Mechanism of Action and Side Effects of Enclomiphene Citrate
Enclomiphene citrate, a selective estrogen receptor modulator (SERM), works by antagonizing hypothalamic-pituitary estrogen receptors to stimulate gonadotropin secretion, which can induce ovulation in women and increase testosterone production in men.
Mechanism of Action
- Enclomiphene citrate is the trans-isomer of clomiphene citrate, which acts as an estrogen receptor antagonist primarily at the hypothalamus and pituitary level 1, 2
- It competes with estrogen for estrogen-receptor binding sites and delays replenishment of intracellular estrogen receptors 1
- This antagonism blocks the negative feedback of estrogen, resulting in increased release of pituitary gonadotropins (FSH and LH) 1, 2
- In women, the increased gonadotropins initiate steroidogenesis and folliculogenesis, resulting in growth of ovarian follicles and increased estradiol levels 1
- In men with secondary hypogonadism, enclomiphene increases testosterone production by elevating LH and FSH levels while maintaining spermatogenesis 2, 3
- Unlike the cis-isomer (zuclomiphene), enclomiphene has less estrogenic activity and a shorter half-life (approximately 24 hours) 1, 4
Side Effects
Common Side Effects
- Vasomotor flushes (hot flashes) 1
- Visual disturbances including blurred vision, spots, and flashes 1
- Mood changes and irritability 1, 5
- Breast tenderness 1, 5
- Ovarian enlargement with pelvic or abdominal pain 1
Reproductive System Effects
- Multiple pregnancies (7.98% incidence in clinical trials): 6.9% twin, 0.5% triplet, 0.3% quadruplet, 0.1% quintuplet 1
- Ovarian cyst formation or enlargement 1
- Ovarian hyperstimulation syndrome, especially with multifollicular development 6
- In men, long-term use may increase estradiol levels 5
Serious but Rare Side Effects
- Visual disorders: cataracts, optic neuritis, retinal vascular spasm, and potentially prolonged or irreversible vision loss 1
- Potential increased risk of borderline or invasive ovarian tumors with prolonged use 1, 7
- Hepatic effects: elevated transaminases, hepatitis 1
- Thromboembolic events: retinal thrombosis 1
Metabolic Effects
- May have favorable effects on fasting plasma glucose in men with metabolic syndrome 2
- Can alter serum lipid profiles 6
Clinical Considerations
- In women with functional hypothalamic amenorrhea (FHA), clomiphene citrate should only be used when there is sufficient endogenous estrogen level 6
- For ovulation induction, lower doses should be used to minimize multiple follicular development and reduce multiple pregnancy risk 6
- In men being treated for hypogonadism, monitoring of testosterone and estradiol levels is important 5, 3
- Long-term studies (>3 years) in men show generally good safety profile with 8% reporting side effects 5
- Unlike exogenous testosterone therapy, enclomiphene citrate maintains fertility in men with hypogonadism 2, 3
Contraindications and Precautions
- Not recommended as first-line treatment for functional hypothalamic amenorrhea 6
- Should be avoided in patients with liver disease, especially those with decompensated cirrhosis 6
- Requires careful monitoring in women undergoing ovulation induction to minimize risk of ovarian hyperstimulation and multiple pregnancies 6
- Visual symptoms should prompt immediate discontinuation and ophthalmologic evaluation 1
Understanding both the mechanism of action and potential side effects of enclomiphene citrate is essential for appropriate patient selection and monitoring to optimize outcomes while minimizing risks.