containing a progestin only, usually
norethindrone (called a “mini-pill”), are taken daily on a continuous
schedule. Progestin-only pills deliver a low, continuous dosage
of drug. These preparations are less effective than combination
products (Figure 26.9), and they may produce irregular menstrual
cycles more frequently. The progestin-only pill may be used for
patients who are breast-feeding (unlike estrogen, progestins do not
have an effect on milk production), are intolerant to estrogen, are
smokers, or have other contraindications to estrogen-
containing
products.
5. Injectable progestin: Medroxyprogesterone acetate is a contraceptive
that is administered via intramuscular or subcutaneous
injection every 3 months. Weight gain is a common adverse effect.
Because this product provides high sustained levels of progestin,
many women experience amenorrhea with medroxyprogesterone
acetate. In addition, return to fertility may be delayed for several
months after discontinuation. Medroxyprogesterone acetate may contribute to bone loss and predispose patients to osteoporosis
and/or fractures. Therefore, the drug should not be continued for
more than 2 years unless the patient is unable to tolerate other
contraceptive options.
6. Progestin implants: After subdermal placement, the etonogestrel
implant offers contraception for approximately 3 years. The
implant is nearly as reliable as sterilization, and the effect is totally
reversible when surgically removed. Principal side effects of the
implant are irregular menstrual bleeding and headaches. The
etonogestrel implant has not been studied in women who weigh
more than 130% of ideal body weight and may be less effective in
this population.
7. Progestin intrauterine device: A levonorgestrel-releasing intrauterine
system offers a highly effective method of contraception for
3 to 5 years depending on the system. It is a suitable method of
contraception for women who desire long-term contraception and
those who have contraindications to estrogen therapy. It should be
avoided in patients with pelvic inflammatory disease or a history of
ectopic pregnancy.
8. Postcoital contraception: Postcoital or emergency contraception
reduces the probability of pregnancy after an episode of coitus
without effective contraception (Figure 26.10) to between 0.2% and
3%. Emergency contraception uses high doses of levonorgestrel
(preferred) or high doses of ethinyl estradiol plus levonorgestrel. For
maximum effectiveness, emergency contraception should be taken
as soon as possible after unprotected intercourse and preferably
within 72 hours. The progestin-only emergency contraceptive regimens
are generally better tolerated than the estrogen–progestin
combination regimens. An alternative emergency contraceptive is
the progesterone agonist/antagonist ulipristal [ue-li-PRIS-tal]. It is
indicated for emergency contraception within 5 days of unprotected
intercourse.
B. Mechanism of action
Estrogen provides a negative feedback on the release of LH and follicle-
stimulating hormone (FSH) by the pituitary gland, thus preventing
ovulation. Progestin also thickens the cervical mucus, thus hampering
the transport of sperm. Withdrawal of the progestin stimulates menstrual
bleeding during the placebo week.
C. Adverse effects
The incidence of adverse effects with oral contraceptives is determined
by the specific compounds and combinations used. The most
common adverse effects with estrogens are breast fullness, fluid
retention, headache, and nausea. Increased blood pressure may also
occur. Progestins may be associated with depression, changes in
libido, hirsutism, and acne. Although rare, thromboembolism, thrombophlebitis,
myocardial infarction, and stroke may occur with use of
oral contraceptives. These severe adverse effects are most common
among women who are over age 35 and smoke. The incidence of
cervical cancer may be increased with oral contraceptives, because women are less likely to use additional barrier methods of contraception
that reduce exposure to human papillomavirus (the primary
risk factor for cervical cancer). [Note: Oral contraceptives are associated
with a decreased risk of cervical and ovarian cancer.] Oral contraceptives
are contraindicated in the presence of cerebrovascular
and thromboembolic disease, estrogen-dependent neoplasms, liver
disease, and pregnancy. Combination oral contraceptives should
not be used in patients over the age of 35 who are heavy smokers.
Drugs that induce the CYP3A4 isoenzyme (for example, rifampin and
bosentan) may significantly reduce the efficacy of oral contraceptives.
Concurrent use of these agents with oral contraceptives should be
avoided, or an alternate barrier method of contraception should be
utilized. Antibiotics that alter the normal gastrointestinal flora may
reduce enterohepatic recycling of the estrogen component of oral
contraceptives, thereby diminishing the effectiveness. Patients should
be warned of the possible interaction between antibiotics and oral
contraceptives, along with the potential need for an alternate method
of contraception during antibiotic therapy.
Androgens
The androgens are a group of steroids that have anabolic and/or masculinizing
effects in both males and females. Testosterone [tess-TOSS-terone],
the most important androgen in humans, is synthesized by Leydig
cells in the testes and, in smaller amounts, by thecal cells in the ovaries
and by the adrenal gland in both sexes. Other androgens secreted by the
testes are 5α-dihydrotestosterone (DHT), androstenedione, and dehydroepiandrosterone
(DHEA) in small amounts. In adult males, testosterone
secretion by Leydig cells is controlled by gonadotropin-releasing hormone
from the hypothalamus, which stimulates the anterior pituitary gland to
secrete FSH and LH. Testosterone or its active metabolite, DHT, inhibits
production of these specific trophic hormones through a negative feedback
loop and, thus, regulates testosterone production (Figure 26.11).
