Книги фарма 2 / Bertram G. Katzung-Basic & Clinical Pharmacology(9th Edition)

Side effects of thyrotropin injections include nausea (11%), headache (7%), and asthenia (3%). Hyperthyroidism can occur in patients with significant metastases or residual normal thyroid. Thyrotropin has caused neurologic deterioration in 7% of patients with brain metastases.

Corticotropin-Releasing Hormone (CRH)

CRH is a hypothalamic hormone that stimulates release of ACTH and -endorphin from the pituitary.

Chemistry & Pharmacokinetics

Structure

Human CRH is a 41-amino-acid peptide. An analog of human CRH is sheep (ovine) CRH, which also contains 41 amino acids. These molecules differ in seven amino acids.

Absorption, Metabolism, and Excretion

CRH is administered intravenously. The first-phase half-lives of human and sheep CRH are 9 minutes and 18 minutes, respectively. The peptide is metabolized in various tissues, and less than 1% is excreted in the urine.

Pharmacodynamics

ACTH released by CRH stimulation of the pituitary subsequently stimulates the adrenal cortex to produce cortisol and androgens. Ovine CRH is more potent than human CRH.

Clinical Pharmacology

CRH is used only for diagnostic purposes. In Cushing's syndrome, CRH has been used to distinguish Cushing's disease from ectopic ACTH secretion. CRH generally elicits an increase in ACTH and cortisol secretion in Cushing's disease but usually not in the ectopic ACTH syndrome. However, exceptions occur frequently, making this test unreliable. A more reliable test depends on differential concentrations of ACTH. In patients with Cushing's disease, ACTH levels in blood drawn from the inferior petrosal sinuses draining the pituitary are more than 2.5 times higher than levels in simultaneously drawn peripheral venous blood. When tumors are associated with ectopic ACTH production, no such difference is observed. Concurrent administration of CRH (ovine) further improves the distinction between blood levels of ACTH when Cushing's disease is present.

Preparations & Dosage

Synthetic human and ovine CRH are available. Sheep CRH is used more frequently because of its longer half-life and slightly greater potency. CRH may be dissolved in water or dilute acid but not in saline. A dose of 1 mg/kg is used for diagnostic testing.

Toxicity

Intravenous bolus doses of 1 mg/kg produce transient facial flushing and, rarely, dyspnea.

Adrenocorticotropin (Corticotropin, ACTH, ACTH1–24)

Adrenocorticotropin is a peptide hormone produced in the anterior pituitary. Its primary endocrine function is to stimulate synthesis and release of cortisol by the adrenal cortex. Corticotropin can be used therapeutically, but a synthetic derivative is more commonly—and almost exclusively—used to assess adrenocortical responsiveness. A substandard adrenocortical response to exogenous corticotropin administration indicates adrenocortical insufficiency.

Chemistry & Pharmacokinetics

Structure

Human ACTH is a single peptide chain of 39 amino acids. The amino terminal portion containing amino acids 1–24 is necessary for full biologic activity. The remaining amino acids (25–39) confer species specificity. Synthetic human ACTH1–24 is known as cosyntropin. The amino terminal amino acids 1–13 are identical to melanocyte-stimulating hormone (-MSH), which has been found in animals but not in humans. In states of excessive pituitary ACTH secretion (Addison's disease or an ACTH-secreting pituitary tumor), hyperpigmentation—caused by the -MSH activity intrinsic to ACTH—may be noted.

ACTH from animal sources is assayed biologically by measuring the depletion of adrenocortical ascorbic acid that follows subcutaneous administration of the ACTH.

Absorption, Metabolism, and Excretion

Both porcine and synthetic corticotropin are given parenterally. Corticotropin cannot be administered orally because of gastrointestinal proteolysis.

The biologic half-lives of ACTH1–39 and ACTH1–24 are under 20 minutes. Tissue uptake occurs in the liver and kidneys. ACTH1–39 is transformed into a biologically inactive substance, probably by

modification of a side chain. ACTH is not excreted in the urine in significant amounts. The effects of long-acting repository forms of porcine corticotropin persist for up to 18 hours with a gelatin complex of the peptide and up to several days with a zinc hydroxide complex.

Pharmacodynamics

ACTH stimulates the adrenal cortex to produce glucocorticoids, mineralocorticoids, and androgens. ACTH increases the activity of cholesterol esterase, the enzyme that catalyzes the rate-limiting step of steroid hormone production: cholesterol pregnenolone. ACTH also stimulates adrenal hypertrophy and hyperplasia. When given chronically in pharmacologic doses, corticotropin causes increased skin pigmentation.

