Enclomiphene Citrate: Recommended Use and Dosage
Primary Indications
Enclomiphene citrate (the trans-isomer of clomiphene citrate) is recommended as first-line ovulation induction therapy for women with ovulatory dysfunction and as an alternative treatment for men with secondary hypogonadism who wish to preserve fertility. 1, 2
Female Infertility: Ovulation Induction
Starting Dosage and Titration
- Begin with 50 mg daily for 5 days as the initial dose for ovulation induction 2
- Start therapy on or about day 5 of the menstrual cycle (either after progestin-induced bleeding or spontaneous uterine bleeding) 2
- If ovulation does not occur after the first course, increase to 100 mg daily for 5 days (given as two 50 mg tablets as a single daily dose) 2
- This second course may be started as early as 30 days after the previous cycle, after excluding pregnancy 2
Maximum Dosing and Duration
- Dosage or duration beyond 100 mg/day for 5 days is not recommended 2
- If ovulation does not occur after three courses of therapy, further treatment with clomiphene citrate is not recommended and the patient should be reevaluated 2
- Long-term cyclic therapy should not exceed approximately six total cycles 2
- If three ovulatory responses occur without pregnancy, further treatment is not recommended 2
Clinical Context for Use
- Clomiphene citrate is recommended for unexplained infertility with a Hunault score <30% (poor prognosis for natural conception) when combined with intrauterine insemination (IUI) 3
- For couples with unexplained infertility and a Hunault score >30%, expectant management for 6-12 months should be attempted first 3
- In mild male infertility (TMSC >10 million), clomiphene citrate with IUI significantly increases live birth rates (OR 2.07,95% CI: 1.22-3.50) 3
- For moderate male infertility (TMSC <10 million), clomiphene citrate can be used but ovarian stimulation does not improve outcomes compared to natural cycle IUI 3
Monitoring and Safety
- When using clomiphene citrate for ovarian stimulation, cancel the cycle, aspirate, or convert to IVF if >2 follicles >15mm develop, or if 1-2 follicles >15mm AND ≥5 follicles >10mm are present to minimize multiple pregnancy risk 3
- Use ≤75 IU gonadotropins per day when combining with other ovarian stimulation agents 3
- Do not apply GnRH agonists or antagonists with clomiphene citrate 3
- Lower doses should be used to minimize multiple follicular development and reduce multiple pregnancy risk 4
Male Hypogonadism: Testosterone Restoration
Indications for Male Use
- Enclomiphene citrate is indicated for men with secondary hypogonadism (testosterone <300-350 ng/dL with low-to-normal LH <9.4-12 IU/L) who wish to preserve fertility 5, 6, 7
- This represents an alternative to exogenous testosterone replacement, which suppresses spermatogenesis 8
Dosing for Male Hypogonadism
- Effective doses range from 12.5 mg to 25 mg daily 6
- The 25 mg daily dose achieved mean testosterone levels of 604 ± 160 ng/dL after 6 weeks of continuous use 6
- All three studied doses (6.25 mg, 12.5 mg, and 25 mg) increased testosterone levels into the normal range 6
- For male oligozoospermia, clomiphene citrate 25 mg daily for 25 days with 5 days rest, continued for 3 months, significantly improved sperm counts 9
Efficacy and Safety in Men
- 88% of men treated for more than 3 years achieved eugonadism, and 77% reported improved hypogonadal symptoms 5
- Treatment duration in studies ranged from 0 to 84 months (mean 25.5 months), demonstrating long-term safety 5
- Enclomiphene citrate maintains sperm concentrations in the normal range while raising testosterone, unlike testosterone gel which markedly reduces spermatogenesis 8
- The medication increases LH and FSH (unlike testosterone replacement which suppresses them), thereby stimulating endogenous testosterone production 6, 7, 8
Mechanism of Action
- Enclomiphene citrate is a selective estrogen receptor antagonist that blocks estradiol from hypothalamic receptor sites 9
- This neutralizes the normal negative feedback control of estrogen, resulting in enhanced secretion of LH-RH, FSH-RH, and gonadotropins 9
- In men, LH stimulates Leydig cells to produce testosterone, which maintains gametogenic function 9
- In women, increased FSH and LH stimulate follicular development and ovulation 2
Side Effects and Contraindications
Common Side Effects
- In men treated long-term (>3 years), side effects included mood changes (5 patients), blurred vision (3 patients), and breast tenderness (2 patients) 5
- Only 8% of men treated for more than 3 years reported side effects 5
- Estradiol levels are significantly increased following clomiphene citrate treatment 5
- Ovarian hyperstimulation syndrome is a potential side effect, especially with multifollicular development 4
Contraindications
- Avoid in patients with liver disease, especially those with decompensated cirrhosis 4
- Should only be used in women with functional hypothalamic amenorrhea when there is sufficient endogenous estrogen level 4
- Exclude pregnancy, ovarian enlargement, or ovarian cyst formation between each treatment cycle 2
Metabolic Effects
- Enclomiphene citrate can alter serum lipid profiles 4
- Both enclomiphene and testosterone gel decreased IGF-1 levels, but suppression was greater in the enclomiphene groups 6
- Treatment did not significantly affect TSH, ACTH, cortisol, or bone markers 6
Key Clinical Pearls
- Clomiphene citrate is the most cost-effective first-line therapy for unexplained infertility, and if pregnancy does not occur after three cycles, moving directly to IVF is the most cost-effective approach 3
- Ovulation most often occurs 5-10 days after a course of clomiphene citrate; coitus should be timed accordingly 2
- The effects on LH and testosterone persist for at least one week after stopping treatment in men 6
- Treatment should be supervised by physicians experienced in management of gynecologic or endocrine disorders 2
- Patients should be chosen for therapy only after careful diagnostic evaluation 2