Tamoxifen vs Enclomiphene: What to Choose and for Whom

Tamoxifen and enclomiphene are estrogen receptor modulators that in men are able to raise testosterone levels. But in practice they are considered for different people and different tasks. The editorial team has gathered the clinical scenarios in which a doctor may lean toward one of the drugs, and the situations in which both are a bad idea.

Questions worth asking before the choice

The choice between two SERMs begins not with a comparison of ‘strength’ but with the goal. What exactly does the patient need: to treat a tumor, reduce painful gynecomastia, raise testosterone, preserve spermatogenesis? For each of these tasks the evidence base of tamoxifen and enclomiphene differs.

The second question is the diagnosis. A rise in LH and testosterone via a SERM is possible only with preserved pituitary and testicular function. If gonadotropins are already high, that is, the problem is in the testicles themselves, no modulator will help. Therefore, before any decision the doctor assesses LH, FSH, testosterone, estradiol, prolactin.

The third is concurrent conditions and medications. A history of thrombosis, liver disease, taking antidepressants that inhibit the CYP2D6 enzyme, and vision problems significantly affect the choice or make SERMs undesirable altogether.

The fourth is availability and regulatory status. Tamoxifen is a registered drug with an official label, whereas enclomiphene has no registration in most countries, including the EU. This means the absence of a controlled pharmacy product and of official recommendations for its use.

• What is the clinical goal of therapy?
• Is the hypogonadism primary or secondary in nature?
• Is fertility important in the near future?
• Are there thrombosis risk factors and drug interactions?
• Does the person fall under anti-doping rules?

For whom tamoxifen is indicated

The main official indications of tamoxifen concern oncology: treating hormone-receptor-positive breast cancer in women and men and reducing the risk of breast cancer in high-risk women. In these situations tamoxifen is prescribed by oncologists, and the duration of treatment is measured in years. The effectiveness of adjuvant therapy is confirmed by the EBCTCG meta-analysis (2011).

In male practice, tamoxifen is used off-label to treat painful or recent gynecomastia. The drug is most effective in the early, ‘proliferative’ phase, when the tissue has not yet been replaced by fibrous tissue. Long-standing gynecomastia is hard to reduce with medication, and then surgical treatment is discussed.

Another well-described situation is the prevention of gynecomastia and breast pain in men with prostate cancer who receive antiandrogen monotherapy. Here tamoxifen is part of the oncological support.

Tamoxifen was also historically used for idiopathic male infertility, but the study results are inconsistent, and modern urological guidelines regard such therapy as empirical with limited evidence.

For whom enclomiphene is considered

Enclomiphene was developed for one group — men with functional secondary hypogonadism who want to raise testosterone without losing fertility. A typical study participant is an overweight man with low testosterone and low or normal gonadotropins (Kim et al., 2016).

Compared with tamoxifen, enclomiphene has a short half-life and, as far as is known, does not accumulate an estrogenic isomer the way ordinary clomiphene does. For the doctor this means a faster response to a change in therapy and faster disappearance of undesirable effects after discontinuation.

At the same time, it is important to honestly assess the limits of the evidence. The enclomiphene studies lasted from a few weeks to a few months, had hundreds rather than thousands of participants, and assessed mainly laboratory indicators. There is no data on the effect on cardiovascular events, bones or quality of life in the long term.

Because of the lack of registration in the EU (the EMA in 2018 refused registration of the drug Encyzix), doctors in Europe and Ukraine, when a SERM is needed for men, more often use clomiphene off-label. A systematic review by Huijben et al. (2022) confirms that clomiphene raises testosterone, but the quality of evidence regarding symptoms is limited.

Special groups and contraindications

For people with a history of deep vein thrombosis, pulmonary embolism or stroke, SERMs as a class are undesirable. Large studies of tamoxifen in women clearly showed an increased thromboembolic risk (Fisher et al., 1998), and there is no reason to believe that in men this risk is absent.

For tamoxifen, drug interactions are separately important: some antidepressants (in particular paroxetine and fluoxetine) inhibit CYP2D6 and reduce the formation of active endoxifen. For oncology patients this is clinically significant, so the doctor may change the antidepressant.

Women of reproductive age are not prescribed tamoxifen outside oncological indications, and during pregnancy it is contraindicated. Enclomiphene is not used in women. Adolescents are prescribed any SERM only for special pediatric indications.

For athletes there is no choice: both drugs are in section S4 of the WADA Prohibited List and are banned at all times. Use is possible only with a therapeutic use exemption, for example in the case of an oncological diagnosis.

Monitoring during therapy

Any SERM therapy in men entails monitoring of effectiveness and safety. The doctor re-assesses total testosterone, LH, estradiol, and also hematocrit, since a rise in testosterone can stimulate the formation of red blood cells.

If the goal is fertility, semen analysis is monitored. Changes in spermatogenesis manifest slowly, so an assessment of the result is possible only after several months, which is due to the duration of the sperm formation cycle.

Any visual disturbances — blurring, flickering, flashes of light — are grounds to stop taking it immediately and consult a doctor. Pain and swelling of a leg, shortness of breath, chest pain are likewise alarming: these are possible signs of thrombosis that require emergency care.

Prolonged use of tamoxifen in women entails gynecological supervision because of the risk of endometrial changes, and in men on long-term therapy — assessment of lipids and liver function at the doctor's discretion.

Editorial conclusions

Tamoxifen is a drug with oncological indications and a solid evidence base, which in men is most often considered for treating recent gynecomastia and as part of oncological support. Enclomiphene is a specialized agent for stimulating one's own testosterone in secondary hypogonadism, but with limited data and without registration in the EU.

For both, the key limitations are the same: ineffectiveness in primary hypogonadism, the thromboembolic risk of the SERM class, and the ban in sport.

The right choice is possible only after examination, and the editorial team considers the unsupervised use of either of these agents without a diagnosis and laboratory monitoring an unjustified risk.

We recommend reading our materials on the mechanistic differences between tamoxifen and enclomiphene, on the comparison of raloxifene with clomiphene, and on gynecomastia in men.

References

1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378(9793):771–784.
2. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90(18):1371–1388.
3. Kim ED, McCullough A, Kaminetsky J. Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement. BJU Int. 2016;117(4):677–685.
4. Huijben M, Lock MTWT, de Kemp VF, et al. Clomiphene citrate for men with hypogonadism: a systematic review and meta-analysis. Andrology. 2022;10(3):451–469.
5. Braunstein GD. Gynecomastia. N Engl J Med. 2007;357(12):1229–1237.
6. Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715–1744.
7. European Medicines Agency. Refusal of the marketing authorisation for Encyzix (enclomiphene). London: EMA; 2018.
8. World Anti-Doping Agency. Prohibited List. Montreal: WADA (чинна редакція).