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Time Mode of Growth Hormone (GH) Entry into the Bloodstream and Steady-State Plasma GH Concentrations, Rather Than Sex, Estradiol, or Menstrual Cycle Stage, Primarily Determine the GH Elimination Rate in Healthy Young Women and Men¹

Division of Endocrinology and Metabolism, Department of Internal Medicine, and National Science Foundation Center for Biological Timing, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Dr. J. D. Veldhuis, Division of Endocrinology and Metabolism, Department of Internal Medicine, Box 202, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908. E-mail: jdv{at}virginia.edu

We have investigated whether a reduced MCR of GH in women will account for their higher serum GH concentrations premenopausally compared with those in men. To this end, we directly compared the half-life (t_1/2) of GH and its volume of distribution (V_o) in 13 young men and 6 comparably aged women, each evaluated at three stages of the normal menstrual cycle (viz. the early follicular, late follicular, and midluteal phases). To estimate nonequilibrium GH kinetics, each subject received octreotide pretreatment to suppress endogenous GH release and then 3 randomly ordered iv bolus doses of recombinant human GH (1, 2, and 4 µg/kg). The resultant peak serum GH concentrations were 18 ± 4, 36 ± 8, and 70 ± 9 µg/L in six women and 17 ± 2, 30 ± 4, and 84 ± 25 µg/L in six men (P = NS, gender contrast). Corresponding V_o values were 66 ± 1, 71 ± 1, and 60 ± 1 mL/kg in women and 69 ± 1, 78 ± 1, and 73 ± 1 mL/kg in men (P = NS). Matching monoexponential GH t_1/2 values were 7.6 ± 0.3, 8.2 ± 0.4, and 8.8 ± 0.7 min in women and 9.8 ± 0.8, 10 ± 1, and 9.5 ± 1 min in men (average 1.7 min longer in men). Regression analysis disclosed no relationship between serum estradiol concentrations and peak serum GH levels, GH t_1/2, or V_o. GH t_1/2 values were also invariant of menstrual cycle stage, e.g. t_1/2 values of 8.1 ± 0.5, 9.1 ± 1.0, and 8.1 ± 0.4 min for the early follicular, late follicular, and midluteal phases, respectively. Corresponding normalized MCRs were 319 ± 39 (early follicular), 340 ± 48 (late follicular), and 340 ± 71 (midluteal) L/m²·day in women and 336 ± 50 L/m²·day in men (P = NS).

In parallel equilibrium infusion studies in men, we administered GH by constant iv infusions for 240 min during octreotide suppression. At doses of 0.5, 1.5, and 4.5 µg/kg·min, steady state GH t_1/2 values were 9 ± 1, 12 ± 1, and 15 ± 1 min (at respective steady state serum GH concentrations of 0.5 ± 0.05, 2.1 ± 0.2, and 7.5 ± 0.5 µg/L). In a third analysis in the same volunteers, stopping the constant iv infusions revealed t_1/2 values of GH decay from equilibrium of 26 ± 5 and 23 ± 2.3 min for the two higher GH infusion rates. In a fourth paradigm, endogenous GH t_1/2 values, as assessed in the same individuals by deconvolution analysis of overnight (10-min sampled) serum GH concentration profiles, averaged 18 ± 1.3 min. This value was intermediate between that of poststeady state decay and iv bolus elimination of GH.

In summary, the foregoing clinical experiments in healthy men and women indicate that 1) the nonequilibrium GH t_1/2, (body surface area-normalized) V_o, and MCR are independent of GH dose, sex, menstrual cycle stage, and serum estradiol concentrations; 2) the GH t_1/2 calculated after iv bolus injection is significantly (50%) shorter than that assessed during or after steady-state GH infusions or endogenously (overnight) by deconvolution analysis; and 3) the descending rank order of GH t_1/2 values in healthy volunteers is approximately: decay from steady state (23 ± 2.3 min) > endogenously secreted GH (18 ± 1.3 min) > during equilibrium infusion (15 ± 1 min) > after bolus infusion (9.8 ± 0.8 min). We thus conclude that for any given body surface area, the elimination properties of GH in men and women reflect predominantly the time mode of hormone entry into the circulation, rather than gender, menstrual cycle stage, or prevailing serum estradiol concentration. Accordingly, differences in serum GH concentrations in premenopausal women compared to those in young men and across the normal menstrual cycle reflect commensurate differences in pituitary GH secretion rates.

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