mise à jour du
10 mars 2005
Journal of Andrology
1997; 18; 1; 21-25
Suppressive effects of chronic hyperprolactinemia on penile erection and yawning following administration of apomorphine to pituitary-transplanted rats
Sato F, Aoki H, Nakamura K, et al.
Department of Physiology, Iwate Medical University, School of Medicine, Japan


Chronic hyperprolactinemia, most typically seen in patients bearing prolactin (PRL)-secreting pituitary adenoma, is known to be associated with coital dysfunction. In male patients, both decreased libido and potency have been reported. Several lines of evidence exist that PRL suppresses LH-testosterone (T) dynamics at the level of the hypothalamus, and serum T levels tend to be low in men with chronic hyperprolactinemia. It is likely that suppression of plasma T exerts some adverse effects on the sexual function and is at least partly responsible for the development of erectile insufficiency in hyperproiactinemia. However, it is curreniy unclear whether T deficiency can explain the major part of the decreased sexual function in this state. Some previous studies have provided evidence that PRL could cause sexual dysfunction through mechanisms that are independent of T dynamics. Thus, there have been reports that PRL directly suppressed the libido center in the central nervous system or the end organ itself, i.e., corpus cavernosum penis.
In our recent studies, we showed that acute exposure of the cavernous tissue to excess PRL had a strong inhibitory effect on the electrically induced penile erection in vivo and that it produced an intense contraction of the cavernous smooth muscles in vitro. These data provided strong evidence for a direct suppressive action of PRL on the cavernous tissues but in no way ruled out possibilities of other mechanisms contributing to the sexual dysfunction in hyperprolactinemia. Considering all of the above information available to date, it is most probable that hyperprolactinemia has more than one site and more than one mode of action in causing impotence. Also, each of the multiple contributing mechanisms may have differential impacts depending upon whether or not the PRL excess takes place acutely or chronically and also depending upon the animal species being examined.
In the present investigation, we examined if an experimental manipulation producing chronic hyperprolactinemia can cause impairment of erectile function via mechanisms that are independent of the T dynamics as we demonstrated with acute exposure to excess PRL. Rats with transplanted pituitaries under the kidney capsules were used as a model of chronic hyperprolactinemia, and apomorphine was employed as an inducer of penile erection. We also compared erectile activities between the pituitary-transplanted rats and castrated rats to obtain some insight into the relative degrees of contribution of excess PRL vs. T deficiency for the genesis of erectile compromise.
Prolactin, when present in excess amounts in the blood circulation, causes impairment of reproductive functions including reduced potency. Since hyperprolactinemia is frequently associated with hypogonadotropic hypogonadism with subnormal plasma T concentrations in men, it is important to clarify the extent to which each of the excess PRL and T deficiencies contributes to the development of impotence. Although T deficiency, when present alone, definitely causes decreased libido and potency, T replacement in hyperprolactinemic patients usually fails to correct erectile insufficiency. Normalization of hyperprolactinemia seems to be essential for a full restoration of potency. Under the experimental conditions we employed in the present studies, hyperprolactinemia with normal plasma T concentration was successfully produced 8 weeks after the pituitary transplantation. Also, independent effect of T deficiency could be studied in the castrated rats that had normal plasma PRL concentrations.
Apomorphine has been shown to produce a syndrome of yawning and penile erection in rats. The increase in both erection and yawning seen after apomorphine administration is in direct contrast to the low spontaneous rates of these behaviors. This phenomenon has provided an effective bioassay for the testing of the influence of various drugs on the erectile function. We profitably applied this model to the study of chronic hyperprolactinemia. Although the precise mechanism of apomorphine-induced erection has not been established, experimental results have suggested that central dopaminergic activation has resulted and that the action of apomorphine was antagonized by agents having central activity, including sulpiride, haloperidol, and metoclopramide but not by agents with only peripheral activity, such as domperidone. Moreover, both penile erection and the yawning response appear to be mediated by central dopamine autoreceptors, with the hypothalamic paraventricular nucleus playing a key role.
Our data indicated that chronic hyperprolactinemic state produced erectile insufficiency with decreased frequency of apomorphine-induced erection in the pituitarytransplanted rats. Since apomorphine is a dopamine agonist, it might have suppressed PRL secretion from the pituitaries in all three groups studied. Nevertheless, it did not equivocate the effects of chronic hyperprolactinemia. It appears that some changes in hormonal milieu, produced as a result of pituitary transplantation (presumably chronic exposure to excess PRL) reduces potency independently of the status of T, as was the case with acute exposure in our recently published studies. The degree of suppression of erection was roughly comparable between the transplanted and castrated rats. This may raise the possibility that excess PRL and T deficiencies are equally important in the genesis of erectile insufficiency in this species. However, apomorphine-induced erection is not a natural physiological erection, and therefore, the relative degree of contribution by the two etiologic factors may be quite different in naturally occurring impotence from our current experimental models. Also, we have to take into consideration a possibility that factor(s) other than PRL excess might be different between the pituitary-transplanted and shamoperated rats. Another important problem in interpreting our data is that serum T concentration in rats is not an exact equivalence to either free or total T in humans because of the total lack of sex-hormone-binding globulin in the former species. This makes it difficult to extrapolate our results to human disease, and it is possible that T plays a greater role in maintaining normal erectile function in the rodent than in humans.
Our present data on chronic hyperprolactinemia do not clearly differentiate between the central vs peripheral site(s) of action of PRL in suppressing potency. However, the fact that the frequency of both erection and yawning decreased to about the same degree in the pituitary-transplanted rats might suggest that the suppressive effect was exerted more through its central action than through a peripheral one. This is because apomorphine-induced erection and yawning appear to share common dopaminergic mechanisms in the central nervous system, whereas little similarities exist in their peripheral activation pathways, including the neurotransmitters involved. Our data, therefore, are consistent with and reinforce previous reports that localized the preoptic-anterior hypothalamic area and a part of the incerto-hypothalamic penventricular system as a site of PRL action to modify the male sex behavior and libido in this species. Although we recently showed that excess PRL exerted considerable anti-erectile effect through direct action on the corpus cavernosum penis, these studies differed from our current experiments in that the PRL excess was introduced acutely instead of chronically and that dogs instead of rats were employed. These differences in the experimental conditions might explain the possible discordance in the results. Since castration produced a differential inhibition, i.e., greater inhibitory effects on the apomorphine-induced erection than yawning, T deficiency may affect, to a relatively greater extent compared to PRL excess, the peripheral component of the activation pathway for penile erection. In this regard, our data may be partly in conflict with those of Heaton et al, who showed that the castrated rats completely failed to produce erection and yawning in response to apomorphine. The reason for this discrepancy is not clear.
There exist some differences in the actions of PRL on the reproductive function among different animal species, such as the luteotropic activity demonstrable with rodents but not with humans. This may explain the normal plasma T concentrations in the face of elevated PRL in the rat in our present study and studies previously reported by others. Thus, the pituitary-transplanted rat provided an excellent model for PRL excess in that the hyperprolactinemia was chronic as in the prolactinoma patients and that the degree of excess PRL, i.e., an average, approximately of an 81/2-fold elevation from the basal concentration, was quite comparable and relevant to the clinical hyperprolactinemia seen in humans. Since an 8-week period in the rat's life cycle probably represents an equivalence to a number of years in human life, we believe that the level of chronicity of hyperprolactinemia in this model is also appropriate.
Prolactin-induced yawning behavior requires an intact nigro-striatal dopamine system Laping NJ, Ramirez VD