Why are luteinizing hormone and follicle‑stimulating hormone low in men receiving intramuscular testosterone therapy, and how should this be managed, especially if fertility preservation is desired?

Low LH and FSH in Patients on IM Testosterone

Intramuscular testosterone therapy suppresses LH and FSH through negative feedback inhibition of the hypothalamic-pituitary-gonadal axis, and if fertility preservation is desired, testosterone must be discontinued and replaced with hCG-based therapy.

Mechanism of Gonadotropin Suppression

Exogenous testosterone administration directly inhibits pituitary secretion of both LH and FSH through negative feedback mechanisms. 1 This suppression occurs through two pathways:

• Direct pituitary inhibition: Testosterone itself exerts negative feedback at the pituitary level, with approximately half of this effect mediated through aromatization to estradiol 2
• Hypothalamic suppression: At supraphysiologic doses, testosterone also inhibits hypothalamic GnRH secretion 1

The degree of suppression varies by testosterone formulation:

• Long-acting intramuscular injections (enanthate, cypionate, undecanoate) decrease FSH by 86.3% and LH by 71.8% 3
• Intermediate-acting transdermal preparations decrease FSH by 60.2% and LH by 59.2% 3
• Short-acting intranasal formulations decrease FSH by 37.8% and LH by 47.3% 3

Clinical Timeline of Suppression

Gonadotropin suppression begins within days of testosterone administration and progresses over the first week:

• LH and FSH levels begin declining by day 5 after a single 125mg intramuscular injection of testosterone enanthate 4
• In men with hypogonadotropic hypogonadism treated with testosterone replacement, FSH suppresses from baseline 2.8 IU/L to 1.1 IU/L, and LH suppresses from 2.3 IU/L to 0.8 IU/L 5
• Approximately 73% of men on testosterone therapy will have at least one LH measurement <1.0 IU/L during treatment, though only 22% maintain complete suppression throughout 6

Critical pitfall: The variability in LH suppression means some men maintain detectable gonadotropin levels despite testosterone therapy, but this does not indicate preserved fertility—spermatogenesis is still severely impaired 6

Impact on Fertility

Testosterone-induced gonadotropin suppression leads to profound impairment of spermatogenesis, potentially causing azoospermia. 7

• Intratesticular testosterone concentrations are 50-100 times higher than serum levels and are essential for spermatogenesis 7
• These concentrations are maintained by LH stimulation of Leydig cells, independent of circulating testosterone 7
• When exogenous testosterone suppresses LH, intratesticular testosterone production ceases, eliminating the hormonal environment required for sperm production 7

Recovery after testosterone discontinuation is unpredictable and may take months to years, with no guarantee of return to baseline fertility 7

Management When Fertility is Desired

If current or future fertility is a concern, testosterone therapy must be discontinued immediately and alternative treatments initiated. 7

Step 1: Discontinue Testosterone

• Stop all forms of exogenous testosterone (intramuscular, transdermal, intranasal) 7
• Allow 2-3 months for testosterone clearance before initiating fertility-directed therapy 7

Step 2: Initiate hCG-Based Therapy

Human chorionic gonadotropin (hCG) substitutes for LH and stimulates endogenous testosterone production while preserving fertility potential:

• hCG stimulates Leydig cells to produce androgens, maintaining intratesticular testosterone concentrations necessary for spermatogenesis 8
• Treatment with hCG followed by FSH analogues successfully initiates spermatogenesis in 75% of men with hypogonadotropic hypogonadism 7
• hCG response correlates with baseline testicular size—larger testes predict better response 7

Step 3: Add FSH if Needed

• If sperm counts remain low after testosterone normalizes on hCG monotherapy, add recombinant or urinary FSH preparations 7, 9
• FSH analogues may improve sperm concentration in men with idiopathic oligozoospermia, though benefits are modest 7

Step 4: Consider Assisted Reproductive Technology

IVF/ICSI offers superior pregnancy rates compared to empiric hormonal therapy and should be discussed early, particularly given female partner age considerations. 7

Monitoring Recommendations

For men who must continue testosterone therapy despite fertility concerns:

• Measure FSH, LH, and testosterone levels at 1-2 months after initiation 10
• Intramuscular formulations require closer monitoring due to greater gonadotropin suppression 3, 6
• Baseline estradiol levels predict degree of LH suppression—higher estradiol correlates with greater suppression 6

Critical warning: Never prescribe testosterone to men desiring fertility, as it provides negative feedback to the hypothalamus and pituitary, suppressing gonadotropin secretion and potentially causing azoospermia that takes months to years to recover 7

Fertility Preservation Strategy

Men with any future fertility concerns should bank sperm before initiating testosterone therapy:

• Collect 2-3 separate ejaculates with 2-3 days abstinence between collections 7
• Split each collection into multiple vials to allow staged use 7
• Once azoospermia develops on testosterone, even microsurgical testicular sperm extraction (micro-TESE) only achieves 40-50% retrieval rates 7