Ectopic sphenoidal ACTH-secreting adenoma revealed by 11C Methionine PET scan: case report.

BACKGROUND: Ectopic ACTH pituitary adenomas (EAPA), located outside the sella turcica and deriving from cellular remnants of Rathke's pouch are a very rare cause of Cushing's syndrome (CS). The diagnosis is often difficult and delayed, even after comprehensive work-up. To our knowledge, we report for the first time an ectopic corticotroph tumor of the posterior wall of the sphenoid sinus, leading to false positive results of bilateral inferior petrosal sinus sampling (BIPPS) and which was finally localized by a co-registered11 C Methionine PET/MR imaging. CASE PRESENTATION: A 48-year-old woman was referred for a high clinical suspicion of ACTH-dependent CS. Biological testing comprising low dose dexamethasone suppression and CRH stimulation tests were indicative of pituitary Cushing's disease, but comprehensive pituitary MRI did not reveal any pituitary adenoma. BIPSS confirmed however a central origin of ACTH secretion (central-to-peripheral ACTH ratio > 100) and revealed a significant right-to-left gradient (6.2), leading to a first right-sided exploratory hypophysectomy, that did not cure the patient. BIPSS images were reviewed and revealed preferential drainage of the left pituitary to the right petrosal sinus, leading us to a left sided exploratory hypophysectomy, which was again unsuccessful. A11 C Methionine PET/MRI was performed and revealed a hypermetabolic lesion adjacent to the posterior wall of the sphenoidal sinus. After surgical resection, this polypoid mass was identified as an ectopic ATCH-secreting pituitary adenoma expressing ACTH and T-Pit and complete remission of hypercortisolism was observed. CONCLUSIONS: In conclusion, we report a case of ACTH-dependent Cushing's syndrome, caused by an ectopic corticotroph adenoma located in the sphenoidal sinus, which perfectly mimicked the biological features of a classical pituitary ACTH adenoma on a comprehensive hormonal evaluation including BIPPS, and the features of a benign naso-sinusal polyp at MRI. We report for the first time a key role of11 C Methionine PET co-registered to high resolution MRI for localizing ectopic adenomas, efficiently guiding surgical removal and leading to complete remission of hypercortisolism.

Evolution of Glucose Tolerance After Treatment of Acromegaly: A Study in 57 Patients.

The aim of our study was to evaluate the evolution of glucose metabolism in 57 patients after treatment of their acromegaly and to determine risk factors for the persistence of abnormal glucose tolerance. Therefore, we performed IGF-I measurements, oral glucose tolerance tests (OGTTs), and HOMA to evaluate insulin sensitivity (HOMA-S) and ß-cell function (HOMA-ß) at diagnosis and at last visit (median follow-up 7 years). At diagnosis of acromegaly, 14 patients (25%) were diabetic and 15 (26%) had impaired glucose tolerance, whereas at the last visit, 32% were diabetic and 26% remained glucose intolerant. There was a decrease in fasting glucose (median - 7.0 mg/dl) in the 20 patients cured by surgery, whereas it increased in the 28 patients controlled under medical therapy (median + 2.0 mg/dl; p<0.05 vs. cured group) and in the 9 patients with active disease (median + 4.0 mg/dl). Loss of ß-cell function was more pronounced in the patients under medical treatment (median - 87.9%) vs. the cured group (median - 30.4%; p<0.05). There was a decrease in HbA1c between diagnosis and last visit in patients under pegvisomant (mean - 19.2 mmol/mol) vs. a small increase in patient treated by somatostatin analogues (+ 3.4 mmol/mol; p<0.05). Independent risk factors for persistent abnormal glucose tolerance were the glucose tolerance status at diagnosis and ongoing treatment with somatostatin analogues. In conclusion, we found that more than 50% of patients still have IGT or diabetes after treatment of acromegaly. Improvement of glucose metabolism is mainly observed in cured patients and in patients treated with pegvisomant.

Venous thromboembolism in Cushing syndrome: results from an EuRRECa and Endo-ERN survey.

