Corticotropin-releasing hormone (CRH)-immunoreactive (IR) axon varicosities target a subset of growth hormone-releasing hormone (GHRH)-IR neurons in the human hypothalamus

It is a general consensus that stress is one of the major factors that suppresses growth. Previous studies revealed that the catecholaminergic and neuropeptide Y (NPY) systems, involved in the activation of stress-related neuronal circuits, influence growth hormone (GH)-release via modulating growth hormone-releasing hormone (GHRH) secretion. Indeed, catecholaminergic and NPY-immunoreactive (IR) axon varicosities abut on the surface of the GHRH neurons forming contacts. These juxtapositions appear to be real synapses and may represent the morphological substrate of the impact of stress on growth. In addition to catecholamines and NPY, there is a vast amount of evidence that corticotropin-releasing hormone (CRH), a major stress hormone, also influences GH secretion. Whether this modulatory effect is direct, or indirect, via the hypothalamic GHRH system, has not been elucidated yet.In the present study, we examined the possibility that CRH influences GH secretion via modulating the GHRH release by direct synaptic mechanisms. Since the verification of these synapses by electron microscopy is problematic in human due to the long post mortem time, in order to reveal the putative CRH-GHRH juxtapositions, light microscopic double label immunohistochemistry was utilized. In the infundibular nucleus, a subset (6%) of the GHRH perikarya received abutting CRH fiber varicosities forming multiple contacts while passing by. No gaps appeared between the contacting elements. The morphology of these CRH-GHRH juxtapositions suggests that, among other neurotransmitters/neuromodulators, CRH influences growth by modulating the hypothalamic GHRH secretion via direct synaptic mechanisms.     

Growth Hormone Releasing Hormone (GHRH) and the GHRH Receptor

Reviews in Endocrine and Metabolic Disorders -     

Potential applications of GH secretagogs in the evaluation and treatment of the age-related decline in growth hormone secretion

The two classes of GH secretagogs—GH-releasing hormone (GHRH) and the GH-releasing peptides and their analogs (GHRP’s)—retain their ability to endogenous GH secretion in healthy and frail elderly subjects. They have very limited utility in assessment of the state of the GH/IGF-I axis except to confirm an intact pituitary, but they are attractive potential alternatives to GH as therapeutic agents. There is wide interest in the possibility that elevating GH and IGF-I might increase muscle mass, physical strength and performance, and possibly sleep and cognition in aging. The GH secretagogs, like GH, can produce a sustained stimulation of this axis; in contrast to GH, they preserve feedback regulation at the pituitary level and stimulate a near-physiologic pulsatile pattern of GH release. GHRP’s and their nonpeptide analogs are also active when given orally, a significant practical advantage. Short-tern treatment studies have shown that GHRH and the GHRP’s can enhance GH secretion and elevate IGF-I and IGFBP-3 levels; that GHRH may promote sleep; and that these agents are generally well tolerated. Longer-term studies, assessing effects upon body composition and physical and psychological function are underway. Prepared for presentation at “Assessment of the Growth Hormone/IGF-I Axis in Aging,” Bethesda, MD, April 14, 1997.     

Effect of <Emphasis Type="Italic">gsp</Emphasis> oncogene on somatostatin receptor subtype 1 and 2 mRNA levels in GHRH-responsive GH3 cells

Growth hormone releasing hormone (GHRH) signals via G protein-coupled receptors (GHRH-R) to enhance intracellular Gαs/adenylyl cyclase/cAMP signaling, which in turn has positive effects on GH synthesis and release, as well as proliferation of the GH-producing cells of the anterior pituitary gland. Some GH-producing pituitary tumors express a constitutively active mutant form of Gαs (gsp oncogene). It has been reported that these tumors are more responsive to octreotide therapy. In this study we used a rat GH-producing cell line (GH3) stably transfected with the human GHRH-R cDNA (GH3-GHRHR cells) as a model to study the effects of gsp oncogene on somatostatin (SRIH) receptor subtype 1 and 2 (sst1 and sst2) mRNA levels. Transient transfection of gsp oncogene in GH3-GHRHR cells for 48 h increased intracellular cAMP levels and GH release. Phosphodiesterase (PDE) 4, sst1 and sst2 mRNA levels were increased by G protein mutation as assessed by real-time RT-PCR. Increased PDE mRNA levels in gsp-transfected cells may be a compensatory mechanism to the constitutive activation of cAMP-dependent pathway by G protein mutation and is consistent with reports of higher PDE expression in human pituitary tumor that express gsp. Our data suggest that higher expression of sst1 and sst2 mRNA induced by the gsp oncogene may be a mechanism by which gsp-positive tumors show a greater response to SRIH. GH3 cells permanently transfected with GHRH-R can be used for in vitro studies of actions of GHRH.     

