madman
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* Enclomiphene is one of two stereoisomers of clomiphene, the other being Zuclomiphene. Whilst zuclomiphene is more oestrogenic, enclomiphene is more anti-oestrogenic. Zuclomiphene is generally antigonadotropic due to its effects on oestrogen receptors, which leads to a subsequent reduction in testosterone production. Essentially, isomerically pure enclomiphene is pro-gonadotropic and can therefore improve secondary hypogonadotropic hypogonadism in men without the same adverse oestrogenic side effects often observed with clomiphene. Clomiphene is currently commonly used in hypogonadotropic hypogonadism in men who wish to minimise a potential impact on fertility or who are intolerant to injections or topical preparations.
* Enclomiphene, a selective oestrogen receptor modulator (SERM) and the trans-isomer of clomiphene, acts by antagonising oestrogen receptors in the pituitary gland, stimulating luteinising hormone (LH) and follicle-stimulating hormone (FSH) secretion to enhance endogenous testosterone and sperm production. Compared with clomiphene, enclomiphene demonstrates fewer oestrogenic side effects and a more favourable safety profile. Evidence from small clinical studies indicates that enclomiphene achieves testosterone levels comparable to transdermal TRT while maintaining spermatogenesis and showing reduced rates of adverse effects such as mood changes and decreased libido.
Introduction
Testosterone deficiency syndrome (TDS) is an underdiagnosed condition associated with physical, psychological, and sexual symptoms, alongside increased risks of osteoporosis, cardiovascular disease, and metabolic disorders. Conventional testosterone replacement therapy (TRT) effectively alleviates symptoms but suppresses the hypothalamic-pituitary-gonadal (HPG) axis, leading to impaired spermatogenesis and reduced fertility. Alternative treatments such as human chorionic gonadotrophin (HCG) and clomiphene citrate can restore endogenous testosterone while preserving fertility, though their efficacy and tolerability vary.
Enclomiphene, a selective oestrogen receptor modulator (SERM) and the trans-isomer of clomiphene, acts by antagonising oestrogen receptors in the pituitary gland, stimulating luteinising hormone (LH) and follicle-stimulating hormone (FSH) secretion to enhance endogenous testosterone and sperm production. Compared with clomiphene, enclomiphene demonstrates fewer oestrogenic side effects and a more favourable safety profile. Evidence from small clinical studies indicates that enclomiphene achieves testosterone levels comparable to transdermal TRT while maintaining spermatogenesis and showing reduced rates of adverse effects such as mood changes and decreased libido.
Although enclomiphene is not currently approved by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA), it may be available off-label through compounding pharmacies. The British Society for Sexual Medicine (BSSM) recognises enclomiphene as a promising oral therapy for men with secondary hypogonadism—particularly those wishing to preserve fertility or intolerant to injectable or transdermal formulations. However, due to the absence of long-term efficacy and safety data, and its unlicensed status in the UK, the BSSM advises that enclomiphene use be limited to experienced clinicians within specialist or research settings, with appropriate patient counselling.
Enclomiphene is a nonsteroidal SERM. Its primary mechanism of action involves antagonising the oestrogen receptor in the pituitary gland. This reduces the negative feedback loop exerted by oestrogen on the HPG axis, leading to increased production of LH and FSH by the pituitary gland. This, in turn, stimulates increased testosterone and sperm production by the testes.
Enclomiphene is one of two stereoisomers of clomiphene, the other being Zuclomiphene. Whilst zuclomiphene is more oestrogenic, enclomiphene is more anti-oestrogenic. Zuclomiphene is generally antigonadotropic due to its effects on oestrogen receptors, which leads to a subsequent reduction in testosterone production. Essentially, isomerically pure enclomiphene is pro-gonadotropic and can therefore improve secondary hypogonadotropic hypogonadism in men without the same adverse oestrogenic side effects often observed with clomiphene. Clomiphene is currently commonly used in hypogonadotropic hypogonadism in men who wish to minimise a potential impact on fertility or who are intolerant to injections or topical preparations.
Enclomiphene is not currently approved by the FDA or the EMA, and its manufacturer discontinued development in 2021. Enclomiphene can be compounded by specialty pharmacies with a prescription and may be used off-label by healthcare providers as an investigational drug. Although unlikely to be expensive, as it is a private prescription only, the cost must be considered until formal licensing occurs.
EFFICACY
One randomised controlled trial involving 44 men with total testosterone less than 12.1 nmol/L compared daily enclomiphene with daily transdermal testosterone. The study found that post-treatment testosterone levels at 24 hours and 6 weeks for enclomiphene were non-inferior to transdermal testosterone [9]. The dosages of enclomiphene studied and corresponding testosterone levels after 6 weeks were shown in Table 1.