Clinical Pharmacology

Diagnostic Uses

ACTH stimulation of the adrenals will fail to elicit an appropriate response in states of adrenal insufficiency. A rapid test for ruling out adrenal insufficiency employs cosyntropin (see below). Plasma cortisol levels are measured before and either 30 minutes or 60 minutes following an intramuscular or intravenous injection of 0.25 mg of cosyntropin. A normal plasma cortisol response is a stimulated peak level exceeding 20 g/dL. A subnormal response indicates primary or secondary adrenocortical insufficiency that can be differentiated using endogenous plasma ACTH levels (which are increased in primary adrenal insufficiency and decreased in the secondary form).

An incremental rise in plasma aldosterone generally occurs in secondary but not primary adrenal insufficiency after cosyntropin stimulation.

ACTH stimulation may distinguish three forms of "late-onset" (nonclassic) congenital adrenal hyperplasia from states of ovarian hyperandrogenism, all of which may be associated with hirsutism. In patients with deficiency of 21-hydroxylase, ACTH stimulation results in an incremental rise in plasma 17-hydroxyprogesterone, the substrate for the deficient enzyme. Patients with 11-hydroxylase deficiency manifest a rise in 11-deoxycortisol, while those with 3-hydroxy- 5 steroid dehydrogenase deficiency show an increase of 17-hydroxypregnenolone in response to ACTH stimulation.

Therapeutic Uses

Corticotropin therapy has been virtually abandoned since it has no therapeutic advantage over direct administration of glucocorticoids.

Dosage

Cosyntropin is the preferred preparation for diagnostic use. The standard diagnostic test dose of 0.25 mg is equivalent to 25 units of porcine corticotropin. ACTH is rarely indicated but is available for use in doses of 10–20 units four times daily. Repository ACTH, 40–80 units, may be administered every 24–72 hours.

Toxicity & Contraindications

The toxicity of therapeutic doses of ACTH resembles that of the glucocorticoids (see Chapter 39: Adrenocorticosteroids & Adrenocortical Antagonists), with the added adverse effect of hyperandrogenism in women. The occasional development of antibodies to animal ACTH or to depot cosyntropin (a preparation not currently available in the USA) has produced anaphylactic reactions or refractoriness to ACTH therapy in a few individuals. Painful swelling occurs at the injection site more often with the zinc hydroxide depot preparation than with the gelatin preparation. Contraindications are similar to those of glucocorticoids. When immediate effects are desired, glucocorticoids are preferable.

There are virtually no adverse effects from diagnostic doses of cosyntropin.

Gonadotropin-Releasing Hormone (GnRH; Luteinizing Hormone-Releasing Hormone [LHRH];

Gonadorelin Hydrochloride)

GnRH is produced in the arcuate nucleus of the hypothalamus. GnRH is secreted into the hypothalamic-pituitary venous plexus and binds to cell surface receptors of the anterior pituitary gonadotroph cells. Pulsatile GnRH secretion is required to stimulate the gonadotroph cell to produce and release luteinizing hormone (LH) and follicle stimulating hormone (FSH).

Divergent production of the two gonadotropins is controlled by the frequency of GnRH pulses. In women, increasing levels of estradiol at midcycle have a positive feedback upon the hypothalamus that increases GnRH secretion, resulting in a sudden increase in LH secretion. This LH-surge induces the ovulation of the dominant ovarian follicle, with subsequent luteinization in the ovary that secretes progesterone; this changes the uterine proliferative endometrium to a secretory endometrium that is receptive to a fertilized ovum.

Ironically, sustained non-pulsatile administration of GnRH or GnRH analogs inhibits the release of FSH and LH by the pituitary in both women and men, resulting in hypogonadism.

Chemistry & Pharmacokinetics

Structure

GnRH is a decapeptide found in all mammals. It is derived from a precursor (proGnRH) with 92 amino acids. Pharmaceutical GnRH is synthetic. Analogs (eg, leuprolide, nafarelin, buserelin, goserelin, and histrelin) with D-amino acids at position 6 and with ethylamide substituted for glycine at position 10 are more potent and longer-lasting than native GnRH.

Absorption, Metabolism, and Excretion

GnRH may be administered intravenously or subcutaneously. GnRH analogs may be administered subcutaneously, intramuscularly, or via nasal spray. The half-life of intravenous GnRH is 4 minutes, and the half-lives of subcutaneous and intranasal GnRH analogs are 3 hours. Degradation occurs in the hypothalamus and pituitary. GnRH analogs have increased affinity for GnRH receptors and reduced susceptibility to degradation.

