Introduction
Clomiphene citrate is a selective estrogen receptor modulator (SERM) primarily used for the treatment of ovulatory dysfunction in women desiring pregnancy. First approved by the FDA in 1967, it remains one of the most commonly prescribed medications for infertility treatment worldwide. Clomiphene represents the first-line pharmacological intervention for anovulatory disorders, particularly in patients with polycystic ovary syndrome (PCOS).
Mechanism of Action
Clomiphene functions as a mixed estrogen agonist/antagonist that binds to estrogen receptors throughout the body, particularly in the hypothalamus. By competitively blocking estrogen receptors at the hypothalamic level, clomiphene disrupts the normal negative feedback loop of estrogen. This deception leads the hypothalamus to perceive low estrogen levels, resulting in increased pulsatile secretion of gonadotropin-releasing hormone (GnRH). The enhanced GnRH secretion stimulates the anterior pituitary to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which subsequently promote follicular development and ovulation.
Indications
FDA-approved indications:- Treatment of ovulatory dysfunction in women desiring pregnancy
- Criteria for appropriate use: Presence of ovulatory dysfunction with otherwise normal pelvic anatomy, normal partner semen analysis, and demonstrated estrogen production
- Male infertility (oligospermia)
- Controlled ovarian stimulation for assisted reproductive technologies
- Diagnostic tool for evaluating the hypothalamic-pituitary-ovarian axis
Dosage and Administration
Standard dosing:- Initial dose: 50 mg orally once daily for 5 days, starting on day 3, 4, or 5 of menstrual cycle
- Dose titration: May increase to 100 mg daily for 5 days in subsequent cycles if ovulation does not occur
- Maximum dose: 100 mg/day for 5 days; higher doses not recommended due to anti-estrogenic effects on endometrium
- Maximum duration: 3-6 cycles due to diminishing success rates and potential ovarian cancer risk
- Renal impairment: No dosage adjustment required
- Hepatic impairment: Use with caution; consider reduced dosing
- Geriatric patients: Not indicated for use
- Male patients: 25-50 mg daily for 25 days with 5-day rest or 50 mg every other day
Pharmacokinetics
Absorption: Rapidly absorbed following oral administration with bioavailability of approximately 70-80% Distribution: Widely distributed throughout the body with high affinity for estrogen-rich tissues; extensively protein bound (>99%) Metabolism: Hepatic metabolism via cytochrome P450 system (primarily CYP2D6 and CYP3A4) to active metabolites including zuclomiphene Elimination: Primarily fecal excretion (approximately 85%) with urinary excretion accounting for remainder; terminal half-life of clomiphene is 5-7 days while zuclomiphene persists for weeks Steady-state: Achieved after multiple doses due to accumulation of active metabolitesContraindications
- Pregnancy
- Liver disease or history of hepatic dysfunction
- Abnormal uterine bleeding of undetermined origin
- Ovarian cysts (not associated with PCOS)
- Uncontrolled thyroid or adrenal dysfunction
- Organic intracranial lesions (e.g., pituitary tumors)
- Hypersensitivity to clomiphene or any component of the formulation
Warnings and Precautions
Ovarian hyperstimulation syndrome (OHSS): Risk increases with higher doses and pre-existing PCOS; monitor for abdominal pain, distension, weight gain Multiple gestation: Approximately 8-10% risk of multiple pregnancy (mostly twins) Visual symptoms: Blurred vision, scotomas, photophobia may occur; discontinue if visual symptoms develop Ovarian enlargement: Common side effect that usually resolves spontaneously Long-term cancer risk: Possible association with borderline ovarian tumors with prolonged use (>12 cycles) Endometrial effects: Anti-estrogenic effects may lead to thin endometrial lining, potentially impairing implantation Ectopic pregnancy: Slightly increased risk reportedDrug Interactions
Strong CYP2D6 inhibitors (e.g., fluoxetine, paroxetine): May decrease conversion to active metabolites, potentially reducing efficacy Dopamine antagonists (e.g., metoclopramide): May diminish prolactin-lowering effect Thyroid hormones: Clomiphene may potentiate thyroid replacement effects Herbal supplements: St. John's wort may decrease serum concentrations Ethanol: Chronic use may reduce efficacyAdverse Effects
Common (>10%):- Hot flashes (10-20%)
- Ovarian enlargement (5-10%)
- Abdominal discomfort/bloating (5-10%)
- Breast tenderness (2-5%)
- Visual disturbances (1-2%)
- Nausea and vomiting
- Headache
- Abnormal uterine bleeding
- Dizziness
- Insomnia
- Ovarian hyperstimulation syndrome
- Ectopic pregnancy
- Ovarian torsion
- Visual changes (may persist)
Monitoring Parameters
Prior to initiation:- Comprehensive fertility evaluation
- Pregnancy test
- Assessment of ovarian morphology (ultrasound)
- Liver function tests
- Thyroid function assessment
- Basal body temperature charting
- Urinary LH surge detection kits
- Mid-luteal phase progesterone levels (to confirm ovulation)
- Follicular monitoring via transvaginal ultrasound (in selected cases)
- Endometrial thickness assessment
- Regular ovarian ultrasound to detect cysts or hyperstimulation
- Pregnancy testing
- Evaluation for OHSS symptoms if conception occurs
Patient Education
Key points to communicate:- Take medication exactly as prescribed at the same time each day
- Understand the timing of intercourse relative to ovulation (typically 5-10 days after last dose)
- Immediately report severe abdominal pain, bloating, nausea, vomiting, or visual changes
- Use ovulation prediction kits to identify fertile window
- Understand the increased possibility of multiple births
- Discontinue medication if pregnancy is suspected
- Keep scheduled monitoring appointments for optimal outcomes
- Be aware that success rates decline after 6 cycles of treatment
- Understand that not all ovulatory cycles will result in pregnancy
- Ovulation occurs in approximately 80% of women
- Pregnancy rate per cycle is approximately 20-40%
- Cumulative pregnancy rate after 3 cycles: ~50%
- Cumulative pregnancy rate after 6 cycles: ~70%
References
1. American College of Obstetricians and Gynecologists. (2019). Management of infertility in women with polycystic ovary syndrome. ACOG Practice Bulletin No. 194. 2. Legro, R. S., et al. (2014). Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. New England Journal of Medicine, 371(2), 119-129. 3. Practice Committee of the American Society for Reproductive Medicine. (2020). Use of clomiphene citrate in women. Fertility and Sterility, 114(2), 229-235. 4. Homburg, R. (2005). Clomiphene citrate—end of an era? A mini-review. Human Reproduction, 20(8), 2043-2051. 5. FDA Prescribing Information: Clomiphene Citrate Tablets. (2021). 6. Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. (2008). Consensus on infertility treatment related to polycystic ovary syndrome. Human Reproduction, 23(3), 462-477. 7. Mikkelson, T. J., et al. (1986). Single-dose pharmacokinetics of clomiphene citrate in normal volunteers. Fertility and Sterility, 46(3), 392-396.