Sigbritt Werner

Characterization of two novel mutations in the glucocorticoid receptor gene in patients with primary cortisol resistance

OBJECTIVE Primary glucocorticoid resistance is characterized by decreased sensitivity to cortisol signalling. We have performed genetic analysis of the glucocorticoid receptor (GR) gene in 12 unrelated patients with primary cortisol resistance as defined by a pathological dexamethasone suppression test.

Stereotactic Radiosurgery with the cobalt-60 Gamma Unit in the treatment of growth hormone producing pituitary tumors.

Stereotactic radiosurgery on the pituitary given with the cobalt-60 gamma unit was used in the treatment of 21 patients with growth hormone (GH)-producing pituitary adenomas and acromegaly. All but one patient had locally invasive macroadenomas, and in the majority of cases, there was parasellar growth. Radiosurgery was the initial treatment for seven patients. Fourteen patients were previously treated by pituitary surgery, eight of whom had undergone conventional external pituitary irradiation as well. All patients had clinical signs of active acromegaly before radiosurgery. The radiation doses given to the previously untreated patients or those who only underwent surgery were 40 to 70 Gy in each of one to three irradiations. The patients with previous external irradiation received a lower dose of 30 to 50 Gy in each of one or two irradiations. The patients were observed during a period of 1 to 21 years from the first radiosurgical session. Two young patients had a clinical remission with a substantial decline of GH levels to near normal serum profiles. Another eight patients obtained reduction of GH levels and clinical activity. More than half of the patients (11 of 21) had minor or no effects from the treatment. There were no complications from the radiosurgery except the development of pituitary insufficiency in 2 of 13 patients who did not undergo previous conventional external irradiation. The remission rates were lower than the results previously reported by us for radiosurgery for Cushings disease. This may be a result of the predominance in the present study of invasive macroadenomas and single treatments and to the lower radiation doses used in the patients who underwent conventional irradiation previously.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of the Peptide PHI-27 on Prolactin Release in vitro

The present study demonstrates that PHI, a peptide belonging to the glucagon-secretin group and thus structurally similar to VIP, can release prolactin from dispersed rat anterior pituitary cells and also causes release of prolactin from hemipituitaries. PHI-like immunoreactivity has previously been demonstrated in a hypothalamic system with nerve endings in the median eminence, and, taken together, these findings suggest that PHI may represent a physiologic prolactin-releasing factor.

Neurons with multiple messengers with special reference in neuroendocrine systems.

Publisher Summary This chapter presents the neurons with multiple messengers with special reference to neuroendocrine systems. Neurons of different types in the periphery and in the central nervous system, including neurosecretory cells, produce, store, and perhaps release more than one messenger molecule. The coexisting messengers in primitive neurons are stored in the same vesicles, as they are in mammalian endocrine cells at present. With the demand for faster communication, new types of vesicles, small synaptic vesicles, developed storing and releasing exclusively classical transmitters, being present in addition to the larger vesicles storing both classical transmitter and peptide(s). Interestingly, the neurosecretory cells, representing an intermediate between endocrine cells and neurons, contain a higher proportion of large dense core vesicles than neurons releasing their messengers at more or less well defined synapses. Studies in the peripheral nervous system suggest that the classical transmitters and peptides are, indeed, co-released and may interact in a cooperative way on effector cells. Therefore, interaction between different messengers released from the same nerve endings may be of several types and may, in a general sense, provide mechanisms for differential responses and for increasing the amount of information transferred at synapses. Multi-messenger transmission may represent a principle for increasing capacity for information transfer in the nervous system, a capacity which already appears enormous when considering just the number of neurons and their nerve endings in the mammalian nervous system. At present, the importance of peptides is in many cases difficult to evaluate, and it cannot be excluded that their role is considerably less significant than that of the classical transmitters.

External irradiation of growth hormone producing pituitary adenomas: Prolactin as a marker of hypothalamic and pituitary effects

Fifty-six patients with acromegaly were treated with external irradiation, 50 Gy, after unsuccessful pituitary surgery. A 50% reduction of pre-irradiation growth hormone levels was obtained in 51/56 patients. This level was reached after 26 +/- 14 months in 33 patients with prolactin levels less than 25 micrograms/l at diagnosis, after 21 +/- 17 months in 18 patients with prolactin greater than or equal to 25 micrograms/l, and after 20 +/- 21 months in 12 patients with prolactin greater than 40 micrograms/l at diagnosis. A further 50% decrease of growth hormone levels was obtained in 40/51 patients 42 +/- 22 months after radiotherapy, indicating that in clearly responsive patients, the growth hormone depression after radiotherapy follows a first order reaction. Four patients did not reach a 50% reduction of growth hormone levels 48-80 months after radiotherapy. During 10 years of follow-up, the growth hormone depression tended to be more pronounced in patients with mixed secretion of growth hormone and prolactin. The reduction of growth hormone levels was not correlated with the irradiated volume or the cumulative radiation effect. Within the first year, prolactin increased within the normal range in normoprolactinemic patients and remained so during follow-up. In hyperprolactinemic patients, prolactin decreased successively but to a lesser extent than growth hormone. Pituitary insufficiencies increased over time and three patients developed GH-insufficiency. Hypothalamic damage as indicated by prolactin changes was a regular phenomenon after radiotherapy.

