Effects of the dopamine agonist cabergoline on the pulsatile and TRH-induced secretion of prolactin, LH, and testosterone in male beagle dogs

Abstract

In the present study, the pulsatile serum profiles of prolactin, LH and testosterone were investigated in eight clinically healthy fertile male beagles of one to six years of age. Serum hormone concentrations were determined in blood samples collected at 15 min intervals over a period of 6 h before (control) and six days before the end of a four weeks treatment with the dopamine agonist cabergoline (5 μg kg⁻¹ bodyweight/day). In addition, the effect of cabergoline administration was investigated on thyrotropin-releasing hormone (TRH)-induced changes in the serum concentrations of these hormones.

In all eight dogs, the serum prolactin concentrations (mean 3.0 ± 0.3 ng ml⁻¹) were on a relatively constant level not showing any pulsatility, while the secretion patterns of LH and testosterone were characterised by several hormone pulses. Cabergoline administration caused a minor but significant reduction of the mean prolactin concentration (2.9 ± 0.2 ng ml⁻¹, p < 0.05) and did not affect the secretion of LH (mean 4.6 ± 1.3 ng ml⁻¹ versus 4.4 ± 1.7 ng ml⁻¹) or testosterone (2.5 ± 0.9 ng ml⁻¹ versus 2.4 ± 1.2 ng ml⁻¹). Under control conditions, a significant prolactin release was induced by intravenous TRH administration (before TRH: 3.8 ± 0.9 ng ml⁻¹, 20 min after TRH: 9.1 ± 5.9 ng ml⁻¹) demonstrating the role of TRH as potent prolactin releasing factor. This prolactin increase was almost completely suppressed under cabergoline medication (before TRH: 3.0 ± 0.2 ng ml⁻¹, 20 min after TRH: 3.3 ± 0.5 ng ml⁻¹). The concentrations of LH and testosterone were not affected by TRH administration.

The results of these studies suggest that dopamine agonists mainly affect suprabasal secretion of prolactin in the dog.

Introduction

In humans and rats, pituitary prolactin release is both pulsatile and nyctohemeral [1], [2], [3], [4]. Also, in female dogs, a pulsatile secretion pattern for prolactin has been demonstrated [5], while in male dogs a pulsatile secretion of this hormone is only suggested considering spontaneously elevated prolactin concentrations found in individual but not all dogs [6]. The pulsatile secretion of pituitary anterior lobe hormones is governed jointly by hypothalamic inhibitory and stimulatory signals [7]. Dopamine has been recognised as the main inhibitory neural signal in the regulation of prolactin release [8], [9]. The ergot-alkaloid cabergoline is a potent dopamine-2 receptor agonist. Its suppressing effect on prolactin secretion has been clearly demonstrated in the bitch [10].

In addition to the major inhibitory dopaminergic tone, several substances are known to have prolactin-releasing activity. Only a few years ago, a specific prolactin-release promoting peptide has been identified and characterised in the hypothalamus [11], [12]. In addition, several other prolactin-stimulating factors have been reported, such as serotonin [13] and thyrotrophin-releasing hormone (TRH) [14], [15], [16], [17], [18]. In a recent study the strong prolactin stimulating effect of TRH was also demonstrated in cattle in vitro and in vivo when compared with the prolactin release induced by a bovine posterior pituitary extract and prolactin releasing peptide [19]. Nevertheless, the exact role of TRH in the physiological regulation of prolactin secretion and the effect of the dopaminergic tone on TRH-induced prolactin secretion are not completely understood [7].

Several studies indicate an interrelationship of the secretion patterns of prolactin and the gonadotrophins. It has been clearly demonstrated that high concentrations of prolactin inhibit GnRH pulsatility in women [20], [21] and are associated with decreased gonadotrophin secretion in sows [22]. In females, lowering of the plasma concentration of prolactin to basal level is usually associated with the return of gonadotrophic pulsatility [20], [22]. In bitches, administration of dopamine agonists during both the luteal phase and anoestrus results in shortening of the interoestrous interval in the bitch [23], [24], [25], [26]. It has been shown that this dopamine agonist-induced shortening of the interoestrous interval in the bitch is associated with an increase in circulating FSH concentration [27].

Also, in men and male rats excessive release of prolactin leads to suppression of gonadotrophin release, which appears to be due to the action of prolactin on the central nervous system [28]. It has been suggested that prolactin is one of the factors, which regulate the sensitivity of gonadotrophin release to negative testosterone feedback. In hyperprolactinemic men, both LH and testosterone concentrations are reduced, implying increased sensitivity of LH release to negative testosterone feedback [29]. In boars, experimentally induced hyperprolactinemia has been shown to decrease basal LH concentrations without affecting LH pulsatility. The LH decrease was accompanied by an increase in testosterone concentrations [30]. Reduction of serum prolactin concentrations by bromocryptine did, however, not initiate a re-increase in LH concentrations. In contrast, maximum prolactin suppression by bromocryptine in male mice and rats was accompanied by a significant elevation of plasma levels of LH and FSH [31]. It is suggested that a direct stimulatory effect of bromocriptine on testicular steroidogenesis may contribute to its therapeutic effects in hyperprolactinemic men [32]. Data on interaction of prolactin on one hand and the LH-testosterone axis on the other hand are missing in male dogs.

The objective of the present study was to characterise the effects of the dopamine-2 receptor agonist cabergoline on the serum profiles of prolactin, LH, and testosterone in male beagles. In addition, the effects of a single intravenous TRH-injection on the secretion of the three hormones as well as on thyroid-stimulating hormone (TSH) and thyroxine (T₄) were studied before and under cabergoline medication.