The adrenal gland is a highly dynamic organ with the ability to respond to changes in its environment with rapid changes in hormone production, and dramatic remodelling of its structure. Our understanding of the role of the melanocortin peptides in this process has been mostly restricted to the anterior pituitary hormone ACTH, via the melanocortin 2 receptor MC2R. The presence of additional melanocortin receptors and their antagonists has been demonstrated in rat and bovine adrenals, but the role of these in humans has not been well explored. An intensive clinical and biochemical work-up of a single patient with ACTH-independent Cushing's syndrome and a gastrointestinal stromal tumour (GIST) was performed. The data presented are consistent with the possibility that her disease was caused by release of some bioactive molecule released from the GIST. We propose that alpha-MSH is a possible candidate for this molecule, on the basis that the GIST immuno-stained for alpha- MSH but not ACTH, that alpha-MSH but not ACTH was present in supernatant from a primary culture, and that alpha-MSH has the potential to stimulate cortisol production from adrenal cells. The precise mechanism for alpha-MSH secretion from the tumour is not fully elucidated, and further work is required to corroborate this hypothesis. The patient had both pigmented skin and pigmented adrenal nodules, and we further demonstrated the presence of the alpha-MSH receptor MC1R was demonstrated with her excised adrenal gland. The pigment was identified as melanin, and we went on to show that same pattern in primary pigmented nodular adrenal disease, and to demonstrate that the zona reticularis in normal adrenal gland contains melanin, and has additional features in common with melanocytic tissues elsewhere in the body. The role of alpha-MSH in normal adrenal function, and the possibility that melanin is also playing an important role, perhaps for its antioxidant properties, is an exciting area for future study.

Abstract Introduction: Tuberculosis carries a high mortality in the days immediately after treatment. It is also the commonest cause of adrenal insufficiency in the developing world. Rifampicin is a potent hepatic enzyme inducer, and may contribute to adrenal insufficiency by accelerating cortisol breakdown. The aim of the study was to determine whether rifampicin induced accelerated catabolism of corticosteroids. Methods: A prospective, randomised study comparing adrenal function in 20 patients with pulmonary tuberculosis in the first five days treated with two different antituberculosis regimens, one containing rifampicin, and the other ciprofloxacin. Results: Demographic, clinical and laboratory results were similar in both groups. Both groups showed a statistically significant and similar decrease in morning cortisol, with similar responses to ACTH stimulation at both 30 and 60 minutes before and after four days of treatment. In the entire cohort, 40% demonstrated an incremental cortisol rise of <250nmol/l after ACTH stimulation on day 1. Mean basal cortisol concentrations were substantially elevated and DHEA-S levels were consistently subnormal, resulting in a high cortisol:DHEA-S ratio. No patient demonstrated overt adrenal insufficiency. There were no significant differences between the two groups before or during therapy for any electrolytes, hormones or calculated serum osmolality. Conclusions: Rifampicin did not additionally impair adrenocortical function during the initial period of therapy.

Controversy exists concerning the possible involvement of serotonin in the pituitary-adrenocortical response to stress. In the present research, a variety of physiological and pharmacological manipulations were used in male rats to study the role of this neurotransmitter in the adrenocortical response to insulin- induced hypoglycemia. First, the effect of insulin stress on hypothalamic 5-HT metabolism was examined, and an increased turnover was found as determined by an enhanced accumulation of 5-HT following monoamine oxidase inhibition. The corticos terone response to insulin was potentiated by prior administration of L-tryptophan, and blocked by pretreatment with valine, an amino acid that competes with tryptophan for transport across the blood-brain barrier. Treatment with the 5-HT receptor blocker methysergide, or serotonin depletion by intraventricular injection of 5 , 7-dihydroxy tryptamine significantly attenuated the insulin- induced rise in circulating corticosterone.