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1.
Br J Ophthalmol ; 93(12): 1660-6, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19692378

ABSTRACT

BACKGROUND/AIMS: Autoimmune optic neuropathy (AON) is characterised by chronically progressive or recurrent visual loss associated with serological or cutaneous evidence of autoimmunity, without a defined systemic autoimmune illness. It may improve with large doses of corticosteroids alone, or in combination with immunosuppressive agents. The aim was to determine the relative effectiveness of various therapeutic regimens in AON. METHODS: All patients in this study fulfilled these criteria: (1) multiple attacks in one eye or attacks in both eyes (at least three total attacks); (2) a minimum of 12 months of neuro-ophthalmic follow-up; (3) serological abnormalities or skin biopsy changes consistent with AON; (4) no diagnosis of a defined collagen vascular disease or neurological autoimmune disease throughout follow-up, with the exception of one patient, later shown to be shown to be neuromyelitis optic antibody positive. RESULTS: Nine cases were found (female = 7, male = 2, ages 8-74). One case received corticosteroids alone, the others received corticosteroids in combination with methotrexate/gammaglobulin (n = 1), methotrexate (n = 1), gammaglobulin (n = 1), chlorambucil (n = 2), cyclophosphamide (n = 1) and azathioprine/chlorambucil (n = 1), and one received multiple combinations of agents. Criteria for diagnosis are proposed. CONCLUSION: As AON is quite rare, no formal recommendation can be made regarding its best therapy, although there is a suggestion that chlorambucil, although potentially toxic, may yield long-term remission.


Subject(s)
Autoimmune Diseases/drug therapy , Optic Nerve Diseases/drug therapy , Adolescent , Adult , Aged , Autoantibodies/blood , Autoimmune Diseases/complications , Autoimmune Diseases/diagnosis , Biopsy , Child , False Positive Reactions , Female , Follow-Up Studies , Glucocorticoids/therapeutic use , Humans , Immunoglobulins, Intravenous/therapeutic use , Immunosuppressive Agents/therapeutic use , Magnetic Resonance Imaging , Male , Middle Aged , Optic Nerve Diseases/complications , Optic Nerve Diseases/diagnosis , Recurrence , Retrospective Studies , Skin/pathology , Treatment Outcome , Vision Disorders/etiology , Vision Disorders/physiopathology , Visual Acuity/drug effects , Young Adult
2.
J Clin Endocrinol Metab ; 94(1): 115-22, 2009 Jan.
Article in English | MEDLINE | ID: mdl-18957506

ABSTRACT

CONTEXT: There is currently no medical therapy for Cushing's disease that targets the pituitary adenoma. Availability of such a medical therapy would be a valuable therapeutic option for the management of this disorder. OBJECTIVE: Our objective was to evaluate the short-term efficacy of the novel multireceptor ligand somatostatin analog pasireotide in patients with de novo, persistent, or recurrent Cushing's disease. DESIGN: We conducted a phase II, proof-of-concept, open-label, single-arm, 15-d multicenter study. PATIENTS: Thirty-nine patients with either de novo Cushing's disease who were candidates for pituitary surgery or with persistent or recurrent Cushing's disease after surgery without having received prior pituitary irradiation. INTERVENTION: Patients self-administered sc pasireotide 600 microg twice daily for 15 d. MAIN OUTCOME MEASURE: Normalization of urinary free cortisol (UFC) levels after 15 d treatment was the main outcome measure. RESULTS: Of the 29 patients in the primary efficacy analysis, 22 (76%) showed a reduction in UFC levels, of whom five (17%) had normal UFC levels (responders), after 15 d of treatment with pasireotide. Serum cortisol levels and plasma ACTH levels were also reduced. Steady-state plasma concentrations of pasireotide were achieved within 5 d of treatment. Responders appeared to have higher pasireotide exposure than nonresponders. CONCLUSIONS: Pasireotide produced a decrease in UFC levels in 76% of patients with Cushing's disease during the treatment period of 15 d, with direct effects on ACTH release. These results suggest that pasireotide holds promise as an effective medical treatment for this disorder.