A small retrospective study involving 66 patients found that the median change in testosterone level with enclomiphene was 5.76 nmol/L after a median treatment duration of 8.9 months [10]. In this study, the side effect rate for patients receiving enclomiphene was significantly lower at 13.8% compared to 47% for patients on clomiphene. Side effects where enclomiphene showed a lower rate compared to clomiphene included decreased libido, decreased energy, depressive thoughts, and mood changes. Unfortunately, no dosage information was provided.
Another small retrospective study involving 78 patients found no statistically significant differences in the pre- and post-treatment mean differences in testosterone, LH, FSH, and semen parameters [11]. However, the study did not compare equivalent doses of enclomiphene and clomiphene in both absolute and relative terms. In the enclomiphene group, 14 (30.4%) men received 12.5 mg every day, and 32 (69.6%) men received 25 mg every day. In the clomiphene group, all men received 50 mg every other day.
ENCLOMIPHENE PHARMACOKINETICS
Given its pharmacodynamic properties and oral delivery, enclomiphene may be particularly suitable as a novel treatment for TDS in men with:
Enclomiphene is contraindicated in those with:
Dosage:
UNDESIRABLE EFFECTS OF ENCLOMIPHENE
BSSM POSITION
Enclomiphene represents a promising therapy that may be used to treat TDS and normalise testosterone while maintaining spermatogenesis, with fewer side effects than clomiphene.
Current evidence is derived from small, short-term studies with limited safety and fertility data.
Although long-term data on enclomiphene as a standalone therapy are lacking, its safety and effectiveness are indirectly supported by decades of widespread use, as it is one of the two isomers within clomiphene citrate.
The BSSM does not recommend its routine use outside specialist settings.
Where prescribed, enclomiphene should be managed by clinicians experienced in male hypogonadism, ideally within research frameworks, and accompanied by appropriate counselling regarding its unlicensed status in the UK. Potential patient groups include men who wish to maintain or improve fertility while being treated for male hypogonadism. It could potentially be used as a possible treatment for any male hypogonadal patient who is intolerant to injectable or topical forms of treatment, with the caveat that there may be limited success in certain types of primary or functional hypogonadism.
* Enclomiphene, a selective oestrogen receptor modulator (SERM) and the trans-isomer of clomiphene, acts by antagonising oestrogen receptors in the pituitary gland, stimulating luteinising hormone (LH) and follicle-stimulating hormone (FSH) secretion to enhance endogenous testosterone and sperm production. Compared with clomiphene, enclomiphene demonstrates fewer oestrogenic side effects and a more favourable safety profile. Evidence from small clinical studies indicates that enclomiphene achieves testosterone levels comparable to transdermal TRT while maintaining spermatogenesis and showing reduced rates of adverse effects such as mood changes and decreased libido.
Introduction
Testosterone deficiency syndrome (TDS) is an underdiagnosed condition associated with physical, psychological, and sexual symptoms, alongside increased risks of osteoporosis, cardiovascular disease, and metabolic disorders. Conventional testosterone replacement therapy (TRT) effectively alleviates symptoms but suppresses the hypothalamic-pituitary-gonadal (HPG) axis, leading to impaired spermatogenesis and reduced fertility. Alternative treatments such as human chorionic gonadotrophin (HCG) and clomiphene citrate can restore endogenous testosterone while preserving fertility, though their efficacy and tolerability vary.
Enclomiphene, a selective oestrogen receptor modulator (SERM) and the trans-isomer of clomiphene, acts by antagonising oestrogen receptors in the pituitary gland, stimulating luteinising hormone (LH) and follicle-stimulating hormone (FSH) secretion to enhance endogenous testosterone and sperm production. Compared with clomiphene, enclomiphene demonstrates fewer oestrogenic side effects and a more favourable safety profile. Evidence from small clinical studies indicates that enclomiphene achieves testosterone levels comparable to transdermal TRT while maintaining spermatogenesis and showing reduced rates of adverse effects such as mood changes and decreased libido.
Although enclomiphene is not currently approved by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA), it may be available off-label through compounding pharmacies. The British Society for Sexual Medicine (BSSM) recognises enclomiphene as a promising oral therapy for men with secondary hypogonadism—particularly those wishing to preserve fertility or intolerant to injectable or transdermal formulations. However, due to the absence of long-term efficacy and safety data, and its unlicensed status in the UK, the BSSM advises that enclomiphene use be limited to experienced clinicians within specialist or research settings, with appropriate patient counselling.