Background: Patients with Cushing syndrome (CS) are at increased risk of venous thromboembolism (VTE). Objective: The aim was to evaluate the current management of new cases of CS with a focus on VTE and thromboprophylaxis. Design and methods: A survey was conducted within those that report in the electronic reporting tool (e-REC) of the European Registries for Rare Endocrine Conditions (EuRRECa) and the involved main thematic groups (MTG's) of the European Reference Networks for Rare Endocrine Disorders (Endo-ERN) on new patients with CS from January 2021 to July 2022. Results: Of 222 patients (mean age 44 years, 165 females), 141 patients had Cushing disease (64%), 69 adrenal CS (31%), and 12 patients with ectopic CS (5.4%). The mean follow-up period post-CS diagnosis was 15 months (range 3-30). Cortisol-lowering medications were initiated in 38% of patients. One hundred fifty-four patients (69%) received thromboprophylaxis (including patients on chronic anticoagulant treatment), of which low-molecular-weight heparins were used in 96% of cases. VTE was reported in six patients (2.7%), of which one was fatal: two long before CS diagnosis, two between diagnosis and surgery, and two postoperatively. Three patients were using thromboprophylaxis at time of the VTE diagnosis. The incidence rate of VTE in patients after Cushing syndrome diagnosis in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Conclusion: Thirty percent of patients with CS did not receive preoperative thromboprophylaxis during their active disease stage, and half of the VTE cases even occurred during this stage despite thromboprophylaxis. Prospective trials to establish the optimal thromboprophylaxis strategy in CS patients are highly needed. Significance statement: The incidence rate of venous thromboembolism in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Notably, this survey showed that there is great heterogeneity regarding time of initiation and duration of thromboprophylaxis in expert centers throughout Europe.

Prevalence and spectrum of SDHx mutations in pheochromocytoma and paraganglioma in patients from Belgium: an update.

Since the early 2000s, the prevalence and spectrum of mutations in genes encoding subunits of succinate dehydrogenase (SDHx) were reported in large cohorts of patients with pheochromocytoma (PC) and paraganglioma (PGL) from most Western countries. Unfortunately, in Belgium, no equivalent work was performed thus far. Therefore, the aim of the work was to look for mutations in SDHx genes and genotype-phenotype correlations in patients with PC and/or PGL from Belgium. Screening of the coding parts of SDHx genes and deletion search were performed in all patients with PC and/or PGL referred to the -Cliniques Universitaires Saint-Luc from 05/2003 to 05/2011. Genetic screening was performed in 59 unrelated head and neck (hn)PGLs (8 fami-lial) and 53 PCs (7 extra-adrenal; 3 metastatic). In hnPGLs, 10 different SDHD mutations (3 substitutions, 5 deletions, 2 splice site mutations) were detected in 16 patients, including 7 familial cases and 9 apparently sporadic cases. In the same subset, we found 8 different SDHB mutations (5 substitutions, 1 splice site mutation, 1 deletion, 1 duplication) in 10 patients with sporadic hnPGL without evidence of malignancy. No SDHx mutation was detected in patients harboring PCs and no SDHC mutation whatsoever. In conclusion, in our multicentric database of PC-PGLs from Belgium, (i) the prevalence of SDHx mutations was high in hnPGLs (44% in the whole subset, 37% of apparently sporadic cases); (ii) in sporadic cases, the prevalence of SDHB mutations was high (20%), similar to that of SDHD (18%); and (iii) no SDHx mutation was found in a subset of mostly adrenal, benign PCs.

Conservative management of complicated Rathke's cleft cyst mimicking pituitary apoplexy.

