Alcohol Ingestion Inhibits the Increased Secretion of Puberty-Related Hormones in the Developing Female Rhesus Monkey*

Abstract

Alcohol (ALC) use and abuse by adolescents has been rising at an alarming rate. Whether ALC consumption during prepubertal years affects specific hormones and the process of sexual maturation is not known. We used immature female rhesus macaques to assess the effects of ALC on circulating levels of hormones known to be critical for the pubertal process. Ten monkeys averaging 20.3 +/- 0.3 months of age were bled by saphenous vein puncture at 0830 and 2030 h each day for 5 consecutive days to determine baseline levels of GH, insulin-like growth factor I, FSH, LH, estradiol (E2), and leptin. For the next 12 months, each day at 1330 h five monkeys were administered ALC (2 g/kg), and five monkeys were administered an isocaloric sucrose solution via a nasogastric approach. Blood was again collected twice daily on 5 consecutive days at 24, 28, and 32 months for hormone analysis. Food consumption and weight gain were similar for ALC-treated and control animals. The expected night-related increase in serum GH occurred during late juvenile development (28-32 months of age) in control animals, but was suppressed (P < 0.05) in ALC-treated animals. This action was paralleled by a decrease (P < 0.01) in serum insulin-like growth factor I. Serum LH and E2 were also depressed by ALC, with their effects most pronounced at 32 months (LH, P < 0.01; E2, P < 0.001). Serum FSH and leptin were not altered. Although ALC did not affect age at menarche, the interval between subsequent menstruations was lengthened (P < 0.05), thereby showing that ALC affected the development of a regular monthly pattern of menstruation. These results demonstrate the detrimental effects of ALC on the activation of hormone secretion that accompanies puberty in female rhesus monkeys. They also suggest that the subsequent growth spurt and normal timing or progression of puberty may be at risk in human adolescents and teenagers consuming even relatively moderate amounts of ALC on a regular basis.

Insulin-like growth factor-1 stimulation of hypothalamic KiSS-1 gene expression is mediated by Akt: effect of alcohol

“…Interestingly, a recent study, in which ALC was administered to prepubertal female rats for 6 days using a specific liquid diet regimen, showed that this more chronic exposure to the drug caused suppression in basal KiSS-1 gene expression, an action that was associated with suppressed basal phosphorylated Akt protein expression (Srivastava et al, 2009). In that study, the ALC also caused suppressed levels of IGF-1 and E 2 , which is associated with ALC-induced delayed purberty and is common following extended exposure to the drug (Dees et al, 2000; Srivastava et al, 1995). It was not possible in that chronic study to discern whether the longer exposure to ALC altered Akt and KiSS-1 expressions by a direct hypothalamic action on the affected neurons, or acted indirectly, as a result of a low IGF-1 signal.…”

“…Over the years we have shown that both acute and chronic ALC exposure alters IGF-1 signaling and causes suppressed LHRH/LH secretion and altered pubertal development in both rats and rhesus monkeys (Dees et al, 2000; Hiney et al, 1998; Srivastava et al, 1995). The KiSS-1/GPR54 system is also an important signaling component controlling LHRH secretion and the time of puberty in rats, rhesus monkeys and humans (Navarro et al, 2004a; 2004b; Seminara et al, 2003; Shahab et al, 2005; Thompson et al, 2004).…”

“…Thus, a drug capable of affecting this brain region could alter the timing of puberty. In this regard, ALC is known to cause delayed vaginal opening in rats (Bo et al, 1982; Dees and Skelley, 1990; Dees et al 1990), delayed development of a normal pattern of menstruation in rhesus monkeys (Dees et al 2000), and altered puberty related hormones in rats, as well as rhesus monkeys and human adolescents (Dees et al, 1990; Dees et al, 2000; Diamond et al, 1986). Studies using rhesus monkeys have shown that these effects are associated with an action within the reproductive control center of the brain to diminish LH-releasing hormone (LHRH) secretion (Dissen et al, 2004).…”

“…Collectively, these results suggest IGF-1 is an important component contributing to early signaling processes controlling LHRH secretion at puberty. The fact that ALC is capable of suppressing circulating levels of IGF-1 in prepubertal rats and rhesus monkeys (Dees et al, 2000; Srivastava et al, 1995) and altering some of the central actions of the peptide in prepubertal rats (Dees et al, 2005; Hiney et al, 1998; 2004) indicates IGF-1 is a target for ALC actions in prepubertal animals.…”

Reduced Nucleus Accumbens SK Channel Activity Enhances Alcohol Seeking during Abstinence

“…SK3 subunit gene expression can be increased through estrogen receptor activation in vitro (Bosch et al, 2002; Jacobson et al, 2003), and SK2 subunit gene expression can be decreased by glucocorticoids acting through NFκβ (Kye et al, 2007). Although acute estrogen can positively influence alcohol seeking (Ford et al, 2004), long-term alcohol exposure can reduce estrogen function (Dees et al, 2000). A similar pattern is apparent for NFkB (Okvist et al, 2007) and perhaps other regulators of gene expression such as CREB (Spanagel, 2009).…”