Classic and current concepts in adrenal steroidogenesis: a reappraisal

ABSTRACT Adrenal steroid biosynthesis and its related pathology are constant evolving disciplines. In this paper, we review classic and current concepts of adrenal steroidogenesis, plus control mechanisms of steroid pathways, distribution of unique enzymes and cofactors, and major steroid families. We highlight the presence of a "mineralocorticoid (MC) pathway of zona fasciculata (ZF)", where most circulating corticosterone and deoxycorticosterone (DOC) originate together with 18OHDOC, under ACTH control, a claim based on functional studies in normal subjects and in patients with 11β-, and 17α-hydroxylase deficiencies. We emphasize key differences between CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) and the onset of a hybrid enzyme - CYP11B1/CYP11B2 -, responsible for aldosterone formation in ZF under ACTH control, in "type I familial hyperaldosteronism" (dexamethasone suppressible). In "apparent MC excess syndrome", peripheral conversion of cortisol to cortisone is impaired by lack of 11β-hydroxysteroid dehydrogenase type 2, permitting free cortisol access to MC receptors resulting in severe hypertension. We discuss two novel conditions involving the synthesis of adrenal androgens: the "backdoor pathway", through which dihydrotestosterone is formed directly from androsterone, being relevant for the fetoplacental setting and sexual differentiation of male fetuses, and the rediscovery of C19 11-oxygenated steroids (11-hydroxyandrostenedione and 11-ketotestosterone), active androgens and important markers of virilization in 21-hydroxylase deficiency and polycystic ovaries syndrome. Finally, we underline two enzyme cofactor deficiencies: cytochrome P450 oxidoreductase which partially affects 21- and 17α-hydroxylation, producing a combined clinical/hormonal picture and causing typical skeletal malformations (Antley-Bixler syndrome), and PAPSS2, coupled to SULT2A1, that promotes sulfation of DHEA to DHEAS, preventing active androgens to accumulate. Its deficiency results in reduced DHEAS and elevated DHEA and androgens with virilization. Future and necessary studies will shed light on remaining issues and questions on adrenal steroidogenesis.

Histologically proven hepatic steatosis associates with lower testosterone levels in men with obesity / 亚洲男科学杂志(英文版)

Men with obesity often present with low testosterone (T) and sex hormone-binding globulin (SHBG) levels. Several mechanisms for this have been proposed, but as SHBG is secreted by hepatocytes and sex steroids undergo hepatic metabolization, this study investigates whether severity and histological components of nonalcoholic fatty liver disease (NAFLD) are associated with sex steroid levels in obese men. This cross-sectional study included 80 obese men (age: 46 ± 11 years; body mass index: 42.2 ± 5.5 kg m-2). Serum levels of total T and estradiol (E2) were measured using liquid chromatography coupled with tandem mass spectroscopy (LC/MS-MS) and SHBG and gonadotropins by immunoassay. Liver biopsies were evaluated using Steatosis, Activity, and Fibrosis scoring. Participants with steatohepatitis had similar median (1stquartile-3rd quartile) total T levels (7.6 [5.0-11.0] nmol l-1 vs 8.2 [7.2-10.9] nmol l-1; P = 0.147), lower calculated free T (cFT) levels (148.9 [122.9-188.8] pmol l-1 vs 199.5 [157.3-237.6] pmol l-1; P = 0.006), and higher free E2/T ratios (10.0 [6.4-13.9] x10-3 vs 7.1 [5.7-10.7] x10-3;.

The problem of medicating women like the men: conceptual discussion of menstrual cycle-dependent psychopharmacology

While hormonal changes during the ovulatory cycles affect multiple body systems, medical management, including medication dosing remains largely uniform between the sexes. Little is known about sex-specific pharmacology in women. Although hormonal fluctuations of the normal menstruating process alters women's physiology and brain biochemistry, medication dosing does not consider such cyclical changes. Using schizophrenia as an example, this paper illustrates how a woman's clinical symptoms can change throughout the ovulatory cycle, leading to fluctuations in medication responses. Effects of sex steroids on the brain, clinical pharmacology are discussed. Effective medication dose may be different at different phases of the menstrual cycle. Further research is needed to better understand optimal treatment strategies in reproductive women; we present a potential clinical trial design for examining optimal medication dosing strategies for conditions that have menstruation related clinical fluctuations.

