Biomedical subjects

G M Besser

Publications and source records attributed to G M Besser.

At least 91 records · Page 5Linked to original sources

PubMed1999

A critical analysis of the value of simultaneous inferior petrosal sinus sampling in Cushing's disease and the occult ectopic adrenocorticotropin syndrome.

The clinical, biochemical, and radiological features of pituitary ACTH-dependent Cushing's syndrome (CS) [Cushing's disease (CD)] are often indistinguishable from those of occult ectopic ACTH-dependent CS (oEAS). We have evaluated, retrospectively, the results of simultaneous bilateral inferior petrosal sinus (IPS) ACTH sampling before and after CRH stimulation in 128 patients with ACTH-dependent CS: 107 patients with CD, 6 with oEAS, 1 with an adrenal adenoma, 1 with a pituitary gangliocytoma, and 1 with Nelson's syndrome; while, in the remaining 12, the source remains unclear. One hundred seven patients received human-sequence CRH (hCRH), and 11 received ovine CRH; another 6 patients underwent stimulation with desmopressin and hCRH, and 4 with desmopressin alone. A successful bilateral IPS catheterization and sampling (IPSCS) rate of 87.5% was obtained only after considerable experience had been gained. Sixty-nine patients with CD underwent successful bilateral IPSCS: the IPS-to-peripheral ratio of plasma ACTH value (IPS/P) rose from 9.5 +/- 1.4 to a maximum ratio of 55.8 +/- 7.5 in 67 patients, after CRH stimulation. The maximum ratio was obtained at 5 min in 60 of the 69 patients with CD; however, all 69 patients obtained a ratio of more than 2, at that time. In contrast, the 6 patients with occult ACTH-secreting neoplasms had a maximal IPS/P ratio of 1.3 +/- 0.16, and this did not change after CRH stimulation. A bilateral IPS/P ratio more than 2, obtained 5 min after CRH stimulation, had a sensitivity of 97% and a specificity of 100% in diagnosing CD. Two patients with proven active CD had an IPS/P ratio of less than 2. After successful bilateral IPSCS, the gradients between the IPS ACTH concentrations [IPS ACTH gradient (IPSG)] of more than 1.4, at 5 min after CRH stimulation, had a sensitivity of 83% in correctly lateralizing the pituitary microadenoma, compared with 72% sensitivity for magnetic resonance imaging (MRI) scanning. Furthermore, when IPSG and MRI findings were contradictory, IPSG was more often correct than MRI scanning. Although oEAS is a relatively uncommon cause of ACTH-dependent hypercortisolism (5.5% in our series), the accurate diagnosis of ACTH-dependent CS and localization of an intrapituitary microadenoma requires bilateral IPSCS with CRH stimulation, provided that the appropriate technical experience is available. hCRH is as effective a secretagogue as ovine CRH, and either may be used. The value of the combination of CRH and desmopressin stimulation requires more detailed investigation.

ACTH Syndrome, Ectopic↗

PubMed1999

Computed tomography appearance of the thymus and anterior mediastinum in active Cushing's syndrome.

Computed tomography (CT) evaluation of the thymus and anterior mediastinum is an important aspect of the investigation of patients with ACTH-dependent Cushing's syndrome in order to exclude an ACTH-secreting carcinoid tumor. We have reviewed the CT imaging of the thymus and anterior mediastinum in a series of 85 patients (55 females; median age 41, range 7-77 yr) with active Cushing's syndrome as there are few data on the range of appearances in hypercortisolemic states. One patient had a thymic carcinoid tumor (24 x 18 mm). Of the others, 28/84 (33%) patients showed thymic remnant tissue, consisting of either nodule(s) at least 5 mm diameter (n = 21, mean diameters 12.5 +/- 5 x 9.6 +/- 4 mm), or triangular bilobed glands (n = 7, mean thickness of the body, right and left limbs 25 +/- 7, 14 +/- 3, and 12 +/- 5 mm). Thymic involution appeared in 56/84 (67%) patients, ranging from small nodule(s) of less than 5mm diameter to linear soft tissue strands and complete fatty replacement. Patients with thymic remnant tissue were younger than those with thymic involution (P < 0.05). The thymic carcinoid tumor could be distinguished from remnant tissue on the basis of age and size. The presence of anterior mediastinal nodule(s) in hypercortisolemia need not imply the presence of a thymic carcinoid tumor, although in older patients this should arouse suspicion.

