Cabergoline (brand names Dostinex® and Cabaser®), an ergot-derivative, is a potent dopamine receptor agonist on D2-Receptors. It also acts on dopamine-receptors in lactophilic hypothalamus cells and causes thereby a suppression of the prolactin-production in pituitary gland.

Pharmacokinetics

Following an oral single dose the drug is resorbed within 0.5 to 4 hours from the GI-Tract with considerable interindividual differences. Meals do not alter the absorption characteristic. Human bioavailibility was not determined, because the drug is intended for oral use only. In mice and rats the absolute bioavailability was 30 and 63%, respectively. Cabergoline is rapidly and to a great extend metabolized in the liver and excreted in bile and far less in urine. All metabolites are less active than the parental drug or inactive. The human elimination halflife is estimated to be 63 to 68 hours in patients with M. Parkinson and 79 to 115 hours in patients with pituitary tumors.

Carcinogenity

In rodents a dose dependent increase in malignant tumors has been found. They are thought to be species-specific. No clinical data exists on carcinogenity in humans.

Uses

Monotherapy of Morbus Parkinson in the early phase.
Combination therapy of Morbus Parkinson in the progressive phase together with levodopa and a decarboxylase-inhibitor like carbidopa.
Adjunctive therapy of prolactin-producing tumors of the pituitary gland (microprolactinomes).
In some countries also : ablactation and dysfunctions associated with hyperprolactinemia (amenorrhea, oligomenorrhea, anovulation, und galactorrhea).

Off-Label/Recreational Uses

It has at times been used as an adjunct to SSRI antidepressants as there is some evidence that it counteracts certain side effects of those drugs such as reduced libido and anorgasmia. It also has been suggested online that it has a possible recreational use in reducing or eliminating the male refractory period.

Contraindications and Precautions

Hypersensitivity to ergot-derivatives
Pediatric Patients (no clinical experience)
Severely impaired liver function or cholestasis
Comedication with drugs metabolized mainly by CYP P450 such as erythromycin and ketoconazole, because increased plasma levels of cabergoline may result.
Cautions : severe cardiovascular disease, Raynaud's Syndrome, gastroduodenal ulcers, active gastrointestinal bleeding, hypotension.

Pregnancy and Lactation

Pregnancy : Approximately 100 female patients became pregnant under therapy with cabergoline for hyperprolactinemic conditions. The incidence of spontanous aborts and congenital abnormalities was comparable to nontreated patients. Nonetheless womem, wishing to become pregnant, should wait a safety period of 4 weeks after discontinuation of cabergoline. Patients becoming pregant under therapy should terminate cabergoline immediately, if possible.
Lactation : In rats cabergoline was found in the maternal milk. Since it is not known, if this effect is also seen in humans, lactating women should not be treated.

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Types of Pituitary Tumors and Management Strategies
From American Family Physician, 2/15/99 by Richard Sadovsky

Pituitary tumors account for 10 percent of all intracranial tumors. Because these tumors are often curable, accurate diagnosis is important. Magnetic resonance imaging (MRI) with gadolinium enhancement has greatly improved pituitary visualization. The goals of treatment include normalization of pituitary secretion, alleviation of symptoms and signs, and shrinkage or elimination of large tumors that might compress vital structures. Shimon and Melmed review the management of pituitary tumors (see the accompanying table).

The authors used the MEDLINE database to search for relevant literature on pituitary tumors. Prolactinoma, the most common hormone-secreting pituitary tumor, accounts for approximately 60 percent of functioning tumors. These tumors are characterized by mildly elevated serum prolactin levels accompanied by amenorrhea, infertility and galactorrhea in women, and higher prolactin levels are accompanied by impotence, loss of libido or infertility in men. Initial medical therapy consists of a dopamine agonist (cabergoline or bromocriptine). Patients should be monitored by regular measurements of serum prolactin levels, pituitary MRI and visual field examinations. Discontinuation of therapy often results in recurrent hyperprolactinemia. Surgery is infrequently necessary for resistant tumors.

Growth hormoneEsecreting adenomas account for 20 percent of functional pituitary tumors. They are often macroadenomas and present with parasellar or suprasellar invasion. Because symptoms of acromegaly develop slowly, diagnosis may be delayed for seven to 10 years. Headaches, hypopituitarism and visual disturbances are common manifestations. Surgery is the preferred treatment for growth hormoneEsecreting adenomas. Somatostatin analogs such as octreotide, which suppress growth hormone secretion, may be used as adjuvant therapy or, in selected cases, as primary treatment. Combined treatment with octreotide and bromocriptine has an additive effect on suppression of growth hormone and insulin-like growth factor I. Bromocriptine has increased bioactivity when administered with octreotide. Sellar irradiation may be used in patients resistant to medical management, but it has a slow response rate (five to 10 years) and a high rate of late hypopituitarism.

Adrenocorticotropin-secreting tumors constitute 15 percent of functional pituitary adenomas. These tumors are usually treated surgically. Transsphenoidal adenomectomy has a cure rate of 80 to 90 percent for microadenomas, but the rate is up to only 50 percent for macroadenomas. Hypopituitarism with permanent hypocortisolism may occur following surgery. If surgery fails to control the condition, pituitary irradiation, possibly combined with medical treatment, can be used. Adjuvant drug therapies include the adrenolytic agent mitotane, ketaconazole, aminoglutethimide and metyrapone, which decrease cortisol levels without affecting adrenocorticotropin hormone levels. Mitotane therapy combined with irradiation is the preferred treatment if surgical treatment fails.

Adenomas secreting thyroid-stimulating hormone (TSH) are rare and result in secondary hyperthyroxinemia and goiter. Surgical excision or debulking is the treatment of choice. Antithyroid medications are not used because of the possibility of increased tumor growth and aggressiveness from the release of the thyrotroph cell from thyroid feedback inhibition. Treatment with a somatostatin analog, such as octreotide, can reduce TSH production when surgery and radiation therapy are not effective. Dopamine agonists are not effective in suppressing TSH secretion from these tumors.

Nonfunctioning pituitary adenomas (gonadotroph-cell adenomas) account for approximately one third of all pituitary tumors and are the most common macroadenomas. The presentation of these tumors is determined by local mass effects, including optic chiasm pressure, neurologic symptoms and deficient pituitary hormone secretion. Hypogonadism may be present. Transsphenoidal surgery is the only way to decrease tumor size and relieve mass effects. These tumors have shown poor response to drug treatment.

Shimon I, Melmed S. Management of pituitary tumors. Ann Intern Med September 15, 1998;129:472-83.

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