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Concept: Adrenal cortex

181

Cushing disease (CD) is a life-threatening disorder attributed to excess pituitary tumor-derived adrenocorticotrophic hormone (ACTH) and adrenal steroid secretion caused by pituitary tumors. Whereas CD was first described in 1932, the underlying genetic basis driving tumor growth and ACTH secretion remains unsolved. Here, we show that testicular orphan nuclear receptor 4 (TR4, nuclear receptor subfamily 2, group C, member 2) is overexpressed in human corticotroph tumors as well as in human and mouse corticotroph tumor cell lines. Forced overexpression of TR4 in both human and murine tumor cells increased proopiomelanocortin transcription, ACTH secretion, cellular proliferation, and tumor invasion rates in vitro. Conversely, knockdown of TR4 expression reversed all phenotypes. Mechanistically, we show that TR4 transcriptionally activates proopiomelanocortin through binding of a direct repeat 1 response element in the promoter, and that this is enhanced by MAPK-mediated TR4 phosphorylation. In vivo, TR4 overexpression promotes murine corticotroph tumor growth as well as enhances ACTH and corticosterone production, whereas TR4 knockdown decreases circulating ACTH and corticosterone levels in mice harboring ACTH-secreting tumors. Our findings directly link TR4 to the etiology of corticotroph tumors, hormone secretion, and cell growth as well as identify it as a potential target in the treatment of CD.

Concepts: Gene, Hypothalamus, Gene expression, Cancer, Tumor, Cortisol, Adrenocorticotropic hormone, Adrenal cortex

171

Most species living in temperate zones adapt their physiology and behavior to seasonal changes in the environment by using the photoperiod as a primary cue. The mechanisms underlying photoperiodic regulation of stress-related functions are not well understood. In this study, we analyzed the effects of photoperiod on the hypothalamic-pituitary-adrenal axis in photoperiod-sensitive Fischer 344 rats. We first examined how photoperiod affects diurnal variations in plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone. ACTH levels did not exhibit diurnal variations under long- and short-day conditions. On the other hand, corticosterone levels exhibited a clear rhythm under short-day condition with a peak during dark phase. This peak was not observed under long-day condition in which a significant rhythm was not detected. To analyze the mechanisms responsible for the photoperiodic regulation of corticosterone rhythms, ACTH was intraperitoneally injected at the onset of the light or dark phase in dexamethasone-treated rats maintained under long- and short-day conditions. ACTH induced higher corticosterone levels in rats examined at dark onset under short-day condition than those maintained under long-day condition. Next, we asked whether melatonin signals are involved in photoperiodic regulation of corticosterone rhythms, and rats were intraperitoneally injected with melatonin at late afternoon under long-day condition for 3 weeks. However, melatonin injections did not affect the corticosterone rhythms. In addition, photoperiodic changes in the amplitude of corticosterone rhythms were also observed in melatonin-deficient C57BL/6J mice, in which expression profiles of several clock genes and steroidgenesis genes in adrenal gland were modified by the photoperiod. Our data suggest that photoperiod regulates corticosterone rhythms by altered adrenal sensitivity through melatonin-independent mechanisms that may involve the adrenal clock.

Concepts: Hypothalamus, Cortisol, Circadian rhythm, Adrenocorticotropic hormone, Adrenal cortex, ACTH stimulation test, Adrenal gland, Anterior pituitary

152

Phenotypic differences among species may evolve through genetic accommodation, but mechanisms accounting for this process are poorly understood. Here we compare hormonal variation underlying differences in the timing of metamorphosis among three spadefoot toads with different larval periods and responsiveness to pond drying. We find that, in response to pond drying, Pelobates cultripes and Spea multiplicata accelerate metamorphosis, increase standard metabolic rate (SMR), and elevate whole-body content of thyroid hormone (the primary morphogen controlling metamorphosis) and corticosterone (a stress hormone acting synergistically with thyroid hormone to accelerate metamorphosis). In contrast, Scaphiopus couchii has the shortest larval period, highest whole-body thyroid hormone and corticosterone content, and highest SMR, and these trait values are least affected by pond drying among the three species. Our findings support that the atypically rapid and canalized development of S. couchii evolved by genetic accommodation of endocrine pathways controlling metamorphosis, showing how phenotypic plasticity within species may evolve into trait variation among species.