Acromegaly caused by growth hormone-releasing hormone-producing tumors: long-term observational studies in three patients

We report on three newly diagnosed patients with extracranial ectopic GHRH-associated acromegaly with long-term follow-up after surgery of the primary tumor. One patient with a pancreatic tumor and two parathyroid adenomas was the index case of a large kindred of MEN-I syndrome. The other two patients had a large bronchial carcinoid. The first patient is still in remission now almost 22 years after surgery. In the two other patients GHRH did not normalize completely after surgery and they are now treated with slow-release octreotide. IGF-I normalized in all patients. During medical treatment basal GH secretion remained (slightly) elevated and secretory regularity was decreased in 24 h blood sampling studies. We did not observe development of tachyphylaxis towards the drug or radiological evidence of (growing) metastases. We propose life-long suppressive therapy with somatostatin analogs in cases with persisting elevated serum GHRH concentrations after removal of the primary tumor. Independent parameters of residual disease are elevated basal (nonpulsatile) GH secretion and decreased GH secretory regularity.     

Novel neuronal and endocrine autoantibody targets in autoimmune polyendocrine syndrome type 1

Context. Although pituitary autoantibodies have frequently been reported in Autoimmune Polyendocrine Syndrome type 1 (APS1), the autoimmune involvement of the hypothalamic-pituitary axis remains to be elucidated. Objective. Our aim was to identify in APS1 patients novel autoantibodies, especially against hypothalamic-pituitary targets, and to correlate their presence with clinical features. Patients. We analyzed 14 APS1 patients from Sardinia, compared to other diseases and healthy donors. Measure(s). We used immunohistochemistry, on tissues substrates from various neuroendocrine organs, to detect autoantibody targets. Immunoenzymatic assays, as well as absorption with specific antigens were used to reveal autoantibodies against growth hormone (GH), luteinizing hormone (LH) and somatocrinin (GHRH). Clinical evaluations included GH secretory and cardiovascular autonomic neuropathy tests. Results. Sera from 12/14 APS1 patients revealed autoantibodies reacting with the hypothalamic-pituitary axis, cerebellum, substantia nigra, and/or adrenal medulla, as well as with GH, LH and/or GHRH. Of APS1 patients, 5 showed GH deficiency, in association (4/5 cases) with autoantibodies to hypothalamic and/or pituitary targets. Hypogonadotrophic hypogonadism was revealed in one APS1 patient, together with autoantibodies against gonadotropes. Autonomic neuropathy was detected in 5 of 10 patients, associated with autoantibodies to adrenal medulla in 2 cases. Of 5 patients with autoantibodies to cerebellar neurons, 2 reported emotional or memory alterations. Conclusions. The majority of Sardinian APS1 patients developed autoantibodies to an assortment of neuroendocrine cells. Novel targets of clinical relevance may include pituitary hormones, uncharacterized pituitary targets, and adrenal medullary cells. An high prevalence of GH deficiency, and possibly of autonomic neuropathy, were also revealed.     

Ectopic Growth Hormone-Releasing Hormone Secretion by a Neuroendocrine Tumor Causing Acromegaly: Long-Term Follow-Up Results

Ectopic secretion of growth hormone-releasing-hormone (GHRH) is a rare cause of acromegaly—representing less than 1% of patients. A 25-year-old woman was admitted to the hospital with acromegaly and a 6 × 6 cm infrahepatic mass. Sellar magnetic resonance imaging indicated diffuse pituitary enlargement consistent with hyperplasia. The infrahepatic mass was resected, and the histopathological diagnosis was a well-differentiated invasive neuroendocrine carcinoma of the duodenum with metastases to local lymph nodes. The tumor cells contained cytoplasmic immunoreactivity for GHRH. Because increased IGF-1 concentrations persisted after the operation, the patient was treated with octreotide long-acting repeatable (LAR) injections of 20 mg/month. Growth hormone and IGF-1 levels normalized. After 6 years of surveillance, a left paraaortic mass was detected by uptake of indium¹¹¹ octreotide. Surgical exploration revealed metastatic neuroendocrine carcinoma in a 2.5-cm lymph node. Postoperatively, the IGF-1 concentration was mildly elevated. Octreotide LAR therapy is being continued at 10 mg/month. This case suggests that octreotide treatment may have a beneficial effect on disease course and can be maintained for as long as 7 years in a patient with acromegaly due to a GHRH-secreting neuroendocrine carcinoma.     