Subject(s)
Oligopeptides/therapeutic use , Pituitary ACTH Hypersecretion/drug therapy , Adrenocorticotropic Hormone/blood , Adult , Aged , Blood Glucose/analysis , Female , Glucagon/blood , Humans , Hydrocortisone/urine , Insulin/blood , Male , Middle Aged , Oligopeptides/adverse effects , Oligopeptides/pharmacokinetics , Pituitary ACTH Hypersecretion/metabolism , Somatostatin/analogs & derivatives
4.
Eur J Endocrinol ; 153(6): 737-40, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16322377

ABSTRACT

In November 2003, the Pituitary Society and the European Neuroendocrine Association sponsored a consensus workshop in Seville to address challenging issues in the medical management of acromegaly. Participants comprised 70 endocrinologists and neurosurgeons with international expertise in managing patients with acromegaly. All participants participated in the workshop proceedings, and the final document written by the scientific committee reflects the consensus opinion of the interactive deliberations. The meeting was supported by an unrestricted educational grant from Ipsen. No pharmaceutical representatives participated in the program planning or in the scientific deliberations.


Subject(s)
Acromegaly/therapy , Acromegaly/drug therapy , Acromegaly/radiotherapy , Acromegaly/surgery , Dopamine Agonists/therapeutic use , Female , Human Growth Hormone/analogs & derivatives , Human Growth Hormone/blood , Human Growth Hormone/therapeutic use , Humans , Insulin-Like Growth Factor I/analysis , Male , Somatostatin/analogs & derivatives , Somatostatin/therapeutic use
5.
J Endocrinol Invest ; 26(12): 1242-7, 2003 Dec.
Article in English | MEDLINE | ID: mdl-15055479

ABSTRACT

The Pituitary Society in conjunction with the European Neuroendocrine Association held a consensus workshop to develop guidelines for diagnosis and treatment of the co-morbid complications of acromegaly. Fifty nine pituitary specialists (endocrinologists, neurosurgeons and cardiologists) assessed the current published literature on acromegaly complications in light of recent advances in maintaining tight therapeutic control of GH hypersecretion. The impact of elevated GH levels on cardiovascular disease, hypertension, diabetes, sleep apnea, colon polyps, bone disease, reproductive disorders, and neuropsychologic complications were considered. Guidelines are proposed for effective management of these complications in the context of overall acromegaly control. When appropriate, requirements for prospective evidence-based studies and surveillance database development are enunciated. Effective management of co-morbid acromegaly complications will lead to improved morbidity and mortality in acromegaly.


Subject(s)
Acromegaly/complications , Diagnosis , Therapeutics , Humans
7.
Minerva Endocrinol ; 27(4): 277-85, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12511850

ABSTRACT

Growth hormone-releasing hormone (GHRH) is a hypothalamic hormone that is essential for normal expansion of the somatotrope lineage during pituitary development. Decreased GHRH secretion and/or action leads to impairment of this process and somatotrope hypoplasia in both humans and experimental animals. Excessive GHRH secretion and/or action result in dysregulated somatotrope proliferation, leading to hyperplasia and neoplastic transformation. Our understanding of the molecular and morphologic bases for these effects from both animal and clinical studies has greatly increased during the past decade. However, many features of the cellular pathways remain to be defined, including the interaction of other genes in the multistep process of somatotrope tumorigenesis.


Subject(s)
Growth Hormone-Releasing Hormone/physiology , Human Growth Hormone/biosynthesis , Pituitary Gland, Anterior/cytology , Amino Acid Sequence , Animals , Animals, Genetically Modified , Cell Division , GTP-Binding Protein alpha Subunits, Gs/genetics , Gene Expression Regulation , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/physiopathology , Humans , Hyperplasia , Hypothalamo-Hypophyseal System/metabolism , Mice , Mice, Knockout , Mice, Mutant Strains , Models, Molecular , Molecular Sequence Data , Mutation , Neuroendocrine Tumors/metabolism , Paraneoplastic Endocrine Syndromes/physiopathology , Pituitary Gland, Anterior/growth & development , Pituitary Gland, Anterior/metabolism , Pituitary Neoplasms/etiology , Pituitary Neoplasms/metabolism , Protein Conformation , Rats , Receptors, Neuropeptide/drug effects , Receptors, Neuropeptide/genetics , Receptors, Neuropeptide/physiology , Receptors, Pituitary Hormone-Regulating Hormone/drug effects , Receptors, Pituitary Hormone-Regulating Hormone/genetics , Receptors, Pituitary Hormone-Regulating Hormone/physiology , Signal Transduction
8.
Surv Ophthalmol ; 46(2): 143-8, 2001.
Article in English | MEDLINE | ID: mdl-11578647

