Piet Uitterlinden

Long-Term Treatment of Acromegaly with the Somatostatin Analogue SMS 201–995

We treated four patients with acromegaly for 8 to 24 weeks with SMS 201-995, the long-acting somatostatin analogue, in dosages of 100 to 300 micrograms a day given subcutaneously. A rapid amelioration of the clinical signs and symptoms and near normalization of laboratory test results occurred in all patients. Mean plasma growth hormone concentrations (+/- S.E.M.), as measured over 24 hours, fell from an initial value of 57 +/- 18 micrograms per liter to 7.5 +/- 2 micrograms per liter at the end of the investigational period. Likewise, levels of plasma somatomedin-C, which were originally elevated in all patients, dropped to the normal or nearly normal range. The suppression of insulin secretion and the resulting hyperglycemia that were observed at the beginning of treatment became less marked as therapy progressed. There was evidence of slight tumor shrinkage in three of the subjects. No side effects were recorded throughout the treatment period. These preliminary results suggest that SMS 201-995 represents an additional option for the management of acromegaly, especially in patients who do not benefit sufficiently from surgery or radiotherapy and do not respond well to treatment with dopaminergic drugs.

Pituitary tumour localization in patients with Cushing's disease by magnetic resonance imaging. Is there a place for petrosal sinus sampling?

OBJECTIVE We wished to analyse the relative value and diagnostic accuracy of bilateral simultaneous inferior petrosal sinus blood sampling for plasma ACTH measurements when compared with pituitary magnetic resonance imaging (MRI) for the preoperative localization of microadenoma (tumour diameter <10 mm) within the pituitary fossa in patients with Cushings disease.

THERAPY OF ACROMEGALY WITH SANDOSTATIN: THE PREDICTIVE VALUE OF AN ACUTE TEST, THE VALUE OF SERUM SOMATOMEDIN‐C MEASUREMENTS IN DOSE ADJUSTMENT AND THE DEFINITION OF A BIOCHEMICAL ‘CURE’

Fifteen acromegalic patient were treated for a mean of 96 weeks with 200–300 μg Sandostatin per day. The mean 24 h GH concentration decreased by 86% from 34.3 ± 6.6 to 4.8 ± 0.7 μ/l (1 μg/l = 46 pmol/1). There was a close correlation between the mean GH levels from 2 to 6 h after the acute administration of 50 μg Sandostatin and the mean 24 h GH levels after chronic therapy (P < 001). Serum Sm‐C levels decreased from 6.9 ± 0.7 to 2.7 ± 0.5 U/ml (−61%) and normalized in eight of these 15 patients. There was a close correlation between the Sm‐C and mean 24 h GH levels after therapy (P < 0001). It is suggested that adjustment of the dose and the number of Sandostatin injections can be made in acromegaly on the basis of the measurement of Sm‐C levels during the follow‐up. This precludes the need of multiple GH determinations throughout the day and/or night. Biochemical ‘cure’(as denned by normalized Sm‐C levels) was reached in eight patients in whom mean 24 h GH levels were suppressed to 3–3 μg/l or less. The normalization of Sm‐C levels was even observed in the presence of two or three GH secretory peaks (never exceeding 7.5–10 μg/l) during the 24 h period occurring towards the next Sandostatin injection.

The somatostatin analogue SOM230, compared with octreotide, induces differential effects in several metabolic pathways in acromegalic patients

Objective  Recently, our first clinical study with the novel multiligand somatostatin (SRIF) analogue SOM230 in acromegalic patients showed that SOM230, due to its beneficial inhibitory effects on GH levels compared with octreotide (OCT), might increase the number of patients that can be biochemically controlled. Since SRIF analogues are also known to interact with other metabolic pathways, IGF‐I, IGFBP‐1, glucose and insulin concentrations on the control day (CD) and on treatment days following a single s.c. injection SOM230 100 and 250 µg, were compared to those following OCT 100 µg.

