Alcohol Alters Luteinizing Hormone Secretion in Immature Female Rhesus Monkeys by a Hypothalamic Action

Abstract

We determined whether the effect of alcohol (ALC) to suppress LH secretion in immature female monkeys is due to a hypothalamic or pituitary site of action. Beginning at 20 months of age, four monkeys received a single intragastric dose of ALC (2.4 g/kg), and four monkeys received an equal volume of a saline/sucrose solution daily until they were 36 months old. For the hypothalamic response test, two basal samples (3.5 ml) were collected at 15-min intervals via the saphenous vein, and then N-methyl-D-L-aspartic acid (NMA; 20 mg/kg) was given iv and four more blood samples collected. Three weeks later, this protocol was repeated except LH-releasing hormone (LHRH) (5 g/kg) was used to test pituitary responsiveness. NMA or LHRH was administered 3 h after the ALC. After the pituitary challenge, each monkey was ovariectomized and 6 wk later, implanted with an indwelling subclavian vein catheter. Blood samples were drawn every 10 min for 8 h to assess effects of ALC on post-ovariectomy LH levels and the profile of LH pulsatile secretion. The hypothalamic challenge showed NMA stimulated LH release in control monkeys, an action that was blocked by ALC. The pituitary challenge revealed that LHRH stimulated LH release equally well in control and ALC-treated monkeys. A post-ovariectomy rise in LH was observed in both groups, but levels were 45% lower in ALC-treated monkeys. This reduction was attributed to an ALC-induced suppression of both baseline and amplitude of pulses. Results demonstrate that the ALC-induced suppression of LH in immature female rhesus monkeys is due to an inhibitory action of the drug at the hypothalamic level. (Endocrinology 145: 4558 -4564, 2004)I N RECENT YEARS, there has been an increase in alcohol (ALC) use and abuse during adolescence, especially by females (1). The adolescent period is a potentially vulnerable time for developing individuals who may be more sensitive to the drug and less tolerant to its detrimental effects than adults. This concept has been supported by work using the rat as an animal model (2, 3). The possibility that ALC could alter neuroendocrine development has been suspected for years because a history of any drug ingestion is routinely conducted to identify potential causes of altered endocrine function or pubertal development. Any detrimental effect of ALC on puberty-related hormones at this critical time of growth and development could elevate the risk for developmental deficits.Research with experimental animals and case reports from humans further suggest that determining the effects of ALC on endocrine development warrants serious consideration. Studies using rats have shown that ALC suppresses the levels of LH and estradiol (E 2 ) and causes delayed female puberty (4 -6). Even though case studies involving ALC use and abuse by adolescent and teenage humans are limited in number and scope, they have suggested that the drug can disrupt endocrine function, stature, and weight distribution in young people (7-9), as well as place them at risk for nutritional deficiencies ...

Manganese protects against the effects of alcohol on hypothalamic puberty-related hormones

“…This supports previous work showing that Mn stimulates LHRH secretion through an action at the hypothalamic level [25, 34]. Conversely, animals that were administered an ALC-liquid diet resulted in suppressed LH levels, an effect that was inversely correlated with the increased content of LHRH within the MBH and therefore, suggesting the release of the hypothalamic peptide was inhibited; hence, supporting the well-documented effect of ALC to act at the hypothalamic level to suppress LHRH/LH secretion [10, 12, 13, 17, 31, 35]. Importantly, other ALC-treated rats that also received Mn supplementation showed increased serum LH and decreased LHRH peptide content in the MBH, similar to the Mn supplemented animals that did not receive ALC.…”

Actions and Interactions of Alcohol and Transforming Growth Factor β1 on Prepubertal Hypothalamic Gonadotropin‐Releasing Hormone

“…This is due to the hypothalamic action of ALC to suppress the secretion of GnRH by blocking the influences of several excitatory neuronal regulators (Dissen et al, 2004; Hiney and Dees, 1991a; Hiney et al, 2010; Nyberg et al, 1993). In addition to neuronal influences, glial-derived factors can also influence GnRH secretion (Hiney et al, 2003; Ma et al, 1997; Mahesh et al, 2006; Ojeda and Skinner, 2006).…”

“…Initial studies showed that prepubertal alcohol (ALC) exposure resulted in delayed pubertal development (Anderson et al, 1981; Bo et al, 1982; Ramaley, 1982). Subsequently, it was revealed that this delayed development in rats, as well as the delayed development of a normal menstruation pattern in rhesus monkeys, was due to an ALC-induced suppression in luteinizing hormone (LH) secretion, suggesting that the drug was indeed acting within the region of the preoptic area (POA) and hypothalamus (Dees and Skelley, 1990; Dees et al, 2000; Dissen et al, 2004). In the rat, the GnRH peptide is mainly synthesized in neuronal cell bodies located within the POA, but is secreted from the median eminence (ME) region at the base of the hypothalamus.…”

“…Prepubertal GnRH secretion is regulated by a decrease in the release of inhibitory neurotransmitters (Terasawa, 1999; Terasawa and Fernandez, 2001), as well as by an increase in numerous excitatory inputs (Dearth et al, 2000; Hiney et al, 1991b, 1996, 2009; Navarro et al, 2004; Ojeda et al, 1990; Sarkar et al, 1981; Urbanski and Ojeda, 1987; 1990). Importantly, it is now well documented that prepubertal ALC exposure acts at the hypothalamic level, at least in part, to suppress the stimulatory actions of excitatory neurotransmitters on GnRH secretion (Dissen et al, 2004; Hiney and Dees, 1991a, Hiney et al, 2003, 2010; Nyberg et al, 1993, 1995). In addition to these excitatory influences regulating GnRH, there are glial-glial and glial-neuronal influences that contribute to GnRH release that may also be affected by ALC.…”

Systemic Administration of Alcohol to Adult Rats Inhibits Leydig Cell Activity: Time Course of Effect and Role of Nitric Oxide

“…And finally, they stimulate the production within the gonads themselves, of signals that also influence steroidogenesis (see references in Rivier, 2002;Selvage and Rivier, 2004). The inhibitory influence of peripherally administered or consumed alcohol on the HPG axis of laboratory rodents (Emanuele and Emanuele, 2001;Rivier et al, 1992;Selvage et al, 2004a), primates (Dissen et al, 2004), and human subjects (Frias et al, 2000(Frias et al, , 2002 can similarly involve decreased LHRH synthesis and release (Canteros et al, 1995;Ching et al, 1988;Dees et al, 1983;Emanuele et al, 1989;Kim et al, 2003;Ogilvie and Rivier, 1997a) because alcohol readily crosses the blood-brain barrier (Gill et al, 1986;Nurmi et al, 1994), and/or the inhibition of testicular proteins essential for sex steroid formation (Chiao et al, 1981;Cicero et al, 1980;Orpana et al, 1990a;Srivastava et al, 2001) because alcohol rapidly penetrates the gonads (Salonen and Eriksson, 1989). While the respective importance of these different mechanisms remains the object of intense research, the use of alcohol as a model of stress presents one distinct advantage: namely, that alcohol can inhibit Leydig cell function following its intracerebroventricular (i.c.v.…”