ABSTRACT

Common signs and symptoms of temporal arteritis include headache, scalp tenderness, jaw claudication, anemia, and an elevated sedimentation rate (ESR). Severe complications can include blindness, retinal artery occlusion, and optic neuropathy. While temporal arteritis may be suggested by patient history, other causes that can mimic its presentation must be considered, especially when visual loss occurs in the setting of a normal funduscopic exam. We report a case of invasive sino-orbital aspergillosis that mimicked the clinical signs and symptoms typically associated with temporal arteritis. A high index of suspicion and appropriate radiological and laboratory studies prevented delays in formulating the correct diagnosis and treatment plan.


Subject(s)
Aspergillosis/diagnosis , Blindness/diagnosis , Eye Infections, Fungal/diagnosis , Meningitis, Fungal/diagnosis , Orbital Diseases/diagnosis , Sinusitis/diagnosis , Aged , Antifungal Agents/therapeutic use , Aspergillosis/drug therapy , Aspergillosis/microbiology , Blindness/drug therapy , Blindness/microbiology , Diagnosis, Differential , Eye Infections, Fungal/drug therapy , Eye Infections, Fungal/microbiology , Fatal Outcome , Giant Cell Arteritis/diagnosis , Humans , Magnetic Resonance Imaging , Male , Meningitis, Fungal/drug therapy , Meningitis, Fungal/microbiology , Orbital Diseases/drug therapy , Orbital Diseases/microbiology , Sinusitis/drug therapy , Sinusitis/microbiology , Tomography, X-Ray Computed
9.
Endocrinology ; 142(11): 4762-70, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11606442

ABSTRACT

We have reported that liver-specific deletion of IGF-I in mice (LI-IGF-I-/-) results in decreased circulating IGF-I and increased GH levels. In the present study, we determined how elimination of hepatic IGF-I modifies the hypothalamic-pituitary GH axis to enhance GH secretion. The pituitary mRNA levels of GH releasing factor (GHRF) receptor and GH secretagogue (GHS) receptor were increased in LI-IGF-I-/- mice, and in line with this, their GH response to ip injections of GHRF and GHS was increased. Expression of mRNA for pituitary somatostatin receptors, hypothalamic GHRF, somatostatin, and neuropeptide Y was not altered in LI-IGF-I-/- mice, whereas hypothalamic IGF-I expression was increased. Changes in hepatic expression of major urinary protein and the PRL receptor in male LI-IGF-I-/- mice indicated an altered GH release pattern most consistent with enhanced GH trough levels. Liver weight was enhanced in LI-IGF-I-/- mice of both genders. In conclusion, loss of liver-derived IGF-I enhances GH release by increasing expression of pituitary GHRF and GHS receptors. The enhanced GH release in turn affects several liver parameters, in line with the existence of a pituitary-liver axis.


Subject(s)
Growth Hormone/metabolism , Insulin-Like Growth Factor I/physiology , Liver/metabolism , Pituitary Gland/metabolism , Animals , Female , Growth Hormone/blood , Growth Hormone/genetics , Growth Hormone-Releasing Hormone/pharmacology , Hypothalamus/metabolism , Insulin-Like Growth Factor I/analysis , Insulin-Like Growth Factor I/genetics , Liver/anatomy & histology , Male , Mice , Mice, Knockout/genetics , Neuropeptides/physiology , Organ Size , Proteins/genetics , RNA, Messenger/metabolism , Receptors, Cell Surface/physiology , Receptors, Prolactin/genetics
10.
Endocrinology ; 142(9): 3764-73, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11517152

