Aims

Men with chronic pain and depression frequently develop FHH, which may be associated with opioid exposure, psychotropic medications, obesity, alcohol excess, sleep disturbance, and hypothalamic-pituitary suppression. These patients commonly present with fatigue, weakness, reduced libido, and low serum testosterone concentrations (ST), and are often treated with testosterone replacement therapy (TRT) that may further suppress gonadotrophin secretion and lead to prolonged TRT dependence. Clomiphene citrate blocks oestrogen-mediated negative feedback at the hypothalamus and pituitary (HP axis), stimulating endogenous luteinising hormone (LH) and follicle-stimulating hormone (FSH) secretion, thereby increasing endogenous testosterone production.

Methods

Twelve men with FHH defined by ST below the lower limit of the assay (<9.5 nmolL) and chronic pain and/or depression received clomiphene citrate 50 mg daily for four weeks. Exclusion criteria included previous anabolic steroid exposure, hyperprolactinaemia, hypothalamic-pituitary tumours, CKD, liver disease, or malignancy. ST, LH, and FSH were measured before/after treatment. Results are presented as mean ± SD and compared using paired Student T-test.

Results

Mean ST increased from 5.1 ± 2.3 nmol/L to 21.4 ± 6.1 nmol/L, representing a mean increase of 16.2 nmol/L (p < 0.0001), with ST normalising (9.5 to 28 nmol/L) in 100%. Mean FSH increased from 3.9 ± 2.4 to 8.2 ± 4.8 IU/L (p = 0.001) and mean LH from 2.8 ± 2.0 to 6.0 ± 2.6 IU/L (p = 0.0004). No patient developed drug-related adverse events. No significant improvements were reported in libido or fatigue. 

Conclusion

Four weeks of clomiphene citrate 50 mg daily normalised ST, LH and FSH in all men with FHH associated with chronic pain and depression reflecting a restoration of endogenous hypothalamic-pituitary-gonadal axis activity. Clomiphene citrate represents a simple, fertility-preserving therapeutic option that may reduce the need for TRT in appropriately selected patients.