A. Bertagna

Long-term treatment with cabergoline, a new long-lasting ergoline derivate, in idiopathic or tumorous hyperprolactinaemia and outcome of drug-induced pregnancy

Cabergoline (CAB), a new long-acting ergoline derivative, was shown to be very effective in reducing PRL levels in normal volunteers and in hyperprolactinemic patients. We evaluated the hormonal changes after discontinuation of long-term therapy with CAB as well as the safety of drug exposure during pregnancy both for mothers and babies. We therefore studied 48 patients (47 females and one male) with pathological hyperprolactinaemia (mean±SE, 117.2±15.2; median 73.2 µg/l), treated for 1–82 months (mean±SE, 28.3±3; median 18). After long-term treatment, CAB was withdrawn in 11 patients and PRL levels were persistently normal for almost 15 days and significantly lower (p <0.05) than basal at 30, 45, 60, 90, 120 days. Three patients had normal PRL levels still at 45 days after treatment discontinuation. Nine patients became pregnant after 1–37 months (mean 12.4) of therapy. In two patients the pregnancy was interrupted spontaneously in one case and voluntarily in the other. In all but one patients, after delivery or three-month breast feeding, PRL levels trended towards reduction. In two cases (one with microadenoma and one with idiopathic hyperprolactinaemia) PRL remained in the normal levels for 1–3 years after delivery. In conclusion CAB is able to inhibit plasma PRL levels for long time (up to 120 days) after withdrawal in patients with pathological hyperprolactinaemia treated with long-term therapy.

Evidence for a positive correlation between serum cortisol levels and IL-1β production by peripheral mononuclear cells in anorexia nervosa

A hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in anorexia nervosa (AN), together with some immunological abnormalities, involving citokine — and particularly Tumor Necrosis-Factor-α (TNF-α) — production by polymorphonuclear cells. The ability of pro-inflammatory cytokines to activate the HPA axis is well known; however, there are no data demonstrating an interdependence between immunological and endocrine response in AN. To investigate the presence of a correlation between immune response and pituitary-adrenal function, plasma ACTH and serum cortisol concentrations were measured in 13 AN patients and in the same number of controls. TNF-α and interleukin (IL)-1β production by ex-vivo unstimulated and LPS-stimulated peripheral mononuclear cells was also assessed. Circulating cortisol concentrations were higher (p<0.01) in AN (156.7±45.1 μg/l, mean±SD) than in controls (105.9±25.7 μg/l). Unstimulated IL-1β release in supernatants of mononuclear cell cultures was slightly but not significantly higher in AN than in controls, while TNF-α release was similar in the two groups. A positive correlation was found between IL-1β concentrations in unstimulated culture supranatants and serum cortisol levels in AN (r=0.782, p=0.002), while in normal subjects there was a trend toward a negative correlation; a slight positive correlation, while not significant, between IL-1β and plasma ACTH, as well as between TNF-α and serum cortisol was also found in AN. These data suggest that the normal relationship between pro-inflammatory cytokines release, particularly IL-1β and cortisol secretion is deranged in AN.

Dehydroepiandrosterone sulfate levels in women. Relationships with age, body mass index and insulin levels.

Sex and age are the major determinants of serum levels of dehydroepiandrosterone sulfate (DHEA-S): they are about twice in men than in women and show a progressive reduction from the end of the puberty to aging in both sexes. It has been reported that DHEA-S levels are also negatively influenced by insulin. Moreover, DHEA-S levels reduction has been associated to increased risk for cardiovascular disease, which connotes hyperinsulinemic states, such as obesity. We have evaluated serum levels of DHEA-S and insulin as function of age and body mass index (BMI) in 376 adult women (age 18.1–89.6 yrs, median 42.2; BMI 15.7–57.8 kg/m2, median 32.7) by multiple regression and piecewise regression analysis. Insulin levels positively associated to BMI (p=0.000002) and DHEA-S levels negatively associated with age (p=0.000001). Considering the whole population, DHEA-S levels were related positively with BMI (p=0.0013) independently of age. DHEA-S were also directly related to insulin levels independently of age (p=0.042), but this association disappeared after correction for BMI. Piecewise regression analysis did not reveal a threshold level for the increase of BMI (p=0.0004). Interestingly, DHEA-S levels and BMI were positively associated before but not after menopause. Taking into account only obese population, (no.=143, age 18.7w–67.3 yrs, mean 39.0, median 39.4) DHEA-S levels were again related negatively with age and positively with BMI, while were unrelated with waist to hip ratio (p=0.391). Our data show that increasing body mass and insulin secretion is not associated to DHEA-S reduction in women. This evidence suggests that DHEA-S is unlikely implicated in the pathogenesis of cardiovascular disease in obese women.

Acute goserelin administration inhibits gonadotropin and androgen secretion in post-menopausal women with ovarian hyperandrogenism

The aim of this study was to verify the effect of goserelin, a GnRH agonist, in women with post-menopausal virilization. Six patients with post-menopausal virilization and increase in 17-hydroxyprogesterone (17-OHP), total (TT) and free testosterone (FT) levels underwent single subcutaneous administration of goserelin, 3.6 mg. Serum 17-OHP, TT, FT, LH, FSH, E2, Δ4 and 3α-androstanediol glucuronide levels were measured before and 4, 8 and 18 days after goserelin administration. Goserelin administration was followed by progressive inhibition of FSH and LH, which fell to premenopausal levels on day 18, and progressive normalization of androgen parameters. The low E2 levels recorded at baseline were further reduced by goserelin administration. Four patients then underwent ovariectomy while in two patients, rejecting surgical treatment, goserelin treatment was protracted up to 6 and 12 months, respectively, with remission of hyperandrogenism. This study shows that in post-menopausal patients with virilization GnRH agonist allows to confirm the diagnosis of gonadotropin-dependent ovarian hyperandrogenism: its administration induces inhibition of gonadotropin levels, normalization of androgen parameters, and remission of virilization when the treatment is protracted in patients waiting for surgery.

“Cured” Prolactinoma Patients After Transsphenoidal Adenomectomy: Prediction of Recurrence

A high successful rate of cure after transsphenoidal adenomectomy has been demonstrated in patients with prolactinoma, especially those with a microadenoma (1–5). However, a high rate of recurrence after apparently successful adenomectomy has been reported in some studies (2,5). This could suggest the presence of a persistent underlying abnormality in the pituitary or the hypothalamus. To identify the persistence of any underlying abnormality of hypothalmic-pituitary control after surgery and to predict relapses, we studied the long-term follow-up and the PRL secretory dynamics in a group of prolactinoma patients determined “cured” after transsphenoidal adenomectomy.