ACTH Syndrome, Ectopic↗

PubMed1999

The growth hormone secretagogue hexarelin stimulates the hypothalamo-pituitary-adrenal axis via arginine vasopressin.

GH secretagogues (GHSs) act via specific receptors in the hypothalamus and the pituitary gland to release GH. GHSs also stimulate the hypothalamo-pituitary-adrenal (HPA) axis via central mechanisms probably involving CRH or arginine vasopressin (AVP). We studied the effects of hexarelin, CRH, and desmopressin, an AVP analog, on the stimulation of the HPA axis in 15 healthy young male volunteers. Circulating ACTH, cortisol, GH and PRL concentrations were measured for 2 h after the injection of hexarelin, CRH, or desmopressin alone and the combination of hexarelin plus CRH or hexarelin plus desmopressin. Symptoms during the tests were assessed by visual analog scales. Hexarelin significantly increased ACTH and cortisol release (area under the curve, 3,444+/-696 ng/L x 125 min and 45,844+/-2,925 nmol/L x 125 min, respectively), and this effect was augmented by the addition of CRH in a dose that on its own produces maximal stimulation (6,580+/-1,572 ng/mL x 125 min and 63,170+/-2,616 nmol/L x 125 min; P = 0.01 and 0.001, respectively), but was not influenced by the addition of desmopressin (3,540+/-852 ng/mL x 125 min and 35,319+/-3,252 nmol/L x 125 min; not significant). CRH on its own caused similar or slightly higher ACTH and cortisol release than hexarelin alone. Desmopressin given alone elicited a rapid rise in circulating ACTH and cortisol, but its effects were less than those of any other treatment and were not augmented by hexarelin. Hexarelin also caused significant GH and PRL release, but these effects were not influenced by the coadministration of CRH or desmopressin. Visual analog scales showed an acute small increment in appetite with hexarelin. Our data suggest that the effect of GHSs on the HPA axis involve at least in part the stimulation of AVP release. In summary, we have shown that in healthy male volunteers, the effect of hexarelin on the HPA axis does not involve CRH, but may occur through the stimulation of AVP release.

Adrenal Glands↗

PubMed1999

Menstrual irregularity in women with acromegaly.

Menstrual irregularity is common in women with acromegaly, occurring in 40-84%. Although it has been attributed to gonadotropin deficiency and/or PRL excess, it has not been evaluated in detail, and its pathogenesis is not well understood. To explore the various possible pathogenic mechanisms, we have analyzed the clinical, endocrinological, and radiological characteristics of 47 women with active acromegaly within the reproductive age range (15-41 yr) with respect to their menstrual pattern; 9 patients (19%) had normal cycles, 7 (15%) had oligomenorrhea, 29 (62%) had amenorrhea, and 2 (4%) had polymenorrhea. Compared to patients with normal cycles (n = 9), patients with menstrual irregularity (oligo/polymenorrhea or amenorrhea; n = 38) were more hirsute, had lower serum estradiol (normal: median, 76.5 pmol/L; range, 20-570; menstrual irregularity: median, 283; range, 140-431; P < 0.01), and sex hormone-binding globulin (SHBG; normal: median, 19.6 nmol/L; range, 5-52; menstrual irregularity: median, 48; range, 18-60; P < 0.01), but similar testosterone levels; in addition, patients with amenorrhea had higher serum GH (normal: median, 100 mU/L; range, 8.8-400; amenorrhea: median, 30; range, 10.7-120; P < 0.05). PRL levels in excess of 1000 mU/L were found in 16 of the 38 patients with menstrual irregularity compared to only 1 of the 9 patients with normal cycles. Patients with menstrual irregularity had a greater impairment of anterior pituitary function than patients with normal cycles. Acromegalic patients who were defined as estrogen sufficient (estradiol, >140 pmol/L) had clinical baseline endocrine profiles and LH responses to GnRH stimulation similar to those in patients with polycystic ovarian disease. There was a positive correlation between GH levels and tumor size (r = 0.35; P < 0.05) and an independent inverse correlation between GH and SHBG levels (r = -0.6; P < 0.01), which persisted even in patients who were estrogen sufficient, but there was no correlation between GH and estradiol levels; in addition, there was a negative correlation between estradiol levels and tumor size (r = -0.42; P < 0.05). Thirty-five of the patients with menstrual irregularity had meso- or macroadenomas and 3 had microadenoma, whereas 6 of the 9 patients with normal cycles had microadenomas. In conclusion, menstrual irregularity is common in women with acromegaly (81% of our patients). Amenorrheic patients have higher GH levels, are mainly estrogen deficient, and tend to have larger tumors than patients with normal cycles. However, the independent negative correlation between GH and SHBG levels suggests that GH may, directly or indirectly, lead to a fall in SHBG, possibly determined by the hyperinsulinemia known to occur in acromegaly. Low SHBG levels may contribute to the menstrual disturbance seen in acromegaly in addition to any gonadotropin deficiency or hyperprolactinemia and may account for hirsutism in the presence of normal testosterone levels.