The short and long-term effects of octreotide on calcium homeostasis in patients with acromegaly

OBJECTIVE The somatostatin analogue octreotide (Sandostatin, Sandoz) is effective in reducing growth hormone levels in patients with acromegaly. Early and transient gastrointestinal side‐effects are frequent. The aim was to evaluate whether gastrointestinal side‐effects during the initial phase of octreotide treatment affect calcium homeostasis, and whether effects on calcium homeostasis are seen during long‐term treatment with octreotide in patients with optimal effect on GH and subjectively normal gastrointestinal function.

Growth Hormone-Binding Protein in Plasma Is Inversely Correlated to Placental Lactogen and Augmented with Increasing Body Mass Index in Healthy Pregnant Women and Women with Gestational Diabetes mellitus

Pituitary growth hormone (GH), prolactin (PRL), placental lactogen (PL), insulin-like growth factor 1 (IGF-1) and GH-binding protein (GHBP) in plasma were determined in 12 women with gestational diabetes mellitus (GDM) and in 12 healthy pregnant women during a breakfast meal tolerance test. The women with GDM showed higher prepregnancy weight, body mass index (BMI), basal levels of glucose, insulin, and C peptide compared to the pregnant controls. No difference was found between the two groups in pituitary GH, PRL, PL and IGF-1 levels. Plasma levels of GHBP were higher in the women with GDM compared to pregnant controls. In all women there was an inverse correlation between PL and pituitary GH as well as between PL and GHBP, suggesting that PL inhibits pituitary GH secretion. A positive correlation between GHBP and BMI was found in all women, and the higher BMI in the GDM women seemed to be the cause of the higher GHBP levels in this group. In all women IGF-1, an indicator of the secretory activity of lactogenic hormones as well as of nutritional state, showed a positive correlation with the birth weights of the infants and was equally indicative in both groups.

The Clinical Implications of DNA Characteristics in Human Pituitary Tumour Disease

DNA analysis was performed in 29 cases of various endocrinological types of human pituitary tumours. The degrees of ploidy and proliferation, expressed as the proportion of cells in S phase, were determined. In 12 cases (41%) aneuploidy occurred. The proportion of aneuploid cells in these tumours was very high, in general around 95% measured. The aneuploid group of pituitary tumours showed a large variation of the percentage of cells in S-phase (range: 3.3–13.7%; mean: 8.3±5.3) in contrast to diploid tumours which showed a considerably smaller variation (range: 3.4–8.8 %; mean: 5.5±2.1). Tatients with aneuploid tumours had a mean age at operation of 42.8±11.1 years in contrast to 51.5±13.8 years for patients with diploid tumours. Aneuploidy occurred more frequently in tumours causing acromegaly with a concomitant secretion of GH and PRL than in other endocrinological types of tumours. Patients with aneuploid tumours had a mean case history of 2.9±1.9 years, as compared to 10.5±4.9 years for patients with ...

DNA Characteristics of Human Pituitary Tumours

Biopsies from pituitary tumours in 8 patients were analysed with DNA flow-cytofluorometry immediately after surgery and after organ culture. Good agreement was found between the degrees of ploidy and of the relative proportions of cells in different phases of the cell cycle, indicating a good stability and reproducibility of pituitary tumour explants in vitro. Analysis of DNA content indicated a homogeneous cell population in tumours before and after explantation. No apparent correlation was observed between hormone secretion rate in diploid and aneuploid tumours, respectively, and DNA characteristics.

Cytokine Inhibition after Glucocorticoid Exposure in Healthy Men with Low versus High Basal Cortisol Levels

Objective: The balance between glucocorticoid (GC) release and GC sensitivity in target cells is believed to be important to maintain homeostasis in the neuroendocrine control of inflammation. We investigated the impact of in vivo exposure to adrenocorticotropic hormone (ACTH) and dexamethasone (DEX) on GC sensitivity measured in vitro in healthy individuals with high versus low baseline cortisol levels. Methods:136 healthy male volunteers were screened twice and sorted according to their 24-hour urinary free cortisol (UFC) excretion. The 10 individuals with the highest UFC (290 ± 87 nmol/24 h) and the 10 with the lowest UFC (168 ± 34 nmol/24 h) were further tested. Measurements were performed at baseline, after a low dose (0.5 μg/1.73 m2) of ACTH challenge and after 2 weeks’ exposure to DEX (0.1 mg twice daily). GC sensitivity was assessed in vitro as the ability of DEX to inhibit lipopolysaccharide-stimulated production of the cytokines interleukin 1-β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in a whole-blood assay. Results:After exposure to DEX in vivo, inhibition of IL-6 and TNF-α decreased. Also, after DEX in vivo, low-cortisol men showed lower inhibition of IL-1β and IL-6, both compared to the high-cortisol group and their own baseline levels. Conclusion: A downregulation of GC sensitivity in leukocytes after exposure to an exogenous GC seems to occur most strongly in men with low cortisol levels.