The overall objective of the research is to determine neuroendocrine mechanisms governing onset of puberty. The domestic sheep, a seasonal breeder, will be used as the animal model to study internal and external determinants for initiation of ovulation. The working hypothesis will be tested that photoperiod and growth-associated cues, by impinging on systems that control pulsatile LH secretion time first ovulation. Experiments will be conducted to determine if melatonin is the pineal product that transduces photoperiodic information in the lamb; prolonged infusions of melatonin by portable pumps will be carried out in maturing females that have denervated pineal glands. This technique, coupled with artificial light treatments, will be used to determine the role of each component of the novel tripartite photoperiod sequence that initiates puberty. This photoperiod sequence, as well as photoperiods that have been developed to delay puberty, will be used as noninvasive probes to examine steroid-dependent and steroid-independent control of LH pulse frequency. The effect of growth rate on photoperiodic requirements for first ovulation will be evaluated under conditions in which body weight is regulated by level of nutrition. Patterns of circulating melatonin will be monitored to determine if photoperiod cues are perceived when growth ceases under limited nutrition. The growth-retarded model, in which puberty is delayed, will be used to study the effects of limited nutrition on control of pulsatile LH secretion by steroid-dependent and steroid-independent mechanisms. During the catch-up growth phase when puberty occurs, it will be determined whether level of nutrition can be used to set the frequency of LH pulses. The relationship between level of tonic LH secretion and the ability to respond to the positive feedback action of estradiol will be examined in growth-restricted lambs treated with a pulsatile infusion of GnRH. Patterns and levels of growth-associated hormones will be monitored during normal sexual development and in delayed puberty induced by inappropriate photoperiod or by inadequate growth. The research will fill and important gap in our knowledge of how the timing of puberty is influenced by external environment in a seasonally breeding species. The results of investigations of nutrition and weight regulation of pulsatile LH secretion will have broad application to the understanding of normal and delayed puberty in children.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Reproductive Biology Study Section (REB)
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Malcolm, Karl D; Jackson, Leslie M; Bergeon, Christine et al. (2006) Long-term exposure of female sheep to physiologic concentrations of estradiol: effects on the onset and maintenance of reproductive function, pregnancy, and social development in female offspring. Biol Reprod 75:844-52
Smith, G D; Jackson, L M; Foster, D L (2002) Leptin regulation of reproductive function and fertility. Theriogenology 57:73-86
Nagatani, S; Thompson, R C; Foster, D L (2001) Prevention of glucoprivic stimulation of corticosterone secretion by leptin does not restore high frequency luteinizing hormone pulses in rats. J Neuroendocrinol 13:371-7
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Nagatani, S; Guthikonda, P; Foster, D L (2000) Appearance of a nocturnal peak of leptin secretion in the pubertal rat. Horm Behav 37:345-52
Ohkura, S; Tanaka, T; Nagatani, S et al. (2000) Central, but not peripheral, glucose-sensing mechanisms mediate glucoprivic suppression of pulsatile luteinizing hormone secretion in the sheep. Endocrinology 141:4472-80
Bucholtz, D C; Chiesa, A; Pappano, W N et al. (2000) Regulation of pulsatile luteinizing hormone secretion by insulin in the diabetic male lamb. Biol Reprod 62:1248-55
Foster, D L; Nagatani, S (1999) Physiological perspectives on leptin as a regulator of reproduction: role in timing puberty. Biol Reprod 60:205-15
Kim, S J; Foster, D L; Wood, R I (1999) Prenatal testosterone masculinizes synaptic input to gonadotropin-releasing hormone neurons in sheep. Biol Reprod 61:599-605
Medina, C L; Nagatani, S; Darling, T A et al. (1998) Glucose availability modulates the timing of the luteinizing hormone surge in the ewe. J Neuroendocrinol 10:785-92

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