3. Neuropharmacological Approaches to the Diagnosis and Treatment of Hyperprolactinemic States

In the past few years the study of the mechanisms involved in the neuroendocrine regulation of prolactin secretion has led in clinical practice to the introduction of several pharmacological tests. It was initially hoped that it would be possible to differentiate between diseases of the hypothalamus and the pituitary that affect prolactin secretion, in particular, between tumoral and “functional” hyperprolactinemia. The most frequently used drugs are the DA-receptor blockers (metoclopramide, sulpiride, chlorpromazine), on the premise that they act at the hypothalamic level, and therefore require the integrity of the CNS for their prolactin-releasing effect. It is now clear that DA antagonists, including chlorpromazine, can directly act on the pituitary (MacLeod and Lehmeyer, 1974; Besser et al., 1980a) to block DA receptors which in turn regulate prolactin release. Hence, their use for diagnostic differentiation between pituitary and hypothalamic causes of hyperprolactinemia is of dubious value.

Although the responses are variable in patients with pituitary tumors and in some prolactin responses to DA antagonists can be seen, certainly most cases of obvious pituitary micro- and macroadenomas show no response to these and other stimuli (e.g., TRH) (Jacobs and Daughaday, 1973; Faglia et al., 1977; Frantz, 1978; Jaquet et al., 1978; Bohnet and McNeilly, 1979). This may be related to the proposed defect in the regulation of catecholamine metabolism in patients with prolactin-secreting tumors (Van Loon, 1978). Since estrogens are known to cause hyperplasia of the lactotropes and to interact with DA mechanisms (Raymond et al., 1978) centrally and at the pituitary level, a cooperative pathogenetic role of estrogens has also been suggested in patients with “post-pill” hyperprolactinemia (Sherman et al., 1978). Moreover, the secretory pattern of prolactin in patients with prolactinomas (no prolactin response to DA antagonist or TRH) can be mimicked in normal subjects by the continuous intake of DA blockers (Healy and Burger, 1978). As the above data suggest that either an intrinsic deficiency in DA secretion or an abnormality of DA receptors can be the cause of hyperprolactinemia, two additional neuropharmacological approaches have recently been proposed. While l-dopa is effective in decreasing prolactin secretion in patients with prolactinomas, the addition of the decarboxylase inhibitor carbidopa nearly completely blocks this effect (Fine and Frohman, 1978) (Fig. 14). In normal subjects prolactin suppression occurred after l-dopa despite simultaneous carbidopa administration. Similarly, the DA reuptake inhibitor, nomifensine, was reported to suppress prolactin in “functional” hyperprolactinemia but not in hyperprolactinemia due to prolactinoma (Muller et al., 1978). The above data were taken as indirect additional evidence of defective hypothalamic DA neurotransmission in patients with tumoral hyperprolactinemia. However, in apparent contrast to the above hypothesis, an enhanced DA tone at the hypothalamic LH-RH neurons (but with a relative deficiency of DA at the lactotropes) in hyperprolactinemic states has been proposed (Quigley et al., 1979). Since these patients respond to DA agonist drugs, a pituitary defect (in the lactotropes) seems extremely unlikely. Fig. 14. Plasma prolactin levels in normal control subjects (A) and in patients with pituitary tumors (B) after administration of l-dopa and l-dopa plus carbidopa, a dopa decarboxylase inhibitor (DDI). (from Fine and Frohman, 1978 with permission of the authors and the editor of Journal of Clinical Investigation) Copyright © 1978

The use of DA-receptor agonists as an inhibiting test for prolactin cannot add any further information since they reduce hyperprolactinemia by virtue of their direct effect at the pituitary, irrespective of its cause.

Despite these experimental data, there is at the moment scanty evidence for intrinsic deficiency of DA secretion or abnormality of DA receptors as the clinical cause of hyperprolactinemia, and neuroactive drugs do not seem to be very helpful in the diagnosis. Hyperprolactinemia due to micro- and macroadenoma (radiologically documented) does not require any further dynamic testing for diagnosis of its origin, while the clinical application of neuropharmacological tools in the “early diagnosis” of pituitary microadenomas needs further validation.