Concepts: Evolution, Metabolism, Endocrinology, Thyroid, Thyroid hormone, Adrenal cortex, Amphibian, Toads

35

Alcohol (ethanol) and resistance exercise can independently affect circulating bioavailable testosterone concentration. PURPOSE: The purpose of this study was to examine the testosterone bioavailability and the anabolic endocrine milieu in response to acute ethanol ingestion following a bout of heavy resistance exercise. METHODS: Eight resistance trained men (mean ± SD: 25.3 ± 3.2 yrs, 87.7 ± 15.1 kg, 177 ± 7 cm) completed two identical acute heavy resistance exercise tests (AHRET: six sets of 10 repetitions of Smith machine squats) separated by 1 week. Post-AHRET participants consumed either 1.086 g of grain ethanol per kg lean mass (EtOH condition) or no ethanol (Placebo condition). Blood samples were collected immediately before exercise (PRE), immediately after exercise (IP), and every 20 min postexercise for 300 min. Samples following IP were pooled into phases (20-40 min, 60-120 min, and 140-300 min after exercise) and analyzed for total (TT) and free testosterone (FT), sex hormone binding globulin (SHBG), cortisol, and estradiol. RESULTS: Peak blood ethanol concentration (0.088 ± 0.015 g·dl) was achieved 60-90 min post-exercise. TT and FT was elevated significantly (p≤0.05) at IP for both conditions. At 140-300 min post-exercise TT, FT, and free androgen index were significantly higher for EtOH (TT: 22.5 ± 12.5 nmol·l ; FT: 40.5 ± 7.6 pmol·l) than for Placebo (TT: 13.9 ± 6.8 nmol·l; FT: 22.7 ± 10.0 pmol·l). No differences between conditions were noted for SHBG, Cortisol, or Estradiol. CONCLUSION: Post-exercise ethanol ingestion affects the hormonal milieu including testosterone concentration and bioavailability during recovery from resistance exercise.

Concepts: Hormone, Ethanol, Luteinizing hormone, Testosterone, Sex hormone-binding globulin, Estradiol, Adrenal cortex, Anabolic steroid

28

Patients with Congenital adrenal hyperplasia due to partial deficiency in the enzyme 21-hydroxlyase can present in childhood or adolescence with signs of adrenal androgen excess. Strategies to reduce the impact of androgen excess in females include cosmetic measures as well as antiandrogens and agents such as the combined oral contraceptive pill. Glucocorticoid may not be appropriate straightaway but can be introduced if other measures are ineffective or when pregnancy is planned.

Concepts: Combined oral contraceptive pill, Testosterone, Androgen, Adolescence, Adrenal cortex, Congenital adrenal hyperplasia, Adrenal gland, Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency

28

A panel of reporter gene assays (RGAs) coupled with a single solid phase extraction (SPE) step was developed and used to screen bottled mineral water for the presence of four classes of endocrine disruptors (EDs), oestrogens, androgens, progestagens and glucocorticoids. Fourteen brands of bottled mineral water in triplicate (42 samples) were analysed. Overall, hormonal activity was found in 78% of the samples. Oestrogenic, androgenic, progestagenic and glucocorticoid activity was found in 38%, 38%, 36% and 55% of the samples, respectively at an average concentration of 10 ng/l 17β-estradiol equivalent (EEQ), 26 ng/l testosterone equivalent (TEQ), 123 ng/l progesterone equivalent (PEQ) and 13.5 ng/l hydrocortisone equivalent (HEQ). The level of oestrogenic, androgenic and progestagenic activity observed is not considered a matter of concern for the consumers' health. It is unknown whether the glucocorticoid levels observed are safe. The ED source, long term exposure and mixture effects remain to be investigated.

Concepts: Estrogen, Testosterone, Androgen, Steroid, Bottled water, Endocrine system, Adrenal cortex, Mineral water

28

The non-invasive measurement of adrenocortical function in cheetahs is an important tool to assess stress in captive and free-ranging individuals, because stress has been suggested to be one of the causes of poor reproductive performance of captive cheetahs. We tested four enzyme immunoassays (EIA) in two captive cheetahs in Germany using adrenocorticotropic hormone (ACTH) challenges and identified the corticosterone-3-CMO EIA to be most sensitive to the increase in faecal glucocorticoid metabolite (fGCM) concentrations after the ACTH challenge. This EIA performed also well in five captive cheetahs in South Africa. The fGCM concentrations across all seven cheetahs increased within 24h by 681% compared to the baseline levels prior to ACTH. Storage of faecal samples at 0-4°C did not strongly affect fGCM concentrations within 24h, simplifying sample collection when immediate storage at -20°C is not feasible. The two cheetahs in Germany also received an injection of [(3)H]cortisol to characterise fGCMs in faecal extracts using high-performance liquid chromatography (HPLC) immunograms. HPLC fractions were measured for their radioactivity and immunoreactive fGCM concentrations with the corticosterone-3-CMO EIA, respectively. The results revealed a polar peak of radiolabelled cortisol metabolites co-eluting with the major peak of immunoreactive fGCMs. Thus, our EIA measured substantial amounts of fGCMs corresponding to the radioactive peaks. The peaks were of higher polarity than native cortisol and corticosterone, suggesting that the metabolites were conjugated, which was confirmed by solvolysis of the HPLC fractions. Our results show that the corticosterone-3-CMO EIA is a reliable tool to assess fGCMs in cheetahs.

