What is the management approach for a male patient with normal Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH) levels and low free testosterone?

Management of Normal FSH and LH with Low Free Testosterone

Men with low free testosterone and normal FSH/LH levels have secondary (hypogonadotropic) hypogonadism and should be offered testosterone replacement therapy after confirming the diagnosis with repeat morning measurements and ruling out reversible causes, particularly hyperprolactinemia and thyroid dysfunction. 1

Diagnostic Confirmation

Initial Laboratory Assessment

• Confirm low testosterone with repeat morning measurements on at least two separate occasions to establish persistent testosterone deficiency before initiating treatment 1, 2
• Measure serum prolactin levels in all patients with low testosterone combined with low or low/normal LH levels to screen for hyperprolactinemia, which is a reversible cause of secondary hypogonadism 1, 3
• Check TSH and free T4, as primary hypothyroidism causes hypogonadotropic hypogonadism that reverses with thyroid hormone replacement 4
• Measure sex hormone-binding globulin (SHBG) to understand testosterone binding dynamics, particularly in obese men who may have low SHBG 5

Critical Imaging Considerations

• Men with total testosterone <150 ng/dL combined with low or low/normal LH should undergo pituitary MRI regardless of prolactin levels, as non-secreting adenomas may be present 1
• If prolactin is elevated on repeat testing, refer immediately to endocrinology and obtain pituitary MRI to evaluate for prolactinoma 1

Pre-Treatment Evaluation

Fertility Assessment

• Men interested in preserving fertility should NOT receive testosterone replacement therapy, as it suppresses spermatogenesis through negative feedback 1, 6
• For fertility-desiring patients, consider selective estrogen receptor modulators (SERMs) like clomiphene citrate as first-line therapy to stimulate endogenous testosterone production while maintaining spermatogenesis 1, 5
• Alternatively, gonadotropin therapy (hCG combined with FSH) can promote testicular growth and spermatogenesis in approximately 80% of patients with hypogonadotropic hypogonadism over 12-24 months 3

Cardiovascular and Hematologic Screening

• Measure baseline hemoglobin/hematocrit before initiating testosterone therapy 1
• Withhold testosterone if baseline hematocrit exceeds 50% until the etiology is investigated 1
• Assess all patients for atherosclerotic cardiovascular disease (ASCVD) risk factors including dyslipidemia, hypertension, diabetes, and smoking 1

Prostate Screening

• Measure PSA in men over 40 years of age prior to testosterone therapy to exclude prostate cancer 1
• Measure serum estradiol in patients presenting with breast symptoms or gynecomastia before starting treatment 1

Treatment Initiation

Testosterone Replacement Therapy

• The recommended starting dose is 40.5 mg of testosterone gel 1.62% (2 pump actuations) applied topically once daily in the morning to shoulders and upper arms 2
• Doses can be adjusted between 20.25 mg (minimum) and 81 mg (maximum) based on pre-dose morning serum testosterone levels 2
• Injectable testosterone is associated with the greatest treatment-induced increases in hemoglobin/hematocrit compared to other formulations 1

Expected Benefits

• Patients should be informed that testosterone therapy may improve erectile function, low sex drive, anemia, bone mineral density, lean body mass, and depressive symptoms 1
• In clinical trials, 81.6% of patients achieved average testosterone concentrations within the normal range (300-1000 ng/dL) by Day 112 of treatment 2

Monitoring Protocol

Dose Titration Schedule

• Check pre-dose morning serum testosterone at approximately 14 days and 28 days after starting treatment or following dose adjustment 2
• Target pre-dose testosterone concentration: 350-750 ng/dL 2
• If testosterone >750 ng/dL: decrease daily dose by 20.25 mg 2
• If testosterone <350 ng/dL: increase daily dose by 20.25 mg 2
• Continue periodic testosterone assessments thereafter 2

Safety Monitoring

• Hematocrit >54% warrants intervention such as dose reduction or temporary discontinuation 1
• Monitor for polycythemia, as this is the most common adverse effect requiring dose adjustment 1
• Assess for symptomatic gynecomastia or breast symptoms; these sometimes abate with continued monitoring 1
• LH and FSH levels will decrease with testosterone treatment due to negative feedback, which is expected and physiologically appropriate 2, 7

Common Pitfalls and Caveats

Secondary Exposure Prevention

• Children and women must avoid contact with unwashed or unclothed application sites, as virilization has been reported in children secondarily exposed to testosterone gel 2
• Application site should be limited to areas covered by a short-sleeve t-shirt 2
• Patients should wash hands immediately after application and cover application sites with clothing 2

Obesity Considerations

• In obese men, increased aromatization of testosterone to estradiol in adipose tissue causes estradiol-mediated negative feedback that suppresses pituitary LH secretion 5
• Weight loss can improve functional hypogonadism in obese men and should be emphasized alongside hormonal therapy 5
• Weight loss is more effective than aromatase inhibitors for managing elevated estradiol in obese men 5

Reversible Causes Must Be Excluded

• Primary hypothyroidism causes reversible hypogonadotropic hypogonadism; thyroid hormone replacement normalizes free testosterone concentrations 4
• Hyperprolactinemia suppresses GnRH pulsatility leading to low LH/FSH; treating the underlying cause (such as prolactinoma) may restore normal testosterone production 1
• The pituitary-testicular axis maintains physiological negative feedback even in hypogonadotropic hypogonadism, so persistently elevated gonadotropins during testosterone replacement suggest inadequate dosing 7