Galectins: Double Edged Swords in the Cross-roads of Pregnancy Complications and Female Reproductive Tract Inflammation and Neoplasia

Galectins are an evolutionarily ancient and widely expressed family of lectins that have unique glycan-binding characteristics. They are pleiotropic regulators of key biological processes, such as cell growth, proliferation, differentiation, apoptosis, signal transduction, and pre-mRNA splicing, as well as homo- and heterotypic cell-cell and cell-extracellular matrix interactions. Galectins are also pivotal in immune responses since they regulate host-pathogen interactions, innate and adaptive immune responses, acute and chronic inflammation, and immune tolerance. Some galectins are also central to the regulation of angiogenesis, cell migration and invasion. Expression and functional data provide convincing evidence that, due to these functions, galectins play key roles in shared and unique pathways of normal embryonic and placental development as well as oncodevelopmental processes in tumorigenesis. Therefore, galectins may sometimes act as double-edged swords since they have beneficial but also harmful effects for the organism. Recent advances facilitate the use of galectins as biomarkers in obstetrical syndromes and in various malignancies, and their therapeutic applications are also under investigation. This review provides a general overview of galectins and a focused review of this lectin subfamily in the context of inflammation, infection and tumors of the female reproductive tract as well as in normal pregnancies and those complicated by the great obstetrical syndromes.

Case-control study on the serum sex steroids levels in prepuberal children with autism / 中华行为医学与脑科学杂志

Objective To investigate the changes of the serum sex steroids levels in prepuberal children with autism,and analyze the possible clinical implications.Methods The serum sex steroids,including folliclestimulating hormone(FSH),luteotropic hormone(LH),testosterone(T),estradiol(E2),progesterone(P),dehydroepiandrosterone sulfate(DHEA-S) and androstenedione were measured in 44 autistic children(35 boys and 9girls,47.5 ± 18.9 months) and 44 normal children(35 boys and 9 girls,45.0 ± 18.7 months),using chemiluminescence immunoassay.Results ①The progesterone levels in autism group were significantly lower than control group((＜ 0.48,2.08) nmoL/L vs (＜ 0.48,6.95) nmol/L,Z =-3.564,P ＜ 0.01),but no statistical differences were observed in other sex steroids levels(P＞ 0.05).②The progesterone levels in ＜ 48 months autism group showed no significant differences from ≥48 months autism group (Z =0.150,P ＞ 0.05).There were no statistical differences in progesterone level between the boys and girls of the autism group(Z=1.972,P＞0.05).Conclusion The progesterone levels are lower in autistic children,and they are not associated with the children's age or gender.This study indicates that the progesterone levels are closely associated with autism.

Efeitos da castração e androgenização neonatal sobre o dimorfismo sexual esquelético e secreção de leptina e corticosterona em ratos / Effects of neonatal castration and androgenization on sexual dimorphism in bone, and leptin and corticosterone secretion

Para estudar os efeitos da castração e androgenização neonatal sobre o dimorfismo sexual esquelético, bem como, secreções de leptina e corticosterona. Ratos Wistar, neonatos foram divididos em quatro grupos do mesmo sexo (n = 06-08 por grupo). Os machos foram castrados ou sham-operados nas primeiras 24h de nascimento. As fêmeas receberam injeções subcutâneas diárias de 100mg de propianato de testosterona em 50μl de óleo de milho, ou somente o veículo durante 05 dias. Os animais foram pesados semanalmente para acompanhar a evolução da massa corporal e eutanasiados aos 20, 40 e 120 dias, onde foram coletados sangue e os fêmures para determinação do comprimento e espessura, realizadas com auxílio de um paquímetro. A densidade mineral óssea areal (DMO areal) foi determinada por meio de um densitômetro de dupla emissão de raios-X e, o ensaio mecânico de flexão foi realizado para a aquisição e cálculo das propriedades estruturais: força máxima, rigidez e tenacidade. As amostras sanguíneas foram utilizadas para determinar as concentrações plasmáticas de cálcio, fósforo e fosfatase alcalina, bem como as concentrações plasmáticas de leptina e corticosterona. Os resultados evidenciam que o ganho de massa corpórea, DMO areal e propriedades biofísicas aumentaram rapidamente com o envelhecimento em todos os grupos, confirmando que em animais controle, o dimorfismo sexual esquelético e o padrão dimórfico de secreção da leptina e corticosterona são evidenciados após a puberdade. No entanto, a exposição neonatal a andrógenos induz alterações no crescimento, com DMO areal e qualidade óssea aumentadas em fêmeas androgenizadas, levando a um padrão masculinizado no desenvolvimento. Por outro lado, machos castrados no período neonatal apresentaram fragilidade óssea, com tenacidade e força máxima reduzidas em todas as fases comparados com machos sham-castrados. Estes resultados sugerem ainda, que a exposição ou ausência de andrógenos no período neonatal pode ser uma das...

