Progesterone regulation of diurnal GnRH pulse frequency in girls across puberty - the impact of physiological increase in androgens

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 548-560-Hyperandrogenic Disorders
Basic/Clinical
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-560
Ruchi Bhabhra*1, Amy Denise Anderson2, Jessicah S. P. Collins2, Christine Michele Burt Solorzano1, John C Marshall2 and Christopher Rolland McCartney2
1Division of Endocrinology, University of Virginia, Charlottesville, VA, 2University of Virginia, Charlottesville, VA
Early puberty is characterized by sleep-entrained increases of LH (by inference GnRH) pulse frequency and amplitude, with minimal daytime (awake) LH pulsatility: the regulatory mechanisms are unknown. Progesterone (P) inhibits the GnRH pulse generator in adult women. In early pubertal girls, P increases 2.3 fold overnight and we hypothesize that higher AM concentrations of P contribute to slow daytime (awake) LH pulse frequency. Exogenous P abolishes daytime LH pulses in early pubertal girls with no effect on nocturnal LH frequency suggesting differential regulation of GnRH frequency depending on sleep status. As puberty progresses daytime LH pulse frequency gradually increases while nocturnal frequency is unchanged. In adult women with hyperandrogenemia (HA), the GnRH pulse generator is less sensitive to feedback inhibition by P, and is reversed by flutamide (androgen receptor antagonist), indicating a role of testosterone (T) in reduced sensitivity to P inhibition. In normal pubertal girls, early AM free T gradually increases during puberty; mean free T = 3.2 pmol/L (Tanner 1), 5.0 pmol/L (Tanner 2), 7.4 pmol/L (Tanner 3), and 12.8 pmol/L (Tanner 4-5). We propose that the normal increase of T across puberty reduces the daytime sensitivity of the GnRH pulse generator to P inhibition, allowing a gradual increase in daytime pulse frequency. In 22 normal weight girls (Tanner 1-3) LH pulse frequency was determined via q 10 min sampling between 1900 to 0700 h. LH pulses were determined in 4-h time blocks, with 1900-2300 h (awake) representing daytime. Eight subjects received 2-3 doses of exogenous P to achieve a mean P of 4.83 ng/mL. In girls not receiving P (n=14), those with free T <4.5 pmol/L (n=9) had few LH pulses (mean ± SEM = 0.6 ± 0.3), while those with free T >4.5 pmol/L (n=5) had more LH pulses (1.8 ± 0.5) during 1900-2300 h. Mean P levels (and overnight rise) were similar in both groups. In girls receiving P, those with free T <4.5 pmol/L (n=4) had no LH pulses during 1900 - 2300 h (awake). In contrast, among girls with free T >4.5 pmol/L (n=4), only 2 girls with the highest T levels showed LH pulse activity: 1 and 4 LH pulses with AM free T of 9.1 and 27 pmol/L, respectively. These data suggest that P plays a role in regulating daytime (awake) GnRH pulsatility in early puberty and that rising T concentrations during puberty antagonize P-mediated suppression of daytime GnRH pulses, allowing the selective increase of daytime GnRH pulse frequency.

Nothing to Disclose: RB, ADA, JSPC, CMB, JCM, CRM

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