Date Published: , 2017
Publisher: National Institute on Alcohol Abuse and Alcoholism
Author(s): William L. Dees, Jill K. Hiney, Vinod K. Srivastava.
Adolescence represents a vulnerable period for developing youth. Alcohol use and misuse are especially problematic behaviors during this time. Adolescents are more sensitive to alcohol and less tolerant of its detrimental effects than are adults. Research in humans and animals has revealed that early alcohol consumption can result in delayed pubertal development. Animal studies have shown that alcohol detrimentally affects neuroendocrine systems within the hypothalamic region of the brain that are associated with the normal, timely onset of the pubertal process. To effectively restore development and shorten recovery time associated with the adverse effects of alcohol on puberty, researchers must first understand the molecular and physiological mechanisms by which alcohol interferes with critical hypothalamic functions.
The onset of puberty results from a complex series of interactions between nerve cells (i.e., neurons) and glial cells (i.e., nonneuronal brain cells) within the hypothalamus that are governed by metabolic signals, as well as genetic and environmental influences. Although age at puberty varies widely between and among mammalian species, the main event that signals puberty onset is basically similar, in that it relies on the increased pulsatile secretory activity of a hypothalamic neuropeptide, luteinizing hormone–releasing hormone (LHRH). This event occurs through the enhanced developmental responsiveness of the LHRH-producing neurons and their nerve terminals to excitatory inputs, such as insulin-like growth factor-1 (IGF-1) (Hiney et al. 1996; Wilson 1998) and the kisspeptins (Kp), a family of neuropeptide products of the KiSS-1 gene (Navarro et al. 2004; Shahab et al. 2005), as well as leptin (Dearth et al. 2000; Lebrethon et al. 2000), transforming growth factor α (Ojeda et al. 1990), and excitatory amino acids (Claypool et al. 2000; Gay and Plant 1987; Urbanski and Ojeda 1990).
Initial studies using both female and male rodents revealed that chronic alcohol administration caused delayed puberty (Anderson et al. 1987; Bo et al. 1982; Ramaley 1982). Over the years, researchers have attempted to correlate the timing of puberty with specific puberty-related hormones following chronic prepubertal alcohol exposure. In female rats, alcohol caused delayed vaginal opening and the age at first estrus (Dees and Skelley 1990; Emanuele et al. 2002), as well as suppressed serum levels of GH and LH but not follicle-stimulating hormone (FSH) (Dees and Skelley 1990). In this regard, the differential effects of alcohol on LH and FSH were not surprising, because this previously had been shown in adult rats (Dees and Kozlowski 1984). Significantly, several studies have shown that prepubertal alcohol exposure in females caused suppressed circulating levels of E2 (Bo et al. 1982; Dees and Skelley 1990; Emanuele et al. 2002), a clear indication of impaired ovarian development and activity. Although less is known about the prepubertal effects of alcohol in males, it has been shown to cause an early suppression in serum LH (Cicero et al. 1990) and to reduce the serum levels of GH and testosterone. Prepubertal alcohol use also can lead to lower testicular weight and smaller secondary sex organs (Anderson et al. 1987; Cicero et al. 1990; Emanuele et al. 1999; Tentler et al. 1997).
Studies in female rats, which showed increased hypothalamic LHRH content after chronic prepubertal alcohol administration (Dees et al. 1990), offered the first indirect evidence that alcohol affects this part of the brain. Subsequently, alcohol was shown to block the stimulatory effects of norepinephrine (Hiney and Dees 1991), IGF-1 (Hiney et al. 1998), leptin (Hiney et al. 1999), and N-methyl-dl-aspartic acid (NMA) (Nyberg et al. 1993) on the in vitro release of prepubertal LHRH. Although important, these collective observations did not rule out the possibility that alcohol also may act at the level of the pituitary.
Alcohol use and misuse by adolescents increases the risk for altered neuro-endocrine function, potentially modifying the timing of pubertal development. This review highlights results of research with animal models showing the site and mechanisms by which alcohol causes puberty-related problems. These studies demonstrate that alcohol acts within the hypothalamus to alter the expression and function of excitatory and inhibitory puberty-related genes and neuro-hormones, which are critical for the timely increase in LHRH secretion and the onset of puberty. More research in this field is needed and would no doubt promote a better understanding of normal mechanisms controlling events leading to increased LHRH release at puberty, as well as the cause-and-effect relationships by which alcohol can differentially affect them.