To study the effects of neonatal castration and androgenization on sexual dimorphism in bone, and leptin and corticosterone secretion, Wistar rats, newborns, were divided into four groups (n = 06-08 per group) of the same sex. Male pups were cryoanesthetized and castrated or sham/castrated by 24 hours after birth; female pups from separate litters were injected SC with testosterone propionate 100 μg in 50μL corn oil or oil vehicle 50μL during 05 days and were euthanized by 20, 40, and 120 postnatal day. Were collected blood samples, and femurs. The animals were weighed weekly to monitor the evolution of body mass, and the length and thickness of the femurs were performed with aid of a caliper. The Areal Bone Mineral Density (areal BMD) was determinate by Dual-energy X-ray Absorptiometry and, Biomechanical Three-Point Bending Testing; these data were used for the acquisition and calculation of the structural properties: Ultimate Strength, Toughness, and Stiffness. The blood samples were subjected to a biochemical assay to estimate the serum levels of calcium, phosphorus and alkaline phosphatase; and serum leptin and corticosterone concentration. The results showed that weight gain, areal BMD and biomechanical properties increased rapidly with aging in all groups, and confirm that in control animals, skeletal sexual dimorphism, and serum leptin concentration, and a dimorphic pattern in serum corticosterone concentration evidenced after puberty. However, the neonatal exposed to androgen induced changes in growth, areal BMD and bone mass quality in androgenized females, leading to a masculinization pattern in development. On the other hand, neonatally castrated males had the bone development and quality of the mechanical properties similar to those control females. These results suggest that the presence or absence of exposure to neonatal androgen may represent at least one covariate that mediates the dimorphic variation in leptin and corticosterone secretion...

Testosterone and estradiol-17b dependent phospholipid catfish, Heteropneustes fossilis (Bloch)biosynthesis in ovariectomized.

Effect of cumulative doses (7, 14 and 28 mgkg-1 body weight) of testosterone (T) and estradiol-17b (E2) on total phospholipids (TP), phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidylinositol (PI) and phosphatidylethanolamine (PE) in tissues were investigated during the gonadal recrudescence, in prespawning phase of the annual reproductive cycle in intact and ovariectomized freshwater catfish, Heteropneustes fossilis. After ovariectomy, the hepatic levels of TP and PE were elevated and remained unaffected for PC, PS and PE when compared with control. In general, T and E2 were stimulatory for a specific class of phospholipid in tissues of intact and ovariectomized catfish. These effects were higher at 14 and 28 mg kg-1 body weight in ovariectomized catfish whereas 7 mgkg-1 body weight of T and E2 have pronounced effect in intact ovaries. In conclusion, the various phospholipid biosynthesis were under T and E2 dependent. Among the phospholipid, the PC was the main constituent and was sex steroid dependent biosynthesis during prespawning phase.

Parâmetros mecânicos, físicos e químicos na avaliação de mandíbulas de ratos deficientes em esteróides sexuais / Mechanical, physical and chemical parameters in evaluation of mandibles of rats deficient in sex steroids