The rational approach to the treatment of hyperprolactinemia is to use DA-agonist compounds, since DA is the most important PIF. l-Dopa was first used (Turkington, 1972). The drug must be converted into DA before it is effective and also increases NE and E synthesis. However, it has a short duration of action, which limits its clinical use. The demonstration that selected ergot alkaloids have a long-lasting prolactin-inhibiting effect (Fluckiger and Wagner, 1968; Pasteels et al., 1971) provided a potent therapeutic means for treating disorders of prolactin secretion, but only relatively recently has this action been attributed to their ability to stimulate DA receptors (Corrodi et al., 1973). These compounds suppress prolactin secretion directly at the pituitary level (MacLeod and Lehmeyer, 1974) like DA, and their in vivo long-lasting activity compared with DA correlates well with the in vitro data and could be accounted for by persistent binding to the pituitary receptors (Fig. 15). Of these compounds, bromocriptine has been studied most widely and has had the widest clinical use. Lisuride and metergoline, compounds related to bromocriptine but lacking a peptide sequence, may be valid alternatives to bromocriptine. Whereas lisuride works on lactotropes through DA-dependent mechanisms (Delitala et al., 1979a), no DA activity for metergoline has been clearly demonstrated (MacLeod and Lamberts, 1979; Besser et al., 1980b). However, both compounds are shorter acting than bromocriptine in vitro. All the clinical features of hyperprolactinemia, irrespective of its origin, can be easily reversed by DA agonist compounds (see Thorner, 1978). Assuming that the pituitary reserve of gonadotropins and other tropins is normal, as it is in the majority of patients with hyperprolactinemia, particularly with microadenoma, normal menstruation and ovulatory cycles are rapidly restored in premenopausal women; usually within weeks, libido usually improves and they become highly fertile. Galactorrhea, if present, usually decreases a few days after the start of therapy. Men also rapidly respond to treatment; galactorrhea disappears and potency is restored with an increase in seminal volume. Occasionally, and particularly in patients with frank pituitary tumors, DA agonists are unable to restore the prolactin level to normal, although they can lower it, and high doses (i.e., more than 20 mg/day of bromocriptine) are necessary to reduce prolactin secretion. In the vast majority of cases, 7.5 mg bromocriptine daily (or 600) μg lisuride daily) is highly effective and only occasionally is it necessary to increase the dose (Thorner and Besser, 1978b). Fig. 15. Rat prolactin concentration in eluate from rat anterior pituitary cell columns exposed to medium containing dopamine (5 μM), bromocriptine (5 nM), lisuride (5 nM), lergotrile (50 nM), and pergolide (5 nM). The blank bars represent prolactin secretion when saline alone was added to the perfusing medium. (from Delitala et al., 1980d , with permission of the authors and the editor of Journal of Endocrinology) Copyright © 1980

A major problem arises when patients on bromocriptine wish to become pregnant, as there is a risk of enlargement of pituitary tumor and optic nerve compression. The risks are greatest with macroadenomas (Gemzell and Wang, 1979) but swelling of the pituitary can also been seen with microadenomas. The risk of this or of pituitary apoplexy in pregnancy is quite definite but the frequency of their occurrence is, happily, quite low. The policies adopted to prevent these possible complications vary. Some workers have recommended that the tumor first be treated by external radiotherapy (Thorner et al., 1979) to prevent tumor swelling, the alternative approach is selective removal of a microadenoma (Hardy, 1973; Bertrand and Tolis, 1979; Bohnet et al., 1979). Patients with definite suprasellar extension should be treated surgically and then an external course of radiotherapy should follow. There is no definitive answer to this problem at the moment. Good evidence now exists that bromocriptine and lisuride therapy lead to reduction in tumor size (as documented by changes in visual field defects, radiological change in fossa size, and clear shrinkage using computerized tomography) (Corenblum et al., 1975; Thorner and Besser, 1978b; Besser et al., 1978; Wass et al., 1979; McGregor et al., 1979; George et al., 1979; Chiodini et al., 1980). Suggestive evidence for tumor shrinkage has also been obtained by comparing the basal levels of serum prolactin before and after long-term therapy with bromocriptine (Von Werder et al., 1978). This direct antitumor effect of bromocriptine is well documented experimentally (Quadri et al., 1972; Lloyd et al., 1975). Patients with microadenomas can be effectively treated with DA agonist compounds. The risks of selective adenomectomy by the transphenoidal route are not negligible and hyperprolactinemia may remain or recur after this procedure (Lancet, 1980).

Although the impact of pharmacological therapy on these tumors remains to be established, and surgery will most certainly not be rendered obsolete, this exciting evidence of tumor shrinkage suggests the potential value of neurotransmitter therapy with selected ergot derivatives in treating patients with prolactinomas or with recurrence of such tumors after previous chiasmal decompression and conventional external megavoltage irradiation of the pituitary.

Cyproheptadine in large doses was also used in the galactorrhea–amenorrhea syndrome as a prolactin-lowering drug (Wortsman et al., 1979) since serotonin probably plays a role in the release of pituitary prolactin. Although small prolactin decreases have been reported in some patients, the drug has no role in the management of hyperprolactinemia.

Puerperal lactation can easily be suppressed by inhibiting prolactin secretion. Ergots are the rational approach in this physiological situation and their value in preventing and suppressing established lactation is now well documented (Varga et al., 1972; Rolland and Schellekens, 1973; Delitala et al., 1977b). The clinical advantages over estrogens are obvious as prolactin levels are lowered by ergots and the blood-clotting system is not affected, as with estrogen administration (Cooke et al., 1976).

In summary, neurotransmitter therapy with DA agonist drugs has resulted in a major change in the management of disordered prolactin secretion. Side effects (nausea, postural hypotension) are usually encountered only at the start of treatment, but they can be effectively minimized by starting with a small dose and then gradually increasing, and administering the tablet with food. Bromocriptine is not teratogenic or carcinogenic (Besser et al., 1977), but it is usually promptly stopped once pregnancy has been confirmed.