Clomiphene

Usage

Clomiphene citrate is primarily used to treat infertility in women who are unable to ovulate or have infrequent ovulation. It belongs to the selective estrogen receptor modulator (SERM) class of medications. Clomiphene works by blocking estrogen receptors at the hypothalamus and pituitary gland, which reduces negative feedback inhibition and increases the release of gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). The increased FSH and LH levels stimulate the ovaries to develop and release mature eggs.

Alternate Names

Clomiphene is also known as clomiphene citrate. Brand names for clomiphene include Clomid and Serophene.

How It Works

Pharmacodynamics: Clomiphene primarily exerts its effect by acting as a partial agonist at estrogen receptors in the hypothalamus, reducing the normal negative feedback mechanism. It leads to increased pulsatile secretion of GnRH, subsequently causing elevated levels of FSH and LH from the anterior pituitary. This hormonal cascade stimulates follicular growth and maturation within the ovaries, culminating in ovulation.

Pharmacokinetics: Clomiphene is well-absorbed orally. It is metabolized in the liver and has several active metabolites, including zuclomiphene and enclomiphene, which contribute to its long half-life, estimated to be around 5-7 days. Elimination occurs mainly through the biliary route, with a smaller percentage being excreted through the kidneys.

Mode of Action/Receptor Binding: Clomiphene primarily binds to estrogen receptors in the hypothalamus and pituitary. Although categorized as a SERM, clomiphene acts more as an antagonist in these tissues, occupying estrogen receptors and inhibiting estrogen’s negative feedback on GnRH release.

Dosage

Standard Dosage

Adults:

The initial recommended dose is 50 mg orally once daily for five days, typically starting on the fifth day of the menstrual cycle. If ovulation doesn’t occur, the dose can be increased to 100 mg daily for five days in subsequent cycles. It’s crucial to confirm the absence of pregnancy before starting a new cycle.

Children:

Clomiphene is not indicated for use in children.

Special Cases:

• Elderly Patients: Use with caution.
• Patients with Renal Impairment: Dose adjustment might be necessary, though specific guidelines are limited. Monitor renal function.
• Patients with Hepatic Dysfunction: Contraindicated in patients with active liver disease or a history of liver dysfunction.
• Patients with Comorbid Conditions: Pre-existing conditions like polycystic ovary syndrome (PCOS) might require lower doses or shorter durations of treatment due to increased sensitivity to gonadotropins and a higher risk of ovarian hyperstimulation syndrome (OHSS). Patients with hyperlipidemia should be monitored closely due to the potential for clomiphene to increase triglyceride levels.

Clinical Use Cases

Clomiphene’s clinical use is primarily focused on ovulation induction in infertile women. It’s not indicated for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.

Dosage Adjustments

Dosage adjustments might be required for individuals with PCOS or those who experience significant side effects. Lower doses (12.5–25 mg) can be considered in women sensitive to the drug.

Side Effects

Common Side Effects:

Hot flashes, abdominal bloating or discomfort, breast tenderness, headache, nausea, and vision changes (blurred vision, double vision).

Rare but Serious Side Effects:

Ovarian hyperstimulation syndrome (OHSS), which can manifest as rapid weight gain, severe pelvic pain, nausea, vomiting, and difficulty breathing.

Long-Term Effects:

Long-term cyclic therapy (more than six cycles) is not recommended. The risk of ovarian cancer with prolonged use is debated but remains a concern.

Adverse Drug Reactions (ADR):

OHSS, severe allergic reactions (anaphylaxis), and persistent visual disturbances.

Contraindications

• Pregnancy
• Liver disease
• Abnormal uterine bleeding of undetermined cause
• Ovarian cysts (unless associated with PCOS)
• Uncontrolled thyroid or adrenal dysfunction
• Hormone-dependent tumors
• Pituitary tumor

Drug Interactions

• Gonadorelin: Concurrent use can diminish the response to gonadorelin.
• Ospemifene: Avoid concomitant use due to similar mechanisms of action.

Pregnancy and Breastfeeding

Clomiphene is contraindicated in pregnancy (Pregnancy Category X). Its use during breastfeeding is generally not recommended, although limited data suggest minimal excretion into breast milk.

Drug Profile Summary

• Mechanism of Action: SERM that stimulates gonadotropin release by inhibiting estrogen’s negative feedback at the hypothalamus and pituitary.
• Side Effects: Hot flashes, abdominal discomfort, breast tenderness, headaches, nausea, vision changes. Rarely, OHSS and allergic reactions.
• Contraindications: Pregnancy, liver disease, abnormal uterine bleeding, ovarian cysts, hormone-dependent tumors.
• Drug Interactions: Gonadorelin, ospemifene.
• Pregnancy & Breastfeeding: Contraindicated in pregnancy; use caution during breastfeeding.
• Dosage: 50 mg daily for 5 days; may be increased to 100 mg if ovulation doesn’t occur.
• Monitoring Parameters: Ovulation status (via ovulation predictor kits, ultrasound, or serum progesterone levels), liver function tests (if indicated), signs of OHSS.

Popular Combinations

Clomiphene is sometimes used in combination with metformin in women with PCOS to improve ovulation rates.

Precautions

• Baseline pelvic examination and assessment of liver function are recommended.
• Monitor for signs of OHSS.
• Advise patients on the potential for multiple pregnancies.
• Caution patients about potential visual disturbances and their impact on driving.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Clomiphene?

A: The initial dose is 50 mg daily for 5 days. If ovulation does not occur, the dose may be increased to 100 mg daily for 5 days in the next cycle.

Q2: What are the common side effects of Clomiphene?

A: Common side effects include hot flashes, abdominal discomfort, breast tenderness, headaches, and nausea.

Q3: How does Clomiphene work?

A: Clomiphene blocks estrogen receptors, leading to an increase in GnRH, FSH, and LH, which stimulates the ovaries to produce and release eggs.

Q4: Who should not take Clomiphene?

A: Clomiphene is contraindicated in pregnant women, patients with liver disease, and those with certain hormonal conditions.

Q5: Can Clomiphene increase the chance of multiple pregnancies?

A: Yes, clomiphene increases the likelihood of twins and, rarely, triplets.

Q6: How long can a patient take Clomiphene?

A: Treatment is generally limited to a maximum of six cycles due to concerns about long-term effects.

Q7: What should patients do if they experience visual disturbances while taking Clomiphene?

A: Patients should discontinue the medication and contact their doctor immediately.

Q8: How is ovulation monitored during Clomiphene treatment?

A: Ovulation can be monitored through ovulation predictor kits, ultrasound, or by measuring serum progesterone levels.

Q9: Can Clomiphene be used in men?

A: While clomiphene has been investigated for male infertility, its use is off-label and not routinely recommended.

Q10: What are the signs and symptoms of Ovarian Hyperstimulation Syndrome (OHSS)?

A: OHSS symptoms can range from mild (abdominal bloating and discomfort) to severe (rapid weight gain, severe pelvic pain, nausea, vomiting, and shortness of breath). Severe OHSS requires immediate medical attention.