Acromegaly↗

PubMed1999

The influence of plasma on basal and ACTH-stimulated in vitro adrenocortical steroidogenesis.

Early descriptions of in vitro ACTH bioassays all emphasised the need to use extracted plasma samples due to interference by an unidentified component. The aim of these studies was to elucidate the effects of whole plasma on ACTH steroidogenic activity in vitro and to identify the responsible factor. A sensitive in vitro dispersed bovine adrenocortical cell bioassay was established. The addition of 10% ACTH-depleted human pooled plasma to the incubation media resulted in basal steroidogenesis equivalent to that achieved with 10(-9) M ACTH1-24 and potentiated the steroidogenic activity of 10(-9) M ACTH1-24 by 7.8-fold. This potentiation was dependent on the concentration of both ACTH and plasma in the media, but did not result from the mitogenic effect of plasma. A pituitary source was excluded and the potentiating activity was not extractable by Vycor glass. Column chromatography demonstrated two peaks of activity corresponding to molecular weights of 650 and 220x10(3) Da. These peaks did not correspond to the plasma binding of 125I-ACTH which resulted from non-specific binding to albumin. Lipoprotein-deficient serum had no effect on either basal or ACTH-stimulated steroidogenesis, but both were restored by the addition of purified lipoproteins. However, novel findings demonstrated a differential effect of low (LDL) and high (HDL) density lipoproteins on basal and ACTH-stimulated steroid production; thus, LDL exerted a greater effect on the former, whilst HDL potentiated the steroidogenic activity of added ACTH more than LDL. The addition of the lipoproteins to lipoprotein-deficient serum restored its basal and ACTH potentiating effects, the cholesterol concentrations of the chromatographic fractions exactly paralleling their ACTH potentiating effect. These findings suggest that not only are lipoproteins the plasma factor(s) which potentiates ACTH steroidogenic activity in in vitro bioassays, but also that they exert differential effects on basal and ACTH-stimulated steroid production.

Adrenocorticotropic Hormone↗

PubMed1999

CT appearance of the adrenal glands in adrenocorticotrophic hormone-dependent Cushing's syndrome.

OBJECTIVE: The purpose of this study was to describe the size and appearance of the adrenal glands on CT in patients with adrenocorticotrophic hormone (ACTH)-dependent Cushing's syndrome and to correlate gland dimensions with circulating cortisol and ACTH levels. MATERIALS AND METHODS: We retrospectively analyzed clinical, biochemical, and imaging data for 53 patients referred for CT of the adrenals as part of an investigation for ACTH-dependent Cushing's syndrome at our institution between 1988 and 1997. Two observers, who were unaware of the endocrine data, measured the body and limb widths of the adrenal glands using an electronic cursor. RESULTS: Of the 53 patients, 37 (70%) were shown to have enlarged adrenal glands on CT. The mean width of the adrenal limbs positively correlated with the circulating cortisol and ACTH levels. The adrenals were larger in patients with ectopic ACTH syndrome than in patients with Cushing's disease (p < .02). Ten patients (19%) had nodules that were 10 mm or greater in diameter. CONCLUSION: The adrenal glands were often enlarged in patients with ACTH-dependent Cushing's syndrome, and the enlargement could be quantified on CT. However, having normalsized adrenals (observed in 30% the patients in our study) did not preclude such a diagnosis. We found that adrenal limb width positively correlates with ACTH and cortisol levels.

