AIs and SERMs in Male Infertility: Clinical Indications
AIs and SERMs are indicated for infertile men with low serum testosterone, but their benefits are limited compared to assisted reproductive technology (ART), and they should not be used as first-line therapy for idiopathic infertility. 1
Primary Indication: Low Testosterone
Clinicians may use aromatase inhibitors (AIs), selective estrogen receptor modulators (SERMs), human chorionic gonadotropin (hCG), or combinations thereof specifically for infertile men with documented low serum testosterone. 1 This represents a conditional recommendation with Grade C evidence level. 1
Mechanism and Expected Outcomes
AIs (letrozole 2.5 mg/day or anastrozole 1 mg/day) work by inhibiting estradiol production, reducing negative feedback on the hypothalamic-pituitary-gonadal axis, thereby increasing FSH, LH, and testosterone production. 2, 3
Treatment significantly increases sperm concentration, total sperm count, serum testosterone levels, and testosterone-to-estradiol ratio (T/E2). 4, 5
SERMs increase endogenous gonadotropin production through estrogen receptor blockade, with similar hormonal effects. 6
Full spermatogenic effects require at least 74 days (approximately 2.5 months) since this is the duration of the spermatogenic cycle. 7, 8
Limited Role in Idiopathic Infertility
For men with idiopathic infertility, clinicians must inform patients that SERMs have limited benefits relative to ART results. 1 This is critical counseling that should occur before initiating empiric therapy. The evidence shows only modest improvements in semen parameters and pregnancy rates with SERMs in this population. 6
Non-Obstructive Azoospermia (NOA): Minimal Evidence
Patients with NOA should be informed of the limited data supporting pharmacologic manipulation with SERMs, AIs, and gonadotropins prior to surgical intervention. 1 This represents a conditional recommendation with Grade C evidence level. 1 Despite limited evidence, some case series report return of sperm to the ejaculate in men with non-obstructive azoospermia treated with AIs. 3
Critical Contraindication
Testosterone monotherapy must never be prescribed for males interested in current or future fertility, as it suppresses spermatogenesis through negative feedback on the hypothalamic-pituitary axis. 1, 6 This is a clinical principle, not merely a recommendation.
Specific Patient Selection Criteria
Best Candidates for AI/SERM Therapy:
Men with low serum testosterone AND abnormal T/E2 ratio (indicating excess aromatase activity). 2, 3
Obese men with hypogonadism symptoms, as obesity increases aromatase activity and can be improved with AI treatment. 2
Men with elevated FSH (>7.6 IU/L) suggesting testicular dysfunction but who still have some spermatogenic potential. 7
Poor Candidates:
Men with idiopathic infertility and normal testosterone levels should be counseled that ART offers superior outcomes. 1
Men with severe oligoasthenoteratozoospermia (OAT) syndrome should be directed toward ICSI as the most reliable path to pregnancy. 8
Practical Treatment Algorithm
Measure baseline hormones: testosterone, estradiol, FSH, LH to identify low testosterone and calculate T/E2 ratio. 7, 2
If low testosterone with abnormal T/E2 ratio: Consider AI therapy (anastrozole 1 mg/day or letrozole 2.5 mg/day) or SERM therapy. 1, 4, 3
Monitor response: Repeat semen analysis after at least 2.5 months (74 days) to assess spermatogenic response. 7, 8
If inadequate response or time-sensitive fertility: Transition to ART (IVF/ICSI), which provides superior pregnancy outcomes. 1, 8
Important Caveats
For men planning assisted reproduction, discontinuing AIs for 2-7 days prior to sperm retrieval may increase fertilization success rates. 4
Genetic polymorphisms of the aromatase gene (CYP19A1) influence treatment efficacy, though routine testing is not yet standard. 2
Side effects are generally mild and well-tolerated with both AIs and SERMs. 2, 5
Medical treatments may delay more effective ART options, emphasizing the importance of timely counseling about realistic expectations. 8