Reproductive Aging and Obstructive Sleep Apnea

• Hypothesis 1: Reduced hypothalamic gonadotropin-releasing hormone (GnRH) outflow in older men underlies the reduced mass of luteinizing hormone (LH) pulses, and is further reduced in men with untreated OSA. The investigator aim to test hypothalamic function by examining the decrement of pulsatile LH secretion to a submaximally inhibitory dose of a selective GnRH-receptor antagonist, ganirelix, in men with untreated (i.e. active) and treated OSA. This decrement will be regressed on age, and a significant reduction in slope with active OSA (vs treated OSA) indicates disease attenuation.
• Hypothesis 2: Untreated OSA further attenuates the age-related erosion of testosterone's negative-feedback control of LH. The investigators aim to assess pituitary function by quantitating LH secretion under enforced androgen deprivation, in men with active and treated OSA. Slopes obtained by age regressions will be compared.
• Hypothesis 3: Impaired Leydig-cell steroidogenesis causes hypoandrogenemia in older men, but the effect of untreated OSA in humans is entirely unknown. Hence the investigators aim to assess testicular function by examining testosterone secretion during experimentally controlled pulsatile i.v. infusion of recombinant human LH under maximal GnRH-receptor blockade, in men with active and treated CPAP. Slopes will again be compared.

Accordingly the immediate goal is to characterize all four of hypothalamic, pituitary, testicular and feedback-dependent control of LH and testosterone secretion to determine which primary mechanism(s) occur(s) and drive(s) alterations at the other loci, in any given subject. To meet this challenge, the investigators will implement an innovative comprehensive analytical platform, that correctly embodies time-lagged, dose-dependent and nonlinear signaling among GnRH, LH and testosterone. To ensure the necessary age continuum, volunteers whose ages span 30-70 years will be study with 3-4 men per decade of life (16 men in total). To assess disease effects, the investigators will compare age regressions between men with active OSA (on sham therapy) against these same men being treated with real CPAP, and if feasible, with a convenient sample of 16 other individually age- and BMI- matched (±2.5 years and ±2.5 kg/m2) normal controls that will be selected from a larger cohort of 100 men being identified in Rochester -Minnesota (MN). The within subject cross-over design controls for possible known and unknown confounders, however BMI will be also restricted and exclude men with diabetes mellitus (by HbA1c).

Study Subject Recruitment: 16 men with OSA will be recruited aged 30-70 years, using the same entry criteria and age range utilized to generate our preliminary data 42. Additionally, body mass index will be restricted to 30-35 kg/m2. Volunteers will be recruited from clinics at University of California, Los Angeles (UCLA) -affiliated medical centers at Harbor and Santa Monica and by advertisement.

Study Design: Randomized sham-controlled cross-over trial, each period of 3 months duration and with one month washout. This design replicates a recently completed study. Another comparable study recently completed in California (and elsewhere in the USA) involved 6 months sham treatment, and many of the 1105 adults recruited had severe OSA.

Dynamic Testing of the Male Gonadal Axis: Enrolled subjects undergo repetitive sampling of peripheral blood (1.5 mL) every 10-min for 5 hr from 0800-1300 h [2 outpatient protocols], for 15 hr overnight (2200 - 1300h) and for 22 hr overnight (1500 - 1300h). Polysomnography (2200-0600h) is performed during the 2 inpatient visits. A terminal i.v. bolus injection of GnRH (100 ng/kg) is given at 1100h during all 4 visits to calibrate endogenous GnRH response. Ganirelix (or saline) is given at 2000h or 1500h: hypothalamic function is tested by partial (submaximal) ganirelix blockade of endogenous GnRH. Oral medications (Δ) are placebo except during pituitary testing when response of LH to androgen depletion is enforced by ketoconazole (KTCZ) with adrenal rescue with dexamethasone (DEX). Here, KTCZ (1000mg) and DEX (0.75mg) are given at 2000h, KTCZ (400mg) at 0800h and DEX (0.75mg) at 1300h. Testis function is assessed by testosterone response to a fixed exogenous LH stimulus: 6 pulses of rh LH (18.75 IU each) every 2 hrs. from 2300h under maximal ganirelix blockade of endogenous LH.