Pharmacodynamics

GnRH binds to receptors on pituitary gonadotrophs. Pulsatile intravenous administration of GnRH every 1–4 hours stimulates FSH and LH secretion. As noted above, GnRH administered continuously or GnRH analogs administered in depot formulations inhibit gonadotropin release.

Clinical Pharmacology

Diagnostic Uses

Delayed puberty in a hypogonadotropic adolescent may be due to a constitutional delay or to hypogonadotropic hypogonadism. The LH response (but not the FSH response) to GnRH can distinguish between these two conditions. Serum LH levels are measured before and then 15, 30, 45, 60, and 120 minutes after a 100 mg intravenous or subcutaneous bolus of GnRH. A peak LH response exceeding 15.6 mIU/mL is normal and suggests impending puberty, whereas an impaired LH response suggests hypogonadotropic hypogonadism due to either pituitary or hypothalamic disease (but may also be seen in constitutional delay of adolescence).

Therapeutic Uses

Stimulation

GnRH can stimulate pituitary function and is used to treat infertility caused by hypothalamic hypogonadotropic hypogonadism in both sexes. A portable battery-powered programmable pump and intravenous tubing allows pulsatile GnRH therapy every 90 minutes.

Suppression

Leuprolide, nafarelin, goserelin, and histrelin are GnRH analog agonists that induce hypogonadism when given continuously. Such GnRH agonists are used to treat prostate cancer, uterine fibroids, endometriosis, polycystic ovary syndrome, and precocious puberty. Many in vitro fertilization programs sequentially use a GnRH analog to suppress endogenous gonadotropin release, along with exogenous gonadotropins to achieve synchronous follicular development.

GnRH analog therapy for the purpose of producing pituitary suppression leads to a transient rise in sex hormone concentration during the first 2 weeks of treatment. This can be deleterious during treatment of prostate cancer, precocious puberty, and infertility.

Dosage: Gonadorelin (GnRH, Factrel)

Gonadorelin hydrochloride is available in a lyophilized powder that is reconstituted and injected either subcutaneously or intravenously.

Diagnostic Use

Gonadorelin has been used to test pituitary luteinizing hormone (LH) responsiveness. Administered as a 100 g test dose, the average times to peak LH levels are 34 minutes (men) or 72 minutes (women) following subcutaneous gonadorelin and 27 minutes (men) or 36 minutes (women) following intravenous gonadorelin. There is considerable individual variation in response.

Female Infertility

Gonadorelin is administered intravenously, 5 g every 90 minutes from a portable pump. The woman is followed carefully with serum estradiol levels, and an ovarian ultrasound examination is done weekly before refilling the GnRH pump. When an ovarian follicle reaches 14 mm in diameter, ovulation is induced with hCG, 5000 units subcutaneously, and the luteal phase is maintained with hCG, 1500 units every 3 days for 12 days.

Male Infertility

For male infertility caused by hypothalamic GnRH deficiency, gonadorelin treatment is begun only

after preparatory hCG injections continued for up to 1 year in men with prepubertal hypogonadotropic hypogonadism. A portable pump infuses gonadorelin intravenously every 90 minutes. Serum testosterone levels and semen analyses must be done regularly. At least 3–6 months of bolus infusions are required before significant numbers of sperm are seen. The preferable alternative to intravenous gonadorelin treatment is subcutaneously administered gonadotropins.

Dosage: Leuprolide (GnRH Analog, Lupron)

Leuprolide is available in solution for daily subcutaneous injection and in slow-release depot preparations in which leuprolide is lyophilized in microspheres given by intramuscular injection.

Endometriosis and Uterine Fibroids

Women with endometriosis receive treatment courses of 6 months' duration. Concomitant low-dose hormone replacement therapy has been reported to diminish bone loss without significantly decreasing clinical effectiveness. Women with uterine fibroids that are symptomatic (menorrhagia, anemia, pain) receive treatment courses of 3 months, by which time women have amenorrhea or reduced menorrhagia; uterine fibroids are reduced in size an average of 37%. Intramuscular depot preparations containing 3.75 mg (monthly) or 11.5 mg (every 3 months) are used.

Prostate Cancer

Leuprolide is usually used in depot form, 7.5 mg intramuscularly monthly, 22.5 mg intramuscularly at 84-day intervals, or 30 mg intramuscularly at 4-month intervals.