Effects of acute administration of acylated and unacylated ghrelin on glucose and insulin concentrations in morbidly obese subjects without overt diabetes

OBJECTIVE To investigate the effects of unacylated ghrelin (UAG) and co-administration of acylated ghrelin (AG) and UAG in morbid obesity, a condition characterized by insulin resistance and low GH levels. DESIGN AND METHOD Eight morbidly obese non-diabetic subjects were treated with either UAG 200 microg, UAG 100 microg in combination with AG 100 microg (Comb) or placebo in three episodes of 4 consecutive days in a double-blind randomized crossover design. Study medication was administered as daily single i.v. bolus injections at 0900 h after an overnight fast. At 1000 h, a standardized meal was served. Glucose, insulin, GH, free fatty acids (FFA) and ghrelin were measured up to 4 h after administration. RESULTS Insulin concentrations significantly decreased after acute administration of Comb only, reaching a minimum at 20 min: 58.2 + or - 3.9% of baseline versus 88.7 + or - 7.2 and 92.7 + or - 2.6% after administration of placebo and UAG respectively (P<0.01). After 1 h, insulin concentration had returned to baseline. Glucose concentrations did not change after Comb. However, UAG administration alone did not change glucose, insulin, FFA or GH levels. CONCLUSION Co-administration of AG and UAG as a single i.v. bolus injection causes a significant decrease in insulin concentration in non-diabetic subjects suffering from morbid obesity. Since glucose concentration did not change in the first hour after Comb administration, our data suggest a strong improvement in insulin sensitivity. These findings warrant studies in which UAG with or without AG is administered for a longer period of time. Administration of a single bolus injection of UAG did not influence glucose and insulin metabolism.

17-BETA -ESTRADIOL-DEPENDENT REGULATION OF SOMATOSTATIN RECEPTOR SUBTYPE EXPRESSION IN THE 7315B PROLACTIN SECRETING RAT PITUITARY TUMOR IN VITRO AND IN VIVO

In the present study, we have investigated the role of estrogens in the regulation of somatostatin receptor subtype (sst) expression in 7315b PRL-secreting rat pituitary tumor cells in vitro and in vivo. sst were undetectable in freshly dispersed cells of the transplantable 7315b tumor. When 7315b cells were cultured in medium containing 10% FCS, the number of high affinity sst increased with prolonged culture time. However, when the medium was supplemented with 10% horse serum (HS) instead of FCS, no sst were detectable on 7315b cells even after three weeks of culturing. In contrast to HS, FCS contains high E2-levels (HS, 8 pm; FCS, 134 pm). The antiestrogen tamoxifen (0.5 μm) significantly inhibited the sst number to 50.5% of the value of untreated FCS-grown cells, suggesting that E2 stimulates sst expression in 7315b rat pituitary tumor cells. E2 (10 nm) induced a rapid increase in sst number in HS-grown 7315b cells. Octreotide (1 μm) significantly inhibited PRL release and the intracellular PRL concen...

IGFBP‐3 is a poor parameter for assessment of clinical activity in acromegaly

OBJECTIVE Elevated serum IGF‐I and IGF binding protein‐3 (IGFBP‐3) levels have been found in patients with active acromegaly. We have studied the relative diagnostic merits of measurements of IGFBP‐3 compared with IGF‐I as a parameter of disease activity in these patients.

Relationship between growth hormone and Somatomedin-C levels in untreated acromegaly, after surgery and radiotherapy and during medical therapy with Sandostatin (SMS 201–995)

