Reproductive function in all vertebrates is controlled by the circhoral release of the neuropeptide, GnRH, into the portal capillary system leading to the anterior pituitary. Despite its primary role in sexual maturation and the maintenance of adult reproductive function, changes in the concentrations and pattern of GnRH release have not yet been reported in any primate species during the menopausal transition and postmenopause. Such knowledge is essential for ascertaining both the mechanisms for, and consequences of, the menopausal process. Here we used a push-pull perfusion method to measure and compare the parameters of pulsatile GnRH release in adult rhesus monkeys at 8.4 +/- 1.5 yr (young adult females, early follicular phase, n = 6) and 28.8 +/- 0.3 yr (aged females, n = 4, of which two monkeys were in the menopausal transition, and two were postmenopausal). Our results demonstrate that: 1) GnRH release is pulsatile in both young and aged monkeys; 2) mean concentrations of GnRH increase during reproductive aging; and 3) GnRH pulse frequency does not differ between aged monkeys and young monkeys in the early follicular phase. We conclude that not only do GnRH neurons have the continued capacity to release GnRH in a pulsatile manner but also they can do so with enhanced GnRH levels in aged primates. To our knowledge, this is the first direct demonstration of elevated pulsatile GnRH concentrations in a primate species during reproductive senescence, a result that may have implications for menopausal symptoms.

We have previously shown that a decrease in ␥-aminobutyric acid (GABA) tone and a subsequent increase in glutamatergic tone occur in association with the pubertal increase in luteinizing hormone releasing hormone (LHRH) release in primates. To further determine the causal relationship between developmental changes in GABA and glutamate levels and the pubertal increase in LHRH release, we examined monkeys with precocious puberty induced by lesions in the posterior hypothalamus (PH). Six prepubertal female rhesus monkeys (17.4 Ϯ 0.1 mo of age) received lesions in the PH, three prepubertal females (17.5 Ϯ 0.1 mo) received sham lesions, and two females received no treatments. LHRH, GABA, and glutamate levels in the stalk-median eminence before and after lesions were assessed over two 6-h periods (0600 -1200 and 1800 -2400) using push-pull perfusion. Monkeys with PH lesions exhibited external signs of precocious puberty, including significantly earlier menarche in PH lesion animals (18.8 Ϯ 0.2 mo) than in sham/controls (25.5 Ϯ 0.9 mo, P Ͻ 0.001). Moreover, PH lesion animals had elevated LHRH levels and higher evening glutamate levels after lesions, whereas LHRH changes did not occur in sham/ controls until later. Changes in GABA release were not discernible, since evening GABA levels already deceased at 18 -20 mo of age in both groups and morning levels remained at the prepubertal levels. The age of first ovulation in both groups did not differ. Collectively, PH lesions may not be a good tool to investigate the mechanism of puberty, and, taking into account the recent findings on the role of kisspeptins, the mechanism of the puberty onset in primates is more complex than we initially anticipated. timing of puberty; luteinizing hormone releasing hormone; lesions in the hypothalamus; primates THE CONCEPT THAT an increase in pulsatile luteinizing hormone releasing hormone (LHRH) release triggers the onset of puberty has been well established (26,44,45). However, the mechanism of the pubertal increase in LHRH release remains unclear (39). It has been reported that children with tumors or hamartomas in the hypothalamus exhibit precocious puberty (37). A previous study from our laboratory showed that bilateral lesions made in the posterior hypothalamus of female rhesus monkeys during the prepubertal stage result in an early rise in luteinizing hormone (LH) release followed by precocious puberty (42). Moreover, similar lesions in ovariectomized prepubertal females result in early pubertal LH increases and accelerated timing of the estrogen positive feedback effect on the LH surge when compared with those in ovariectomized sham control females (35), indicating that the hypothalamic lesion-induced LH increase in prepubertal monkeys is independent of ovarian steroid hormones and is suggestive that lesions cause changes in the control mechanism of the LHRH neurosecretory system.A series of studies in our laboratory indicate that an increase in LHRH release is associated with a decrease in ␥-aminobutyric acid (GABA) followed by ...