ENCLOMIPHENE PHARMACODYNAMICSEnclomiphene is a nonsteroidal SERM. Its primary mechanism of action involves antagonising the oestrogen receptor in the pituitary gland. This reduces the negative feedback loop exerted by oestrogen on the HPG axis, leading to increased production of LH and FSH by the pituitary gland. This, in turn, stimulates increased testosterone and sperm production by the testes.
Enclomiphene is one of two stereoisomers of clomiphene, the other being Zuclomiphene. Whilst zuclomiphene is more oestrogenic, enclomiphene is more anti-oestrogenic. Zuclomiphene is generally antigonadotropic due to its effects on oestrogen receptors, which leads to a subsequent reduction in testosterone production. Essentially, isomerically pure enclomiphene is pro-gonadotropic and can therefore improve secondary hypogonadotropic hypogonadism in men without the same adverse oestrogenic side effects often observed with clomiphene. Clomiphene is currently commonly used in hypogonadotropic hypogonadism in men who wish to minimise a potential impact on fertility or who are intolerant to injections or topical preparations.
Enclomiphene is not currently approved by the FDA or the EMA, and its manufacturer discontinued development in 2021. Enclomiphene can be compounded by specialty pharmacies with a prescription and may be used off-label by healthcare providers as an investigational drug. Although unlikely to be expensive, as it is a private prescription only, the cost must be considered until formal licensing occurs.
EFFICACY
One randomised controlled trial involving 44 men with total testosterone less than 12.1 nmol/L compared daily enclomiphene with daily transdermal testosterone. The study found that post-treatment testosterone levels at 24 hours and 6 weeks for enclomiphene were non-inferior to transdermal testosterone [9]. The dosages of enclomiphene studied and corresponding testosterone levels after 6 weeks were shown in Table 1.
A small retrospective study involving 66 patients found that the median change in testosterone level with enclomiphene was 5.76 nmol/L after a median treatment duration of 8.9 months [10]. In this study, the side effect rate for patients receiving enclomiphene was significantly lower at 13.8% compared to 47% for patients on clomiphene. Side effects where enclomiphene showed a lower rate compared to clomiphene included decreased libido, decreased energy, depressive thoughts, and mood changes. Unfortunately, no dosage information was provided.
Another small retrospective study involving 78 patients found no statistically significant differences in the pre- and post-treatment mean differences in testosterone, LH, FSH, and semen parameters [11]. However, the study did not compare equivalent doses of enclomiphene and clomiphene in both absolute and relative terms. In the enclomiphene group, 14 (30.4%) men received 12.5 mg every day, and 32 (69.6%) men received 25 mg every day. In the clomiphene group, all men received 50 mg every other day.
ENCLOMIPHENE PHARMACOKINETICS
Given its pharmacodynamic properties and oral delivery, enclomiphene may be particularly suitable as a novel treatment for TDS in men with:
- - Needle aversion
- - Skin disorders or intolerance to topical preparations
- - Desire for future fertility
Enclomiphene is contraindicated in those with:
- - History of liver disease
- - Uncontrolled adrenal or thyroid dysfunction
- - Certain pituitary conditions
- - Allergy to clomiphene or enclomiphene
Dosage:
- - Begin with 6.25 mg daily, increasing weekly as tolerated up to 25 mg daily. The dosage may be further increased to 50 mg daily if there is an inadequate clinical or biochemical response.
UNDESIRABLE EFFECTS OF ENCLOMIPHENE
- - Headache (1.6%)
- - Hot flushes (1.1%)
- - Nausea (1.0%)
- - Muscle Spasms (0.9%)
- - Dizziness (0.7%)
BSSM POSITION
Enclomiphene represents a promising therapy that may be used to treat TDS and normalise testosterone while maintaining spermatogenesis, with fewer side effects than clomiphene.
Current evidence is derived from small, short-term studies with limited safety and fertility data.
Although long-term data on enclomiphene as a standalone therapy are lacking, its safety and effectiveness are indirectly supported by decades of widespread use, as it is one of the two isomers within clomiphene citrate.
The BSSM does not recommend its routine use outside specialist settings.
Where prescribed, enclomiphene should be managed by clinicians experienced in male hypogonadism, ideally within research frameworks, and accompanied by appropriate counselling regarding its unlicensed status in the UK. Potential patient groups include men who wish to maintain or improve fertility while being treated for male hypogonadism. It could potentially be used as a possible treatment for any male hypogonadal patient who is intolerant to injectable or topical forms of treatment, with the caveat that there may be limited success in certain types of primary or functional hypogonadism.