O aumento da expectativa de vida vem elevando a ocorrência das alterações degenerativas comuns à terceira idade, como a osteoporose. Essa doença sistêmica também frequente no hipogonadismo, afeta o metabolismo ósseo comprometendo inclusive a mandíbula. O objetivo deste estudo foi avaliar de que forma a deficiência de esteróides sexuais, induzida por orquiectomia ou ovariectomia, influencia o processo de remodelação óssea da mandíbula de ratos por períodos experimentais crônicos. Ratos Wistar, com 3 meses, foram divididos em três grupos experimentais: controles (C), castrados (ORQ; OVX) e castrados com tratamento hormonal (ORQ + PT - propionato de testosterona, 0,4 mg/100g PC/dia; OVX + BE - benzoato de estradiol, 0,7 ug/100g PC/dia). As fêmeas foram previamente avaliadas por citologia vaginal e somente as que apresentaram o ciclo estral regular foram utilizadas. A massa corporal foi verificada semanalmente e ao final dos períodos experimentais (90, 120 e 150 dias) os animais foram sacrificados. O sangue foi coletado e o soro armazenado para posterior análise. As mandíbulas, fêmures e colunas foram excisados, medidos e preparados para análises da densidade mineral óssea e das propriedades físicas e biomecânicas. Observamos que com a castração, machos apresentaram baixo ganho de massa corporal (90d: 12%, 120d: 24% e 150d: 13% a menos que C, p<0,05), ao contrário das fêmeas (90d: 38% e 120d: 41% a mais que C, p<0,05). As medidas de todos os ossos foram menores tanto em machos como em fêmeas (♂ - 90d: vértebra 11.8%, fêmur 4.4%, côndilo MD 9.4%, côndilo VL 16.6%; 120d: vértebra 13.6%, fêmur 4%, côndilo mandibular MD 9%, côndilo mandibular VL 22.2%; 150d: vértebra 16.8%, fêmur 6%, côndilo mandibular MD 21.6%, côndilo mandibular VL 29.1% e ♀ - 90d: vértebra 7.7, fêmur 5.6%, côndilo mandibular MD 29.1%, côndilo mandibular VL 11.8%; 120d: vértebra 15.9%, fêmur 6.1%, côndilo mandibular MD 33.6%, côndilo mandibular VL 14.8%; 150d: vértebra 21.6%, fêmur 5.42%...

The increase in the life expectancy has been raising the occurrence of common degenerative alterations in aging population, as osteoporosis. This systemic disease is also frequent in hypogonadism and affects the bone metabolism, included mandibular bone. The aim of this study was to evaluate how sex steroid deficiency, induced by orchiectomy (ORX) or ovariectomy (OVX), influences on mandible bone remodeling of rats, in groups of chronic experimental periods. Wistar rats, 3 mouths, had been divided in three groups: controls (C), castrated (ORX; OVX) and castrated with hormonal treatment (ORX+TP - testosterone propionate, 0,4 mg/100g BW/day; OVX+EB - estradiol benzoate, 0.7 ug/100g BW/day). Females were previously evaluated by vaginal cytology and only rats with regular estrous cycle were used. The corporal mass was weekly verified and after experimental periods (90, 120 and 150 days), the animals were sacrificed. The blood was collected and serum stored for posterior analysis. Mandibles, femurs and columns were excised, measured and prepared to analyses of bone mineral density and physical and biomechanical properties. After castration, males presented low gain in body mass (90d: 12%, 120d: 24% and 150d: 13% lower than C, p<0,05), in contrast of females (90d: 38% and 120d: 41% upper than C, p<0,05). The measures of all bones were lower in males and in females (♂ - 90d: vertebrae 11.8%, femur 4.4%, mandibular condyle MD 9.4%, mandibular condyle VL 16.6%; 120d: vertebrae 13.6%, femur 4%, mandibular condyle MD 9%, mandibular condyle VL 22.2%; 150d: vertebrae 16.8%, femur 6%, mandibular condyle MD 21.6%, mandibular condyle VL 29.1% and ♀ - 90d: vertebrae 7.7%, femur 5.6%, mandibular condyle MD29.1%, mandibular condyle VL11.8%; 120d: vertebrae 15.9%, femur 6.1%, mandibular condyle MD 33.6%, mandibular condyle VL 14.8% and 150d: vertebrae 21.6%, femur 5.42%, mandibular condyle MD 29.1%, mandibular condyle VL 15.1% lower than C, p<0,05), in all experimental periods...

Dimorfismo sexual inmunitario: ¿pueden los esteroides sexuales polarizar el perfil de citocinas Th1/Th2? / Immune sexual dimorphism: Can sex steroids affect the Thl/Th2 cytokine profile?

