Page 691 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 37 Hypothalamic & Pituitary Hormones 677

In the pharmacologic use of GnRH and its analogs, pulsa- An impaired LH response suggests hypogonadotropic hypogonad-
tile intravenous administration of gonadorelin every 1–4 hours ism due to either pituitary or hypothalamic disease, but does not
stimulates FSH and LH secretion. Continuous administration rule out constitutional delay of puberty.
of gonadorelin or its longer-acting analogs produces a biphasic
response. During the first 7–10 days, an agonist effect results B. Suppression of Gonadotropin Production
in increased concentrations of gonadal hormones in males and 1. Controlled ovarian stimulation—In the controlled ovar-
females; this initial phase is referred to as a flare. After this period, ian stimulation that provides multiple mature oocytes for assisted
the continued presence of GnRH results in an inhibitory action reproductive technologies such as in vitro fertilization, it is criti-
that manifests as a drop in the concentration of gonadotropins and cal to suppress an endogenous LH surge that could prematurely
gonadal steroids (ie, hypogonadotropic hypogonadal state). The trigger ovulation. This suppression is most commonly achieved by
inhibitory action is due to a combination of receptor downregula- daily subcutaneous injections of leuprolide or daily nasal applica-
tion and changes in the signaling pathways activated by GnRH.
tions of nafarelin. For leuprolide, treatment is commonly initiated
with 1 mg daily for about 10 days until menstrual bleeding occurs.
Clinical Pharmacology At that point, the dose is reduced to 0.5 mg daily until hCG is
administered (Figure 37–3). For nafarelin, the beginning dosage
The GnRH agonists are occasionally used for stimulation of is generally 400 mcg twice a day, which is decreased to 200 mcg
gonadotropin production. They are used far more commonly for when menstrual bleeding occurs.
suppression of gonadotropin release.
2. Endometriosis—Endometriosis is defined as the presence of
A. Stimulation estrogen-sensitive endometrium outside the uterus that results in
1. Female infertility—In the current era of widespread avail- cyclical abdominal pain in premenopausal women. The pain of
ability of gonadotropins and assisted reproductive technology, the endometriosis is often reduced by abolishing exposure to the cycli-
use of pulsatile GnRH administration to treat infertility is uncom- cal changes in the concentrations of estrogen and progesterone that
mon. Although pulsatile GnRH is less likely than gonadotropins are a normal part of the menstrual cycle. The ovarian suppression
to cause multiple pregnancies and OHSS, the inconvenience and induced by continuous treatment with a GnRH agonist greatly
cost associated with continuous use of an intravenous pump and reduces estrogen and progesterone concentrations and prevents
difficulties obtaining native GnRH (gonadorelin) are barriers to cyclical changes. The preferred duration of treatment with a GnRH
pulsatile GnRH. When this approach is used, a portable battery- agonist is limited to 6 months because ovarian suppression beyond
powered programmable pump and intravenous tubing deliver this period can result in decreased bone mineral density. When relief
pulses of gonadorelin every 90 minutes. of pain from treatment with a GnRH agonist supports continued
Gonadorelin or a GnRH agonist analog can be used to initi- therapy for more than 6 months, the addition of add-back therapy
ate an LH surge and ovulation in women with infertility who are (estrogen or progestins) reduces or eliminates GnRH agonist-
undergoing ovulation induction with gonadotropins. Tradition- induced bone mineral loss and provides symptomatic relief without
ally, hCG has been used to initiate ovulation in this situation. reducing the efficacy of pain relief. Leuprolide and goserelin are
However, there is some evidence that gonadorelin or a GnRH administered as depot preparations that provide 1 or 3 months of
agonist is less likely than hCG to cause OHSS. continuous GnRH agonist activity. Nafarelin is administered twice
daily as a nasal spray at a dose of 0.2 mg per spray.
2. Male infertility—It is possible to use pulsatile gonadorelin for
infertility in men with hypothalamic hypogonadotropic hypogo- 3. Uterine leiomyomata (uterine fibroids)—Uterine leio-
nadism. A portable pump infuses gonadorelin intravenously every myomata are benign, estrogen-sensitive, smooth muscle tumors
90 minutes. Serum testosterone levels and semen analyses must in the uterus that can cause menorrhagia, with associated anemia
be done regularly. At least 3–6 months of pulsatile infusions are and pelvic pain. Treatment for 3–6 months with a GnRH agonist
required before significant numbers of sperm are seen. As described reduces fibroid size and, when combined with supplemental iron,
above, treatment of hypogonadotropic hypogonadism is more com- improves anemia. The effects of GnRH agonists are temporary,
monly done with hCG and hMG or their recombinant equivalents. with gradual recurrent growth of leiomyomas to previous size
within several months after cessation of treatment. GnRH ago-
3. Diagnosis of LH responsiveness—GnRH may be useful nists have been used widely for preoperative treatment of uterine
in determining whether delayed puberty in a hypogonadotropic leiomyomas, both for myomectomy and hysterectomy. GnRH
adolescent is due to constitutional delay or to hypogonadotropic agonists have been shown to improve hematologic parameters,
hypogonadism. The LH response (but not the FSH response) shorten hospital stay, and decrease blood loss, operating time, and
to a single dose of GnRH may distinguish between these two postoperative pain when given for 3 months preoperatively.
conditions; however, there can be significant individual overlap
in the LH response between the two groups. Serum LH levels are 4. Prostate cancer—Androgen deprivation therapy is the
measured before and at several times after an intravenous or sub- primary medical therapy for prostate cancer. Combined antian-
cutaneous bolus of GnRH. An increase in serum LH with a peak drogen therapy with continuous GnRH agonist and an andro-
that is greater than 5–8 mIU/mL suggests early pubertal status. gen receptor antagonist is as effective as surgical castration in