ACTH Syndrome, Ectopic↗

PubMed1998

Mutation and expression analysis of the p27/kip1 gene in corticotrophin-secreting tumours.

The molecular mechanisms leading to Cushing's disease are unclear. Inhibitors of cyclin-cyclin dependent kinase (CDK) complexes are regulators of the cell cycle and may function as tumour suppressor genes, many of which have been involved in the pathogenesis of several human malignancies. A member of this family, the p27/kip1 gene, maps to chromosome 12p13 and encodes an inhibitor of several cyclin-CDK complexes; these control the progression of the cell cycle from G1 to S-phase. Complete lack of p27/kip1 function, as occurs in the p27/kip1 'knockout' mouse, produces a complex phenotype associated with the development of pituitary tumours, specifically those of the intermediate lobe corticotrophs. We therefore investigated whether structural and functional abnormalities of the p27/kip1 gene and loss at the chromosome 12p13 region were present in human corticotrophin (ACTH)-secreting pituitary tumours. We studied 21 pituitary tumours, of which 20 were ACTH-secreting (two of these had biochemical and histological features of 'intermediate-lobe' tumours and one was malignant) while the remaining tumour was a prolactinoma; three ectopic secretors of ACTH (two bronchial and one thymic carcinoid); and a non-secretory thymic carcinoid. The whole coding region of the p27/ kip1 gene was screened for mutations by PCR-SSCP analysis and/or direct sequencing, while tumour mRNA expression was analysed by means of a semi-quantitative duplex PCR. Three polymorphic microsatellite markers of the 12p13 region were used to assess loss of heterozygosity (LOH) in 12 samples. Finally, tumour p27/kip1 protein expression was assessed by immunohistochemistry using a monoclonal antibody in 12 samples suitable for analysis. No sequence abnormalities were found in any of the samples other than a previously-described polymorphism. No LOH was observed in the tumours analysed. p27/kip1 mRNA expression was similar in tumour samples in comparison with normal pituitaries. Seven of the eight corticotroph tumours analysed by immunohistochemistry stained positive for p27/kip1, including the intermediate lobe. The only malignant pituitary tumour in the original series showed an absence of staining for p27/kip1. In addition, the three carcinoid tumours studied were negative on immunohistochemistry. Of a further three malignant pituitary tumours assessed, two (including a prolactinoma) were essentially negative, while the third was moderately positive. We conclude that mutations of the p27/kip1 gene, deletions of the 12p13 area or changes in expression, are not a general feature of corticotroph tumours, even those with intermediate lobe characteristics. However, other mechanisms of p27/kip1 inactivation, such as an abnormality at the post-translational level, may be related to more aggressive histological subtypes of ACTH-secreting and possibly other pituitary tumours.

Adrenocorticotropic Hormone↗

PubMed1998

Severe prolonged hypocalcaemia following pamidronate for malignant hypercalcaemia.

Hypercalcaemia of malignancy is a frequent occurrence. First line treatment of this condition involves the use of bisphosphonates. This report sets out the clinical findings in a patient presenting with metastatic breast cancer and hypercalcaemia (corrected serum calcium 3.72 mmol/l) who had received previous surgery for a parathyroid adenoma. After treatment with pamidronate, profound, prolonged (more than 60 days) symptomatic hypocalcaemia was observed. We discuss the possible explanations for these observations and conclude that a normal parathyroid reserve is probably necessary for the smooth normalization of blood calcium when bisphosphonates are used to treat malignant hypercalcaemia.

Adenocarcinoma↗

PubMed1998

Luteinizing hormone secreting adrenal tumour as a cause of precocious puberty.

A boy aged 6 years presented with genital precocity, enlarged testes and advanced linear growth. An ovoid mass 3-4 cm in diameter was identified by MRI scan in the right adrenal gland. Serum concentrations of LH, testosterone, alpha-subnuit, dehydroepiandrosterone sulphate, androstenedione and oestradiol were persistently elevated. LH was unresponsive to bolus i.v. injection of GnRH or to GnRH analogue therapy. Serum FSH was normal. After removal of the adrenal tumour, serum LH, alpha-subunit, testosterone and adrenal androgen levels fell to normal. In incubation medium of cultured disaggregated tumour cells, LH concentrations were greater than twice the mean serum concentration and 4-5-fold higher than in the medium of cultured non-neoplastic adrenal cells. Specific immunostaining of the tumour was positive for LH and alpha-subunit in many areas and these were not found in the adjacent non-neoplastic adrenal. Testicular biopsy showed almost complete spermatogenesis although germinal cell types were numerically lower than in normal men. These findings are consistent with an adrenocortical adenoma secreting LH being the cause of the patient's precocious puberty.