Summary: Complicated Rathke's cleft cyst (RCC) is a rare occurrence of symptomatic bleeding or growth of a previously asymptomatic (and often undiagnosed) intrasellar cyst derived from remnants of Rathke's pouch, situated on the midline between the adeno- and neurohypophysis. Symptoms may be identical to those of pituitary apoplexy: acute onset of headache, hypopituitarism, and neurological disturbances. Both syndromes may also exhibit a similar appearance of a large haemorrhagic sellar mass at initial radiological evaluation. We report on two patients who presented with headache and complete hypopituitarism. Based on the initial MRI, they were first diagnosed with pituitary apoplexy but managed conservatively with hormone therapy alone because of the absence of severe visual or neurological threat. Upon follow-up at 4 months, clinical evolution was good in both patients but their pituitary mass had not reduced in size and, after careful radiologic reviewing, was more indicative of a large midline complicated RCC. In conclusion, the diagnosis of complicated RCC is challenging because it can mimic pituitary apoplexy clinically, biologically, and radiologically. Clinicians should distinguish between the two entities using specific radiological signs or evolution of the mass at MRI if the patient does not undergo surgery. To our knowledge, we report conservative management of this rare condition for the first time, though it seems appropriate in the absence of neurological compromise or visual compression. Long-term follow-up is however mandatory. Learning points: Complicated Rathke's cleft cyst can mimic pituitary apoplexy, presenting with sudden onset of headache, hypopituitarism, and visual and neurological compromise in the most severe cases. At diagnosis, pituitary MRI may not be able to differentiate between the two entities, showing a large haemorrhagic mass inside the sella, with little or no normal pituitary tissue visible. Patients are often diagnosed with apoplexy at this stage and may undergo pituitary surgery. When surgery has not been performed initially in these patients, repeat imaging at 3-6 months is unchanged and does not show the expected involution usually seen after adenoma apoplexy. Conservative management with hormonal replacement seems a valid option in the absence of visual or neurological deficits that would require trans-sphenoidal surgery.

Transient efficacy of octreotide and pasireotide (SOM230) treatment in GIP-dependent Cushing's syndrome.

We studied a 55-year old woman presenting with features of Cushing's syndrome associated with metabolic abnormalities including severe hypertension and type 2 diabetes. Urinary free cortisol excretion was within normal limits, but an unusual diurnal cortisol rhythm was observed with low morning and high postprandial levels, associated with the absence of cortisol suppression after dexamethasone, suggesting the possibility of GIP-dependent Cushing's syndrome. The diagnosis was confirmed by further investigations, showing significant plasma cortisol responses after a mixed meal test and after oral, but not intravenous glucose administration, as well as ACTH-independent bilateral macronodular adrenal hyperplasia (AIMAH). An aberrant increase in cortisol was also observed after glucagon and terlipressin injections. The patient was first treated with octreotide 100-250 µg thrice daily for 6 months, then with the new multi-ligand somatostatin analogue (SOM 230) 450-900 µg twice daily for 3 months. Although inducing a significant acute suppression of post-prandial cortisol response, both drugs had no effects on the clinical and metabolic abnormalities associated with Cushing's syndrome and new tests performed at the end of each treatment period confirmed escape of post-meal cortisol suppression to therapy. The patient finally underwent a bilateral adrenalectomy, which markedly improved her medical condition and allowed in vitro confirmation by real time RT-PCR quantification of a high aberrant expression of GIP receptor mRNA in adrenal tissue. This case report illustrates the lack of sustained efficacy of somatostatin analogues on GIP-dependent Cushing's syndrome, independent of their affinity for the different somatostatin receptor subtypes.

Two-site automated chemiluminescent assay for measurement of immunoreactive renin.

Measurement of renin is important for the clinical assessment of hypertensive patients and for the screening for primary aldosteronism. The aim of this study was to evaluate the performances of an automated immunoassay for measurement of immunoreactive renin. Functional sensitivity, in vitro stability, and reference values were determined. Method comparison with the plasma renin activity assay was also performed. Our results demonstrate that the Liaison(®) direct renin assay may assist the clinician in the assessment of hypertensive patients and in the screening for primary aldosteronism.

Functional Prognostic value of optical coherence tomography in optic chiasmal decompression: A preliminary study.

