Page 687 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 37 Hypothalamic & Pituitary Hormones 673

The kidney appears to play an important role in its metabolism range in 97%. Pegvisomant does not inhibit GH secretion and
and excretion. may lead to increased GH levels and possible adenoma growth.
Somatostatin has limited therapeutic usefulness because of No serious problems have been observed; however, increases in
its short duration of action and multiple effects in many secre- liver enzymes without liver failure have been reported.
tory systems. A series of longer-acting somatostatin analogs that
retain biologic activity have been developed. Octreotide, the most THE GONADOTROPINS
widely used somatostatin analog (Figure 37–2), is 45 times more
potent than somatostatin in inhibiting GH release but only twice (FOLLICLE-STIMULATING HORMONE
as potent in reducing insulin secretion. Because of this relatively & LUTEINIZING HORMONE) & HUMAN
reduced effect on pancreatic beta cells, hyperglycemia rarely occurs CHORIONIC GONADOTROPIN
during treatment. The plasma elimination half-life of octreotide is
about 80 minutes, 30 times longer than that of somatostatin. The gonadotropins are produced by gonadotroph cells, which
Octreotide, 50–200 mcg given subcutaneously every 8 hours, comprise 7–15% of the cells in the pituitary. These hormones
reduces symptoms caused by a variety of hormone-secreting serve complementary functions in the reproductive process.
tumors: acromegaly, carcinoid syndrome, gastrinoma, gluca- In women, the principal function of FSH is to stimulate ovar-
gonoma, insulinoma, VIPoma, and ACTH-secreting tumor. Other ian follicle development. Both FSH and LH are needed for
therapeutic use indications include diarrhea—secretory, HIV asso- ovarian steroidogenesis. In the ovary, LH stimulates androgen
ciated, diabetic, chemotherapy, or radiation induced—and portal production by theca cells in the follicular stage of the menstrual
hypertension. Somatostatin receptor scintigraphy, using radiola- cycle, whereas FSH stimulates the conversion of androgens to
beled octreotide, is useful in localizing neuroendocrine tumors estrogens by granulosa cells. In the luteal phase of the menstrual
having somatostatin receptors and helps predict the response to cycle, estrogen and progesterone production is primarily under the
octreotide therapy. Octreotide is also useful for the acute control control first of LH and then, if pregnancy occurs, under the con-
of bleeding from esophageal varices. trol of human chorionic gonadotropin (hCG). Human chorionic
Octreotide acetate injectable long-acting suspension is a slow- gonadotropin is a placental glycoprotein nearly identical with LH;
release microsphere formulation. It may be instituted after a brief its actions are mediated through LH receptors.
course of shorter-acting octreotide has been demonstrated to be In men, FSH is the primary regulator of spermatogenesis,
effective and tolerated. Injections into alternate gluteal muscles are whereas LH is the main stimulus for testosterone synthesis in
repeated at 4-week intervals in doses of 10–40 mg. Leydig cells. FSH helps maintain high local androgen concen-
Adverse effects of octreotide therapy include nausea, vomit- trations in the vicinity of developing sperm by stimulating the
ing, abdominal cramps, flatulence, and steatorrhea with bulky production of androgen-binding protein in Sertoli cells. FSH
bowel movements. Biliary sludge and gallstones may occur after also stimulates the conversion by Sertoli cells of testosterone to
6 months of use in 20–30% of patients. However, the yearly estrogen that is also required for spermatogenesis.
incidence of symptomatic gallstones is about 1%. Cardiac effects FSH, LH, and hCG are available in several pharmaceutical
include sinus bradycardia (25%) and conduction disturbances forms. They are used in states of infertility to stimulate spermato-
(10%). Pain at the site of injection is common, especially with the genesis in men and to induce follicle development and ovulation
long-acting octreotide suspension. Vitamin B deficiency may in women. Their most common clinical use is for the controlled
12
occur with long-term use of octreotide. ovarian stimulation that is the cornerstone of assisted reproductive
A long-acting formulation of lanreotide, another octapeptide technologies such as in vitro fertilization (IVF, see below).
somatostatin analog, is approved for treatment of acromegaly.
Lanreotide appears to have effects comparable to those of octreo- Chemistry & Pharmacokinetics
tide in reducing GH levels and normalizing IGF-I concentrations.
All three hormones—FSH, LH, and hCG—are heterodimers that
share an identical α subunit in addition to a distinct β subunit
Pegvisomant that confers receptor specificity. The β subunits of hCG and
Pegvisomant is a GH receptor antagonist used to treat acromegaly. LH are nearly identical, and these two hormones are used inter-
It is the polyethylene glycol (PEG) derivative of a mutant GH, changeably. All the gonadotropin preparations are administered
B2036. Pegylation reduces its clearance and improves its overall by subcutaneous or intramuscular injection, usually on a daily
clinical effectiveness. Like native GH, pegvisomant has two GH basis. Half-lives vary by preparation and route of injection from
receptor binding sites. However, one of its GH receptor binding 10 to 40 hours.
sites has increased affinity for the GH receptor, whereas its second
GH receptor binding site has reduced affinity. This differential A. Menotropins
receptor affinity allows the initial step (GH receptor dimeriza- The first commercial gonadotropin product containing both FSH
tion) but blocks the conformational changes required for signal and LH was extracted from the urine of postmenopausal women.
transduction. In clinical trials, pegvisomant was administered This purified extract of FSH and LH is known as menotropins,
subcutaneously to patients with acromegaly; daily treatment for or human menopausal gonadotropins (hMG). From the early
12 months or more reduced serum levels of IGF-I into the normal 1960s, these preparations were used for the stimulation of follicle