What are the dosing regimen, contraindications, adverse effects, monitoring requirements, and alternative therapies for clomiphene citrate (Clomid) used to induce ovulation?

Clomiphene Citrate (Clomid): Clinical Guide

Primary Recommendation

Clomiphene citrate is the first-line oral agent for ovulation induction in anovulatory women with adequate endogenous estrogen levels, typically achieving ovulation in approximately 80% of patients, but should be limited to 6-12 treatment cycles and requires ultrasound monitoring of at least the first cycle to prevent multiple pregnancy and ovarian hyperstimulation. 1, 2, 3

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Indications

Clomiphene is indicated specifically for:

• Anovulatory infertility in normogonadotropic women (WHO Group II), particularly those with polycystic ovary syndrome, as recommended by ACOG 1, 4
• Women must have adequate endogenous estrogen levels (demonstrated by vaginal smears, endometrial biopsy, urinary estrogen assay, or bleeding response to progesterone) 2, 5
• Not recommended for functional hypothalamic amenorrhea unless estrogen levels have recovered, as evidence does not support its effectiveness in this population 6

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Contraindications

Absolute contraindications include:

• Pregnancy 2
• Ovarian cysts or enlargement (except in polycystic ovary syndrome) 2
• Abnormal vaginal bleeding until neoplastic lesions are excluded 2
• Liver disease, particularly decompensated cirrhosis 1, 7
• Hypogonadotropic hypogonadism with insufficient endogenous estrogen 1, 5
• Primary pituitary or ovarian failure 2

Relative contraindications:

• Uterine fibroids require caution due to potential enlargement 2
• Elevated body mass index is consistently associated with decreased response 3

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Dosing Regimen

Standard protocol:

• Start on cycle day 3-7 (typically day 5) after spontaneous or progestin-induced withdrawal bleeding 2
• Initial dose: 50 mg daily for 5 days 2, 8
• Dose escalation: Increase to 100 mg, then 150 mg daily (×5 days) in subsequent cycles for non-response or poor ovulatory response 2, 8
• Duration: Limit to 6-12 treatment cycles total (including 3 ovulatory cycles), as cumulative conception rates plateau by cycle 12 and prolonged use may increase ovarian tumor risk 2, 3, 4

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Monitoring Requirements

Essential monitoring includes:

• Pelvic examination prior to first and each subsequent treatment course to exclude ovarian enlargement 2
• Ultrasound monitoring of at least the first cycle to assess follicular response, choose appropriate dosing for subsequent cycles, and minimize risks of hyperstimulation and multiple pregnancy 3, 4
• Basal body temperature charting or other ovulation detection methods to confirm ovulation 2
• Endometrial biopsy should be performed prior to therapy in women of advancing age to exclude endometriosis and endometrial carcinoma 2

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Adverse Effects and Complications

Major risks:

• Multiple pregnancy: More triplets and higher-order pregnancies result from ovulation induction than IVF; ultrasound monitoring is critical 4
• Ovarian hyperstimulation syndrome (OHSS), particularly with multifollicular development 1, 7, 4
• Thinner endometrium compared to gonadotropin therapy, potentially impairing implantation 1, 5
• Altered serum lipid profile 1, 7
• Possible increased risk of borderline or invasive ovarian tumors with prolonged use beyond 12 cycles 3

Other adverse effects:

• Decreased libido, reduced energy, and mood alterations (less common with enclomiphene alternative) 1
• Poor cervical mucus due to antiestrogenic effects 9
• In males: testicular tumors and gynecomastia have been reported, though causality is unestablished 2

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Alternative Therapies

When clomiphene fails or is contraindicated:

• Letrozole (aromatase inhibitor): May be more effective than clomiphene with fewer antiestrogenic effects on endometrium and cervical mucus; does not deplete estrogen receptors and generally results in monoovulation 9
• Gonadotropin injections: Effective alternative for clomiphene-resistant patients 4
• Metformin and insulin-sensitizing drugs: Under evaluation for obesity, hyperandrogenemia, and insulin resistance in clomiphene-resistant patients 4
• Laparoscopic ovarian drilling: Appears as effective as gonadotropin therapy for clomiphene resistance 4
• Pulsatile GnRH therapy: Particularly for functional hypothalamic amenorrhea, with 80% ovulation rates 6

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Clinical Pitfalls and Caveats

Critical considerations:

• Weight reduction is essential in anovulatory women with elevated BMI before initiating therapy, as obesity is the only factor consistently associated with decreased response 3
• Do not use for male infertility, as there are no adequate studies demonstrating effectiveness 2
• Not recommended for combined therapy with other ovulation-inducing drugs or for IVF programs, as no standard regimen exists 2
• Increased LH immediately post-clomiphene predicts adverse pregnancy outcome in women who conceive 3
• Exclude other infertility factors (thyroid disorders, adrenal disorders, hyperprolactinemia, male factor) before attributing failure solely to clomiphene resistance 2