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19176号 / 医博第4018号 / 新制||医||1010(附属図書館) / 32168 / 京都大学大学院医学研究科医学専攻 / (主査)教授 小川 修, 教授 柳田 素子, 教授 三森 経世 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro / Alterações nutricionais, hormonais e ambientais nos períodos críticos do desenvolvimento como a gestação e/ou lactação podem influenciar a estrutura e a fisiologia de órgãos e tecidos, predispondo ao aparecimento de doenças na vida adulta. Esse fenômeno é conhecido como programação metabólica. O fumo materno na gestação/lactação tem sido associado ao sobrepeso/obesidade na infância e na vida adulta em ambos os sexos. Porém, estudos evidenciam diferenças entre os gêneros em resposta a exposição à nicotina. Já foi demonstrado que muitas mulheres param de fumar na gestação, mas a maioria destas volta a fumar na lactação. Anteriormente, mostramos que machos adultos cujas mães foram expostas à nicotina na lactação, desenvolveram obesidade central, hiperleptinemia e hipotireoidismo. Como a nicotina afeta a função adrenal e como catecolaminas e glicocorticóides têm efeitos bem conhecidos sobre o tecido adiposo, avaliamos a função da medula adrenal e o conteúdo de leptina no tecido adiposo e músculo de machos e fêmeas cujas mães foram expostas à nicotina na lactação. Dois dias pós-parto, implantamos minibombas osmóticas nas ratas lactantes dividas em: NIC infusão de nicotina (6mg/Kg/dia s.c.) por 14 dias, e C infusão de salina pelo mesmo período. Estas lactantes foram divididas de acordo com o sexo das proles. O sacrifício das proles de ambos os sexos ocorreu aos 15 (fim da exposição à nicotina) e 180 dias de vida. Aos 15 dias, os machos da prole NIC apresentaram aumento de MGV absoluta e relativa ao peso corporal (+72% e +73% respectivamente), hiperleptinemia (+35%), hipercorticosteronemia (+67%), maior peso adrenal (+39%), conteúdo de catecolaminas totais (absoluto: +69% e relativo: +41%), embora diminuição da enzima TH (-33%). Quando adultos, os machos programados exibiram maior massa corporal (+10%), MGV absoluta (+47%) e relativa (+33%), além de hiperleptinemia (+41%) e maior conteúdo de leptina no TAV (+23%). Esses animais também apresentaram hipercorticosteronemia (+77%), maior conteúdo de catecolaminas totais absoluto e relativo (+79% e +89% respectivamente) e de TH (+38%) embora tenham menor secreção de catecolaminas in vitro estimulada por cafeína (-19%) e maior expressão do ADRB3 no TAV (+59%). Em relação as fêmeas da prole NIC aos 15 dias de vida, estas apresentaram menor massa corporal (-6%) e hiperleptinemia (+41%) embora sem alteração da MGV. Aos 180 dias, as fêmeas da prole NIC apresentaram menor conteúdo de leptina no TAS (-46%) e maior conteúdo de leptina no músculo solear (+22%) e diminuição da expressão do ADRB3 no TAV (-39%). Concluímos que a nicotina materna afeta ambos, medula adrenal e tecido adiposo de forma gênero dependente, tanto em curto prazo (quando a nicotina está presente no leite materno), quanto em longo prazo (repercussões na vida adulta). De forma geral, as fêmeas da prole NIC apresentam alterações mais discretas do que os machos em ambos os períodos estudados. / Nutritional, hormonal and environmental changes during critical periods of life (pregnancy and/or lactation) are associated with future changes in the structure and physiology of body tissues and systems, influencing some diseases in adulthood. This phenomenon is known as metabolic programming. Maternal smoking during pregnancy/lactation has been associated with overweight/obesity in childhood and adulthood in both genders. However, studies have shown gender differences in response to nicotine exposure. Although many women quit smoking during pregnancy, data reveal that most women who stop smoking during gestation relapse during lactation. Previously, we showed that adult male rats whose mothers received nicotine during lactation developed overweight, hyperleptinemia and hypothyroidism. Because nicotine affects the adrenal function and, as glucocorticoids and catecholamines have well known effects on adipose tissue, we evaluated adrenal medulla function and leptin content in adipose tissue and muscle of males and females whose dams were nicotine-treated during lactation. On postnatal (PN) day 2, dams were subcutaneously implanted with osmotic minipumps releasing nicotine (6mg/Kg/day) for 14 days of lactation (NIC) or saline. Male and female offspring were killed at 15 and 180 days-old. In PN15, males of NIC group presented higher absolute (+72%) and relative (+73%) VFM, hyperleptinemia (+35%), hypercorticosteronemia (+67%), higher adrenal weight (+39%) and adrenal catecholamine content (absolute: +69% and relative: +41%) although lower TH content (-33%). In PN180, these males displayed higher body mass (+10%), absolute (+47%) and relative (+33%) VFM, hyperleptinemia (+41%), higher leptin content in VAT (+23%), hypercorticosteronemia (+77%), higher adrenal catecholamine content (absolute:+79% and relative:+89%), higher TH expression (+38%), lower in vitro catecholamine release (-19%) and higher ADRB3 content in VAT (+59%). Females of NIC group at PN15 presented lower body mass (-6%) and hyperleptinemia (+41%) but no change in VFM. In PN180, these females showed lower leptin content in SAT (-46%), higher leptin content in muscle (+22%) and lower ADRB3 content in VAT (-39%). Thus, we evidenced a sex dimorphism in the model of programming by maternal nicotine exposure during lactation. The medullary adrenal function and corticosteronemia in adult rat were programmed only in male offspring while the female offspring displayed relevant alterations in leptin content.

Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro / Alterações nutricionais, hormonais e ambientais nos períodos críticos do desenvolvimento como a gestação e/ou lactação podem influenciar a estrutura e a fisiologia de órgãos e tecidos, predispondo ao aparecimento de doenças na vida adulta. Esse fenômeno é conhecido como programação metabólica. O fumo materno na gestação/lactação tem sido associado ao sobrepeso/obesidade na infância e na vida adulta em ambos os sexos. Porém, estudos evidenciam diferenças entre os gêneros em resposta a exposição à nicotina. Já foi demonstrado que muitas mulheres param de fumar na gestação, mas a maioria destas volta a fumar na lactação. Anteriormente, mostramos que machos adultos cujas mães foram expostas à nicotina na lactação, desenvolveram obesidade central, hiperleptinemia e hipotireoidismo. Como a nicotina afeta a função adrenal e como catecolaminas e glicocorticóides têm efeitos bem conhecidos sobre o tecido adiposo, avaliamos a função da medula adrenal e o conteúdo de leptina no tecido adiposo e músculo de machos e fêmeas cujas mães foram expostas à nicotina na lactação. Dois dias pós-parto, implantamos minibombas osmóticas nas ratas lactantes dividas em: NIC infusão de nicotina (6mg/Kg/dia s.c.) por 14 dias, e C infusão de salina pelo mesmo período. Estas lactantes foram divididas de acordo com o sexo das proles. O sacrifício das proles de ambos os sexos ocorreu aos 15 (fim da exposição à nicotina) e 180 dias de vida. Aos 15 dias, os machos da prole NIC apresentaram aumento de MGV absoluta e relativa ao peso corporal (+72% e +73% respectivamente), hiperleptinemia (+35%), hipercorticosteronemia (+67%), maior peso adrenal (+39%), conteúdo de catecolaminas totais (absoluto: +69% e relativo: +41%), embora diminuição da enzima TH (-33%). Quando adultos, os machos programados exibiram maior massa corporal (+10%), MGV absoluta (+47%) e relativa (+33%), além de hiperleptinemia (+41%) e maior conteúdo de leptina no TAV (+23%). Esses animais também apresentaram hipercorticosteronemia (+77%), maior conteúdo de catecolaminas totais absoluto e relativo (+79% e +89% respectivamente) e de TH (+38%) embora tenham menor secreção de catecolaminas in vitro estimulada por cafeína (-19%) e maior expressão do ADRB3 no TAV (+59%). Em relação as fêmeas da prole NIC aos 15 dias de vida, estas apresentaram menor massa corporal (-6%) e hiperleptinemia (+41%) embora sem alteração da MGV. Aos 180 dias, as fêmeas da prole NIC apresentaram menor conteúdo de leptina no TAS (-46%) e maior conteúdo de leptina no músculo solear (+22%) e diminuição da expressão do ADRB3 no TAV (-39%). Concluímos que a nicotina materna afeta ambos, medula adrenal e tecido adiposo de forma gênero dependente, tanto em curto prazo (quando a nicotina está presente no leite materno), quanto em longo prazo (repercussões na vida adulta). De forma geral, as fêmeas da prole NIC apresentam alterações mais discretas do que os machos em ambos os períodos estudados. / Nutritional, hormonal and environmental changes during critical periods of life (pregnancy and/or lactation) are associated with future changes in the structure and physiology of body tissues and systems, influencing some diseases in adulthood. This phenomenon is known as metabolic programming. Maternal smoking during pregnancy/lactation has been associated with overweight/obesity in childhood and adulthood in both genders. However, studies have shown gender differences in response to nicotine exposure. Although many women quit smoking during pregnancy, data reveal that most women who stop smoking during gestation relapse during lactation. Previously, we showed that adult male rats whose mothers received nicotine during lactation developed overweight, hyperleptinemia and hypothyroidism. Because nicotine affects the adrenal function and, as glucocorticoids and catecholamines have well known effects on adipose tissue, we evaluated adrenal medulla function and leptin content in adipose tissue and muscle of males and females whose dams were nicotine-treated during lactation. On postnatal (PN) day 2, dams