DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1840 Finally, some clinicians use a long-cycle regimen, in which the estrogen
is administered continuously over a 3-month cycle and the progestin
is only added every third month.
Other therapies for vasomotor symptoms include phytoestrogens
(e.g., soy products), herbal extracts (e.g., black cohosh), selective
serotonin reuptake inhibitors (e.g., fluoxetine, controlled-release
paroxetine, sertraline), clonidine, and gabapentin (Nelson, 2008).
However, hormone replacement remains the most effective therapy
for vasomotor symptoms in menopausal women, and it is reasonable,
after a discussion of the relative risks and benefits, to consider
hormone replacement therapy in this setting. Current recommendations
advise using estrogen replacement at the lowest possible effective
dose and for the shortest duration to treat moderate to severe
vasomotor symptoms and vaginal dryness. For vaginal dryness
alone, topical preparations are preferred.
SECTION IX
SPECIAL SYSTEMS PHARMACOLOGY
Androgen Therapy. Based on the roles of androgens in normal
female physiology and the observed decrease in circulating androgen
levels after menopause, some have proposed that therapy with
androgens will improve parameters such as libido and sexual satisfaction.
Given the lack of a clearly defined disorder related to androgen
deficiency in women, the absence of long-term safety data, and
the lack of an approved formulation in a dose appropriate for
women, one panel of experts recently concluded that the routine
treatment of postmenopausal women with androgens was inappropriate
(Wierman et al., 2006).
Endometriosis
Endometriosis is an estrogen-dependent disorder that
results from endometrial tissue ectopically located outside
of the uterine cavity (Farquhar, 2007). It predominantly
affects women during their reproductive years,
with a prevalence of 0.5-5% in fertile women and 25-40%
in infertile women. Diagnosis typically is made at
laparoscopy, either prompted by unexplained pelvic pain
(dysmenorrhea or dyspareunia) or infertility. Although
poorly understood, the infertility is thought to reflect
involvement of the fallopian tubes with the underlying
process and, possibly, impaired oocyte maturation.
Inasmuch as the proliferation of ectopic endometrial
tissue is responsive to ovarian steroid hormones,
many symptomatic approaches to therapy aim to produce
a relatively hypoestrogenic state. Combination
oral contraceptives have been standard first-line treatment
for symptoms of endometriosis, and ample evidence
from observational trials supports their benefit.
The predominant mechanism of action is believed to be
suppression of gonadotropin secretion, with subsequent
inhibition of estrogen biosynthesis. Progestins (e.g.,
medroxyprogesterone, dienogest) also have been used
to promote decidualization of the ectopic endometrial
tissue. The levonorgestrel intrauterine system, which is
approved for contraception, also has been used off label
for this indication, as well as for menorrhagia.
As an alternative to steroid hormones, stable GnRH agonists
can suppress gonadotropin secretion and thus effect medical castration.
Drugs that carry an indication for endometriosis include leuprolide
(LUPRON), goserelin (ZOLADEX), and nafarelin (SYNAREL); other GnRH
agonists also may be used off label for this purpose (see Chapter 38).
Due to significant decreases in bone density and symptoms of estrogen
withdrawal, “add-back” therapy with either a low-dose synthetic
estrogen (e.g., conjugated equine estrogens, 0.625-1.25 mg) or a highdose
progestin (e.g., norethindrone, 5 mg) has been used when the
duration of therapy has exceeded 6 months (Olive, 2008). A number
of clinical trials have shown that such combination regimens can provide
symptomatic relief in patients with endometriosis. Danazol
(DANOCRINE), a synthetic androgen that inhibits gonadotropin production
via feedback inhibition of the pituitary-ovarian axis, also is FDAapproved
for endometriosis therapy; it rarely is used now because of
its significant adverse effects, including hirsutism and elevation of
hepatic transaminases. In Europe and elsewhere, the antiprogestin
gestrinone has been employed. By virtue of their ability to block the
terminal step in estrogen biosynthesis, inhibitors of aromatase are
under investigation for endometriosis (reviewed by Barbieri, 2008),
often in conjunction with GnRH agonists, combination oral contraceptives,
or a progestin.
When fertility is the goal, no medical therapy has proven efficacy,
and surgical approaches (e.g., laparoscopic excision of
endometriotic implants, lysis of adhesions) or assisted reproduction
technology (e.g., in vitro fertilization) should be considered.
Hirsutism
Hirsutism, or increased hair growth in the male distribution,
affects ~10% of women of reproductive age. It
can be a relatively benign, idiopathic process or part of
a more severe disorder of androgen excess that includes
overt virilization (voice deepening, increased muscle
mass, male pattern balding, clitoromegaly) and often
results from ovarian or adrenal tumors. Specific etiologies
associated with hirsutism include congenital adrenal
hyperplasia, polycystic ovary syndrome (PCOS),
and Cushing’s syndrome. After excluding serious
pathology such as a steroid-producing malignancy, the
treatment largely becomes empirical (Martin et al.,
2008). Nonpharmacological approaches include
bleaching, depilatory treatments (e.g., shaving, treatment
with hair-removing chemicals), or methods that
remove the entire hair follicle (e.g., plucking, electrolysis,
laser ablation).
Pharmacotherapy is directed at decreasing androgen
production and action. Initial therapy often involves
treatment with combination oral contraceptive pills,
which suppress gonadotropin secretion and thus the production
of ovarian androgens. The estrogen also
increases the concentration of sex hormone–binding
globulin, thereby diminishing the free concentration of
testosterone. The full effect of this suppression may take
up to 6-9 months. Some experts prefer combination oral