ABSTRACT

Excessive GHRH stimulation leads to somatotrope hyperplasia and, ultimately, pituitary adenoma formation in the metallothionein promoter-driven human GHRH (hGHRH) transgenic mouse. This pituitary phenotype is similar to that observed in humans with ectopic production of GHRH. In both mice and man, GHRH hyperstimulation also results in dramatic increases in circulating GH and IGF-I. To determine whether GH/IGF-I modulates the development and growth rate of GHRH-induced pituitary tumors, pituitary growth and histology were evaluated in mice generated from cross-breeding metallothionein promoter-driven hGHRH transgenic mice with GH receptor binding protein (GHR) gene disrupted mice (GHR(-/-)). Expression of the hGHRH transgene in 2-month-old GHR intact (GHR(+)) mice resulted in the doubling of pituitary weight that was largely attributed to an increase in the number of GH-immunopositive cells. Pituitary weight of GHR(+) hGHRH mice did not significantly change between 2 and 6 months of age, whereas at 12 months, weights increased up to 100-fold those of GHR(+) pituitaries, and 70% of the glands contained grossly visible adenomas. All adenomas stained positively for GH, whereas some showed scattered PRL staining. Pituitaries of GHR(-/-) mice were half the size of those of GHR(+) mice. Although reduced in size, the histological features of GHR(-/-) mouse pituitaries were suggestive of somatotrope hyperplasia. Despite evidence of somatotrope hyperplasia, pituitaries from GHR(-/-) mice as old as 28 months of age were similar in size to those of 2-month-old mice and did not show signs of adenoma formation. Expression of the hGHRH transgene in GHR(-/-) mice did not significantly increase pituitary size between 2 and 6 months of age. However, at 12 months the majority of GHR(-/-), hGHRH pituitaries developed adenomas with mean pituitary weight and histological features similar to those of GHR(+), hGHRH mice. These observations demonstrate that intact GH signaling is not required for GHRH tumor formation. Although the majority of GHR(+), hGHRH and GHR(-/-), hGHRH pituitaries developed tumors by 12 months of age, a small subset remained morphologically indistinct from those at 2 months of age. These observations taken together with the fact that overt tumor formation is preceded by a static pituitary growth phase between 2 and 6 months, indicates that protective mechanisms are in place to maintain pituitary mass despite hGHRH hyperstimulation.


Subject(s)
Adenoma/etiology , Growth Hormone-Releasing Hormone/pharmacology , Growth Hormone/physiology , Pituitary Gland, Anterior/pathology , Pituitary Neoplasms/etiology , Signal Transduction/physiology , Aging/physiology , Animals , Gene Expression/physiology , Humans , Hyperplasia , Male , Metallothionein/genetics , Mice , Mice, Inbred Strains , Mice, Knockout/genetics , Phenotype , Pituitary Gland/cytology , Pituitary Gland/physiology , Promoter Regions, Genetic/physiology , Receptors, Somatotropin/deficiency , Receptors, Somatotropin/genetics , Receptors, Somatotropin/physiology , Reference Values , Transgenes/genetics
12.
J Neuroophthalmol ; 21(2): 132-7, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11450904

ABSTRACT

OBJECTIVE: To familiarize the reader with the neuro-ophthalmic manifestations of sarcoidosis. MATERIALS AND METHODS: All patients underwent systemic evaluations (chest radiograph, magnetic resonance imaging and/or computed tomography, serum angiotensin-converting enzyme level, and gallium scan). Histologic confirmation was preferred (11 of 15 patients underwent biopsy, ten of whom [82%] had positive biopsies, and four refused). Otherwise, the diagnosis of clinical sarcoidosis was based on laboratory evaluation. RESULTS: We report our experience with 15 patients who had neuro-ophthalmic manifestations of sarcoidosis other than optic neuropathy or chiasmal disease. Eight of 15 (53%) did not have known sarcoidosis at the time of presentation. Thirteen of 15 (87%) patients demonstrated lesions consistent with sarcoidosis on magnetic resonance imaging of the brain. Treatment with corticosteroids and/or other immunomodulatory agents was necessary in all cases. CONCLUSIONS: Neuro-ophthalmic manifestations of sarcoidosis are rare. They may be the presenting signs of otherwise occult disease. Suspicion and inclusion in the differential are a key to establishing the diagnosis. A strategy for the detection and evaluation of these cases is presented.


Subject(s)
Cranial Nerve Diseases/diagnosis , Eye Diseases/diagnosis , Sarcoidosis/diagnosis , Adolescent , Adult , Aged , Brain/pathology , Cranial Nerve Diseases/drug therapy , Eye Diseases/drug therapy , Female , Glucocorticoids/therapeutic use , Humans , Magnetic Resonance Imaging , Middle Aged , Prednisone/therapeutic use , Retrospective Studies , Sarcoidosis/drug therapy
13.
Am J Ophthalmol ; 131(5): 661-2, 2001 May.
Article in English | MEDLINE | ID: mdl-11336948

ABSTRACT

PURPOSE: To report a case of a young woman with a history of sarcoidosis who developed retinal granulomas. METHODS: Case report. RESULTS: A 33-year old woman with history of sarcoidosis with involvement of the central nervous system, confirmed by skin biopsy, bronchoscopy, and neuroimaging, presented with visual loss and was found to have choroidal and optic nerve granulomas in the left eye, and subsequently developed retinal granulomas in the left eye. CONCLUSION: Retinal granuloma is a rare manifestation of sarcoidosis.