Central Precocious Puberty

Leuprolide aqueous solution is started at a dosage of 0.05 mg/kg body weight injected subcutaneously daily. If the clinical response is inadequate, the dose can be increased by increments of 0.01 mg/kg body weight. Pediatric depot preparations are also available. The dose can be titrated upward according to the endocrine response.

Leuprolide is indicated for treatment of central precocious puberty (onset of secondary sex characteristics before 8 years in girls or 9 years in boys). Prior to use, central precocious puberty must be confirmed by a puberty gonadotropin response to GnRH and a bone age at least 1 year beyond chronologic age. Pretreatment evaluation must also include sex steroid levels compatible with precocious puberty and not congenital adrenal hyperplasia; a hCG level to exclude a chronic gonadotropin-secreting tumor; an MRI of the brain to exclude an intracranial tumor; and an ultrasound examination of the adrenals and ovaries or testes to exclude a steroid-secreting tumor.

Dosage: Nafarelin (GnRH Analog, Synarel) Nasal Solution

Nafarelin is available as Synarel, a nasal preparation. The head should be tilted back and 30 seconds allowed to elapse between each spray. Nafarelin is rapidly absorbed by the nasal mucosa. Maximum serum levels occur in 10–40 minutes. Rhinitis is a common side effect. Sneezing should be avoided after administration. Nasal decongestants must not be used for 2 hours following each dose.

Endometriosis

Treatment is begun between days 2 and 4 of the menstrual cycle. The initial dose is one spray (0.1 mL, 0.2 mg) into one nostril in the morning and another spray into the opposite nostril in the

evening. Amenorrhea occurs in about 65%, 80%, and 90% of women at 2, 3, and 4 months of treatment, respectively. About 60% of women become symptom-free by the end of treatment, and of these, about 50% remain symptom-free 6 months after cessation of treatment. Withdrawal menstrual bleeding occurs commonly during the first 2 months of nafarelin therapy. If bleeding persists despite good patient compliance, the dosage may be increased to one spray into each nostril twice daily.

Central Precocious Puberty

The recommended initial daily dose of nafarelin for central precocious puberty is 1.6 mg/d. This is achieved with two unit dose sprays (each spray contains 0.1 mL, 0.2 mg) into each nostril twice daily. If adequate suppression of puberty is not achieved, the dose may be increased to 1.8 mg/d, given as 3 sprays (total) three times daily. Pretreatment evaluation and follow-up are the same as for leuprolide.

Uterine Fibroids

Nafarelin nasal spray has been used to shrink uterine fibroids and reduce menometrorrhagia, dysmenorrhea, and pelvic discomfort. Required doses range from 50 g to 400 g intranasally twice daily for 3–6 months.

Dosage: Goserelin (GnRH Analog, Zoladex) Implants

Goserelin acetate is available in the form of implantable cylinders, 1–1.5 mm in diameter, that are placed subcutaneously in the upper abdominal area. Goserelin is metabolized in the liver and excreted in the urine. Clearance is greater in women than in men. Stimulation of gonadotropins occurs in the first weeks of therapy, followed by suppression.

Endometriosis, Breast Cancer, and Dysfunctional Uterine Bleeding

Implants containing 3.6 mg of goserelin are injected subcutaneously every 28 days.

Prostate Cancer

Implants containing 10.8 mg goserelin are injected subcutaneously every 12 weeks.

Toxicity

GnRH (gonadorelin) may cause headache, light-headedness, nausea, and flushing. Local swelling often occurs at subcutaneous injection sites. Generalized hypersensitivity dermatitis has occurred after long-term subcutaneous administration. Rare acute hypersensitivity reactions include bronchospasm and anaphylaxis. Sudden pituitary apoplexy and blindness has been reported following administration of GnRH to a patient with a gonadotropin-secreting pituitary tumor.

GnRH analog (leuprolide, nafarelin, goserelin) treatment of women may cause hot flushes and sweats (89%) and headaches (29%). Depression, diminished libido, generalized pain, vaginal dryness, and breast atrophy may also occur. Ovarian cysts may develop within the first 2 months of therapy and generally resolve by 6 weeks, but may persist and require discontinuation of therapy. Osteoporosis may occur with prolonged use, so patients may be monitored with bone densitometry prior to repeated treatment courses. Cholesterol and triglyceride levels may rise. Contraindications include pregnancy and breast-feeding.