PURPOSE: To assess the predictive value for functional recovery of Ganglion Cell Complex Layer (GCC) and Retinal Nerve Fiber Layer (RNFL) measurements obtained by Optical Coherence Tomography (OCT) in patients undergoing chiasmal decompression and to define potential OCT thresholds for visual recovery. METHODS: We measured preoperative GCC and RNFL thickness in patients with a sellar and/or perisellar tumor compressing the optic chiasm. Visual recovery was defined as recovery of mean deviation (MD) and pattern standard deviation (PSD) using Humphrey visual field testing after 12 successful decompressions (24 eyes). Receiver operating characteristic curve (ROC) analysis was used to identify the best thresholds. RESULTS: Robust global and focal OCT thresholds were found. Superior GCC≥63µm had the best functional prognostic value (AUC=1) for visual improvement. Mean GCC ≥ 67µm and mean RNFL≥75µm also had excellent predictive values (AUC>0.9). CONCLUSION: In this preliminary study, significant preoperative OCT thresholds for early visual recovery after chiasmal decompression were identified, mainly regarding GCC measurements. Further studies on larger cohorts with closely scheduled follow-up could refine our results.

ESE Clinical Practice Guideline on functioning and nonfunctioning pituitary adenomas in pregnancy.

Pregnancies are rare in women with pituitary adenomas, which may relate to hormone excess from secretory subtypes such as prolactinomas or corticotroph adenomas. Decreased fertility may also result from pituitary hormone deficiencies due to compression of the gland by large tumours and/or surgical or radiation treatment of the lesion. Counselling premenopausal women with pituitary adenomas about their chance of conceiving spontaneously or with assisted reproductive technology, and the optimal pre-conception treatment, should start at the time of initial diagnosis. The normal physiological changes during pregnancy need to be considered when interpreting endocrine tests in women with pituitary adenomas. Dose adjustments in hormone substitution therapies may be needed across the trimesters. When medical therapy is used for pituitary hormone excess, consideration should be given to the known efficacy and safety data specific to pregnant women for each therapeutic option. In healthy women, pituitary gland size increases during pregnancy. Since some pituitary adenomas also enlarge during pregnancy, there is a risk of visual impairment, especially in women with macroadenomas or tumours near the optic chiasm. Pituitary apoplexy represents a rare acute complication of adenomas requiring surveillance, with surgical intervention needed in some cases. This guideline describes the choice and timing of diagnostic tests and treatments from the pre-conception stage until after delivery, taking into account adenoma size, location and endocrine activity. In most cases, pregnant women with pituitary adenomas should be managed by a multidisciplinary team in a centre specialised in the treatment of such tumours.

T2-weighted magnetic resonance imaging characterization of prolactinomas and association with their response to dopamine agonists.

PURPOSE: Recent work supports the use of T2-weighted MRI intensity as a tool for treatment stratification in acromegaly. Our study aimed to establish if the pattern of T2 intensity could be a predictor of hormonal and/or tumoral response to dopamine agonists (DAs) in prolactinomas. METHODS: This was a retrospective study performed in two academic centers. We characterized the magnetic resonance T2-weighted aspect of prolactinomas (signal intensity and homogeneity in the whole tumors) before DA therapy and correlated this pattern to the prolactin (PRL) concentration at diagnosis and to hormonal and tumoral responses after 1 year of medical treatment. We separately analyzed a subgroup of prolactinomas visually very bright in more than 50% of the surface ("cystic" tumors). RESULTS: Out of 70 prolactinomas, 80% were T2 hyperintense and 40% were heterogeneous. At diagnosis, heterogeneous prolactinomas were more frequent in men (68% vs. 28.9%, p ≤ 0.011), larger (median area 304.5 mm2 vs. 56.5 mm2, p ≤ 0.021), taller (mean height 18.6 mm vs. 9.9 mm, p < 0.001), more secreting (median PRL ULN_area 23 µg/L/cm2 vs. 12.6 µg/L/cm2, p ≤ 0.032) and had poorer hormonal response to DA as compared with homogeneous prolactinomas. "Cystic" tumors were diagnosed almost exclusively in women and secreted less prolactin, but showed similar hormonal and tumoral response as "non-cystic" tumors. In homogeneous prolactinomas, the T2-weighted intensity ratio was correlated to prolactin secretion, although not significantly, and did not predict hormonal and tumoral response to DA. CONCLUSIONS: Our study confirms that hypo/isointense prolactinoma is a rare finding and suggests for the first time that the heterogeneity of prolactinoma T2 signal at diagnosis might be correlated with a different clinical behavior and could be used as a negative predictor factor of hormonal response to DA.

