Clomiphene

Clomiphene citrate is a nonsteroidal triphenylethylene selective estrogen receptor modulator (SERM). It is a mixture of two geometric isomers, enclomiphene (trans) and zuclomiphene (cis), with zuclomiphene making up roughly 30% to 50%. It is FDA approved as 50 mg oral tablets (Clomid and generics). Compounded oral preparations are made pursuant to patient-specific prescriptions.

FDA-labeled indication: treatment of ovulatory dysfunction in women desiring pregnancy, including those with polycystic ovary syndrome, after exclusion of pregnancy, ovarian cysts, abnormal uterine bleeding and liver disease, and with adequate endogenous estrogen. It is not indicated for primary pituitary or ovarian failure.

Prescribers also use clomiphene off-label in men with secondary (hypogonadotropic) hypogonadism and in male-factor infertility, to raise endogenous gonadotropins and testosterone while maintaining spermatogenesis. Lake Hills also prepares clomiphene in combination with anastrozole or DHEA on prescription.

Clomiphene competes with estradiol at estrogen receptors in the hypothalamus, blocking negative feedback. GnRH pulse frequency rises, and the pituitary releases more LH and FSH. In women, this promotes follicular development and ovulation; in men, LH stimulates testicular testosterone production and FSH supports spermatogenesis.

Clomiphene also has weak estrogen agonist activity, mainly attributed to zuclomiphene, and antiestrogenic effects on the endometrium and cervical mucus. It has no androgenic, antiandrogenic or progestational activity.

Clomiphene is readily absorbed orally. It is metabolized in the liver, with CYP2D6 forming active hydroxylated metabolites of enclomiphene and CYP3A4 also contributing, and is excreted mainly in feces via bile with enterohepatic recirculation. The elimination half-life is about 5 days. Zuclomiphene is eliminated more slowly and accumulates with repeated dosing; radiolabeled drug has been detected in feces up to 6 weeks after a dose.

• Pregnancy.
• Hypersensitivity to clomiphene or any component.
• Liver disease or a history of liver dysfunction.
• Abnormal uterine bleeding of undetermined origin.
• Ovarian cysts or enlargement not due to polycystic ovary syndrome.
• Uncontrolled thyroid or adrenal dysfunction.
• An organic intracranial lesion such as a pituitary tumor.

• Visual symptoms: blurring, scotomata, phosphenes and afterimages can occur, and may be prolonged or persist. Discontinue and arrange an ophthalmologic evaluation; visual symptoms can make driving or operating machinery hazardous.
• Ovarian hyperstimulation syndrome and ovarian enlargement: use the lowest dose that produces ovulation, and withhold further courses until ovaries return to baseline size.
• Multiple pregnancy, mostly twins, is more frequent than in spontaneous conception.
• Prolonged use: an association with ovarian tumors has been suggested with extended treatment; labeling does not recommend use beyond about six courses.
• Hypertriglyceridemia, sometimes with pancreatitis, has been reported, particularly with pre-existing or familial hypertriglyceridemia or higher doses.
• Men: estradiol rises with gonadotropin stimulation and can cause breast tenderness or gynecomastia; hematocrit can rise; mood changes and, rarely, thromboembolic events have been reported.
• Use caution in patients with depression, psychosis or a history of thromboembolic disease.

No formal interaction studies are described in labeling. CYP2D6 inhibitors (for example paroxetine, fluoxetine, bupropion) and CYP2D6 genotype can alter exposure to clomiphene's active metabolites. Exogenous testosterone and anabolic steroids suppress the hypothalamic-pituitary-gonadal axis that clomiphene acts on.

In men, clomiphene is sometimes prescribed together with anastrozole, which lowers estradiol, or with DHEA, a sex-steroid precursor; combined use calls for monitoring of testosterone and estradiol rather than avoidance.

Women: hot flashes, ovarian enlargement, abdominal or pelvic discomfort and bloating, nausea and vomiting, breast discomfort, headache, abnormal uterine bleeding, visual symptoms and thinning of cervical mucus. Men: breast tenderness or gynecomastia, mood changes or irritability, headache, visual symptoms, acne and increased hematocrit. Rare: hepatic enzyme elevation, pancreatitis with hypertriglyceridemia, thromboembolism.

Contraindicated in pregnancy; pregnancy is excluded before each treatment course. Animal studies showed fetal harm at high doses. It is not known whether clomiphene is excreted in human milk, and clomiphene can reduce lactation; it is generally avoided during breastfeeding.

Women: pregnancy test and pelvic examination or ultrasound before each course, confirmation of ovulation, baseline liver function, and symptoms of ovarian enlargement or visual change. Men: total testosterone, estradiol, LH and FSH, hematocrit, lipids, liver function, PSA as appropriate for age, semen analysis when fertility is a goal, and mood and visual symptoms.

• Clomid (clomiphene citrate tablets USP) Prescribing Information.
• Evaluation and Management of Testosterone Deficiency: AUA Guideline. American Urological Association.
• AHFS Drug Information. American Society of Health-System Pharmacists.