Enclomiphene vs TRT: Drug Comparison

Enclomiphene is a non-steroidal selective estrogen receptor modulator (SERM) sometimes used to treat male secondary hypogonadism, or low testosterone caused by problems with the hypothalamus or pituitary gland. The medication is derived from another SERM called clomiphene citrate, and while enclomiphene is not approved by the United States Food and Drug Administration (FDA) to treat any condition on its own, it is available through compounding pharmacies.

Enclomiphene is designed to stimulate testosterone production while minimizing the estrogenic side effects sometimes seen with clomiphene, such as breast tissue growth. It works by blocking estrogen signals in the brain, which increases the release of certain hormones, like luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These hormones then tell the testicles to produce more natural testosterone.

Enclomiphene is taken as a daily pill, usually in doses of 12.5 milligrams (mg) to 25 mg.

Enclomiphene boosts testosterone while helping the body maintain its natural hormone production and sperm count, making it a good alternative to traditional testosterone replacement therapies for men who want to preserve their fertility.

There are many different forms of testosterone available as medication for testosterone replacement therapy (TRT). The information below is about the brand name medication Depo-Testosterone^®, which is an injectable medication that contains the active ingredient testosterone cypionate.

Depo^®-Testosterone is an injectable form of testosterone cypionate, a synthetic version of testosterone used in TRT for men with hypogonadism, a condition where the body does not naturally produce enough testosterone. This hormone is essential for maintaining muscle mass, bone density, libido, mood stability, and overall energy levels in men. 

Depo-Testosterone works by supplementing low testosterone levels, helping to restore normal bodily functions. It’s typically administered as a deep intramuscular injection in the gluteal muscle, with dosages commonly ranging from 50 to 400 milligrams (mg) every two to four weeks, depending on individual needs and medical guidance.

Common side effects include acne, increased red blood cell count, fluid retention, mood swings, and changes in libido. More serious risks involve high blood pressure, an increased risk of blood clots, sleep apnea, and prostate enlargement. Long-term use may also suppress natural testosterone production, potentially leading to testicular shrinkage and reduced sperm count.

Selective estrogen receptor modulator

Androgen

Enclomiphene is not approved as a drug in the United States

Depo-Testosterone (testosterone cypionate) is indicated for:

• Replacement therapy in the male in conditions associated with symptoms of deficiency or absence of endogenous testosterone:

  • Primary hypogonadism (congenital or acquired) — testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome; or orchidectomy

  • Hypogonadotropic hypogonadism (congenital or acquired) — gonadotropin or LHRH deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation

• Typically taken orally

• Often prescribed at 6.25 mg, 12.5 mg, and 25 mg doses

• Typically administered intramuscularly every 2–4 weeks

• Comes as an injection

Information about enclomiphene is limited

The following adverse reactions in the male have occurred with some androgens:

• Endocrine and urogenital: Breast tissue growth in men and excessive frequency and duration of penile erections. Oligospermia may occur at high dosages

• Skin and appendages: Hirsutism, male pattern of baldness, seborrhea, and acne

• Cardiovascular disorders: Heart attack, stroke

• Fluid and electrolyte disturbances: Retention of sodium, chloride, water, potassium, calcium, and inorganic phosphates

• Gastrointestinal: Nausea, cholestatic jaundice, alterations in liver function tests, rarely hepatocellular neoplasms and peliosis hepatis

• Hematologic: Suppression of clotting factors II, V, VII, and X, bleeding in patients on concomitant anticoagulant therapy, and polycythemia

• Nervous system: Increased or decreased libido, headache, anxiety, depression, and generalized paresthesia

• Allergic: Hypersensitivity, including skin manifestations and anaphylactoid reactions

• Vascular disorders: Venous thromboembolism

• Special senses: Rare cases of central serous chorioretinopathy (CSCR)

• Miscellaneous: Inflammation and pain at the site of intramuscular injection

Information about enclomiphene is limited

• Known hypersensitivity to the drug

• Males with carcinoma of the breast

• Males with known or suspected carcinoma of the prostate gland

• Women who are pregnant

• Patients with serious cardiac, hepatic or renal disease

• Drug interactions: Androgens may increase sensitivity to oral anticoagulants, concurrent administration of oxyphenbutazone and androgens may result in elevated serum levels of oxyphenbutazone, in diabetic patients the metabolic effects of androgens may decrease blood glucose and insulin requirements

Information about enclomiphene is limited

• Patients with benign prostatic hypertrophy may develop acute urethral obstruction

• Priapism or excessive sexual stimulation may develop

• Oligospermia may occur after prolonged administration or excessive dosage

• Testosterone cypionate should not be used interchangeably with testosterone propionate because of differences in duration of action

• Testosterone cypionate is not for intravenous use

• Patients should be instructed to report any of the following: nausea, vomiting, changes in skin color, ankle swelling, too frequent or persistent erections of the penis

• Hemoglobin and hematocrit levels (to detect polycythemia) should be checked periodically in patients receiving long-term androgen administration

• Serum cholesterol may increase during androgen therapy

• Androgens may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4

• High blood calcium may occur in immobilized patients

• Prolonged use of high doses of androgens (principally the 17-α alkyl-androgens) has been associated with development of hepatic adenomas, hepatocellular carcinoma, and peliosis hepatis

• Geriatric patients treated with androgens may be at an increased risk of developing prostatic hypertrophy and prostatic carcinoma although conclusive evidence to support this concept is lacking

• There have been postmarketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products, such as testosterone cypionate

• Long term clinical safety trials have not been conducted to assess the cardiovascular outcomes of testosterone replacement therapy in men

• Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids

• Edema, with or without congestive heart failure, may be a serious complication in patients with pre-existing cardiac, renal or hepatic disease

• Breast tissue growth in males may develop and occasionally persists in patients being treated for hypogonadism

• The preservative benzyl alcohol has been associated with serious adverse events, including the "gasping syndrome", and death in pediatric patients

• Androgen therapy should be used cautiously in healthy males with delayed puberty

• This drug has not been shown to be safe and effective for the enhancement of athletic performance

• Pregnancy: The use of testosterone in women who are pregnant is contraindicated

• Breastfeeding: Depo-Testosterone is not recommended for use in nursing mothers

Information about enclomiphene is limited. It is the active isomer of clomiphene.

*This information is from the label for brand name Depo-Testosterone^®. See the Full Prescribing Information for more complete information. Testosterone cypionate, the active ingredient in Depo-Testosterone, may also be the active ingredient in other medications, and this information may not be accurate for all medications that include the active ingredient testosterone cypionate.