Enclomiphene in women: are there any medical indications?

Enclomiphene is often discussed in the context of men's hormones, but women increasingly ask whether it has a medical role for them. Our editorial team explains how it relates to clomifene, what is licensed and what remains speculation.

What enclomiphene is

Enclomiphene is one of the two geometric isomers that make up clomifene (clomiphene) citrate, a selective oestrogen receptor modulator (SERM) used in reproductive medicine since the 1960s. Commercial clomifene is a mixture of roughly 60% enclomiphene (the trans-isomer) and 40% zuclomiphene (the cis-isomer).

The two isomers behave differently. Enclomiphene acts mainly as an oestrogen receptor antagonist at the hypothalamus and has a relatively short half-life. Zuclomiphene has weaker antagonist and some oestrogen-like activity and is eliminated much more slowly, so it accumulates with repeated dosing, as early pharmacokinetic work by Mikkelson and colleagues showed.

By blocking oestrogen's negative feedback in the hypothalamus, enclomiphene increases the release of gonadotrophin-releasing hormone and therefore of luteinising hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary. In women, FSH drives follicle development in the ovary; in men, LH and FSH stimulate testosterone and sperm production.

Enclomiphene as a single isomer was developed mainly as a potential treatment for secondary hypogonadism in men. Phase II and III trials, including those by Kaminetsky and Wiehle and colleagues, showed that it raised testosterone while preserving sperm counts. However, it did not receive marketing approval from the US Food and Drug Administration, and it is not a licensed medicine in the UK.

Is there any medical indication in women?

Put simply, enclomiphene on its own currently has no licensed indication for women in the UK, the EU or the US. Its medical relevance for women comes through clomifene, the mixture of which it is the main component.

Clomifene citrate is licensed for the treatment of ovulatory dysfunction in women who wish to become pregnant, most commonly in polycystic ovary syndrome (PCOS). It is a prescription-only medicine, and in the UK its use is supervised by fertility specialists or gynaecologists with access to ultrasound monitoring, as recommended by NICE fertility guidance.

• Licensed use (clomifene): induction of ovulation in anovulatory infertility, particularly PCOS.
• Investigational use (enclomiphene): secondary hypogonadism in men – not approved.
• No established indication: enclomiphene for women's fitness, body composition, mood or "hormonal balance".

The therapeutic landscape has also shifted. The international PCOS guideline led by Teede and colleagues, updated in 2023, recommends letrozole as the first-line pharmacological option for ovulation induction in PCOS, following the large trial by Legro and co-workers in 2014, which found higher live-birth rates with letrozole than with clomifene.

Why the isomer matters in women

Some researchers have speculated that a purified enclomiphene preparation might give a "cleaner" profile than clomifene, with less accumulation of zuclomiphene and possibly fewer oestrogen-like effects on the endometrium and cervical mucus – a known drawback of clomifene in fertility treatment. This idea is plausible from a pharmacological standpoint.

However, plausibility is not evidence. There are no robust clinical trials showing that enclomiphene alone improves pregnancy or live-birth rates in women compared with clomifene or letrozole. Until such data exist, it remains a hypothesis rather than a treatment option.

Risks and side effects relevant to women

Because enclomiphene is investigational, its safety in women has not been characterised. What is known about clomifene provides a guide to the type of effects that may be expected from medicines acting on this pathway, but not their exact frequency.

Visual symptoms deserve special mention. The product information for clomifene advises stopping treatment and seeking ophthalmological assessment if they occur. Effects on the endometrium and cervical mucus can also make conception less likely despite successful ovulation.

Using an unlicensed product bought online adds further risks: uncertain purity, unknown isomer ratio and no medical supervision. Self-medication with a drug that stimulates the ovaries, outside fertility care, is not appropriate.

Anti-doping status

SERMs, including clomifene and enclomiphene, are prohibited at all times for both male and female athletes under section S4 (hormone and metabolic modulators) of the WADA Prohibited List. Women who are prescribed clomifene for fertility and who compete under anti-doping rules need to apply for a Therapeutic Use Exemption through UK Anti-Doping or their international federation.

Editorial team's conclusions

Enclomiphene is the main isomer of clomifene, but on its own it has no approved medical indication for women. Its development focused on men with secondary hypogonadism and did not result in approval.

For women, the established role belongs to clomifene and, increasingly, letrozole in supervised ovulation induction, particularly for PCOS. Claims that enclomiphene could benefit women outside fertility care are not supported by evidence.

Women considering any hormone-acting drug should start with a consultation with their GP or a reproductive specialist.

You may also wish to read our articles on PCOS and exercise, on letrozole and mood, and on how SERMs work.

References

1. Mikkelson TJ, Kroboth PD, Cameron WJ, et al. Single-dose pharmacokinetics of clomiphene citrate in normal volunteers. Fertil Steril. 1986;46(3):392–396.
2. Kaminetsky J, Werner M, Fontenot G, Wiehle RD. Oral enclomiphene citrate stimulates the endogenous production of testosterone and sperm counts in men with low testosterone: comparison with testosterone gel. J Sex Med. 2013;10(6):1628–1635.
3. Wiehle RD, Fontenot GK, Wike J, et al. Enclomiphene citrate stimulates testosterone production while preventing oligospermia: a randomized phase II clinical trial comparing topical testosterone. Fertil Steril. 2014;102(3):720–727.
4. Legro RS, Brzyski RG, Diamond MP, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014;371(2):119–129.
5. Teede HJ, Tay CT, Laven JJE, et al. Recommendations from the 2023 international evidence-based guideline for the assessment and management of polycystic ovary syndrome. J Clin Endocrinol Metab. 2023;108(10):2447–2469.
6. National Institute for Health and Care Excellence. Fertility problems: assessment and treatment. Clinical guideline CG156. London: NICE; 2013.
7. https://legalsteroidshopusa.com/product/dianabol-10mg-pharmagroup/