Neuroactive Compounds in the Diagnosis and Treatment of Neuroendocrine Disorders

The notion gained from the preceding sections that in the CNS a host of neuropeptides and neurotransmitters interact functionally to ensure the physiological secretion of AP hormones leads to the ultimate conclusion that their dysfunction may be the trigger for specific neuroendocrine disorders.

The principal diagnostic and therapeutic uses of CNS-acting compounds will be succinctly reviewed here. Mention of the clinical applications of regulatory hormones has already been made in the specific subsections.

A. Growth Hormone Deficiency and Excess. The ability of GHRH to affect somatotroph function cannot be used as a test for identifying patients with inadequate spontaneous growth hormone secretion, owing to the poor inter- and intraindividual reproducibility of the growth hormone responses to GHRH. Because the major factors that plague evaluation of the growth hormone response to GHRH are fluctuations in the hypothalamic function and release of somatostatin, compounds such as pyridostigmine, which deprive the pituitary from inhibitory somatostatin inputs, given in advance to GHRH, appear to be useful for a full evaluation of pituitary somatotroph function and, thus, differentiation from a primary hypothalamic origin of the disease.

The finding that most adults and children with growth hormone deficiency show variable but unequivocal rises in plasma growth hormone levels after administration of GHRH suggests that growth hormone deficiency is rarely due to a functional impairment of somatotrophs but is more likely to be due to hypothalamic dysfunction. Pituitary growth hormone is present but not secreted, probably due to lack of GHRH synthesis and/or release.

The presence of low but detectable GHRH levels in the cerebrospinal fluid of children with idiopathic growth hormone deficiency is suggestive of dysfunction of neurons regulating the release of GHRH from GHRH-containing neurons. In this context, recent attempts to stimulate growth hormone release in children with idiopathic growth hormone deficiency, intrauterine growth retardation, constitutional growth delay by treatment with DA agonists (L-dopa, bromocriptine), or a2-adrenergic agonists (Clo) must be considered. In all, the results obtained seem to be promising, although broadening and confirmation of these findings are awaited. Finally, administration of pyridostigmine alone or combined with GHRH has been considered for the treatment of short stature, but results obtained so far are elusive.

Evidence that in acromegalic patients direct DA agonists induce a consistent suppression of the elevated growth hormone levels in about 60% of patients for a direct action on DA receptors located on the somatotrophs was the rationale for the use of ergot drugs, bromocriptine, lisuride, pergolide, and cabergoline. Apart from lowering plasma human growth hormone levels, clinical and metabolic improvements have been reported following the institution of medical therapy, although apparently patients benefit from but are not cured by chronic treatment with ergot drugs. The introduction of potent analogues of somatostatin capable of long-lasting reductions in plasma growth hormone levels will limit the therapeutic use of ergot derivatives in acromegaly.

B. Hypogonadotropic Hypogonadism. Secondary amenorrhea is by far the most common symptom attributable to pituitary function in women. It is usually transient and unaccompanied by structural abnormalities of hypothalamus, pituitary, or ovary (hypothalamic amenorrhea). Suptary, or ovary (hypothalamic amenorrhea). Supporting evidence for a role of opioid peptides in the etiology of amenorrhea is derived from studies of amenorrheic women treated with naloxone. A clear increment in LH levels was observed in women with amenorrhea and/or hyperprolactinemia, suggesting that the acyclicity was due, at least in part, to the effect of an increased opioid peptide tone on GnRH and gonadotropin secretion. Thus, opioid antagonists may represent a useful therapeutic approach in these cases.

C. Cushing's Disease. The awareness that a host of neurotransmitters and neuropeptides are involved in the regulation of ACTH secretion, and the evidence that some neuroactive drugs initially thought to act on the hypothalamus to decrease CRH activity actually may act at the pituitary level account for a medical approach to therapy in Cushing’s disease. Thus far, drugs used in this context encompass cyproheptadine, whose use relied on the known stimulatory action of the 5-HT neuronal system on the hypothalamo-pituitary adrenal axis, bromocriptine and sodium valproate, ultimately capable to stimulate DA and GABA receptors located on the corticotrophs. Although on distinct cases some clinical and biochemical remission is evident, the role of the medical therapy in Cushing's disease is ancillary to transsphenoidal microsurgery.

D. Prolactinomas. Prolactin-secreting tumors, either < 10 mm diameter (microprolactinomas) or higher (macroprolactinomas), are the most frequently occurring neoplasms in the human pituitary. Clinically, hyperprolactinemia is associated with amenorrhea, galactorrhea, infertility, decreased libido, impotence, and, in macroprolactinomas, visual disturbances. In patients with microprolactinomas, DA agonist-ergot-related drugs represent a primary medical therapy. Administration of these drugs causes immediate and sustained prolactin suppression with restoration of fertility in women and normalization of hyperprolactinemic hypogonadism in men.

Usually within 2 mo of the return of menstruation, ovulation and adequacy of the luteal phase is achieved and galactorrhea disappears. In men, libido and potency return to normal and, if reduced, the seminal volume also is normalized. When treatment is started, bromocriptine, the drug most commonly used, and other ergolines may cause different neurovegetative symptoms due to activation of central and peripheral DA receptors. Thus, low doses of drugs that are increased slowly and taken during a meal rather than after food are mandatory to minimize the side effects.

Two long-acting injectable preparations of bromocriptine are available whose injection in patients with prolactinoma is followed by a prompt and steep prolactin decrease lasting for weeks or months. In many cases, shrinkage of the pituitary tumor can also be documented. Only transient and mild to moderate side effects are noticed.

The effects of medical therapy are particularly noteworthy in macroprolactinomas because these tumors are rarely cured by surgery and with radiotherapy subsequent hypopituitarism is common. It is now evident that reduction of tumor size as documented by tomographic scan and amelioration of visual disturbances can be anticipated in about 75% of the patients. Interestingly, a tumor shrinks only when prolactin secretion is inhibited by dopaminergic stimulation, but tumor size may remain unaltered despite the reduction of prolactin secretion. From the foregoing evidence, it appears that medical treatment of macroprolactinomas is more appropriate than neurosurgical transsphenoidal exploration for the primary treatment of the disease.

The critical issue is whether or not this therapy effects a real cure of the disease. Overall, it would seem that only in a minority of patients does longterm medical treatment result in a persisting correction of the underlying cause of the adenoma. Possibly, more prolonged drug regimens, different drug doses, or newer DA agonists will prove more effective in this context.