Subject(s)
Granuloma/etiology , Retinal Diseases/etiology , Sarcoidosis/complications , Adult , Choroid Diseases/diagnosis , Choroid Diseases/etiology , Female , Fundus Oculi , Granuloma/diagnosis , Humans , Optic Nerve Diseases/diagnosis , Optic Nerve Diseases/etiology , Retinal Diseases/diagnosis , Sarcoidosis/diagnosis , Visual Acuity
14.
J Neuroophthalmol ; 21(1): 18-21, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11315975

ABSTRACT

OBJECTIVE: To report the diagnosis, radiologic findings, and therapy of a 51-year-old female with systemic lupus erythematosus (SLE) who, while on hydroxychloroquine maintenance therapy, presented with a junctional scotoma indicative of chiasmal disease. This visual loss developed after she had been tapered off corticosteroids. MATERIALS AND METHODS: An interventional case report of a female that was given acute therapy with 1-gram daily of intravenous methylprednisolone sodium succinate for 5 days, followed by maintenance methotrexate and a slow taper of oral prednisone. Magnetic resonance imaging (MRI) scans, visual acuity, color vision, and threshold visual fields were performed. RESULTS: The MRI scan showed chiasmal involvement, which may occur in SLE in absence of any other evidence of systemic activity. Therapy led to visual function returning to 20/20 OD and 20/20 OS, with normal Ishihara plates OU and only minimal paracentral depressions OU. She has been able to be weaned off prednisone while on methotrexate maintenance. CONCLUSIONS: Chiasmal involvement may occur in SLE in absence of any other evidence of systemic activity. Maintenance with hydroxychloroquine may not be adequate to prevent this rare cause of visual loss in SLE. Aggressive therapy of chiasmal involvement in SLE, even when the visual loss is profound, may lead to visual restoration, which was virtually complete in this case. Methotrexate may be an alternate agent for patients who break through with optic neuropathy while on hydroxychloroquine.


Subject(s)
Blindness/physiopathology , Lupus Erythematosus, Systemic/complications , Optic Chiasm/pathology , Optic Neuritis/etiology , Blindness/etiology , Color Perception , Female , Glucocorticoids/therapeutic use , Humans , Hydroxychloroquine/therapeutic use , Lupus Erythematosus, Systemic/diagnosis , Lupus Erythematosus, Systemic/drug therapy , Magnetic Resonance Imaging , Middle Aged , Optic Chiasm/drug effects , Optic Chiasm/physiopathology , Optic Neuritis/diagnosis , Optic Neuritis/drug therapy , Optic Neuritis/physiopathology , Visual Acuity , Visual Fields
15.
Endocrinology ; 142(3): 1117-23, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11181526

