Cushing's disease has not recurred in any patient with an undetectable serum cortisol (< 50 nmol/l) post-operatively. Serum cortisol should be regarded as a tumour marker in Cushing's disease and the aim of transsphenoidal hypophysectomy for Cushing's disease should be to render the immediate post-operative serum cortisol undetectable.

In our experience metyrapone remains a most useful agent for controlling cortisol levels in the management of Cushing's syndrome of all types.

Cabergoline is a new long-acting dopamine agonist that is very effective and well tolerated in patients with pathological hyperprolactinemia. The aim of this study was to examine, in a very large number of hyperprolactinemic patients, the ability to normalize PRL levels with cabergoline, to determine the effective dose and tolerance, and to assess the effect on clinical symptoms, tumor shrinkage, and visual field abnormalities. We also evaluated the effects of cabergoline in a large subgroup of patients with bromocriptine intolerance or -resistance. We retrospectively reviewed the files of 455 patients (102 males and 353 females) with pathological hyperprolactinemia treated with cabergoline in 9 Belgian centers. Among these patients, 41% had a microadenoma; 42%, a macroadenoma; 16%, idiopathic hyperprolactinemia; and 1%, an empty sella. The median pretreatment serum PRL level was 124 microg/L (range, 16-26,250 microg/L). A subgroup of 292 patients had previously been treated with bromocriptine, of which 140 showed bromocriptine intolerance and 58 showed bromocriptine resistance. Treatment with cabergoline normalized serum PRL levels in 86% of all patients: in 92% of 244 patients with idiopathic hyperprolactinemia or a microprolactinoma and in 77% of 181 macroadenomas. Pretreatment visual field abnormalities normalized in 70% of patients, and tumor shrinkage was seen in 67% of cases. Side effects were noted in 13% of patients, but only 3.9% discontinued therapy because of side effects. The median dose of cabergoline at the start of therapy was 1.0 mg/week but could be reduced to 0.5 mg/week once control was achieved. Patients with a macroprolactinoma needed a higher median cabergoline dose, compared with those with idiopathic hyperprolactinemia or a microprolactinoma: 1.0 mg/week vs. 0.5 mg/week, although a large overlap existed between these groups. Twenty-seven women treated with cabergoline became pregnant, and 25 delivered a healthy child. One patient had an intended abortion and another a miscarriage. In the patients with bromocriptine intolerance, normalization of PRL was reached in 84% of cases, whereas in the bromocriptine-resistant patients, PRL could be normalized in 70%. We confirmed, in a large-scale retrospective study, the high efficacy and tolerability of cabergoline in the treatment of pathological hyperprolactinemia, leaving few patients with unacceptable side effects or inadequate clinical response. Patients with idiopathic hyperprolactinemia or a microprolactinoma, on average, needed only half the dose of cabergoline as those with macroprolactinomas and have a higher chance of obtaining PRL normalization. Cabergoline also normalized PRL in the majority of patients with known bromocriptine intolerance or -resistance. Once PRL secretion was adequately controlled, the dose of cabergoline could often be significantly decreased, which further reduced costs of therapy.

Intrathecal administration of opioids is a very efficient tool in the long-term control of intractable nonmalignant pain. However, despite the well known role of opioids in endocrine regulation, few data are available about possible effects on hypothalamic-pituitary function during this treatment.Seventy-three patients (29 men and 44 women; mean age, 49.2 Ϯ 11.7 yr) receiving opioids intrathecally for nonmalignant pain were enrolled for extensive endocrine investigation. At the time of hormonal determination, the mean duration of opioid treatment was 26.6 Ϯ 16.3 months; the mean daily dose of morphine was 4.8 Ϯ 3.2 mg. The control group consisted of 20 patients (11 men and 9 women; mean age, 54.2 Ϯ 14.0 yr) with a comparable pain syndrome but not treated with opioids.Decreased libido or impotency was present in 23 of 24 men receiving opioids. The serum testosterone level was below 9 nmol/L in 25 of 29 men and was significantly lower than that in the control group (P Ͻ 0.001). The free androgen index was below normal in 18 of 29 men and was significantly lower than that in the control group (P Ͻ 0.001). The serum LH level was less than 2 U/L in 20 of 29 men and was significantly lower than that in the control group (P Ͻ 0.001). Serum FSH was comparable in both groups. Decreased libido was present in 22 of 32 women receiving opioids. All 21 premenopausal females developed either amenorrhea or an irregular menstrual cycle, with ovulation in only 1. Serum LH, estradiol, and progesterone levels were lower in the opioid group. In all 18 postmenopausal females significantly decreased serum LH (P Ͻ 0.001) and FSH (P ϭ 0.012) levels were found. The 24-h urinary free cortisol excretion was below 20 g/day in 14 of 71 opioid patients and was significantly lower than that in the control group (P ϭ 0.003). The peak cortisol response to insulin-induced hypoglycemia was below 180 g/L in 9 of 61 opioid patients and was significantly lower than that in the nonopioid group (P ϭ 0.002). The insulin-like growth factor I SD score was below Ϫ2 SD in 12 of 73 opioid patients and was significantly lower than that in the control group (P ϭ 0.002). The peak GH response to hypoglycemia was below 3 g/L in 9 of 62 subjects and was significantly lower than that in the control group (P ϭ 0.010). Thyroid function tests and PRL levels were considered normal. No metabolic disturbances were recorded, apart from significantly decreased high density lipoprotein cholesterol levels (P ϭ 0.041) and elevated total/high density lipoprotein cholesterol ratio (P ϭ 0.008) in the opioid group compared to the control group. Supplementation with gonadal steroids improved sexual function in most patients.In conclusion, of all patients receiving intrathecal opioids, the large majority of men and all women developed hypogonadotropic hypogonadism, about 15% developed central hypocorticism, and about 15% developed GH deficiency. These findings suggest that further investigations are required to determine the need for systematic endocrine work-up in these pa...

Context: Macroprolactinomas poorly responsive to dopamine-agonists are often more aggressive and are usually termed 'resistant' but this clinical concept has always been defined empirically. Objective: To define resistance to cabergoline (CAB) on the basis of a dose-response relationship established in a large series of macroprolactinoma patients and to assess the influence of gender and tumor invasiveness on the response to treatment. Design: Retrospective study. Methods: One hundred and twenty-two patients (72 women and 50 men) primarily treated with CAB for at least 1 year were included. Main outcome measures were serum prolactin (PRL) and tumor size. Results: Normalization of PRL was obtained in 115 out of the 122 patients (94%). The majority of patients (96/115, 83%) were controlled with a CAB dose %1.5 mg/week. Most of the other patients (19/26) had only a partial resistance, responding to a further increase of the CAB dose. Beyond the dose of 3.5 mg/week, there was no clear advantage in further increasing the dose instead of continuing the treatment at the same dose. Most tumors (98/119 assessable cases, 82%) showed a significant shrinkage during CAB treatment. It was more likely to occur in cases of PRL normalization. Both cavernous sinus invasion and male gender were significantly and independently associated with partial or complete resistance to treatment. Conclusions: Most macroprolactinomas primarily treated with CAB are adequately controlled with doses %1.5 mg/week. About 20% of patients, mainly men and/or those with invasive tumors will require a higher dose of CAB. We suggest defining such patients as resistant to CAB.