OR16-5 Feedback on LH in Testosterone-Clamped Men Depends on the Mode of Testosterone Administration and Body Composition

Context. Investigations of testosterone (T)-mediated feedback on LH secretion are few and contradictory. Discrepancies may reflect the choice of androgen, as well as dose, route and/or pattern (continuous vspulsatile) of administration. Moreover, for controlled T feedback studies, endogenous T secretion must be shut down and replaced by iv T infusion. Objective. The goal of this study was to quantify feedback in relation to the infused T pattern (pulsatile vs nonpulsatile) with the hypotheses that: 1) feedback by T pulses is less inhibitory, 2) T feedback operates partly at the pituitary level, 3) T feedback is controlled in part by body composition. Design. This was a placebo-controlled, blinded, and prospectively randomized crossover study comprising 16 men (age range 23-54 yr and BMI between 22.3-34.2 kg/m(2)). Subjects received ketoconazole (1600 mg over 22 h to block endogenous T secretion: serum T below 85 ng/dL) followed by pulsatile or continuous iv T addback (total T dose 5 mg/22 h). Cortisol inhibition was treated with low-dose dexamethasone.   Setting. The study was performed in a Clinical Translational Research Unit. Interventions. Subjects underwent 14 h of blood sampling at 10-min intervals, starting at 0600 h. T was given continuously starting at 0900 h or as 45-min squarewave pulses every 90 min. To test pituitary feedback, a bolus iv injection of 33 ng/kg GnRH was given at 1630 h. Outcome measures. Log-transformed LH and T concentration ratios before and after GnRH administration. In addition, a four-parameter logistic regression between serum T concentration and LH secretion rate (calculated by deconvolution analysis) was used to independently estimate feedback of T on LH. Results. Despite higher T (total, bioavailable and free T) concentrations during pulsatile feedback, LH concentrations and secretion rates, whether driven by endogenous or exogenous GnRH, were similar to those during continuous infusion, indicating diminished pulsatile T feedback. This interpretation was corroborated by the right-shift (i.e. towards higher T concentrations) of the T-LH inhibitory dose-response curve. During continuous and pulsatile T infusion, LH concentrations and LH:T ratios depended positively on BMI to a similar extent before and after GnRH administration.  Under both feedback regimens, basal but not pulsatile LH secretion correlated negatively with CT-estimated abdominal visceral fat mass. Age was not a significant covariate over the limited range explored. Conclusion. In summary, pulsatile T is less effective as a negative feedback signal on LH secretion than continuous T administration, as demonstrated by two independent methods. This difference in feedback strength was evident for exogenous GnRH-stimulated LH release as well, and thus occurs probably in part at the pituitary level, while not excluding additional hypothalamic involvement.