GnRH and Reproduction
Neuroendocrine Regulation of GnRH and Behavior During Aging in Birds

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Abstract

Avian species exhibit a great variety of life-long patterns in reproduction. Japanese quail are relatively short lived and undergo an age-related loss of reproductive function, making this species an excellent model for the study of the basic biology of aging. Because individuals age at variable rates, sexual behavior has provided a useful index to assess reproductive status of individuals of the same chronological age. Further, exogenous testosterone restores sexual behavior in reproductively senescent male quail, thereby providing evidence for a continued ability of the system to respond. In addition, we have been studying hypothalamic neuroendocrine systems that regulate the endocrine as well as behavioral components of reproduction. Overall, our findings point to the hypothalamic neuroendocrine systems as the site of initial age-related alterations that contribute to the reproductive deterioration. Specifically, we studied adrenergic, opioid peptide, vasotocin, and aromatase systems to understand their relationship to the cGnRH-I system and their potential role in the deterioration of the cGnRH-I system during aging. Our findings provide evidence for qualitative and quantitative alterations in the aromatase enzyme system, which can be partially restored with exogenous testosterone. In addition, other neuronal systems, including the vasotocin system, decline with the loss of gonadal steroids and are restimulated with exogenous testosterone. We will synthesize the data relative to these neuroendocrine systems with attention to the effects of gonadal steroids on these systems during aging.

Introduction

Our view of the role of the gonadal steroids in endocrine and behavioral components of male reproduction has changed as we gain greater understanding of the reproductive system at all levels. Androgens and estrogens act at all stages of the life cycle, including sexual differentiation, maturation, adult function, and aging [43]. Often, changing patterns in production and plasma concentrations of these steroids have been the first clue for a role of steroids on specific target tissues. For example, increasing plasma androgen levels herald sexual maturation of the male and the initiation of sexual behavior. Testicular function accompanies this maturation-related process, thereby providing a synchronization of endocrine and behavioral components of reproduction by acting on specific brain circuitries. Several studies have demonstrated the presence of sexually dimorphic structures in cerebral areas involved in the control of behavioral aspects of reproduction and the importance of gonadal hormones in determining these differences during embryonic or early postnatal life (the so called organizational effects) or their later initiation and maintenance (activational effects; 2, 43). Often the relationship of these steroids and sexual behavior have been regarded as cause and effect in that courtship and mating behavior do not occur in the absence of some threshold level of gonadal steroid. There are many examples that support this relationship including studies in which the castrated male ceases sexual behavior and testosterone (T) replacement therapy restored sexual behavior (for a review see [43]). As mentioned above, this relationship also holds for sexual maturation in that plasma androgen levels increase with initiation of gonadal function to affect target areas in the brain, resulting in the stimulation of sexual behavior. This apparent cause–effect relationship breaks down during aging in mammals. In mammals, there appears to be a “disconnect” in that when males fully cease courtship and mating behavior, an external supply of T is not capable of restoring sexual behavior. In contrast to this, in quail the sexual behavior can be restored in senescent individuals by administration of exogenous T [37].

The focus of our present research is on how the process of aging is affecting neural circuitries (mainly hypothalamic) that control sexual behavior as well as neuroendocrine aspects of reproduction. This process ultimately leads to reproductive senescence (complete loss of both endocrine and behavioral components of reproductive function). The study of age-related changes in the gonadotropin releasing hormone (GnRH) system is central to this question, but being that the GnRH producing neurons are part of complex neural circuitries, it is equally important to consider possible interactions of neurotransmitter or neuropeptide systems and their response to gonadal steroids during the process of aging (Fig. 1). Our data have been collected in the male Japanese quail. However, there is a great deal of similarity between data from mammals and birds, and we will refer those data as appropriate.

Section snippets

Testosterone and Sexual Behavior During Aging in Quail

There is a great deal of variability in the sexual behavior of old male quail. Around 18 months of age, some individuals become spontaneously sexually inactive (senescent), whereas a large number of individuals still retain (frequently at a lower level than adult birds) sexual activity. Plasma levels of androgen decrease in all middle-age birds (18–30 months of age) and do not differ significantly between active and inactive males, even if the inactive males have normally lower circulating

How is the Aromatase System Influenced in Senescent Males?

In young sexually mature birds, aromatase-containing cells are clustered within three nuclei: the medial preoptic nucleus (POM) in the preoptic area, the nucleus of the stria terminalis (nST) in the limbic complex, and the nucleus ventromedialis in the posterior hypothalamus [10]. ARO synthesis is stimulated by circulating T and the activity of this enzyme is strongly dimorphic [48]. In the POM, a loss of ARO-IR cells was observed in young castrated males coincident with the loss of male sexual

How is the Avian GnRH System Affected During Aging?

Immunocytochemical studies have been conducted by many laboratories, including our own, on the distribution of chicken gonadotropin releasing hormones (cGnRH-I and II) in the avian brain (for a review see [56]) of sexually mature individuals. In particular, studies have concentrated on cGnRH-I because of evidence that implicates this form of GnRH in the regulation of avian reproduction [49]. According to immunohistochemical data in quail, cGnRH-I cell bodies are localized primarily in the

Aging and GnRH: Which Neuropeptide Systems Modulate Release and are Likely to Signal Aging?

It is likely that alterations in the regulatory neuropeptides, notably the opioid peptides, are the primary contributors to the age-related deterioration in hypothalamic response. A great deal of research has focused on CNS alterations during aging, especially those changes that relate to disease states such as Alzheimers disease or other dementia. Therefore, it is not surprising that neurotransmitter systems are considered fundamental to the changing function that occurs during aging. Many of

Catecholamines

The catecholamines have been of interest in the regulation of both endocrine and behavioral responses in many species for some time. There is clear evidence for noradrenergic stimulation of cGnRH release in vitro and in vivo 30, 31, 36. In birds, catecholamine concentrations change with the ovulatory cycle [27]. Furthermore, catecholamine-containing neurons and high density of immunoreactive (IR) fibers are found in the preoptic area [5], which contains GnRH neurons 21, 51and regulates sexual

Conclusions

A great deal of information has been collected relative to aging in male quail. This now allows us to investigate the mechanisms involved in the age-related deterioration of hypothalamic function, particularly as it relates to cGnRH-I synthesis and release. Further, it is important to note that the deterioration of endocrine components of reproduction, as seen in the demise of the cGnRH-I system occur with loss of behavioral components of reproduction. This points to a fundamental synchrony of

Acknowledgements

This study was supported by the Maryland Agriculture Experimental Station, and by grants from MURST (40% to A. Fasolo, 60% to C.V.P. and G.C.P.), CNR (93.00372, 94.02462 to G.C.P.), NATO (CRG 92.1267 to G.C.P. and M.A.O.), EU (94-0472), USDA, and NRI.

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