Giuseppe Oppizzi

Low Doses of Dopamine Agonists in the Long-Term Treatment of Macroprolactinomas

To evaluate the long-term effects of dopamine agonists in the treatment of macroprolactinoma, we studied prolactin levels and tumor size for 30 to 88 months (57 +/- 14, mean +/- S.D.) in 38 patients treated with bromocriptine or lisuride. Elevated prolactin levels became normal in 30 patients, and the tumor shrank in 29. After two years of treatment, we attempted to reduce the maintenance dose (5 to 20 mg of bromocriptine per day or 0.4 to 0.8 mg of lisuride per day); in 21 patients no changes in prolactin levels or tumor size were observed over 6 to 52 months with 0.625 to 10 mg of bromocriptine per day or 0.05 mg of lisuride per day. However, it was possible to withdraw the drug in only one patient. We conclude that dopamine agonists are usually effective treatments for macroprolactinoma and that after a response has been obtained, it can be maintained in many patients with a greatly reduced dose.

Bone mineral density in acromegaly: the effect of gender, disease activity and gonadal status

objective Data on bone mineral density (BMD) in acromegaly are conflicting as most previous studies collectively evaluated eugonadal and hypogonadal patients of both sexes, with or without active disease. We have evaluated BMD in 152 acromegalic patients of both sexes with varying disease activity and gonadal status.

Scintigraphic imaging of pituitary adenomas: An in vivo evaluation of somatostatin receptors

We have performed pituitary scintigraphy with the somatostatin (SS) analog pentetreotidean by (111In-P) in patients with GH-secreting adenoma or with “clinically non functioning” adenoma (NFA) to evaluate the presence and the functionality of SS receptors (SS-R). 111In-P pituitary accumulation was expressed as Activity Ratio (AR): the ratio between the uptake of radioactivity by the adenoma and that of the normal brain tissue. In subjects without pituitary disease, AR ranged from 1.6 to 2.2 and a value lower than 2.2 was thus arbitrarily considered as normal. In 15 out of the 17 patients with GH-secreting adenoma, an accumulation of the radioligand was shown. Median AR was 3.8 (range 1–6.9; in 14 AR were greater that 2.2) and ARs were directly correlated (r=0.54; p<0.05) with the suppressibility of plasma GH levels by octreotide (OC) acute administration. In two patients who repeated scintigraphy during chronic OC treatment, AR values were reduced. In all the 22 patients with NFA an accumulation of 111In-P at the pituitary level was observed and median AR was 3.0 (range 1.5–20; in 14 greater that 2.2). In vitro autoradiography of surgical specimens in 6 NFA patients revealed SS-R in 4 cases with high scintigraphic AR and negative results in two cases with low AR. Scintiscan was repeated during chronic OC treatment in 5 patients with high score: AR decreased in one patient, increased in three, and did not change in the other patient. No changes in tumor size were shown in any of these patients. A total of 8 patients (3 GH secreting and 5 NFA) had “normal” AR values Conclusions: in acromegaly scintigraphy with 111In-P visualizes functioning pituitary SS-R coupled to intracellular events that control hormonal hypersecretion and tumor growth. In contrast, in spite of the positivity of 111ln-P imaging in most patients with NFA, their receptors might have a defect in the coupling-transduction process, as they are not inhibited by OC treatment and no tumor shrinkage is observed.

Effects of tamoxifen on GH and IGF-I levels in acromegaly

Tamoxifen (TAM), a non steroid partially competitive antagonist to the estrogen receptors, has been reported to decrease plasma GH and IGF-I levels both in vitro and in vivo. These data prompted us to evaluate GH and IGF-I changes in acromegaly after acute and chronic TAM administration. Nineteen acromegalic patients (6 M, 13 F, aged 30–70 years) were studied in a prospective open study. Acute TAM test (20 mg po) did not induce any significant change in GH and IGF-I levels. Chronic TAM treatment (20 mg/day for a month and 40 mg/day for another month) induced a transient increase in GH levels (from 9 [3–139] µg/l [median, range] to 12 [3-188] µg/l, p=0.0025) and a persistent decrease in IGF-I levels (from 785 [500-1200] µg/l to 553 [209-1420] µg/l, p=0.0034). Individual IGF-I values decreased in 13 patients and reached the normal range in 4 of them. At TAM withdrawal hormonal levels increased up to pretreatment values. There was no correlation between GH and IGF-I changes and results were not influenced by age, sex or gonadal status. In this setting it is likely that the observed decrease in plasma IGF-I levels is dependent on TAM activity at the hepatic level.

Reenlargement of macroprolactinomas during bromocriptine treatment: report of two cases.

We report two cases with macroprolactinoma who during medical treatment with bromocriptine showed a normalization of PRL levels and a reduction of tumor size as documented by computed tomography. After a few months of therapy both patients suddenly complained of worsening of their visual fields and a computed tomography demonstrated a reenlargement of the tumor mass; whereas in one patient PRL levels remained always within normal range, in the other patient, who was taking spiramycin for an intercurrent illness, there was also an escape of the hormonal secretion from the inhibitory effect of bromocriptine. The first patient underwent surgery, whereas in the second patient continuation of bromocriptine and interruption of antibiotic treatment resulted in progressive improvement in visual fields and a reduction of tumor size again. We want to stress that in patients with macroprolactinomas responsive to the medical treatment both in terms of PRL secretion and of tumor size reduction, an escape from the effects of bromocriptine, although infrequently, may occur.

