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Impact of Growth Hormone Resistance on Female Reproductive Function: New Insights from Growth Hormone Receptor Knockout Mice¹

^a Department of Physiology, School of Medicine, Southern Illinois University, Carbondale, Illinois 62901-6512 ^b Department of Medicine and Cellular and Molecular Physiology, Division of Endocrinology, Diabetes, and Metabolism, Hershey Medical Center, The Pennsylvania State University, Hershey, Pennsylvania 17033 ^c Edison Biotechnology Institute, Konneker Research Laboratories, Ohio University, Athens, Ohio 45701 ^d Department of Biomedical Sciences, College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701

We examined multiple aspects of reproductive function in growth hormone receptor gene knockout (GHR-KO) and normal mice to clarify the role of growth hormone in female reproduction. In adult animals, estrous cycle duration was comparable in all mice housed individually but was significantly longer in group-housed GHR-KO females. Histological evaluation of ovaries of adult females at estrus showed that the numbers of preovulatory follicles and corpora lutea were significantly reduced in GHR-KO mice, as was the plasma estradiol level. The number of atretic preovulatory follicles was reduced in GHR gene-ablated animals. Although reverse transcription polymerase chain reaction analysis revealed reduced ovarian insulin-like growth factor I (IGF-I) mRNA expression in GHR-KO females, the expression of several steroidogenic enzyme mRNAs did not differ between groups. The numbers of active corpora lutea and uterine implantation sites were reduced in GHR-KO females at Day 7 of gestation. When young females were mated to normal males, latency to first mating and age of the female at first mating were significantly delayed in GHR-KO females, but maternal age at first conception was similar between groups. Significantly fewer virgin GHR-KO females exhibited pseudopregnancies when initially placed with vasectomized normal males than did normal female counterparts. Growth hormone resistance and IGF-I insufficiency negatively impacted 1) follicular development/ovulation rate, 2) sexual maturation, 3) production of and responsiveness to pheromonal signals, and 4) the ability of virgin females to respond to coitus by activation of luteal function. Although GHR-KO female mice are fertile, they exhibit quantitative deficits in various parameters of reproductive function.

¹ This work was supported in part by NIH grants HD-37672 (A.B.) and HD-24565 (J.H.) and the Ohio State Eminent Scholar Program, including a gift from Milton and Lawrence Goll (J.K.).

² Correspondence: Denise J. Zaczek, Department of Physiology, School of Medicine, Southern Illinois University, Life Science II, Room 250, Carbondale, IL 62901. FAX: 618 453 1517; dzaczek{at}siumed.edu

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