GnRH analog (leuprolide, goserelin) treatment in men causes serum testosterone levels to rise for about 1 week; this can precipitate pain in men with bone metastases. In men with vertebral metastases, initial growth of tumor can produce neurologic symptoms. It can also temporarily worsen symptoms of urinary obstruction. Within about 2 weeks, serum testosterone levels fall to the hypogonadal range. Other adverse effects in men include hot flushes and sweats (59%), edema (13%), gynecomastia, decreased libido, decreased hematocrit, and asthenia. For men with prostate cancer, GnRH agonists are often given together with an antiandrogen (see Chapter 40: The Gonadal Hormones & Inhibitors), which may exacerbate hypogonadal symptoms while reducing the risk of exacerbation of bone pain.

GnRH analog (leuprolide, nafarelin) treatment of children is generally well tolerated. However, temporary exacerbation of precocious puberty may occur during the first few weeks of therapy. Injection site reactions occur in about 5%. Nafarelin nasal spray may cause or aggravate sinusitis.

Dosage: Cetrorelix Acetate for Injection (GnRH Antagonist)

Cetrorelix is a synthetic decapeptide that reversibly binds to pituitary GnRH receptors without activating them. Cetrorelix thus inhibits the secretion of FSH and LH in a dose-dependent manner by competing with natural hypothalamic GnRH for pituitary cell surface receptors. At the doses used for in vitro fertilization, cetrorelix produces an immediate suppression of LH; this delays the LH surge and thus delays ovulation. At higher doses, cetrorelix also suppresses FSH secretion, thus inhibiting the secretion of estradiol from the ovaries.

Cetrorelix is absorbed rapidly following subcutaneous injection, with maximum plasma concentrations occurring 1–2 hours after administration. Following a subcutaneous dose of 3 mg, the duration of action is at least 4 days; daily administration of 0.25 mg maintains GnRH antagonism.

in VItro Fertilization (IVf)

GnRH antagonists produce less ovarian hyperstimulation during IVF than do GnRH analogs. Cetrorelix suppresses endogenous FSH and LH while recombinant FSH (rFSH) is being given to prepare the ova for ovulation-induction by hCG administration. Ovarian stimulation is commenced with rFSH on the second or third day of the menstrual cycle. When serum estradiol rises to levels that indicate sufficient ovarian stimulation (requiring 5–9 days), cetrorelix is administered subcutaneously in order to prevent a natural LH that could cause premature spontaneous ovulation, obviating laparoscopic harvest of the ova. Cetrorelix may be administered subcutaneously in a dose of 3 mg, followed by 0.25 mg daily if hCG stimulation has not been given within the next 4 days. Alternatively, cetrorelix may be given subcutaneously in doses of 0.25 mg subcutaneously daily, beginning on the fifth or sixth day of FSH stimulation and continued daily until hCG is administered.

Endometriosis

Cetrorelix has been given in doses of 3 mg by subcutaneous injection of a depot preparation once weekly for 8 weeks.

Uterine Fibroids

Cetrorelix has been given in doses of 3 mg by subcutaneous injection every 4 days for 2–4 weeks prior to surgery. Therapy is commenced on the first day of the menstrual cycle.

Follicle-Stimulating Hormone (FSH)

Follicle-stimulating hormone is a glycoprotein hormone consisting of two chains and, like LH, is produced by gonadotroph cells in the anterior pituitary. FSH and LH regulate gonadal function by increasing cAMP in the target gonadal tissue. FSH, like other pituitary glycoproteins, is composed of a common alpha subunit that promotes hormone action and a unique beta subunit that confers specificity. The principal function of FSH is to stimulate gametogenesis and follicular development in women and spermatogenesis in men. FSH acts on the immature follicular cells of the ovary and induces development of the mature follicle and oocyte. Both LH and FSH are needed for proper ovarian steroidogenesis. LH stimulates androgen production by these cells, and FSH stimulates androgen conversion into estrogens by the granulosa cells. In the testes, FSH acts on the Sertoli cells and stimulates their production of androgen-binding protein.

FSH has been commercially available since the 1960s. It was first extracted from the urine of postmenopausal women, which contains a substance with FSH-like properties (but with 4% of the potency) and an LH-like substance. This purified extract of FSH and LH, derived from the urine of postmenopausal women, remains available and is known as menotropins, or human menopausal gonadotropins (hMG). A purified preparation of human FSH, also extracted from the urine of postmenopausal women, contains virtually no LH and is know as urofollitropin, or urinary FSH (uFSH). In 1996, a synthetic modified form of FSH became available, known as follitropin alpha, or recombinant FSH (rFSH). Preparations of rFSH have batch-to-batch consistency and are free from possible urinary contaminants. The cost of rFSH is about three times that of hMG. It is controversial whether in vitro fertilization protocols using rFSH are significantly more successful than protocols using uFSH or hMG.

