Circulating levels of the components of the GH/IGF-1/IGFBPs axis total and intact IGF-binding proteins (IGFBP) 3 and IGFBP 4 and total IGFBP 5, as well as PAPPA, PAPPA2 and Stanniocalcin-2 levels are not altered in response to energy deprivation and/or metreleptin administration in humans

Abstract

Objective: It remains unclear whether food deprivation induces changes in components of the GH/IGF-1/IGFBPs axis and if yes, which ones are mediated by leptin, an adipocyte secreted hormone regulating neuroendocrine response to energy deprivation in animals and humans. We aimed to investigate components of the axis that have not been studied to date, i.e. IGF-binding proteins (IGFBPs) and related proteases (total and intact IGFBP 3 and IGFBP 4, total IGFBP 5, PAPPA, PAPPA2 and Stanniocalcin-2), during acute (short-term fasting in healthy subjects) and chronic (women with hypothalamic amenorrhea [HA] due to excessive exercise) energy deprivation and whether metreleptin administration, in replacement, supraphysiologic or pharmacologic levels, may mediate any changes of circulating levels of the above molecules in healthy individuals and in women with hypothalamic amenorrhea.

Methods: We studied: 1) 11 healthy men and women during three four day admissions i.e. a baseline admission in the fed isocaloric state and two admissions in the complete food deprivation state for 72-h with either placebo (resulting in a hypoleptinemic state) or metreleptin administration in doses designed to normalize circulating leptin levels for the duration of the study, 2) 15 healthy men and women during three 72-hour long admissions in a complete food deprivation state receiving three escalating doses of metreleptin designed to bring circulating leptin levels to physiologic, supraphysiologic, or pharmacologic levels, and 3) 18 women with HA randomized to either metreleptin treatment in replacement doses or placebo for nine months.

Results: There were no significant changes in the circulating profiles of the above molecules in the fasting vs. fed state and/or with metreleptin administration during acute and chronic energy deprivation.

Conclusions: The studied components of the GH/IGF-1/IGFBPs axis are not affected by energy deprivation, leptin deficiency associated with energy deprivation, or by metreleptin administration in physiologic, supraphysiologic or pharmacologic doses.

Keywords: Fasting; Hypothalamic amenorrhea; IGFBPs; Leptin; PAPPA; Stanniocalcin-2.