Adenoma↗

PubMed1998

Normal final height and apparent cure after pituitary irradiation for Cushing's disease in childhood: long-term follow-up of anterior pituitary function.

Pituitary-dependent Cushing's syndrome is rare in childhood. Two patients are reported who had unsuccessful transsphenoidal microadenomectomy and therefore underwent pituitary radiotherapy. In both patients there was progressive normalization of hypothalamo-pituitary-adrenal function and at 8 and 10 years after radiotherapy their Cushing's syndrome remained in remission clinically and biochemically. Most importantly, they have both achieved adult heights within their respective expected ranges with close clinical observation and replacement growth hormone therapy. Thyroid and gonadal function is normal and neither patient requires any other hormone replacement therapy. Pituitary radiotherapy is thus a safe, effective and well tolerated second-line therapy for paediatric Cushing's disease. Collaboration between the paediatric and adult departments and an experienced radiotherapist contributed to the successful outcome of these two patients.

Adolescent↗

PubMed1998

Serum collagen crosslinks as markers of bone turn-over during GH replacement therapy in growth hormone deficient adults.

OBJECTIVES: Bone metabolism is an important target for GH replacement therapy. However, in adults, treatment periods exceeding 12 months are required for a positive effect of GH on bone mineral density. Thus, to detect an early effect of GH on bone, markers of bone turn-over are important. Pyridinoline (PYR) and deoxypyridinoline (DPYR) are well-defined sensitive markers of bone resorption, but to date only urinary assays have been available. We report the use of a novel assay to measure changes in serum PYR and DPYR in GH deficient (GHD) adults during GH replacement therapy. STUDY DESIGN: The study consisted of a 6-month randomized, double-blind, placebo-controlled study of the administration of GH (Genotropin) (0.25 IU/Kg/week (0.125 IU/kg/week for the first four weeks)) followed by a 6-month open phase of GH therapy. PATIENTS: Thirty-five GHD adults (17 women; mean age 39.8 years; range 21.1-59.9) on conventional hormone replacement therapy as required, were studied. MEASUREMENTS: Bone formation was analysed using serum bone alkaline phosphatase (BAP) and serum osteocalcin (OC). Bone resorption was analysed using serum pyridinoline (PYR) and serum deoxypyridinoline (DPYR). Bone mineral density (BMD) was determined by dual energy X-ray absorptiometry (DEXA). RESULTS: After 6 months placebo treatment there were no significant changes in any of the bone markers analysed, nor in BMD. In the active arm of the study there was a significant increase in serum OC, BAP, PYR and DPYR (P = 0.03, P = 0.004, P = 0.003 and P = 0.01, respectively), remaining significantly elevated over their baseline levels for the subsequent 6 months of treatment (P = 0.04, P = 0.009, P = 0.003 and P = 0.04, respectively). No changes were observed in BMD in any of the groups after 6 months GH treatment. In the active arm of the study, after 12 months GH treatment there was a significant increase in BMD at both the lumbar spine and femoral neck (P = 0.01 for both sites). CONCLUSIONS: In summary, the present study confirms that administration of GH treatment to GHD adult patients significantly activates bone remodelling, with the effect of GH both in bone formation and bone resorption markers being maximal after 6 months of treatment. The serum assay for PYR and DPYR has a number of practical and theoretical advantages over the urine assay and gave similar results to those previously reported for the urine assay.

Adult↗

PubMed1998

Carcinoid tumours presenting as breast cancer: the utility of radionuclide imaging with 123I-MIBG and 111In-DTPA pentetreotide.