Long-term effects of GLP-1 receptor agonists in type 2 diabetic patients: A retrospective real-life study in 131 patients.

AIM: We evaluate retrospectively long-term effects of GLP-1 receptor agonists in type 2 diabetic patients treated between 2008 and 2016. METHODS: 131 patients treated by GLP-1 receptor agonists (GLP-1RAs) were included. The objective was to evaluate the evolution of glycated hemoglobin (HbA1c) during a period up to 4 years. The secondary objectives consisted of analysing the long-term effects of treatment on body mass index (BMI), blood pressure and lipids; reporting the proportion of patients who reached HbA1c objectives; estimating the time before treatment failure and determining predictive factors of failure. We also compared twice-daily exenatide to once-daily liraglutide on the major parameters. RESULTS: HbA1c improved significantly, mostly during the first year of treatment (-1.2%), and this effect was maintained after 4 years (-1.4% vs. baseline). At 1 year, 26% and 47% of subjects achieved HbA1c levels <7.0% and 7.5%, respectively. Treatment failure was observed in 51% of patients after a mean duration of GLP-1RA treatment of 50 months. Half of patients had failed after 42 months. Baseline HbA1c greater than 9.0% and male gender were predictive factors of treatment failure. BMI also decreased: -0.9 kg/m2 the first year, -1.9 kg/m2 after 4 years. No significant difference was found between patients treated with exenatide and liragutide over time. CONCLUSIONS: The beneficial effects of GLP-1RAs on HbA1c reached a plateau after the first year of treatment and are maintained at 4 years only in one third of patients. Failure occurred predominantly in men with a baseline HbA1c greater than 9%.

Endocrine and metabolic disorders in young adult survivors of childhood acute lymphoblastic leukaemia (ALL) or non-Hodgkin lymphoma (NHL).

BACKGROUND: Treatments of acute lymphoblastic leukaemia (ALL) and non-Hodgkin lymphoma (NHL), involving various combinations of chemotherapy (chemo), cranial irradiation (CI) and/or bone marrow transplantation after total body irradiation (BMT/TBI), are often successful but may have several long-term harmful effects. OBJECTIVE: To evaluate late endocrine and metabolic complications in adult survivors of childhood ALL and NHL, in relation with the different therapeutic schemes received. DESIGN: Endocrine and metabolic parameters were determined in 94 patients (48 men, mean age: 24 +/- 5 years) with a former childhood ALL (n = 78) or NHL (n = 16) and subgrouped according to their previous treatment: chemo only (group I; n = 44), chemo + CI (group II; n = 32) and chemo + BMT/TBI (group III; n = 18). RESULTS: Severe GH deficiency (peak < 3.0 ng/ml after glucagon) was observed in 22% and 50% of patients of groups II and III, respectively, while hypothyroidism was mainly observed in group III (56%). Moreover, 83% of men developed hypogonadism after BMT/TBI, compared to 17% and 8% in groups I and II, respectively (P < 0.05), and all grafted women had ovarian failure, in contrast with other female patients in whom menarche had occurred spontaneously. Patients with BMT/TBI had also an adverse metabolic profile, with insulin resistance in 83% and dyslipidaemia in 61%. CONCLUSIONS: This study reveals a high prevalence of endocrine and metabolic disorders in young adult survivors of childhood ALL or NHL, this frequency mainly depending on the treatment received. Treatment with BMT/TBI is the most detrimental and many of these patients will develop GHD, hypothyroidism, hypogonadism, insulin resistance and dyslipidaemia.

