What are the common side effects of Clomiphene (clomifene citrate) in women of childbearing age with a history of infertility or polycystic ovary syndrome (PCOS) and in men with low testosterone or infertility?

Clomiphene Side Effects

Clomiphene citrate is generally well tolerated, but common side effects include ovarian enlargement (13.6%), hot flashes (10.4%), abdominal bloating (5.5%), nausea (2.2%), breast discomfort (2.1%), visual symptoms (1.5%), and headache (1.3%), with most adverse effects being mild and transient. 1

Most Common Side Effects in Women

Reproductive System Effects

• Ovarian enlargement occurs in 13.6% of patients and represents the most frequent adverse effect, which can be complicated by ovarian cysts, adnexal torsion, or ovarian hemorrhage 1
• Ovarian hyperstimulation syndrome is a potentially serious complication, particularly with multifollicular development, and requires careful monitoring 2, 3
• Abnormal uterine bleeding affects 1.3% of patients, including intermenstrual spotting and menorrhagia 1

Vasomotor and General Symptoms

• Hot flashes (vasomotor flushes) occur in 10.4% of patients and are among the most bothersome symptoms 1
• Abdominal-pelvic discomfort, distention, or bloating affects 5.5% of patients 1
• Nausea and vomiting occur in 2.2% of cases 1
• Breast discomfort is reported in 2.1% of patients 1

Visual Disturbances

• Visual symptoms affect 1.5% of patients and include blurred vision, lights, floaters, waves, photophobia, diplopia, scotomata, and phosphenes 1
• Post-marketing reports include more serious visual disorders such as macular edema, optic neuritis, retinal hemorrhage, retinal thrombosis, and temporary or prolonged loss of vision that may be irreversible 1
• Headaches occur in 1.3% of patients 1

Less Common but Important Side Effects

Metabolic Effects

• Clomiphene can alter serum lipid profiles, which requires consideration in patients with cardiovascular risk factors 2, 3
• Elevated serum desmosterol levels may occur with prolonged therapy due to direct interference with cholesterol synthesis 1
• Estradiol levels are significantly increased following clomiphene treatment 4

Psychiatric Effects

• Depression, nervous tension, mood changes, anxiety, irritability, and psychosis have been reported 1
• In men, mood changes can be severe enough to impair work function, with symptoms including anxiety, decreased appetite, and mood alterations appearing as early as five days after treatment initiation 5
• These psychiatric symptoms typically resolve within one week of discontinuation 5

Reproductive Complications

• Multiple pregnancy rate is elevated at approximately 10%, which is a significant consideration when counseling patients 6
• Endometrial dysfunction and adverse effects on cervical mucus may paradoxically impair fertility in some women 7
• Thinner endometrial thickness compared to gonadotropin treatment, though this does not appear to affect pregnancy rates 8

Serious but Rare Adverse Events

Cardiovascular

• Acute myocardial infarction has been reported in young women without traditional cardiac risk factors, associated with coronary artery thrombosis 9
• This represents a life-threatening complication that physicians must be aware of, particularly in patients with any cardiovascular risk factors 9

Oncologic Concerns

• Ovarian cancer has been infrequently reported in patients receiving fertility drugs 1
• While infertility itself is a primary risk factor for ovarian cancer, epidemiologic data suggest that prolonged use of clomiphene may increase the risk of borderline or invasive ovarian tumors 1
• Post-marketing reports include various neoplasms affecting multiple organ systems, though causality is difficult to establish 1

Congenital Anomalies

• Post-marketing reports include various congenital malformations such as neural tube defects, cardiac abnormalities, Down syndrome, cleft lip and palate, and limb abnormalities (ectromelia including amelia, hemimelia, and phocomelia) 1

Hepatic

• Transaminase elevation and hepatitis have been reported 1
• Clomiphene is contraindicated in patients with liver disease, especially decompensated cirrhosis 2, 3

Side Effects in Men (Off-Label Use)

Common Effects

• In men treated for hypogonadism, only 8% reported side effects when used for more than 3 years 4
• The most common side effects in men include mood changes (reported in 5 patients), blurred vision (3 patients), and breast tenderness (2 patients) in a cohort treated for extended periods 4
• Psychiatric effects can be particularly problematic in men, with anxiety, decreased appetite, and mood changes severe enough to require treatment discontinuation 5

Safety Profile

• Long-term use (up to 84 months) appears safe in men, with 88% achieving eugonadism and 77% reporting improved symptoms 4
• No significant adverse events were reported in any patient treated with clomiphene for hypogonadism in long-term studies 4

Critical Contraindications and Precautions

• Contraindicated in patients with liver disease, especially decompensated cirrhosis 2, 3
• Should only be used when sufficient endogenous estrogen levels are present (not appropriate for hypogonadotropic hypogonadism) 2, 3
• Visual disorders represent a contraindication to continued use 7
• Risk of congenital anomalies should be discussed with patients 7

Clinical Monitoring Recommendations

• Lower doses (50 mg) should be used initially to minimize multiple follicular development and reduce multiple pregnancy risk, as side effects are avoided and efficacy is similar to 100 mg doses 3, 7
• Close monitoring for mood changes is essential, especially during the initial weeks of treatment 5
• Patients should be advised to report visual symptoms immediately, as these may indicate serious complications requiring discontinuation 1
• Cardiovascular risk factors should be assessed before initiating therapy, given rare but serious reports of myocardial infarction 9