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Development of Leydig Cells in the Insulin-Like Growth Factor-I (IGF-I) Knockout Mouse: Effects of IGF-I Replacement and Gonadotropic Stimulation¹

Population Council and The Rockefeller University, New York, New York 10021

Targeted gene deletion of insulin-like growth factor-I (IGF-I) results in diminished numbers of Leydig cells (LCs) and lower circulating testosterone (T) levels in adult males. The impact of endogenous IGF-I withdrawal on proliferation (labeling index, LI) and differentiation of LCs was investigated, testing for restorative effects of IGF-I replacement and/or LH stimulation. With IGF-I replacement in mutant mice, LIs increased more than 200% (P < 0.05). LC numbers were also increased by 200%, whereas the numbers of intermediate cell progenitors (PLCs) were unchanged compared to mutant vehicle controls. LIs of PLCs in wild-type males increased by 200% after LH stimulation, and LC numbers increased by 50% compared to vehicle-treated controls (P < 0.05). In contrast, there was no effect of LH on LI in mutant mice, but LC numbers still increased by 30% (P < 0.05). Additive effects on LI and cell numbers were observed in response to IGF-I plus LH in mutants, implying that the two hormones use separate signaling pathways. Serum T and LH levels in wild-type and mutant males were equivalent. Exogenous LH increased T production 8-fold in wild-type males (P < 0.01). In mutant mice, neither LH stimulation nor IGF-I alone affected serum T levels, but IGF-I plus LH stimulation increased serum T 2-fold (P < 0.05). These data support the conclusions that 1) IGF-I is a critical autocrine and/or paracrine factor in the control of adult LC numbers and function; and 2) LH is not a direct mitogenic factor for LCs, and acts in part through IGF-I to stimulate proliferative activity.

¹ Supported by NIH HD32588. A preliminary form of this study was presented at the 84th Annual Meeting of the Endocrine Society, San Francisco, California, and the 35th Annual Meeting of the Society for the Study of Reproduction, Baltimore, Maryland, 2002.

² Correspondence: Matthew P. Hardy, Population Council, 1230 York Avenue, New York, NY 10021. FAX: 212 327 7678; mhardy{at}popcbr.rockefeller.edu

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