Cabergoline for Cushing's disease: a large retrospective multicenter study.

OBJECTIVE: The efficacy of cabergoline in Cushing's disease (CD) is controversial. The aim of this study was to assess the efficacy and tolerability of cabergoline in a large contemporary cohort of patients with CD. DESIGN: We conducted a retrospective multicenter study from thirteen French and Belgian university hospitals. METHODS: Sixty-two patients with CD received cabergoline monotherapy or add-on therapy. Symptom score, biological markers of hypercortisolism and adverse effects were recorded. RESULTS: Twenty-one (40%) of 53 patients who received cabergoline monotherapy had normal urinary free cortisol (UFC) values within 12 months (complete responders), and five of these patients developed corticotropic insufficiency. The fall in UFC was associated with significant reductions in midnight cortisol and plasma ACTH, and with clinical improvement. Compared to other patients, complete responders had similar median baseline UFC (2.0 vs 2.5xULN) and plasma prolactin concentrations but received lower doses of cabergoline (1.5 vs 3.5 mg/week, P < 0.05). During long-term treatment (>12 months), cabergoline was withdrawn in 28% of complete responders because of treatment escape or intolerance. Overall, sustained control of hypercortisolism was obtained in 23% of patients for 32.5 months (19-105). Nine patients on steroidogenesis inhibitors received cabergoline add-on therapy for 19 months (1-240). Hypercortisolism was controlled in 56% of these patients during the first year of treatment with cabergoline at 1.0 mg/week (0.5-3.5). CONCLUSIONS: About 20-25% of CD patients are good responders to cabergoline therapy allowing long-term control of hypercortisolism at relatively low dosages and with acceptable tolerability. No single parameter, including the baseline UFC and prolactin levels, predicted the response to cabergoline.

Baseline characteristics and response to GH replacement of hypopituitary patients previously irradiated for pituitary adenoma or craniopharyngioma: data from the Pfizer International Metabolic Database.

OBJECTIVE: To test the hypothesis whether the effects of GH replacement therapy in adults could be affected by prior pituitary irradiation, the baseline characteristics and response to GH were evaluated in adults with severe GH deficiency (GHD), who had received or not irradiation for the treatment of pituitary adenoma or craniopharyngioma. DESIGN: Data from 447 patients, who had received radiotherapy (427 in addition to surgery), and 630 patients, who were operated on but not irradiated for their tumour, were retrieved from Pfizer International Metabolic Database (KIMS) and compared at baseline and 1 and 2 years following the onset of GH replacement. RESULTS: Irradiated and non-irradiated patients exhibited the expected phenotype of GHD at baseline. However, irradiated patients had a greater impairment in the quality of life (QoL), a higher fat mass, lower high-density lipoprotein cholesterol levels and a lower bone mineral content (BMC) than non-irradiated patients. Treatment with GH induced similar changes in both groups. After 1 year of GH replacement, there was an increase in serum IGF-I and fat-free mass, a reduction in fat mass and an improvement in QoL, all changes being equivalent in irradiated and non-irradiated patients. The lipid profile also improved with the irradiated patients showing a better response. These beneficial effects were maintained and the BMC also increased in both groups by the second year of treatment. CONCLUSIONS: This analysis shows that prior irradiation for pituitary adenoma or craniopharyngioma does not compromise the beneficial effects of GH replacement therapy.

Contributions of growth hormone receptor and postreceptor defects to growth hormone resistance in malnutrition.

Malnutrition results in poor growth and is associated with resistance to growth hormone (GH) action. The mechanisms involved in the GH resistance depend on the severity and the timing of the nutritional insult. Stringent dietary restrictions such as fasting may produce GH resistance by reducing the number of GH receptors. Less severe nutritional deprivation such a short-term protein restriction may cause GH insensitivity mainly through postreceptor mechanisms.

Involvement of STAT5 (signal transducer and activator of transcription 5) and HNF-4 (hepatocyte nuclear factor 4) in the transcriptional control of the hnf6 gene by growth hormone.

