What is the best course of action for a male patient with fluctuating testosterone levels, elevated luteinizing hormone (LH) and follicle-stimulating hormone (FSH), normal prolactin, and elevated estradiol and sex hormone-binding globulin (SHBG) levels?

Elevated LH with Normal-High Testosterone and Markedly Elevated SHBG

This patient does NOT have testosterone deficiency and should NOT receive testosterone therapy—the elevated LH (17.0 IU/L) with normal-high total testosterone (855-933 ng/dL) indicates compensated primary testicular dysfunction, while the markedly elevated SHBG (122.0 nmol/L) is reducing bioavailable testosterone and driving the compensatory LH elevation. 1, 2

Primary Clinical Assessment

The key to understanding this case is recognizing the interplay between SHBG and the hypothalamic-pituitary-gonadal axis:

• Calculate free testosterone using equilibrium dialysis (gold standard) or calculated free testosterone to determine actual androgen availability, as the elevated SHBG is binding a significant portion of total testosterone 2
• The elevated LH with normal testosterone represents compensated testicular dysfunction, where the testes require supraphysiologic LH stimulation to maintain normal testosterone production—this is a biomarker for deteriorating testicular function but not yet frank hypogonadism 3
• Normal prolactin (3.5 ng/mL) rules out hyperprolactinemia as a cause of gonadal axis dysfunction 1

Understanding the SHBG Elevation

The SHBG level of 122.0 nmol/L (typically normal range 10-57 nmol/L) is creating a functional androgen deficiency despite normal total testosterone:

• Elevated SHBG reduces free testosterone availability, which triggers compensatory LH elevation through reduced negative feedback at the hypothalamic-pituitary level 2, 4
• Common causes of elevated SHBG include: hyperthyroidism, liver disease, aging, certain medications, and genetic factors—these must be systematically evaluated 2
• The slightly elevated estradiol (37.3 pg/mL) may contribute to SHBG elevation, though this level is not dramatically high 4

Diagnostic Algorithm

Step 1: Identify the cause of elevated SHBG 2

• Measure thyroid function tests (TSH, free T4) to exclude hyperthyroidism
• Assess liver function tests to exclude hepatic dysfunction
• Review medications that increase SHBG (anticonvulsants, estrogens)
• Consider genetic causes if other etiologies excluded

Step 2: Confirm free testosterone status 2

• Measure free testosterone by equilibrium dialysis (preferred) or calculate free testosterone index
• If free testosterone is low with symptoms, this represents functional hypogonadism requiring treatment
• If free testosterone is normal, symptoms are unlikely related to androgen deficiency

Step 3: Evaluate for primary testicular pathology 1

• Perform testicular examination for size, consistency, masses, and varicocele
• The elevated FSH (11.1 IU/L, upper normal range) combined with elevated LH suggests mild primary testicular dysfunction
• Consider karyotype testing if testicular volume is reduced or if infertility is a concern

Management Strategy

If free testosterone is LOW (functional hypogonadism):

• For men desiring fertility preservation: Use selective estrogen receptor modulators (SERMs) like clomiphene citrate rather than testosterone replacement, as these will further increase LH/FSH and stimulate endogenous testosterone production while maintaining spermatogenesis 1, 2
• For men not concerned with fertility: Testosterone replacement therapy is appropriate if symptomatic, but recognize that exogenous testosterone will suppress the already-elevated LH and may worsen testicular function over time 1
• Address the underlying SHBG elevation to potentially improve free testosterone without hormonal therapy 2

If free testosterone is NORMAL:

• No testosterone therapy is indicated, as total testosterone is already in the normal-high range and symptoms are unlikely androgen-related 2
• Focus on treating the underlying cause of elevated SHBG to normalize the gonadal axis 2
• The elevated LH represents compensated testicular dysfunction and is a risk factor for future development of primary hypogonadism—monitor annually with repeat testosterone and LH 3

Monitoring Protocol

• Initial follow-up at 1-2 months after addressing SHBG causes or initiating therapy to assess response 2
• Repeat morning total testosterone, free testosterone, LH, FSH, and SHBG at 3-6 month intervals for the first year 2
• Annual monitoring thereafter with attention to development of frank primary hypogonadism (testosterone <300 ng/dL with elevated LH) 3
• If on SERM therapy: Monitor for symptomatic response, testosterone levels, estradiol levels, and hematocrit 2

Critical Pitfalls to Avoid

• Do not initiate testosterone replacement based on elevated LH alone when total testosterone is normal—this represents compensated dysfunction, not deficiency 3
• Do not ignore the markedly elevated SHBG—this is the key abnormality driving the compensatory LH elevation and must be investigated 2, 4
• Do not assume symptoms are androgen-related without confirming low free testosterone, as many symptoms attributed to "low T" have other causes 2
• Do not use testosterone therapy in men desiring fertility—this will suppress spermatogenesis; use SERMs instead 1, 2
• Recognize that elevated LH with normal testosterone predicts future development of primary hypogonadism and requires longitudinal monitoring 3