Clomiphene
Clomiphene is a selective estrogen receptor modulator used to induce ovulation in selected women with anovulatory infertility. Taken as a 5-day course early in the menstrual cycle, typically under fertility specialist supervision.
- Chemical formula
- C26H28ClNO
- CAS number
- 911-45-5
- ATC code
- G03GB02
- Molecular weight
- 405.96 g/mol
- Drug class
- Selective estrogen receptor modulator (ovulation induction)
- Also known as
- Clomiphene citrate, MRL-41
What is it?
Clomiphene is a non-steroidal selective estrogen receptor modulator (SERM) approved in 1967 for the treatment of anovulatory infertility in selected women. It is one of the most widely used first-line ovulation induction agents and is on the WHO Essential Medicines List. The molecule is marketed under various brand names (Clomid, Serophene) with widely available authorised generics. Clomiphene treatment is typically initiated and monitored by a fertility specialist.
Mechanism of action
Clomiphene acts as a competitive antagonist of estrogen receptors at the hypothalamus, blocking the negative feedback that estrogen normally exerts on hypothalamic gonadotropin-releasing hormone production. The reduced negative feedback increases pituitary release of FSH and LH, which in turn stimulates ovarian follicle development and ovulation. The molecule's effect is most pronounced in women with intact hypothalamic-pituitary-ovarian axis function but anovulation due to functional disorders such as polycystic ovary syndrome.
Pharmacokinetics
After oral administration, clomiphene is rapidly absorbed and undergoes hepatic metabolism with enterohepatic recirculation. Peak plasma concentrations are reached within several hours. The molecule has a long terminal half-life (approximately 5 days for the trans-zuclomiphene isomer), with measurable concentrations persisting for weeks after a 5-day course. This prolonged exposure is part of the reason clomiphene is dosed in cycles rather than continuously. Elimination is primarily through faeces.
Indications
Clomiphene is approved for the treatment of anovulatory infertility in women with intact pituitary-ovarian function — particularly polycystic ovary syndrome (PCOS) — when other causes of infertility have been excluded or are being addressed. It is not indicated for women with primary ovarian failure, hypopituitarism, hyperprolactinaemia or untreated thyroid disease. According to fertility guidelines, clomiphene is one of several first-line ovulation induction options.
Safety profile
Common adverse effects include hot flashes, mood swings, breast tenderness, ovarian enlargement and visual disturbances (typically reversible on discontinuation). The most clinically important risks are multiple pregnancy (twin rate approximately 7-9%) and ovarian hyperstimulation syndrome (rare with clomiphene at standard doses). Persistent visual disturbances require discontinuation. According to the prescribing information, clomiphene should not be used for more than 6 cycles without re-evaluation.
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Frequently asked questions
How is clomiphene taken? ▾
Clomiphene is typically prescribed as a 5-day course starting on day 2 to 5 of the menstrual cycle, with doses ranging from 50mg to 150mg per day depending on prior response. According to fertility guidelines, the lowest effective dose is preferred. Ovulation typically occurs 5 to 10 days after the last clomiphene tablet. Response is monitored by basal body temperature charting, ovulation predictor kits, mid-luteal progesterone testing, or ultrasound monitoring depending on the clinical setting.
How effective is clomiphene for fertility? ▾
Approximately 70-85% of women with anovulatory infertility ovulate in response to clomiphene at adequate doses, with cumulative pregnancy rates of approximately 30-40% over 6 cycles in suitable candidates. According to fertility guidelines, clomiphene is most effective in women with PCOS and least effective in those with hypothalamic amenorrhea or premature ovarian failure. If pregnancy does not occur after 3-6 cycles of ovulatory clomiphene, alternative approaches should be considered.
What is the risk of multiple pregnancy with clomiphene? ▾
The twin rate with clomiphene is approximately 7-9%, higher than the spontaneous twin rate of about 1-2%. Triplets and higher-order multiples are rare but possible. According to fertility guidelines, monitoring with ultrasound during clomiphene cycles can identify when multiple follicles are developing, allowing the cycle to be cancelled if needed. Women considering clomiphene should be counselled about the increased multiple-pregnancy risk and the implications for prenatal care.
Why might clomiphene not work? ▾
Clomiphene resistance occurs in approximately 15-30% of women, particularly those with PCOS and higher BMI, insulin resistance or higher androgen levels. According to fertility guidelines, clomiphene-resistant women may benefit from letrozole, gonadotropin therapy, ovarian drilling or weight loss interventions. Other reasons for clomiphene failure include underlying causes of infertility (tubal, male factor) that clomiphene cannot address.
Are there long-term safety concerns with clomiphene? ▾
Clomiphene at standard doses (5-day cycles, up to 6 cycles) has a generally favourable long-term safety profile. Earlier concerns about increased ovarian cancer risk have not been confirmed in larger more recent studies. Persistent visual disturbances during treatment require discontinuation. According to current guidelines, clomiphene should not be used for more than 6 cycles without re-evaluation; longer courses are not associated with improved pregnancy outcomes.
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