HNF-6 is a tissue-restricted transcription factor that participates in the regulation of several genes in liver. We reported earlier that in adult rats, HNF-6 mRNA concentration in liver drops to almost undetectable levels after hypophysectomy and returns to normal after 1 week of GH treatment. We now show that this results from a rapid effect of GH, and we characterize its molecular mechanism. In hypophysectomized rats, HNF-6 mRNAs increased within 1 h after a single injection of GH. The same GH-dependent induction was reproduced on isolated hepatocytes. To determine whether GH regulates hnf6 expression at the gene level, we studied its promoter. DNA binding experiments showed that 1) the transcription factors STAT5 (signal transducer and activator of transcription 5) and HNF-4 (hepatocyte nuclear factor 4) bind to sites located around -110 and -650, respectively; and 2) STAT5 binding is induced and HNF-4 binding affinity is increased in liver within 1 h after GH injection to hypophysectomized rats. Using transfection experiments and site-directed mutagenesis, we found that STAT5 and HNF-4 stimulated transcription of an hnf6 gene promoter-reporter construct. Furthermore, GH stimulated transcription of this construct in cells that express GH receptors. Consistent with our earlier finding that HNF-6 stimulates the hnf4 and hnf3beta gene promoters, GH treatment of hypophysectomized rats increased the liver concentration of HNF-4 and HNF-3beta mRNAs. Together, these data demonstrate that GH stimulates transcription of the hnf6 gene by a mechanism involving STAT5 and HNF-4. They show that HNF-6 participates not only as an effector, but also as a target, to the regulatory network of liver transcription factors, and that several members of this network are GH regulated.

Sexually dimorphic expression of the growth hormone-releasing hormone gene is not mediated by circulating gonadal hormones in the adult rat.

The sexual dimorphism characterizing GH secretion in the rat is thought to be related to differences in the hypothalamic synthesis and release of the GH-regulating peptides, GH-releasing hormone (GHRH), and somatostatin. Therefore, the influence of gender and sex steroid hormones on hypothalamic expression of the GHRH gene in adult rats were examined. GHRH messenger RNA (mRNA) levels were measured in individual rat hypothalami by Northern hybridization analysis using a 32P-labeled complementary DNA encoding rat GHRH. Destruction of hypothalamic GHRH neurons by neonatal treatment with monosodium glutamate caused similar 3-fold reductions in the levels of GHRH mRNA in adult male and female animals. In three separate experiments, hypothalamic GHRH mRNA concentrations in male rats were 2- to 3-fold greater than in randomly cycling females (four or five rats per group; P less than 0.01). In spite of the greater abundance of GHRH mRNA abundance in the male rat hypothalamus, circulating gonadal steroids lacked the ability to modulate GHRH gene expression in adult animals, since neither gonadectomy nor pharmacological sex steroid replacement changed GHRH mRNA levels in the hypothalamus of male and female adult rats. Furthermore, GHRH mRNA concentrations in female rats were similar during the proestrus, estrus, and diestrus phase of the estrous cycle. Also, GH inhibited hypothalamic GHRH gene expression in a sex-specific manner. Exposure to high levels of GH secreted by the MtTW15 tumor for 4 weeks reduced GHRH mRNA concentrations 7-fold in male rats (P less than 0.001) but only 2-fold in females (P less than 0.05). These studies demonstrate that GHRH gene expression in the rat hypothalamus is sexually dimorphic. Basal mRNA levels are greater in male rats, and expression in male hypothalami is more sensitive to feedback inhibition by GH than expression in females. There is no evidence for regulation of GHRH mRNA levels by either testosterone or estrogen in adult rats. These gender differences in GHRH gene expression likely contribute to the generation of a sex-specific pattern of GH secretion.

Neonatal treatment with monosodium glutamate: effects of prolonged growth hormone (GH)-releasing hormone deficiency on pulsatile GH secretion and growth in female rats.