ABSTRACT

Elevation of circulating GH acts to feed back at the level of the hypothalamus to decrease GH-releasing hormone (GHRH) and increase somatostatin (SRIF) production. In the rat, GH-induced changes in GHRH and SRIF expression are associated with changes in pituitary GHRH receptor (GHRH-R), GH secretagogue receptor (GHS-R), and SRIF receptor subtype messenger RNA (mRNA) levels. These observations suggest that GH regulates its own synthesis and release not only by altering expression of key hypothalamic neuropeptides but also by modulating the sensitivity of the pituitary to hypothalamic input, by regulating pituitary receptor synthesis. To further explore this possibility, we examined the relationship between the expression of hypothalamic neuropeptides [GHRH, SRIF, and neuropeptide Y (NPY)] and pituitary receptors [GHRH-R, GHS-R, and SRIF receptor subtypes (sst2 and sst5)] in two mouse strains with alterations in the GH-axis; the GH receptor/binding protein gene-disrupted mouse (GHR/BP-/-) and the metallothionein promoter driven human GHRH (MT-hGHRH) transgenic mouse. In GHR/BP-/- mice, serum insulin-like growth factor I levels are low, and circulating GH is elevated because of the lack of GH negative feedback. Hypothalamic GHRH mRNA levels in GHR/BP-/- mice were 232 +/- 20% of GHR/BP+/+ littermates (P < 0.01), whereas SRIF and NPY mRNA levels were reduced to 86 +/- 2% and 52 +/- 3% of controls, respectively (P < 0.05; ribonuclease protection assay). Pituitary GHRH-R and GHS-R mRNA levels of GHR/BP-/- mice were elevated to 275 +/- 55% and 319 +/- 68% of GHR/BP+/+ values (P < 0.05, respectively), whereas the sst2 and sst5 mRNA levels did not differ from GHR/BP intact controls as determined by multiplex RT-PCR. Therefore, in the absence of GH negative feedback, both hypothalamic and pituitary expression is altered to favor stimulation of GH synthesis and release. In MT-hGHRH mice, ectopic hGHRH transgene expression elevates circulating GH and insulin-like growth factor I. In this model of GH excess, endogenous (mouse) hypothalamic GHRH mRNA levels were reduced to 69 +/- 6% of nontransgenic controls, whereas SRIF mRNA levels were increased to 128 +/- 6% (P < 0.01). NPY mRNA levels were not significantly affected by hGHRH transgene expression. Also, MT-hGHRH pituitary GHRH-R and GHS-R mRNA levels did not differ from controls. However, sst2 and sst5 mRNA levels in MT-hGHRH mice were increased to 147 +/- 18% and 143 +/- 16% of normal values, respectively (P < 0.05). Therefore, in the presence of GH negative feedback, both hypothalamic and pituitary expression is altered to favor suppression of GH synthesis and release.


Subject(s)
Carrier Proteins/physiology , Growth Hormone-Releasing Hormone/physiology , Growth Hormone/physiology , Metallothionein/physiology , Receptors, G-Protein-Coupled , Receptors, Somatotropin/physiology , Animals , Carrier Proteins/genetics , Feedback , Growth Hormone-Releasing Hormone/genetics , Humans , Hypothalamus/metabolism , Metallothionein/genetics , Mice , Mice, Transgenic/genetics , Neuropeptide Y/genetics , Neuropeptides/metabolism , Pituitary Gland/metabolism , RNA, Messenger/metabolism , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Receptors, Ghrelin , Receptors, Somatostatin/genetics , Receptors, Somatotropin/genetics
16.
Ophthalmology ; 108(1): 80-81, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11150268
17.
Endocrinology ; 141(10): 3556-63, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11014208

ABSTRACT

The role of individual components of the hypothalamic-pituitary-GH axis in the modulation of pituitary somatostatin (SRIF) receptor subtype (sst1-5) synthesis was assessed using multiplex RT-PCR to measure receptor messenger RNA (mRNA) levels in normal rats and spontaneous dwarf rats (SDRs). In SDRs, a strain with no immunodetectable GH, pituitary sst1 and sst2 mRNA levels were elevated, sst5 mRNA levels were reduced, and sst3 and sst4 mRNA levels did not significantly differ from those in normal controls. Treatment of SDRs with GH (72 h), but not insulin-like growth factor I, significantly decreased sst2 mRNA levels and increased sst4 and sst5 mRNA levels above vehicle-treated control levels. To test whether more rapid changes in circulating GH levels could alter SRIF receptor subtype expression, normal rats were infused (iv) with GH-releasing hormone (GHRH) for 4 h in the presence or absence of SRIF antiserum. GHRH infusion increased pituitary sst1 and sst2 and decreased sst5, but had no effect on sst3 and sst4 mRNA levels. Immunoneutralization of SRIF, which produced a rise in circulating GH levels, did not alter basal or GHRH-mediated SRIF receptor subtype expression. These observations indicate that acute suppression of SRIF tone does not regulate pituitary SRIF receptor subtype mRNA levels in vivo. The possibility that elevated circulating GH concentrations induced by GHRH infusion were responsible for the observed changes in SRIF receptor subtype mRNA levels was examined by infusing SDRs with GHRH for 4 h. GHRH did not increase sst1 mRNA levels in SDRs above their already elevated value. However, GHRH infusion produced an increase in sst2 and a decrease in sst5 mRNA levels similar to those observed in normal rats, indicating that the acute effects of GHRH on SRIF receptor subtype expression are independent of circulating GH levels. Primary rat pituitary cell cultures were incubated with GHRH (10 nM) or forskolin (10 microM) for 4 h to determine whether GHRH could directly mediate SRIF receptor subtype mRNA. GHRH treatment increased sst1 and sst2 mRNA levels and decreased sst5 mRNA levels, but had no effect on sst3 and sst4, similar to the results in vivo. The effect of forskolin mimicked that of GHRH on sst1, sst2, and sst5 mRNA, suggesting that GHRH acts through cAMP to directly mediate gene transcription or mRNA stability of these SRIF receptor subtypes. In addition, forskolin reduced sst3 and sst4 expression. These results strongly suggest that rat pituitary sst1, sst2, and sst5 mRNA levels are regulated both in vivo and in vitro by GHRH. The stimulatory action of GHRH on sst1 and sst2 and the inhibitory action on sst5 indicate that these receptor subtypes have independent and unique roles in the modulation of pituitary GH release.