were subcutaneously implanted with osmotic minipumps releasing nicotine (6mg/Kg/day) for 14 days of lactation (NIC) or saline. Male and female offspring were killed at 15 and 180 days-old. In PN15, males of NIC group presented higher absolute (+72%) and relative (+73%) VFM, hyperleptinemia (+35%), hypercorticosteronemia (+67%), higher adrenal weight (+39%) and adrenal catecholamine content (absolute: +69% and relative: +41%) although lower TH content (-33%). In PN180, these males displayed higher body mass (+10%), absolute (+47%) and relative (+33%) VFM, hyperleptinemia (+41%), higher leptin content in VAT (+23%), hypercorticosteronemia (+77%), higher adrenal catecholamine content (absolute:+79% and relative:+89%), higher TH expression (+38%), lower in vitro catecholamine release (-19%) and higher ADRB3 content in VAT (+59%). Females of NIC group at PN15 presented lower body mass (-6%) and hyperleptinemia (+41%) but no change in VFM. In PN180, these females showed lower leptin content in SAT (-46%), higher leptin content in muscle (+22%) and lower ADRB3 content in VAT (-39%). Thus, we evidenced a sex dimorphism in the model of programming by maternal nicotine exposure during lactation. The medullary adrenal function and corticosteronemia in adult rat were programmed only in male offspring while the female offspring displayed relevant alterations in leptin content.

Thesis (PhD)-- Stellenbosch University, 2013. / ENGLISH ABSTRACT: Although the effect of inhaled corticosteroids (ICS) on the hypothalamic- pituitary-adrenal axis (HPA) has been regarded as a “benign physiological response”, a survey published in 2002 suggested that adrenal crisis is more common in asthmatic children on ICS than previously thought. Relying on clinical features to detect chronic adrenal insufficiency secondary to corticosteroids may not be wise, as these are non-specific and can therefore easily be missed. Accurate biochemical assessment of the whole axis to detect subclinical HPA suppression (HPAS) is thus desirable. A review of the literature indicates that basal adrenal function tests, including plasma cortisol profiles, do not identify which children can appropriately respond to stress. There is no evidence to suggest that the degree of the physiological adjustment of the HPA to ICS and/or nasal steroids (by reducing basal cortisol production), predicts HPAS. Cortisol profiles should therefore only be used to demonstrate differences in systemic activity of various ICS and delivery devices. Only two tests, considered as gold standard adrenal function tests [the insulin tolerance test (ITT) and the metyrapone test] can assess the integrity of the whole axis. / AFRIKAANSE OPSOMMING: Die outeurs van ´n opname wat in 2002 gepubliseer is stel voor dat ´n bynierkrisis meer algemeen by asmatiese kinders, wat inhalasie kortikosteroïede ontvang, voorkom as wat voorheen gedink is. Dit is strydig met die gevestigde opvatting dat die effek van IKS op die hipotalamiese-hipofise-bynier-as (HHB) ’n “goedaardige fisiologiese reaksie” is. Die kliniese kenmerke van kroniese bynierontoereikendheid sekondêr tot die gebruik van kortikosteroïede (KS) is nie-spesifiek en gevolglik onbetroubaar. ´n Akkurate biochemiese toets van subkliniese HBB onderdrukking (HHBO) sou gevolglik waardevol wees. ´n Literatuur oorsig toon dat toetse van basale bynierfunksie, insluitend plasma kortisol (K) profiele, nie kinders uitken wat toepaslik op stres sal reageer nie. Daar is geen bewyse dat die graad van fisiologiese aanpassing van die HHB, soos aangedui deur laer K-vlakke, na die gebruik van IKS en/of nasale steroïede (NS), HHBO voorspel nie. Serum K profiele is dus slegs van waarde om die sistemiese aktiwiteit van verskillende IKS en toedieningsstelsels te ondersoek. Slegs twee toetse, naamlik die insulien toleransie toets (ITT) en die metyrapone -(MTP)-toets (wat beide as die goue standaard van bynier funksie beskou word), kan die integriteit van die hele as meet. / Stellenbosch University / Medical Research Council / SA Thoracic Society / Harry Crossley Foundation / Red Cross Children’s Hospital.