Administration of monosodium glutamate (MSG) to neonatal rodents produces permanent lesions of hypothalamic arcuate neurons that secrete GH-releasing hormone (GHRH). The present study was intended to determine the consequences of GHRH deficiency on the pulsatile GH secretory pattern and growth in MSG-treated female rats and to compare these effects with those observed in male littermates. Male and female rats were injected with MSG [4 mg/g body wt (BW), sc] or saline (controls) on days 2, 4, 6, 8, and 10 after birth. Immunoreactive GHRH concentrations were decreased in the hypothalamus (by 60%) and in the median eminence (by 95%) of adult male and female MSG-treated rats. In contrast, somatostatin concentrations were unaffected. BW and linear growth were severely impaired in male MSG-treated rats, but in MSG-lesioned females BW was not different from controls, and the attenuation of longitudinal growth was less severe and the obesity more pronounced than in males. These sex differences occurred despite similar reductions (by 55%) in serum insulin-like growth factor I concentrations in male and female MSG-treated rats. MSG treatment also produced decreases in pituitary wt and GH content (by 60%), independent of sex. Pulsatile GH secretion was studied by serial blood sampling of chronically cannulated, freely moving rats. Plasma GH patterns were analyzed by the PULSAR program. Compared to controls, treatment with MSG led to a marked inhibition (by 90%) of GH secretion in both sexes. Significant reductions in GH pulse amplitude (-95%) and pulse duration (-62%) were observed in males, whereas pulse amplitude (-85%), pulse frequency (-67%), and baseline GH concentrations (-80%) were markedly reduced in females. The GH responses to an iv bolus injection of rat GHRH (1 microgram/rat) was severely blunted in both male and female MSG-treated rats. This study demonstrates that GHRH deficiency in female rats results in a marked inhibition of GH pulses, as in males, but also causes severe and sex-specific reductions in GH basal secretion and pulse frequency. These observations suggest that hypothalamic GHRH secretion in female rats is more continuous than in males and is a determinant of the elevated interpulse secretion of GH. Moreover, body wt and linear growth are less severely affected by arcuate lesions in female animals, compared to males. These sex-related differences in growth rates may result in part from the tendency of female MSG-lesioned rats to become more obese than males, and the development of obesity, in turn, may antagonize the factors that tend to slow linear growth.(ABSTRACT TRUNCATED AT 400 WORDS)

Acute down-regulation of the somatogenic receptors in rat liver by a single injection of growth hormone.

Prolonged continuous administration of GH induces somatogenic receptors in rat liver. However, because GH secretion is pulsatile and the effect of acute changes in serum GH concentrations on liver GH receptors is unknown, we measured total (MgCl2-treated homogenates) and free (water-treated homogenates) GH-binding sites in the livers of hypophysectomized (hypox) rats killed between 1 and 24 h after a single sc injection of rat GH (100 micrograms/100 g BW; n = 29). Control hypox rats (n = 10) were studied immediately or 3 h after injection of vehicle. GH injection caused profound decreases in both total and free liver GH receptors, but these changes followed different kinetic patterns. Free receptors declined rapidly (to 17% of control), reaching a nadir at the same time (1 h) as the maximal GH concentration in serum. These free receptors then increased, returning to normal 12 h after GH injection. In contrast, total GH receptors were slightly increased at 1 h, decreased to their minimal value at 6 h (53% of control), and returned to normal at 12 h. Serum immunoreactive somatomedin-C/insulin-like growth factor I concentrations peaked 12 h after GH injection. Total and free liver GH receptors were quantitated in hypox rats that had been injected 3 h previously with doses of rat GH from 2.5-500 micrograms/100 g BW or with vehicle. Both total and free binding sites decreased in a dose-dependent manner; the maximal responses were 40% and 90% below control values, respectively. Half-maximal reductions in GH binding were achieved when 10 micrograms GH/100 g BW were given. These data suggest that a surge of GH in serum leads to a time- and dose-dependent down-regulation of the liver somatogenic binding sites and are consistent with ligand-induced internalization and degradation of the receptor.