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.
Discussion
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.