Secondary tumours of any type in the breast are rare. A review of the literature demonstrated only 23 cases of carcinoid tumours with associated breast metastasis, as distinct from primary carcinoid tumours of the breast. Distant metastases from carcinoid tumours are correlated with poor prognosis and survival. Although both primary and metastatic mammary carcinoid tumours are uncommon, the recognition of the true origin of the tumours may be of importance owing to the different clinical management and prognosis of the two conditions. Recently, radionuclide-labelled imaging techniques have been applied to the localization of such lesions, based on isotope uptake by receptors present in these neuroendocrine tumours. We report two new cases of carcinoid tumours with breast metastases, the primaries being in the ileocaecal valve and the bronchus, respectively. The diagnosis of a carcinoid tumour was based on the clinical, biochemical, histopathological and immunostaining features. Furthermore, these patients had both 123I-MIBG and 111In pentetreotide scintigraphy performed. These radionuclides play a useful role in the localization and potentially in the management of carcinoid tumours and their distant metastases.

3-Iodobenzylguanidine↗

PubMed1998

Characterization of mutations in patients with multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors of the parathyroids, pancreatic islets, and anterior pituitary. The MEN1 gene, on chromosome 11q13, has recently been cloned, and mutations have been identified. We have characterized such MEN1 mutations, assessed the reliability of SSCP analysis for the detection of these mutations, and estimated the age-related penetrance for MEN1. Sixty-three unrelated MEN1 kindreds (195 affected and 396 unaffected members) were investigated for mutations in the 2,790-bp coding region and splice sites, by SSCP and DNA sequence analysis. We identified 47 mutations (12 nonsense mutations, 21 deletions, 7 insertions, 1 donor splice-site mutation, and 6 missense mutations), that were scattered throughout the coding region, together with six polymorphisms that had heterozygosity frequencies of 2%-44%. More than 10% of the mutations arose de novo, and four mutation hot spots accounted for >25% of the mutations. SSCP was found to be a sensitive and specific mutational screening method that detected >85% of the mutations. Two hundred and one MEN1 mutant-gene carriers (155 affected and 46 unaffected) were identified, and these helped to define the age-related penetrance of MEN1 as 7%, 52%, 87%, 98%, 99%, and 100% at 10, 20, 30, 40, 50, and 60 years of age, respectively. These results provide the basis for a molecular-genetic screening approach that will supplement the clinical evaluation and genetic counseling of members of MEN1 families.

Adolescent↗

PubMed1998

Emergency and prolonged use of intravenous etomidate to control hypercortisolemia in a patient with Cushing's syndrome and peritonitis.

We report the emergency and prolonged use of etomidate to control circulating cortisol levels in a patient with Cushing's syndrome secondary to ectopic ACTH production from a pancreatic islet cell tumor. Duodenal perforation and peritonitis complicated an episode of salmonella septicemia, precluding the use of conventional oral medical adrenolytic therapy. Endogenous cortisol secretion was abolished by parenteral etomidate, allowing serum cortisol levels to be controlled with an iv infusion of hydrocortisone over an 8-week period in intensive care before definitive pancreatic surgery.

Adenoma, Islet Cell↗

PubMed1998

Expression of the growth hormone secretagogue receptor in pituitary adenomas and other neuroendocrine tumors.

Synthetic GH secretagogues (GHSs; GH-releasing peptides and their nonpeptide mimetics) stimulate GH release, activate the hypothalamo-pituitary-adrenal axis, and release PRL in vivo. Patients with acromegaly show an exuberant GH response to GHSs, whereas patients with pituitary-dependent ACTH-secreting tumors show an exaggerated rise in ACTH and cortisol. We, therefore, studied the presence of GHS receptor (GHS-R) messenger ribonucleic acid (RNA) in 38 human pituitary tumors of different cell types, 3 ectopic ACTH-secreting tumors, a pancreatic gastrinoma, 3 insulinomas, and a non-secreting thymic carcinoid as well as in 7 normal pituitary glands. Certain pituitary tumors were also studied by in vitro cell culture with measurement of secreted GH, ACTH, PRL, FSH, LH, alpha-subunit, and TSH. RNA was extracted from tissue samples and, after RT, a duplex PCR reaction with primers for the GHS-R gene and for the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase was performed, allowing semiquantitation of GHS-R expression. All the somatotroph adenomas (n = 8) showed a 2-10 times higher expression of the GHS-R gene compared to normal pituitaries. Higher than normal expression was shown in 5 of 18 tumors from patients with ACTH-secreting pituitary adenomas and in 1 of 3 ectopic ACTH-secreting carcinoid tumors. Two of the pituitary ACTH-secreting adenoma samples showed completely absent expression of the GHS-R, 8 showed expression similar to that of normal pituitary tissue, and 3 of the corticotroph adenoma tissue samples and 2 ectopic ACTH-secreting tumors showed a very low level of expression. One of 4 prolactinoma samples showed a high level of expression, 1 showed expression similar to that of normal pituitary, and 2 samples showed a very low level of expression. Nonfunctioning pituitary adenoma samples showed either absent or very low level expression of the GHS-R. The pancreatic gastrinoma sample showed expression similar to that of normal pituitary tissue, whereas 3 insulinomas showed low level expression of the GHS-R gene; a nonsecreting thymic carcinoid tumor showed no detectable expression. In summary, although GHS-R messenger RNA is abundant in human somatotroph adenomas, it is also present in other pituitary adenomas, particularly ACTH-secreting tumors. These findings may explain the in vivo responses to GHSs in patients harboring such tumors. It also appears from our study that GHS-R may be expressed in other neuroendocrine tumors.

