Role of Enclomiphene (Clomiphene Citrate) in Treating Fertility Issues
Clomiphene citrate is effective for treating female ovulatory dysfunction but has limited FDA approval for male infertility, though it may be used off-label as a selective estrogen receptor modulator (SERM) to improve testosterone levels and sperm parameters in men with secondary hypogonadism.
Female Fertility Applications
Clomiphene citrate is FDA-approved for treating ovulatory dysfunction in women desiring pregnancy 1. It is most effective for:
- Women with polycystic ovary syndrome (PCOS)
- Amenorrhea-galactorrhea syndrome
- Psychogenic amenorrhea
- Post-oral-contraceptive amenorrhea
- Certain cases of secondary amenorrhea
According to ACOG guidelines, clomiphene citrate is the first-line treatment for ovulation induction in women with PCOS who wish to conceive, with approximately 80% of women ovulating and half of those conceiving 2.
Administration Protocol for Women:
- Start on approximately day 5 of the menstrual cycle
- Limited to about six cycles total (including three ovulatory cycles)
- Requires pelvic examination prior to first and each subsequent treatment course
- Women must have adequate endogenous estrogen levels for optimal response
Male Fertility Applications
While the FDA label specifically states "There are no adequate or well-controlled studies that demonstrate the effectiveness of clomiphene citrate in the treatment of male infertility" 1, it is commonly used off-label for this purpose.
The AUA/ASRM guidelines (2021) support the use of selective estrogen receptor modulators (SERMs) like clomiphene citrate for:
- Men with low serum testosterone who are concerned about fertility 2
- Men with hypogonadotropic hypogonadism (HH) 2
Mechanism in Men:
Enclomiphene (the trans-isomer of clomiphene citrate) acts as an estrogen receptor antagonist that:
- Blocks negative feedback of estrogen at the hypothalamus and pituitary
- Increases endogenous LH and FSH production
- Stimulates testicular testosterone production while maintaining spermatogenesis 3, 4
Clinical Benefits in Men:
- Increases serum testosterone to physiological levels 4
- Maintains or improves sperm counts and parameters 4, 5
- Preserves fertility potential, unlike exogenous testosterone therapy which suppresses spermatogenesis 6
In a study by Kaminetsky et al. (2013), enclomiphene citrate significantly increased sperm counts in all treated men (to 75-334 × 10^6/mL range), while testosterone gel therapy was largely ineffective in improving sperm parameters 4.
Important Considerations and Limitations
For Women:
- Risk of multiple pregnancy due to multiple follicular development
- Potential for ovarian hyperstimulation syndrome, particularly in PCOS patients
- Not recommended for long-term use beyond 12 cycles due to potential ovarian tumor risk 7
- Requires ultrasound monitoring to minimize risks
For Men:
- Off-label use (not FDA-approved for male infertility)
- The AUA/ASRM guidelines note that "clinicians should inform the man with idiopathic infertility that the use of SERMs has limited benefits relative to results of ART" 2
- Limited data supporting pharmacologic manipulation with SERMs prior to surgical intervention in men with non-obstructive azoospermia 2
Contraindications:
- Should not be used with testosterone therapy, as exogenous testosterone suppresses spermatogenesis 6
- Should not be used concurrently with finasteride during fertility treatment 6
- Not recommended for men with primary testicular failure
Alternative Approaches for Male Infertility
For men with low total motile sperm count (<5 million motile sperm after processing), the AUA/ASRM guidelines suggest:
- Considering assisted reproductive technologies (ART) such as IVF/ICSI 2
- For hypogonadotropic hypogonadism, treatment with exogenous gonadotropins or pulsatile GnRH may be more appropriate 2
Monitoring Recommendations
- Regular hormone level monitoring (testosterone, LH, FSH)
- Periodic semen analysis to assess response
- In women, ultrasound monitoring of follicular development
Enclomiphene citrate represents a promising option for men with secondary hypogonadism who wish to maintain fertility, but its benefits must be weighed against the limited FDA approval and the potential need for more definitive ART interventions in cases of severe male factor infertility.