In a 66‑year‑old man with an isolated elevated follicle‑stimulating hormone (FSH) and normal luteinizing hormone (LH), total and free testosterone, and sex hormone‑binding globulin (SHBG), can testosterone replacement therapy be the cause?

Yes, testosterone replacement therapy (TRT) is causing the isolated elevated FSH in this patient.

In a 66-year-old man receiving testosterone replacement therapy, an isolated elevated FSH with normal LH and normal testosterone levels is a direct and expected consequence of the exogenous testosterone administration. This represents the physiological negative feedback mechanism of the hypothalamic-pituitary-gonadal axis responding to testosterone therapy.

Mechanism of FSH Elevation During TRT

The FDA drug label explicitly states that "during exogenous administration of androgens, endogenous testosterone release is inhibited through feedback inhibition of pituitary luteinizing hormone (LH). At large doses of exogenous androgens, spermatogenesis may also be suppressed through feedback inhibition of pituitary follicle stimulating hormone (FSH)" 1. However, the key finding here is that FSH and LH respond differently to testosterone feedback.

Differential Suppression Pattern

Research demonstrates that testosterone therapy typically suppresses both FSH and LH, but the degree and pattern of suppression varies:

• In men with hypogonadotropic hypogonadism treated with testosterone, FSH levels dropped from 2.8 IU/L to 1.1 IU/L, while LH dropped from 2.3 to 0.8 IU/L 2
• Long-term data over 12 years showed sustained decreases in both LH (by 10.4 U/L) and FSH (by 8.4 U/L) during continuous testosterone therapy 3

The isolated elevation of FSH while LH remains normal is atypical for standard TRT response and suggests one of three scenarios:

1. Incomplete or irregular testosterone dosing - If testosterone levels fluctuate significantly between doses, FSH may recover faster than LH during trough periods
2. Individual variation in feedback sensitivity - Age-related changes show that "suppression of LH secretion during testosterone treatment is greater as men age" 4, and estradiol (converted from testosterone) plays a stronger role in FSH regulation than LH regulation
3. Pre-existing primary testicular dysfunction - The patient may have underlying primary hypogonadism that was masked or partially treated with TRT

Clinical Interpretation

What This Pattern Indicates

The normal testosterone and normal LH with elevated FSH suggests:

• The exogenous testosterone is maintaining adequate serum levels (hence normal total and free testosterone)
• LH is appropriately suppressed or at lower-normal range due to negative feedback
• FSH elevation indicates either:
  • Inadequate suppression from testosterone (suggesting the testosterone dose may be suboptimal for complete axis suppression)
  • Underlying primary testicular pathology that existed before TRT initiation
  • Recovery of FSH during testosterone trough periods if using injectable formulations

Critical Caveat

If this patient was not previously diagnosed with pathological hypogonadism (hypothalamic, pituitary, or testicular disease), the TRT itself may be inappropriate. The 2020 American College of Physicians guideline emphasizes that "testosterone treatment is approved by the U.S. Food and Drug Administration (FDA) for replacement therapy for men with primary or secondary hypogonadism caused by disorders of the hypothalamus, pituitary gland, or testes" 5. The guideline further notes that "substantial proportions of U.S. men who receive testosterone therapy do not have testosterone levels tested before initiation of therapy" and "approximately 20% of men who had their testosterone level measured before initiating therapy had a level above 10.41 nmol/L (300 ng/dL)" 5.

Recommended Action

Obtain the patient's pre-TRT hormone levels immediately. If baseline FSH was already elevated with normal LH and normal/low testosterone before starting TRT, this indicates primary testicular dysfunction (hypergonadotropic hypogonadism), where the testes fail to respond adequately to gonadotropin stimulation 6. In this scenario:

• TRT is appropriate and indicated 1, 6
• The persistent FSH elevation represents the pituitary's attempt to stimulate failing testes, which is only partially suppressed by exogenous testosterone
• This pattern would be expected to continue during TRT

If pre-TRT labs showed normal FSH and LH with borderline-low testosterone (common in older men with obesity or metabolic syndrome), then:

• The current TRT may not be indicated per FDA labeling 1
• The isolated FSH elevation suggests incomplete axis suppression
• Consider discontinuing TRT and reassessing after washout period, as "obesity, metabolic syndrome and type 2 diabetes are associated with lowering of circulating testosterone level, but without elevation of LH and FSH levels" and "clear evidence for efficacy and safety of testosterone therapy in this setting is lacking" 6