Acromegaly↗

PubMed1998

Optimizing growth hormone replacement therapy by dose titration in hypopituitary adults.

Although growth hormone (GH) replacement therapy is increasingly utilized in the management of adult hypopituitary patients, optimum dosing schedules are poorly defined. The use of weight-based or surface area-based dosing may result in overtreatment, and individual variation in susceptibility on the basis of gender and other factors is now being recognized. To optimize GH replacement and to explore further gender differences in susceptibility, we used a dose titration regimen, starting at the initiation of GH replacement therapy, in 50 consecutive adult-onset hypopituitary patients, and compared the results with those in 21 patients previously treated using a weight-based regimen. Titrated patients commenced GH 0.8 IU/day subcutaneously (0.4 IU/day if hypertensive or glucose tolerance impaired). Serum insulin-like growth factor I (IGF-I) was measured at 0, 2, 4, 6, 8, 10, and 12 weeks in all patients. Serum IGF binding protein 3 and acid labile subunit were measured at the same time points in 17 patients (8 male, 9 female). Patients were reviewed every 4 weeks and the dose of GH increased, if necessary, to achieve a serum IGF-I level between the median and the upper end of the age-related reference range. There was no significant difference between mean serum IGF-I at 2 and 4 weeks, or between 6 and 8 weeks, indicating that the full effects of a change in dose are evident within 2 weeks of that change. Maintenance doses were significantly higher in females than males [1.2 (0.8-2.0) vs. 0.8 (0.4-1.6) IU/day; median (range); P < 0.0001], and the median time to achieve maintenance dose was significantly shorter in males [4 (2-12) vs. 9 (2-26) weeks; P < 0.0001]. Median maintenance dose was lower overall than in a group of 21 patients initially commenced on GH using a weight-based dosing schedule, with subsequent adjustment of dose during clinical follow-up [1.5 (0.4-3.2) IU/day; P = 0.02]. Reduction in waist measurement and waist to hip ratio at 6 and 12 months was similar in females (P < 0.001) and males (P < 0.01). Well-being improved significantly after 3 months of GH therapy (14.2 +/- 5.9 vs. 7.4 +/- 4.5 SD; P < 0.0001), and there were no gender differences. Adult Growth Hormone Deficiency Assessment (AGHDA) scores at 6 months were similar to maintenance scores in patients commenced on weight-based regimens. Measurements of ALS and IGFBP-3 added no useful extra information to IGF-I in managing the dose titration. The practical scheme outlined for dose titration of GH replacement resulted in rapid achievement of lower maintenance doses than those achieved using conventional weight-based regimens without loss of efficacy. It was particularly important in female patients who demonstrated decreased overall sensitivity to GH and required higher doses to achieve the same effects as males. This constitutes the first report of a uniform titration regimen based on a defined target range of serum IGF-I in a large patient cohort.

Adolescent↗

PubMed1998

The role of cytotoxic chemotherapy in the management of aggressive and malignant pituitary tumors.

