Cannabinoids and Reproduction

In the 1980s a great number of papers dealt with the effects of THC on reproduction and on neuroendocrine function. THC increased gonadotropin-releasing hormone (GnRH) (Collu 1976). Kumar et al. (1983) found that hypothalamic GnRH content was increased in ovariectomized rats after a single dose of THC. An accumulation of GnRH in dense-core vesicles was observed in the hypothalamic median eminence after THC treatment, (Doms et al. 1981). Ayalon et al. (1977) and Tyrey (1984) postulated that THC acted primarily through central neuroendocrine mechanisms, since its effects could be reversed by administration of exogenous GnRH. In contrast, Wenger et al. (1987) found no changes in GnRH content in the (anterior) hypothalamus after THC administration, and in in vitro studies it was demonstrated that THC did not alter the release or storage of gonadotropins and did not modify the responsiveness of cultured anterior pituitary cells to GnRH.

Since the early studies by Marks (1973) on the inhibitory effects of THC on pituitary luteinizing hormone (LH) secretion, a number of papers reported similar effects (Smith et al. 1980; Steger et al. 1980; Wenger et al. 1987). THC suppresses the tonic circulating level of LH in male rats (Chakravarty et al. 1982) and episodic LH secretion in female animals (Tyrey 1980).

Studies by Chakravarty et al. (1975) in intact female rats, by Kramer (1974) in male rats, by Dalterio et al. (1981) in male mice, and by Rettori et al. (1988) in male rats in vitro, have shown that administration of THC can lower prolactin (PRL) release.

AEA has similar effects on reproductive hormones as THC. AEA temporarily decreases serum LH level, and this effect lasts up to 2-3 h (Gonzales et al. 2000; Wenger et al. 1999). PRL levels can also be decreased by endocannabinoid treatment (Wenger et al. 1999). Sexual differences in CB1 receptor density have been detected in the medial basal hypothalamus (MBH) (Rodriguez de Fonseca 1994). The density was higher in diestrus and decreased in oestrus. Gonzales et al. (2000) reported that AEA content in both the hypothalamus and anterior pituitary might be controlled by circulating sex steroids. AEA effects on the control of the regulation of reproduction are mediated by CB1 receptors located in the hypothalamus and in the anterior pituitary (Fernandez-Ruiz et al. 1997; Romero et al. 1998; Wenger et al. 1997). Recently it has been demonstrated that AEA changes dopaminergic turnover, thus altering inhibitory dopaminergic effects on PRL secretion (Scorticati et al. 2003).

CB1 receptor inactivation suppresses reproductive hormone secretion (Wenger et al. 2001). Serum LH and testosterone (T) levels significantly decreased in mutant (CB1-/-) mice (Table 1). Results from this investigation also indicated that cannabinoids regulate neuroendocrine function through the activation of CB1

Table 1. Luteinizing hormone (LH) and testosterone (T) content in central cannabinoid receptor (CBi receptor) knockout mice (data from Wenger et al. 2001)

LH mg/pituitary

LH ng/ml serum

T nmol/testis

CBi+/+

0.71±0.24

5.15±0.8

39.57±4.23

CBi"'"

0.76±0.3

2.6±0.24*

19.89±3.2**

+/+, Wild-type mice; / , CBi receptor knockout mice. n=8-10inall groups. *p<0.01 vs +/+ (±SEM). **pLT0.001vs+/+(±SEM).

+/+, Wild-type mice; / , CBi receptor knockout mice. n=8-10inall groups. *p<0.01 vs +/+ (±SEM). **pLT0.001vs+/+(±SEM).

Table 2. Anterior pituitary hormone content changes after AEA administration1

LH

FSH

PRL

ACTH

44

-

44

tt

44, Significant decrease (p<0.01 or higher); ft, significant increase (p<0.01 or higher); ACTH, adrenocor-ticotrophic hormone; AEA, anandamide; LH, luteinizing hormone; FSH, follicle-stimulating hormone; PRL, prolactin.

44, Significant decrease (p<0.01 or higher); ft, significant increase (p<0.01 or higher); ACTH, adrenocor-ticotrophic hormone; AEA, anandamide; LH, luteinizing hormone; FSH, follicle-stimulating hormone; PRL, prolactin.

receptors. This regulation seems to be mainly through inhibition of hormone release at the pituitary level and may or may not also involve the hypothalamus. Table 2 summarizes the effects of endocannabinoids on anterior pituitary hormone content. Interestingly, cannabinoids do not affect the secretion/release of follicle-stimulating hormone (FSH), and it remains to be ascertained whether or not they may modulate the purported FSH-releasing factor (Samson et al. 1980).

A direct regulatory role for endocannabinoids in normal human anterior pituitary gland and pituitary adenomas has also been postulated (Pagotto et al. 2001). Pituitary adenomas had higher AEA and 2-AG concentrations, pointing to a role for endocannabinoids in the development of pituitary adenomas too.

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