Concepts: Cortisol, Chromatography, High performance liquid chromatography, Cushing's syndrome, Adrenocorticotropic hormone, Adrenal cortex, Addison's disease, Cheetah

28

The Adrenocorticotropic hormone (ACTH) and Pro-opimelanocortin (POMC) 1-28 N-terminal peptide (N-POMC(1-28)) have been shown to act as an adrenal mitogen in vivo. A possible role for cyclin E in the zona glomerulosa (ZG) proliferation, following ACTH and/or N-POMC(1-28) administration, has been previously demonstrated. In this study, we investigated the effect of ACTH and N-POMC(1-28) on the expression of adrenal cortex proteins related to cell cycle control such as cyclins D and P27(kip1). The administration of N-POMC upregulated cyclin D1 and D2 expression in the outer zone of the adrenal cortex; cyclin D3 expression was upregulated in the cortex inner zone even after administration of ACTH. Both ACTH and N-POMC peptides induced a decrease in the P27(kip1) expression in the ZG. These novel findings suggest that the POMC-derivate peptides, ACTH and N-POMC, promote proliferation in the adrenal cortex by upregulating the D2 and D3 cyclins and downregulating the P27(kip1) expression.

Concepts: Proteins, Protein, Cell cycle, Cyclin, Cortisol, Adrenocorticotropic hormone, Adrenal cortex, Cyclin E

28

Inhaled corticosteroids (ICS) are drugs of choice for persistent asthma. Less than 500 µg/d of fluticasone are believed to be safe. We found 92 cases of adrenal suppression in PubMed; among these cases there were 13 children who took 500 µg/d or less of fluticasone. Adrenal insufficiency was diagnosed in a 7-year-old boy on 460 µg ICS for 16 months, with a diagnosis of chronic persistent asthma. A random cortisol was nondetectable as was an early morning cortisol. ICS have greatly improved the day-to-day lives of children with chronic persistent asthma. Parents of children younger than 12 years, who use at least 400 µg of inhaled fluticasone (or bioequivalent), must be given oral and written instructions about warning symptoms of hypocortisolism. Major stress such as surgery, gastrointestinal, bronchopulmonary, or other systemic infections, and heat stress may mandate a written plan of action for use by hospital physicians.

Concepts: Asthma, Aldosterone, Corticosteroid, Glucocorticoid, Cortisol, Epinephrine, Adrenal cortex, Adrenal insufficiency

28

Non-invasive measurement of urinary corticosterone and testosterone metabolites in amphibians provides opportunities for endocrine studies of responses to physiological and psychological stressors. Typically, corticosterone metabolite concentrations increase in frog urine within 1-2h of a mild capture and handling stress protocol. However, no study has investigated the effect of duration of manual restraint on the changes in corticosterone and reproductive hormones in amphibians. We quantified urinary corticosterone and testosterone metabolite responses for 8h following various durations of manual restraint (control, 5, 15 or 30min) in adult male cane toads (Rhinella marina) under controlled laboratory conditions. All toads had a corticosterone stress response over 8h to our standard capture and handling stressor. The mean corticosterone stress response was significantly higher after 15 or 30min restraint in comparison to the control (no restraint) or to 5min restraint. Manual restraint for 5, 15 or 30min caused a significant reduction in urinary testosterone concentrations over 8h. We also provide a novel method of quantifying plasticity in corticosterone stress responses in amphibians with respect to restraint duration using the concept of a “reaction norm”. The reaction norm, which was calculated as slope of the regression line of integrated corticosterone response against restraint duration, was 9.69 (pg corticosterone/μg creatinineh)/min for male toads. In summary, corticosterone and testosterone responses to restraint are affected by restraint duration in male toads. Glucocorticoid reaction norms can be applied to study the change in physiological stress hormonal response with respect to restraint duration in other amphibian species.

Concepts: Reproduction, Hormone, Adrenal cortex, Amphibian, Frog, Toad, Toads, True toad