EVIDENCE FOR A DOPAMINERGIC ACTIVITY OF METHYSERGIDE IN HUMANS

The acute administration of 2 mg of methysergide significantly reduced plasma prolactin levels in nine normal subjects and in seven hyperprolactinaemic patients. The prolactin lowering effect of this drug was abolished by sulpiride. Moreover methysergide lowered plasma GH levels in four out of nine acromegalic patients, who were also responsive to a dopaminergic drug such as bromocriptine. Although methysergide did not significantly blunt the TRH‐induced prolactin release, our data suggest that this drug may affect GH and prolactin release through a dopaminergic mechanism of action. This effect should be taken into account when methysergide is employed as antiserotoninergic drug in neuroendocrinological studies.

From macroprolactinoma to concomitant ACTH-PRL hypersecretion with Cushing’s disease

Multiple pituitary hormone hypersecretions have been already described, but the combination of PRL and ACTH excess is rare. This report deals with a 42-yr-old woman affected by macroprolactinoma (PRL 12,720 μg/l, huge tumor with extrasellar extension at imaging). After one year on dopaminergic treatment causing PRL normalization and tumor shrinkage, she developed hypercortisolism (UFC 1,000 μg/24 h, ACTH 200 ng/l). Cushing’s disease was diagnosed. After neu-rosurgery (at immunocytochemistry mixed ACTHPRL adenoma was shown) hypercortisolism remitted, whereas pathological hyperprolactinemia with tumor remnant in cavernous sinus persisted and hypopituitarism developed. The patient reported seems atypical for the following reasons: 1) the concomitant PRL and ACTH hypersecretions; 2) the clinical presentation with hypercortisolism following hyperprolactinemia; 3) the surgical cure of hypercortisolism with persisting hyperprolactinemia.

Effect of chronic bromocriptine administration on tumor size in patients with “nonsecreting” pituitary adenomas

The effect of chronic bromocriptine administration (7.5–20 mg/day for 1 -32 months) on the size of “nonsecreting” pituitary adenomas (NPA) was studied in 20 patients. Brain computed tomography showed a marked reduction of the adenoma in one patient after 1 month of treatment (7.5 mg/day); further scans taken 2 and 15 months later, under the same bromocriptine dose, did not show any other variations in the tumoral mass. In the remaining 19 patients, no changes in tumor size were documented by CT during the treatment. Four patients had a worsening of visual fields during bromocriptine administration and they were referred for neurosurgery. In conclusion, bromocriptine was ineffective in reducing tumor size in all but one patient with NPA and; in some cases, it did not prevent tumor growth as is suggested by the worsening of visual fields. Thus, bromocriptine treatment, at least at the doses capable of shrinking macroprolactino-mas, seems to be of limited value in patients with NPA.

Effect of the new ergot derivative terguride on plasma PRL and GH levels in patients with pathological hyperprolactinemia or acromegaly.

Terguride, a derivative of lisuride, has been shown to possess a mixed dopaminergic-antidopaminergic activity in experimental models. We have studied the effects on PRL and GH levels of 0.2 mg po of terguride in 8 normal subjects, in 15 patients with pathological hyperprolactinemia (PHP) and in 17 patients with active acromegaly. In PHP, PRL levels were significantly reduced up to 300 min after terguride with a nadir (45 ± 4.0 % SE) significantly lower (p< 0.05) than the one observed in the 8 normal subjects (72 ± 3.5%). There was no significant difference in plasma PRL levels after 0.2 mg terguride or lisuride in 7 out of 15 patients tested with both drugs. Terguride did not significantly modify GH levels in PHP and in normals but when considering basal and peak (occurring between 60 and 150 min) GH values, a significant difference was found (p< 0.01 ). Mean peak of GH did not differ significantly between PHP (5.0 ± 1.1 ng/ml) and normals (6.8 ± 1.7 ng/ml). Plasma GH levels of 17 acromegalics were not modified by 0.2 mg of terguride but were significantly reduced by 2.5 mg of bromocriptine. Terguride and bromocriptine reduced PRL levels in acromegalics (p< 0.01 ) without any significant difference between the two drug. 0.2 mg terguride b i d given for 15 days to 7 healthy volunteers significantly reduced both basal and sulpiride (25 mg im) — stimulated PRL levels. Side effects were observed only in 4 out of 47 subjects tested with terguride and in 8 out of 34 tested with bromocriptine.

Cushing's disease and marked hyperprolactinemia in a patient with a pituitary macroadenoma: effectiveness of bromocriptine treatment.

The case of a young boy bearing a pituitary PRL secreting adenoma (20–30,000 ng/ml) with the unusual association of clinical and endocrinological features of Cushing’s disease successfully treated with bromocriptine is described. Brain computed tomography evidenced a huge pituitary adenoma leading to visual field defects and raised intracranial pressure. Due to the very large size of the tumor, which rendered the complete neurosurgical removal unlikely, medical treatment with bromocriptine (10 mg/day) was started. Follow-up for more than six months demonstrated an impressive reduction of tumor size, the lowering of prolactin levels into the normal range, the normalization of visual field, and the regression of both clinical and biochemical signs of hypercortisolism.