These preparations are used in states of infertility to stimulate ovarian follicle development in women and spermatogenesis in men. In both sexes, they must be used in conjunction with a luteinizing hormone, ie, human chorionic gonadotropin (hCG), to permit ovulation and implantation in women and testosterone production and full masculinization in men.

Pharmacokinetics

Over a 7- to 12-day course of daily hMG or urofollitropin administration (intended to mimic the follicular phase of the ovarian cycle in women with hypothalamic amenorrhea), FSH levels gradually rise to twice their baseline level. LH levels increase to 1.5 times their baseline with hMG, but they do not rise with urofollitropin.

Pharmacodynamics

Ovarian follicular growth and maturation will occur during hMG or FSH treatment of gonadotropin-deficient women. Ovulation requires administration of chorionic gonadotropin when adequate follicular maturation has occurred.

In men with gonadotropin deficiencies, pretreatment with chorionic gonadotropin produces external sexual maturation; addition of a subsequent course of hMG (or rFSH plus hCG) will stimulate spermatogenesis and lead to fertility.

Clinical Pharmacology

FSH or hMG are indicated for pituitary or hypothalamic hypogonadism with infertility. Anovulatory women with the following conditions may benefit from hMG: primary amenorrhea,

secondary amenorrhea, polycystic ovary syndrome, and anovulatory cycles. Both hMG and FSH are used by in vitro fertilization programs for controlled ovarian hyperstimulation.

Over 50% of men with hypogonadotropic hypogonadism become fertile after hMG or hCG/FSH administration.

Dosage

An ampule of menotropins contains 75 IU or 150 IU of FSH and an equal amount of LH. One international unit of LH is approximately equivalent to 0.5 IU of hCG. An ampule of urofollitropin contains 75 IU of FSH and less than 1 IU of LH. Human menopausal gonadotropins, FSH, and hCG are administered intramuscularly.

Women

In hypothalamic hypogonadism and for in vitro fertilization, one or two ampules are administered daily for 5–12 days until evidence of adequate follicular maturation is present. Serum estradiol levels should be measured and a cervical examination performed every 1 or 2 days. When appropriate follicular maturation has occurred, hMG or FSH is discontinued; the following day, hCG (5000–10,000 IU) is administered intramuscularly to induce ovulation.

Men

Following pretreatment with 5000 IU of hCG three times weekly for up to 12 months to achieve masculinization and a normal serum testosterone level, menotropins is administered as one ampule (75 units) three times weekly in combination with hCG, 2000 IU twice weekly. At least 4 months of combined treatment are usually necessary before spermatozoa appear in the ejaculate. If there is no response, the menotropins dose may be doubled. When adding menotropins to hCG therapy, the dose of hCG must be reduced to keep serum testosterone in the high normal range and avoid hyperandrogenism.

Toxicity & Contraindications

Overstimulation of the ovary with hMG can lead to uncomplicated ovarian enlargement in approximately 20% of patients. This usually resolves spontaneously. A more serious complication, the "hyperstimulation syndrome," occurs in 0.5–4% of patients. It is characterized by hMG-induced ovarian enlargement, ascites, hydrothorax, and hypovolemia, sometimes to the point of shock. Hemoperitoneum (from a ruptured ovarian cyst), fever, or arterial thromboembolism can occur. The frequency of multiple births is approximately 20%. A reported 25% incidence of spontaneous abortions may be due to earlier diagnosis of pregnancy in treated than in untreated patients, with recognition of very early abortion. There may, however, be abnormal development and premature degeneration of corpus luteum in some treated patients. Gynecomastia occasionally occurs in men. An association between ovarian cancer and fertility drugs has been reported (Spirtas et al, 1993). However, it is not known which, if any, fertility drugs are causally related to cancer.

Human menopausal gonadotropin, uFSH or rFSH should be administered only by a physician experienced in treating infertility. Before treatment of women, a thorough gynecologic evaluation must be performed to rule out uterine, tubal, or ovarian diseases as well as pregnancy. In cases of irregular bleeding, uterine cancer should be ruled out.

Luteinizing Hormone (LH) & Human Chorionic Gonadotropin (hCG)