Subject(s)
Growth Hormone/physiology , Pituitary Gland/metabolism , Animals , Colforsin/pharmacology , Dwarfism/genetics , Dwarfism/metabolism , Growth Hormone/pharmacology , Growth Hormone-Releasing Hormone/pharmacology , Protein Isoforms/genetics , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Somatostatin/genetics , Reference Values , Reverse Transcriptase Polymerase Chain Reaction
18.
Recent Prog Horm Res ; 55: 269-90; discussion 290-1, 2000.
Article in English | MEDLINE | ID: mdl-11036941

ABSTRACT

Somatotrope function requires consideration of both growth hormone (GH) secretion and cellular proliferation. The regulation of these processes is, to a large extent, controlled by three hypothalamic hormones: GH-releasing hormone (GHRH), somatostatin (SRIF), and an as-yet-unidentified GH secretagogue (GHS). Each binds to G protein-linked membrane receptors through which signaling occurs. Our laboratory has used a series of genetic and transgenic models with perturbations of individual components of the GH regulatory system to study both somatotrope signaling and proliferation. Impaired GHRH signaling is present in the lit mouse, which has a GHRH receptor (R) mutation, and the dw rat, which has a post-receptor signaling defect. Both models also have impaired responses to a GHS, implying an interaction between the two signaling systems. The spontaneous dwarf rat (SDR), in which a mutation of the GH gene results in total absence of the hormone, shows characteristic changes in the hypothalamic regulatory hormones due to an absence of GH feedback and alterations in the expression of each of their pituitary receptors. Treatment of SDRs with GHRH and a GHS has allowed demonstration of a stimulatory effect of GHRH on GHRH-R, GHS-R, and SRIF type 2 receptor (SSTR-2) expression and an inhibitory effect on SSTR-5 expression. GH also modifies the expression of these receptors, though its effects are seen at later time periods and appear to be indirect. Overall, the results indicate a complex regulation of GH secretion in which somatotrope receptor, as well as ligand expression, exerts an important physiological role. Both the SDR and the GH-R knockout (ko) mouse have small pituitaries and decreased somatotropes, despite elevated GHRH secretion and intact GHRH-R signaling. Introduction of the hGHRH transgene into GH-R ko mice confirmed that the proliferative effects of GHRH require GH/insulin-like growth factor-I (IGF-I) action. The results offer new insights into factors participating in somatotrope proliferation.


Subject(s)
Growth Hormone/physiology , Neurosecretory Systems/physiology , Animals , Cell Division , Growth Hormone-Releasing Hormone/physiology , Humans , Mice , Models, Neurological , Neurosecretory Systems/cytology , Rats , Signal Transduction , Somatostatin/physiology
19.
J Neuroendocrinol ; 12(6): 481-5, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10844575

ABSTRACT

Glucocorticoids regulate growth hormone (GH) secretion by modulating both hypothalamic and pituitary function. At the level of the pituitary, glucocorticoids increase GH and GH-releasing hormone receptor (GHRH-R) gene expression. To test if glucocorticoids might also regulate the pituitary expression of the recently identified GH secretagogue (GHS) receptor, GHS-R; adult male rats were adrenalectomized or sham operated, and treated with the synthetic glucocorticoid (dexamethasone, 200 microg/day) or vehicle for 8 days. Pituitary GHS-R mRNA levels were assessed by reverse transcriptase polymerase chain reaction (RT-PCR). Adrenalectomy decreased pituitary GHS-R mRNA to 45% of vehicle-treated, sham-operated rats (P < 0.05). Administration of dexamethasone increased GHS-R mRNA levels in sham-operated as well as in adrenalectomized rats (199 +/- 24% (P < 0.05) and 369 +/- 48% (P < 0.01) of vehicle-treated controls). Addition of dexamethasone to primary rat pituitary cell cultures increased GHS-R mRNA levels in a dose- and time-dependent manner while the transcriptional inhibitor, actinomycin D, completely blocked the stimulatory action of dexamethasone. Taken together, these results suggest glucocorticoids directly increase pituitary GHS-R mRNA levels by stimulating GHS-R gene transcription.


