The overall objective is to understand how the female determines when she has achieved a size to begin puberty and why during poor nutrition sexual maturity is not attained. In this regard, we wish to know how the developing brain monitors physiologic size and well-being to increase the secretion of gonadotropins which initiate the first reproductive cycle. Our studies will concentrate on mechanisms regulating the pattern of luteinizing hormone (LH) secretion, since an increase in frequency of episodic discharges of LH times the onset of puberty.
The specific aims of the proposed research are: 1) to determine if a reduced frequency or amplitude of GnRH secretion is responsible for hypogonadotropism during nutritionally induced growth retardation, 2) to define blood-borne signals which relate information about metabolic state to the system governing the frequency of pulsatile LH secretion, and 3) to determine brain mechanisms modulating LH secretion by nutritional and growth-related signals. Several experimental approaches and methodologies will be used to attain our objectives. We have developed a model system, the nutritionally growth-limited lamb without ovaries, which is characterized by very slow LH pulses. The mechanism governing LH secretion is very sensitive to changes in level of nutrition. Ad libitum feeding produces a rapid increase (2-7 days) in frequency of LH secretion, and following subsequent reduction of feed level, an equally rapid decrease in LH pulse frequency. To determine if the changes in LH pulse frequency associated with alteration in diet in our model reflect changes in amplitude or frequency, the pattern and level of GnRH in the pituitary portal circulation will be characterized in relation to that for LH in the peripheral circulation. To define blood- borne signals which communicate with the mechanism governing GnRH secretion, combinations of glucose and amino acids will be infused into our model; various types of parenteral nutrition will be used to determine if energy alone is an important signal. The activity of the adrenal axis will also be examined. Two experimental approaches will be adopted to study central mechanisms limiting LH secretion in the undernourished state. Firstly, a pharmacologic approach will be used to investigate whether endogenous opioid and/or serotoninergic mechanisms inhibit pulsatile LH secretion in the restricted-diet lamb. Secondly, an immunocytochemical analysis of GnRH neurons will be carried out in restricted-diet lambs and in lambs returned to ad libitum diet. This will determine whether undernutrition and realimentation alter the morphology and number of GnRH immunoreactive neurons. This combined approach will reveal whether the hypogonadotropic state induced by chronic undernutrition results from a decrease in GnRH synthesis and, thus, limited availability of GnRH, or from an active inhibition of GnRH secretion and degradation. The results of this project have relevance to the understanding of puberty, and more broadly, to other physiologic states in which size and well-being are monitored by the brain to determine if fertility should begin or be maintained.
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