Abstract. Several conflicting reports have been published with regard to the relationships between circulating growth hormone (GH), Somatomedin‐C (SM‐C) levels and clinical activity during different stages of therapy of acromegaly. We did not find a significant correlation between (fasting, post‐prandial and mean 24‐h) plasma GH and SM‐C concentrations in twenty‐two untreated acromegalic patients. There was a statistical significant correlation, however, if only the GH levels below 100 μg l‐1 were considered (n=18 patients, P<0·01). The distribution of molecular forms of GH (‘little’, ‘big’ and ‘big‐big’) did not differ between the four patients with GH levels above 100 μg l‐1 and in four patients with levels between 40 μg l‐1 and 80 μg l‐1. Therefore, it is suggested that GH levels of 80–100 μg l‐1 maximally activate Somatomedin‐C production in man and that further increases in GH in general will not result in a further increase in SM‐C generation. There was a significant correlation between GH and SM‐C levels in forty‐nine acromegalic patients after surgery and/or radiotherapy (P<0·001). In twenty‐three of thirty‐one patients with elevated SM‐C levels the disease was subjectively still active, while this was the case in none of the patients with normal SM‐C levels. In eight patients the disease was considered not to be clinically active any more, despite slightly increased SM‐C levels. During long‐term therapy of ten acromegalic patients for 16–108 weeks (mean 66±10) with 200–300 μg Sandostatin subcutaneously, clinical activity of the disease disappeared well before mean 24–h GH and SM‐C levels reached the normal levels. There was a close correlation between mean 24‐h GH and SM‐C levels during Sandostatin therapy (P<0·001). ‘Clinical cure’ during this medical treatment was reached in five patients, as reflected by disappearance of subjective complaints, normalization of SM‐C levels and 24‐h mean GH levels of 2·8±0·2 μg l‐1.

ON THE USE OF A NEW SOMATOSTATIN ANALOGUE IN THE TREATMENT OF HYPOGLYCAEMIA IN PATIENTS WITH INSULINOMA

A novel potent analogue of somatostatin, the octapepide SMS 201–995 was tested as a therapeutic manoeuvre to prevent hypoglycaemia in patients with insulinoma. We investigated the acute effects of a single 50 μg dose of the analogue administered s.c. in three patients, comparing the results in two of them with those obtained after administration of saline (control) and native somatostatin. In addition two patients were treated for up to 5 d with two or three daily s.c. injections (daily dose of analogue ranging from 100 to 300 μg). In two of the three patients SMS 201–995 suppressed circulating insulin levels by more than 50% and increased plasma glucose to hyperglycaemic levels for 6–8 h after a single injection. No undesirable effects of the administration of the analogue were observed. As opposed to insulin suppression obtained with native somatostatin, no rebound increase in insulin levels was observed after administration of the analogue. We conclude that SMS 201–995 prevented hypoglycaemia in two out of three patients with insulinoma. The advantage of s.c. administration, the long duration of action and the absence of a rebound phenomenon give this analogue a place in the pre‐operative management of patients with insulinoma.

Expression and Functional Analysis of Dopamine Receptor Subtype 2 and Somatostatin Receptor Subtypes in Canine Cushing’s Disease

Cushings disease (CD) is a severe disorder characterized by chronic hypercortisolism due to an ACTH-secreting pituitary adenoma. Transsphenoidal adenomectomy is the treatment of choice in humans with CD, but recurrences occur frequently. Finding an effective and safe medical treatment for CD may improve long-term clinical outcome. The recent demonstration of expression of somatostatin receptor subtypes (mainly sst5) and dopamine receptor subtype 2 (D2) in human corticotroph adenomas offers the possibility for medical treatment of CD with novel somatostatin analogs and dopamine agonists. Investigation of the effects of these drugs is hampered by the low incidence of CD in humans. Interestingly, CD is a frequent disorder in dogs with striking clinical similarities with CD in humans. Therefore, we investigated the expression and functional role of D2 and somatostatin receptors in corticotroph adenoma cells from 13 dogs with active CD that underwent therapeutic hypophysectomy and normal anterior pituitary cells from five dogs. Quantitative RT-PCR and immunohistochemistry revealed that both in CD and normal anterior pituitary, sst2 was the predominant receptor subtype expressed, whereas D2 was modestly expressed and sst5 was expressed only at very low levels. In primary cultures of canine adenomas (n = 7), the sst2-preferring agonist octreotide also showed the strongest ACTH-suppressive effects. In conclusion, canine corticotroph adenomas provide an interesting model to study CD, but differences in somatostatin and dopamine receptor expression between humans and dogs should be taken into account when using dogs with CD as a model to evaluate efficacy of novel somatostatin analogs and dopamine agonists for human CD.