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Effects of Chronic Hyperghrelinemia on Puberty Onset and Pregnancy Outcome in the Rat

Department of Cell Biology, Physiology and Immunology, University of Cordoba (R.F.F., V.M.N., M.L.B., E.M.V., E.A., L.P., M.T.-S.), 14004 Cordoba, Spain; Research Institute of Animal Production (A.V.S.), 94992 Nitra, Slovakia; and Departments of Physiology (S.T., C.D.) and Medicine (F.F.C.), University of Santiago de Compostela, 15705 Santiago de Compostela, Spain

Address all correspondence and requests for reprints to: Dr. Manuel Tena-Sempere, Physiology Section, Department of Cell Biology, Physiology, and Immunology, Faculty of Medicine, University of Cordoba, Avenida Menéndez Pidal s/n, 14004 Cordoba, Spain. E-mail: fi1tesem{at}uco.es.

Ghrelin, the endogenous ligand of the GH secretagogue receptor, has been recently involved in a wide array of biological functions, including signaling of energy insufficiency and energy homeostasis. On the basis of the proven reproductive effects of other regulators of energy balance, such as the adipocyte-derived hormone leptin, we hypothesized that systemic ghrelin may participate in the control of key aspects of reproductive function. To test this hypothesis, the effects of daily treatment with ghrelin were assessed in rats, pair-fed with control animals, in two relevant reproductive states, puberty and gestation, which are highly dependent on proper energy stores. Daily sc injection of ghrelin (0.5 nmol/12 h; between postnatal d 33 and 43) significantly decreased serum LH and testosterone levels and partially prevented balanopreputial separation (as an external index of puberty onset) in pubertal male rats. On the contrary, chronic administration of ghrelin to prepubertal females, between postnatal d 23 and 33, failed to induce major changes in serum levels of gonadotropins and estradiol, nor did it modify the timing of puberty, as estimated by the ages at vaginal opening and first estrus. Moreover, females treated with ghrelin at puberty subsequently displayed normal estrous cyclicity and were fertile. Conversely, ghrelin administration (0.5 nmol/12 h) during the first half of pregnancy (d 1–11) resulted in a significant decrease in pregnancy outcome, as estimated by the number of pups born per litter, without changes in the number of successful pregnancies at term or gestational length. Overall, our data indicate that persistently elevated ghrelin levels, as a putative signal for energy insufficiency, may operate as a negative modifier of key reproductive states, such as pregnancy and (male) puberty onset.

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