Inhibition of luteinizing hormone secretion by testosterone in men requires aromatization for its pituitary but not its hypothalamic effects: evidence from the tandem study of normal and gonadotropin-releasing hormone-deficient men.
Level 3 - non-randomized controlled study
Prospective non-randomized interventional controlled study
PubMed 18073301 · doi:10.1210/jc.2007-2156
What was done
A prospective three-arm interventional physiological study investigated the hypothalamic versus pituitary sites of negative feedback of testosterone (T) and estradiol (E2) on luteinizing hormone (LH). Thirty-three men (22 normal men and 11 men with GnRH deficiency due to idiopathic hypogonadotropic hypogonadism [IHH]) underwent medical castration and aromatase inhibition using high-dose ketoconazole for 7 days. Participants received either: 1) no sex steroid add-back; 2) testosterone enanthate (125 mg IM) starting on day 4; or 3) estradiol transdermal patches (37.5 µg/day) starting on day 4. Frequent blood sampling was conducted every 10 minutes for 12 hours at baseline, days 3–4, and days 6–7 to measure mean LH, LH pulse amplitude, and GnRH pulse frequency.
What was found
In normal men, ketoconazole increased mean LH 3-fold on days 3–4. Testosterone add-back reduced mean LH from 34.6 ± 3.9 to 17.4 ± 3.6 IU/L (P < 0.05) by slowing GnRH pulse frequency from 13.3 ± 0.4 to 6.7 ± 1.0 pulses/12 h (P < 0.005), while LH pulse amplitude increased from 6.9 ± 1.0 to 12.1 ± 1.4 IU/L (P < 0.005). Estradiol add-back reduced mean LH from 36.4 ± 5.6 to 19.0 ± 2.4 IU/L (P < 0.005) by slowing GnRH pulse frequency from 11.4 ± 0.2 to 8.6 ± 0.4 pulses/12 h (P < 0.05), with no effect on LH pulse amplitude. In IHH men, testosterone add-back caused no suppression of mean LH levels or LH amplitude, whereas estradiol normalized mean LH and decreased LH pulse amplitude from 14.7 ± 1.7 to 12.0 ± 1.5 IU/L (P < 0.05).
Why it matters
This study demonstrates that testosterone inhibits LH secretion directly at the hypothalamus through androgenic pathways without requiring aromatization, whereas its pituitary negative feedback action depends entirely on conversion to estradiol.
Limits
The sample size is small (n = 33 across three arms). The intervention duration was short (7 days), which may not reflect chronic feedback mechanisms. The abstract does not specify whether arm allocation was randomized.
Cited by
- supports In males, negative feedback to the hypothalamus and pituitary regulating gonadotropin and testosterone production is primarily mediated by estradiol produced through aromatization, rather than by testosterone directly.