Humans and Rodents Both Exhibit Gender Differences in Plasma GH Profiles

Release of GH from the pituitary gland is not constant over time, but rather is intermittent, or pulsatile. GH secretion in humans begins at the end of the first trimester of gestation. Integrated daily GH secretion in humans is greatest during adolescence and declines with age thereafter. Notable sex differences in the neuroendocrine regulation of pituitary GH release have been observed in humans. Premenopausal women have two- to threefold higher daily GH secre tion rates than men due to a two- to threefold higher GH pulse amplitude in women. However, both males and females exhibit the same GH pulse frequency. Normal young men experience 6-10 secretory bursts per day, the majority of which occur during sleep at night. Interpulse plasma GH levels are undetectable. Women exhibit higher serum GH peaks in the late follicular stage of the menstrual cycle, when serum estrogen levels are elevated. Estrogen is believed to be an important mediator of the sex differences in human plasma GH profiles, which in part originate in the reduced somatostatin inhibitory action that occurs in females. The reduced effectiveness of glucose ingestion at fully suppressing serum GH levels in females compared to males may also manifest this sex difference in somatostatin inhibitory activity. These sex differences in GH release are likely to be physiologically important, in view of the profound effects that sex-dependent GH patterns are demonstrated to have on linear skeletal growth and GH action in target tissues in rodent models (see below).

In comparison to humans, rodents display a dramatic sexual dimorphism in the pulsatility of GH secretion, which is directly regulated by the temporal pattern of hypothalamic hormone secretion. This temporal pattern is, in turn, sex dependent, and is established by gonadal steroid imprinting during the neonatal period. Male rats exhibit a highly regular pattern of plasma GH pulsatility that is characterized by high peaks of GH (~200 ng/mL) each ~3.5 h, followed by an interpulse period lasting up to ~2 h, during which circulating GH is essentially undetectable (1-2 ng/mL). By contrast, adult female rats are characterized by much more frequent, and irregular, pulses of pituitary GH secretion, resulting in sustained periods during which there is a near-continuous presence of GH in circulation at levels > 20-40 ng/mL. In addition, young female rats have nocturnal surges of GH of high amplitude and short duration that are analogous to the high-amplitude nocturnal GH peaks seen in pubertal girls. These sex-dependent plasma GH profiles mediate the sex-dependent effects of GH on longitudinal bone growth and body weight beginning at puberty, as well as the sex-dependent expression in rodents of a large number of liver gene products, including hormone receptors, cytochromes P450, and other liver enzymes. Recent studies on GH signaling, described later in this chapter, have shed light on the cellular and molecular mechanisms through which the temporal pattern of GH stimulation dictates these sex-dependent patterns of liver gene expression.

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