Does Enclomiphene Cause Gynecomastia?
Enclominophene is a non-steroidal selective estrogen receptor modulator (SERM). It is an improved version of clomiphene citrate, which is a drug that has been used for treatment of hypogonadism in men, and, historically, for ovulatory dysfunction in women as it increases the levels of follicle-stimulating and luteinising hormones [1].
Enclomiphene works by blocking the estrogen receptors, therefore promoting gonadotropin-dependent testosterone secretion by the testes. Consequently, it can be used to promote serum testosterone levels in men with secondary hypogonadism, which is a hormonal disorder resulting in decreased sperm count and sexual function. Enclomiphene therapy can restore physiological testosterone secretion while maintaining testicular volume and, potentially, spermatogenesis [1].
Additionally, through observing a favourable effect on plasma glucose levels, a role of enclomiphene in metabolic syndrome treatments was described [1]. Therefore, enclomiphene also shows promise in treatment of complications associated with diabetes, as well as obesity / metabolic syndrome (syndrome X). As this can also result in secondary hypogonadism, enclomiphene presents as a promising drug.
Despite showing promise in clinical trials (enclomiphene has been concluded to have an identical efficacy at restoring testosterone levels than conventional testosterone replacement therapy), the approval process for the drug has been halted by both FDA and EMA as of April 2021. This was due to conclusions that enclomiphene did not provide a clinical benefit to treat male hypogonadism over other therapies.
However, despite not meeting the clinical benefit benchmarks, the safety profile of enclomiphene was conlcuded to be very good - the side effects described were mostly general side effects which occur with every medication, such as headaches, nausea or hot flushes.
What is Gynecomastia?
Gynecomastia is a common clinical condition in men characterised by benign (non-cancerous) enlargement of the breast glandular tissue. This occurs due to an imbalance between androgen (testosterone) and estrogen tissue levels. It can occur unilaterally or bilaterally (affect one or both breasts), and present acutely, as a painful, tender mass beneath the areoal region, or chronically, as a steady growth.
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Additionally, gynecomastia can occur as a consequence of treatment with certain drugs (for example certain heart or hypertension medication) [2, 3, 4]. In some cases, gynecomastia occurs idiopathically (without known cause), or in puberty when the hormonal balance rapidly changes with growth [3, 5].
Diagnosis and treatment of gynecomastia
Gynecomastia is primarily diagnosed through a physical examination. This can be followed up by blood testing for hormonal functions, and potentially imaging tests and a biopsy if breast cancer is suspected [6, 7].
The main objective of gynecomastia treatment is cosmetic outcome. There are three options available:
- observation - in some cases, gynecomastia resolves on its own. This is true particularly with gynecomastia in puberty.
- hormone therapy - the aim is to restore the physiological estrogen / androgen balance allowing for the gynecomastia to resolve. This is recommended with the acute presentation, and had a 30% response rate, however, it is not recommended with the chronic form [2, 5, 8],
- surgery - if the gynecomastia is chronic, persists for a year or more and progresses, surgery may be the preferred treatment choice. The surgical approaches include liposuction or direct excision.
Enclomiphene and gynecomastia: What is the link?
As enclomiphene was never used medically in men on a large scale, the data on the potential link between enclomiphene and gynecomastia are scarce. However, the safety profile of enclomiphene appears good, with gynecomastia not being indicated as one of the adverse effects.
In a study of enclomiphene versus clomiphene for hypogonadism in men [9], gynecomastia was considered an adverse effect warranting end of treatment for the patient, however, the publication does not mention how many patients in the trial experienced gynecomastia.
However, emclomiphene promotes gonadotropin-dependent testosterone secretion by the testes, which could potentially have implications for conditions like gynecomastia that involve hormonal imbalances. It could be hypothesised that due to its role in increasing testosterone levels, enclomiphene could result in development of gynecomastia, but alternatively also be used in some cases as potential treatment. However, further research is required to describe this link.