Pituitary tumors are mostly benign lesions, although 5-35% are locally invasive. A small number exhibit a more aggressive course, infiltrating dura, bone and sinuses, and are designated highly aggressive. However, the presence of metastases separate from the pituitary in the central nervous system or at a distance is necessary to designate pituitary tumors as carcinomas, i.e. truly malignant. When conventional therapeutic modalities fail, systemic chemotherapy remains the last option. We report seven such patients, three with highly aggressive and four with malignant pituitary tumors (n=4) four women; median age, 32 yr; range, 23-48 yr), who received one or more courses of chemotherapy with lomustine and 5-fluorouracil (median, two courses; range, one to six courses). Three patients with systemic metastatic disease had a shorter survival (median, 5 months; range, 1-14 months) than the one patient with central nervous system metastases alone (10 yr). A patient with an aggressive nonmetastatic prolactinoma who initially responded to chemotherapy died from another nondisease-associated cause. Two patients, one with an aggressive and one with a metastatic tumor, achieved symptomatic improvement with a median duration of 6 months. A hormonal reduction greater than 50% was observed in two of seven patients; only one patient who had an aggressive tumor obtained an objective tumor response. The median survival from the time of initiation of chemotherapy in patients with malignant tumors ranged from 3-65 months. Two patients with malignant tumors developed disease progression while receiving chemotherapy; no patient with extracranial metastases showed a response. Treatment was well tolerated, with minimal individual side-effects. Three patients with no response to initial treatment received different chemotherapeutic regimens with no additional response. All patients with metastatic malignant tumors eventually died. Treatment with cytotoxic chemotherapy is noncurative, and current experience is limited. Until another more specific form of treatment is available, chemotherapy may still be of some value in patients with highly aggressive and malignant pituitary tumors, at least in achieving a temporary remission or delay in progression. The combination of lomustine/5-fluorouracil proved easy to administer with minimal toxicity, although the response rate was only 14%. Until a more specific treatment is found, an optimal chemotherapeutic regimen needs to be established.

Adult↗

PubMed1998

Menstrual abnormalities in women with Cushing's disease are correlated with hypercortisolemia rather than raised circulating androgen levels.

Menstrual irregularity is a common complaint at presentation in women with Cushing's syndrome, although the etiology has been little studied. We have assessed 45 female patients (median age, 32 yr; range, 16-41 yr) with newly diagnosed pituitary-dependent Cushing's syndrome. Patients were subdivided into 4 groups according to the duration of their menstrual cycle: normal cycles (NC; 26-30 days), oligomenorrhea (OL; 31-120 days), amenorrhea (AM; > 120 days), and polymenorrhea (PM; < 26 days). Blood was taken at 0900 h for measurement of LH, FSH, PRL, testosterone, androstenedione, dehydroepiandrosterone sulfate, estradiol (E2), sex hormone-binding globulin (SHBG), and ACTH; cortisol was sampled at 0900, 1800, and 2400 h. The LH and FSH responses to 100 micrograms GnRH were analyzed in 23 patients. Statistical analysis was performed using the nonparametric Mann-Whitney U and Spearman tests. Only 9 patients had NC (20%), 14 had OL (31.1%), 15 had AM (33.3%), and 4 had PM (8.8%), whereas 3 had variable cycles (6.7%). By group, AM patients had lower serum E2 levels (median, 110 pmol/L) than OL patients (225 pmol/L; P < 0.05) or NC patients (279 pmol/L; P < 0.05), and higher serum cortisol levels at 0900 h (800 vs. 602 and 580 nmol/L, respectively; P < 0.05) and 1800 h (816 vs. 557 and 523 nmol/L, respectively; P < 0.05) and higher mean values from 6 samples obtained through the day (753 vs. 491 and 459 nmol/L, respectively; P < 0.05). For the whole group of patients there was a negative correlation between serum E2 and cortisol at 0900 h (r = -0.50; P < 0.01) and 1800 h (r = -0.56; P < 0.01) and with mean cortisol (r = -0.46; P < 0.05). No significant correlation was found between any serum androgen and E2 or cortisol. The LH response to GnRH was normal in 43.5% of the patients, exaggerated in 52.1%, and decreased in 4.4%, but there were no significant differences among the menstrual groups. No differences were found in any other parameter. In summary, in our study 80% of patients with Cushing's syndrome had menstrual irregularity, and this was most closely related to serum cortisol rather than to circulating androgens. Patients with AM had higher levels of cortisol and lower levels of E2, while the GnRH response was either normal or exaggerated. Our data suggest that the menstrual irregularity in Cushing's disease appears to be the result of hypercortisolemic inhibition of gonadotropin release acting at a hypothalamic level, rather than raised circulating androgen levels.

Adolescent↗