Subject(s)
Dexamethasone/pharmacology , Gene Expression Regulation/drug effects , Glucocorticoids/pharmacology , Receptors, Neuropeptide/genetics , Receptors, Pituitary Hormone-Regulating Hormone/genetics , Adrenalectomy , Animals , Dactinomycin/pharmacology , Dose-Response Relationship, Drug , Male , Nucleic Acid Synthesis Inhibitors/pharmacology , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Time Factors
20.
Oncogene ; 19(15): 1875-84, 2000 Apr 06.
Article in English | MEDLINE | ID: mdl-10773877

ABSTRACT

p27Kip1 (p27) controls cell cycle progression by binding to and inhibiting the activity of cyclin dependent kinases. Disruption of the p27 gene in mice (p27-/-) results in increased body growth with a disproportionate enlargement of the spleen, thymus, testis, ovary and pituitary. The increase in pituitary size is due to selective hyperplasia of the intermediate lobe (IL) while the anterior lobe (AL) is not overtly affected. p27 heterozygous mice (p27+/-), as well as p27-/- mice, are hypersensitive to radiation- and chemical-induced tumors compared to wildtype (p27+/+) littermates. Therefore, unlike classical tumor suppressors, only a reduction in p27 levels is necessary to predispose tissues to secondary tumor promoters. Consistent with these studies is the fact that the p27 gene sequence and mRNA levels appear normal in human pituitary adenomas while p27 protein levels are decreased. Therefore, a reduction in p27 levels could be sufficient to sensitize pituitary cells to tumorigenic factors. To test this hypothesis, metallothionein promoter-driven, human growth hormone-releasing hormone (MT-hGHRH) transgenic mice, that exhibit somatotrope hyperplasia before 9 months of age and subsequent adenoma formation with 30 - 40% penetrance, were crossbred with p27+/- mice for two successive generations to produce p27+/+, p27+/- and p27-/- mice that expressed the hGHRH transgene. At 10 - 12 weeks of age, p27-/- and p27+/+, hGHRH mice were larger than their p27+/+ littermates and displayed characteristic hyperplasia of the IL and AL, respectively. Expression of the hGHRH transgene in both p27+/- and p27-/- mice selectively expanded the population of somatotropes within the AL, where pituitaries of p27+/-, hGHRH and p27-/-, hGHRH mice were two- and fivefold larger than p27+/+, hGHRH pituitaries, respectively. There was also a synergistic effect of hGHRH transgene expression and p27-deficiency on liver, spleen and ovarian growth. At 6 - 8 months of age, 83% of p27+/-, hGHRH mice displayed macroscopic AL adenomas (>100 mg), while all pituitaries from p27+/+, hGHRH mice remained hyperplastic (<20 mg). In contrast to the dramatic effects of p27-deficiency on hGHRH-induced organ growth, elimination of p53, by crossbreeding MT-hGHRH mice to p53-deficient mice, did not augment the hyperplastic/tumorigenic effects of hGHRH transgene expression. Taken together these results demonstrate that a reduction in p27 expression is sufficient to sensitize somatotropes to the proliferative actions of excess GHRH, resulting in the earlier appearance and increased penetrance of hGHRH-induced pituitary tumors.


Subject(s)
Adenoma/genetics , Cell Cycle Proteins , Cyclin-Dependent Kinases/antagonists & inhibitors , Growth Hormone-Releasing Hormone/pharmacology , Microtubule-Associated Proteins/genetics , Microtubule-Associated Proteins/metabolism , Pituitary Neoplasms/genetics , Tumor Suppressor Proteins , Age Factors , Animals , Cyclin-Dependent Kinase Inhibitor p27 , Genes, Tumor Suppressor , Humans , Hyperplasia , Liver/pathology , Mice , Mice, Transgenic , Pituitary Gland/pathology , Spleen/pathology
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