The androgens are required for 1) normal maturation in the male, 2)
sperm production, 3) increased synthesis of muscle proteins and hemoglobin,
and 4) decreased bone resorption. Synthetic modifications of
the androgen structure modify solubility and susceptibility to enzymatic
breakdown (thus prolonging the half-life of the hormone) and separate
anabolic and androgenic effects.
A. Mechanism of action
Like the estrogens and progestins, androgens bind to a specific
nuclear receptor in a target cell. Although testosterone itself is the
active ligand in muscle and liver, in other tissues it must be metabolized
to derivatives, such as DHT. For example, after diffusing into the
cells of the prostate, seminal vesicles, epididymis, and skin, testosterone
is converted by 5α-reductase to DHT, which binds to the receptor.
B. Therapeutic uses
Androgenic steroids are used for males with primary hypogonadism
(caused by testicular dysfunction) or secondary hypogonadism (due
to failure of the hypothalamus or pituitary). Anabolic steroids can be used to treat chronic wasting associated with human immunodeficiency
virus or cancer. An unapproved use of anabolic steroids is to
increase lean body mass, muscle strength, and endurance in athletes
and body builders (see below). DHEA (a precursor of testosterone
and estrogen) has been touted as an antiaging hormone as well as a
“performance enhancer.” There is no definitive evidence that it slows
aging, however, or that it improves performance at normal therapeutic
doses. Danazol [DAH-nah-zole], a weak androgen, is used in the
treatment of endometriosis (ectopic growth of the endometrium) and
fibrocystic breast disease. [Note: Danazol also possesses antiestrogenic
activity.] Weight gain, acne, decreased breast size, deepening
voice, increased libido, and increased hair growth are among the
adverse effects.
C. Pharmacokinetics
1. Testosterone: This agent is ineffective orally because of inactivation
by first-pass metabolism. As with the other sex steroids,
testosterone is rapidly absorbed and is metabolized to relatively
or completely inactive compounds that are excreted primarily in
the urine. C17-esters of testosterone (for example, testosterone
cypionate or enanthate) are administered intramuscularly. [Note:
The addition of the esterified lipid makes the hormone more lipid
soluble, thereby increasing its duration of action.] Transdermal
patches, topical gels, and buccal tablets of testosterone are
also available. Figure 26.12 shows serum levels of testosterone
achieved by injection and by a transdermal patch in hypogonadal
men. Testosterone and its esters demonstrate a 1:1 relative ratio of
androgenic to anabolic activity.
2. Testosterone derivatives: Alkylation of the 17α position of testosterone
allows oral administration of the hormone. Agents such
as fluoxymesterone [floo-ox-ee-MESS-teh-rone] have a longer
half-life in the body than that of the naturally occurring androgen.
Fluoxymesterone is effective when given orally, and it has a 1:2
androgenic-to-anabolic ratio. Oxandrolone [ox-AN-droe-lone] is
another orally active testosterone derivative with anabolic activity
3 to 13 times that of testosterone. Hepatic adverse effects have
been associated with the 17α-alkylated androgens.
D. Adverse effects
1. In females: Androgens can cause masculinization, acne, growth
of facial hair, deepening of the voice, male pattern baldness,
and excessive muscle development. Menstrual irregularities may
also occur. Testosterone should not be used by pregnant women
because of possible virilization of the female fetus.
2. In males: Excess androgens can cause priapism, impotence,
decreased spermatogenesis, and gynecomastia. Cosmetic changes
such as those described for females may occur as well. Androgens
can also stimulate growth of the prostate.
3. In children: Androgens can cause abnormal sexual maturation
and growth disturbances resulting from premature closing of the
epiphyseal plates 4. General effects: Androgens can increase serum LDL and lower
serum high-density lipoprotein levels. Whether these changes in
the lipid profile predispose patients to heart disease is unknown.
Androgens can also cause fluid retention, leading to edema.
5. In athletes: Use of anabolic steroids (for example, DHEA) by
athletes can cause premature closing of the epiphysis of the long
bones, which stunts growth and interrupts development. High
doses taken by young athletes may result in reduction of testicular
size, hepatic abnormalities, increased aggression (“roid rage”),
major mood disorders, and other adverse effects described above
Antiandrogens
Antiandrogens counter male hormonal action by interfering with the
synthesis of androgens or by blocking their receptors. Finasteride [fin-
AS-ter-ide] and dutasteride [doo-TAS-ter-ride] inhibit 5α-reductase
resulting in decreased formation of dihydrotestosterone. These
agents are used for the treatment of benign prostatic hyperplasia (see
Chapter 32). Antiandrogens, such as flutamide [FLOO-tah-mide],
bicalutamide [bye-ka-LOO-ta-mide], enzalutamide [enz-a-LOO-tamide],
and nilutamide [nye-LOO-ta-mide], act as competitive inhibitors
of androgens at the target cell and are effective orally for the
treatment of prostate cancer (see Chapter 46).