Age-related Variations in the Neuroendocrine Control,More Than Impaired Receptor Sensitivity,Cause The Reduction in the GH-releasing Activity of GHRPs in Human Aging

The mechanisms underlying the reduction in the GH-releasing activity of GHRPs in aging are still unclear. Aim of our study was to verify in man whether age-related impairment of the neurohormonal control of GH secretion and/or receptor alterations are involved in the reduced GH response to GHRPs in aging. To this goal, in 16 normal elderly subjects (E, 66–81 yr) and 12 young controls (Y, 24–28 yr) we studied the effects of 1.0, 2.0 and 3.0 g/kg iv Hexarelin (HEX), a synthetic hexapeptide, or GHRH, as well as the interaction among HEX (2.0 g/kg), GHRH (2.0 g/kg) and arginine (ARG, 0.5 gr/kg) on GH secretion. In Y the GH response to increasing doses of HEX (1.0 vs. 2.0 vs. 3.0 g/kg; AUC0;v–120 ± SEM: 1728.4 ± 406.4 vs. 2265.9 ± 298.4 vs. 2934.3 ± 482.2 g//L/h, p < 0.05 for 1.0 vs. 2.0 g/kg) and GHRH (649.6 ± 111.4 vs. 792.2 ± 117.6 vs. 1402.6 ± 363.0 g/L/h) showed a progressive increase. Two g/kg HEX and 1 g/kg GHRH were the maximal effective doses. Similarly, in E the GH response to increasing doses of HEX (336.7 ± 50.0 vs. 742.8 ± 157.9 vs. 1205.1 ± 178.1 g/L/h, p < 0.05 for 1.0 vs. 2 g/kg, p < 0.001 for 1.0 vs. 3.0 g/kg and p < 0.03 for 2.0 vs. 3.0 g/kg) and GHRH (183.8 ± 27.3 vs. 260.9 ± 17.3 vs. 356.1 ± 46.3 g/L/h, p < 0.005 for 1.0 vs. 3.0 g/kg and p < 0.05 for 2.0 vs. 3.0 g/kg) showed a progressive increase. In E the GH response to 3 g/kg HEX or GHRH were clearly higher than those to 2 g/kg. However, at each dose the GH responses to HEX or GHRH in E were lower (p < 0.05) than those in Y. In Y the GH response to HEX + GHRH was synergistical (4259.2 ± 308.0 g/L/h, p < 0.05). ARG strikingly potentiated the GHRH-induced GH rise (2640.8 ± 273.6 g/L/h, p < 0.01) but not the HEX-induced one (2371.7 ± 387.2 g/L/h) as well as the synergistical effect of HEX and GHRH (4009.1 ± 360.8 g/L/h). In E the GH response to HEX and GHRH was still synergistical (1947.7 ± 306.0 g/L/h, p < 0.05) but these responses were lower than those in young (p < 0.01). On the other hand, in E ARG restored the GH response to GHRH (1858.9 ± 172.8 g/L/h, p < 0.01) and even those to HEX (2069.5 ± 528.7 g/L/h, p < 0.01) and HEX + GHRH (4406.0 ± 1079.2 g/L/h, p < 0.05). Our present results indicate that the impairment of GHRP and GHRH receptor activity may have a role in the reduction of the somatotrope responsiveness in aging. However, the age-related reduction in the GH-releasing activity of GHRPs seems mainly dependent on age-related variations in the neural control, i.e. concomitant GHRH hypoactivity and somatostatinergic hyperactivity.     

单次及多次GHRH兴奋试验对鉴别下丘脑性和垂体性生长激素缺乏的价值评估

50例特发性生长激素缺乏症(IGHD)患者在一次静脉注射GHRH后,其中36％病例GH反应阳性(GH峰值≥5μg/L);用GHRH_(1-44)引发5日后,41％的GH反应阴性患者GH细胞转为有反应,使GH反应阳性率增至62％;继续用GHRH_(1-44)引发至10日未能再增加阳性反应率。结果提示,许多下丘脑性IGHD患者的垂体GH细胞,由于长期缺乏内源性GHRH兴奋,分泌功能低下,致对单次静脉注射GHRH无反应;但连续用外源性GHRH兴奋5日后,垂体GH细胞分泌功能逐渐恢复而有阳性反应。因此,5日GHRH兴奋试验对下丘脑性和垂体性IGHD已具有鉴别诊断意义。