Cytokine secretion is a crucial aspect in immune system modulation. The secretion pattern of these molecules determines the immune response type that will confront a particular antigen, and this pattern can be at least of two types. A Thl pattern, effective to eliminate mainly intracellular pathogens and a Th2 pattern, crucial to eradicate extra cellular pathogens. There are many immunological factors that affect expression of these proteins and auto regulate the Th1/Th2 balance, but there are few evidences about effect of other protagonists of mammals physiology. This review focuses on the regulation of the Th1/Th2 cytokine secretion pattern of immune cells by sexual steroids. The evidences indicate that cytokines and steroids form a common chemical language effective to keep the balance between immune and endocrine systems. Alterations of this delicate network can explain different pathologies where gender-associated differences exist and where sexual steroids are crucial factors.

La secreción de citocinas es uno de los aspectos más importantes en la modulación de la respuesta inmune. El patrón de secreción de estas moléculas determina el tipo de respuesta inmune que confrontará a un antígeno particular. Ésta puede ser al menos de dos tipos: la respuesta Th1 (encargada principalmente de controlar patógenos intracelulares) y la respuesta Th2 (involucrada en el control de patógenos extracelulares). Existe una autorregulación del balance del tipo de respuesta Th1/Th2 por mecanismos inmunológicos que pueden afectar la expresión de estas proteínas, pero poco se sabe con respecto al papel de otros protagonistas de la fisiología de los mamíferos. En esta revisión se discuten los trabajos referentes al efecto de los esteroides sexuales en la regulación de la secreción de citocinas Th1/Th2 por parte de células del sistema inmune. Las evidencias indican que las citocinas y los esteroides constituyen un lenguaje químico común para el funcionamiento balanceado de los sistemas inmune y endocrino. La alteración de la delicada comunicación entre estos sistemas puede explicar diversas patologías en que existe susceptibilidad asociada al sexo, y en las que los esteroides sexuales son factores clave.

The Effects of Sex Steroids on the Maxi-K Channel Activity of Human Vas Deferens / 대한비뇨기과학회지

Purpose: We investigated the effects of sex steroids on the maxi-K channel activities of the single smooth muscle cells of the human vas deferens. Materials and Methods: Human vas deferens cells were isolated using proteolytic enzymes (collagense and papain), and then they were employed for an electrophysiological study with using the inside-out patch clamp configurations. The intracellular calcium concentrations were adjusted between 0.1mum to 1mum, and the membrane potentials were depolarized. Results: The maxi-K channels were identified by their single channel conductance and calcium dependency. The application of 10ng/dl estrogen induced a significant increment of the maxi-K channel activities. The effects were not affected by the change of the intracellular calcium concentration. The other sex steroids (progesterone and testosterone) rarely affected the maxi-K channel activities. Conclusions: Estrogen has stimulatory effects on the maxi-K channel activity of human vas deferens. This suggests that estrogen may relax the human vas deferens via maxi-K channel activation.

Endocrinological studies for artificial breeding of the Japanese ibis, Nipponia nippon, an endangered avian species in Asia.

Once the Japanese ibis, or the Japanese crested ibis, was widely distributed in Asia including Japan, Korea, China and Siberia, and was not a rare species. However, this species started to disappear over its entire range beginning in the late 19th or early 20th century. Currently, only a single population of 15-20 individuals survives in wild in Yang Xian, Shaanxi, China. Several individuals, mostly immature birds, are kept in captivity in Beijing zoo. One of them is an adult male captured in 1981 in Japan and sent to Beijing zoo for breeding two years ago. In Japan, only, a single old female survives in captivity. Scientists of the Japanese Ibis Preservation Center in Sado Island and Ueno zoo, Tokyo, had attempted several times to breed Japanese ibises in captivity, but they have failed in all of their attempts. In Beijing zoo, a similar attempt is now being carried out. As the basis of an artificial breeding programme of this and other species of birds, the authors have attempted to establish a noninvasive method for estimation of gonadal activities of birds and also a method to induce a complete series of the ovarian activity, i.e., ovarian growth, ovulation and oviposition, by means of hormone administration to some species of birds. In this communication, the author briefly reports recent results of these attempts in addition to results of measurements of gonadotropin levels in plasma of captive Japanese ibises and white ibises, a closely related species, Threskiornis aethiopicus.

Plasma prolactin, gonadotropins sex steroids and cortisol determined during reproduction period in Thai subjects.

Radioimmunoassay measurements of plasma hormones : gonadotropins (Gn), Luteinizing hormone (LH) and follicle stimulating hormone (FSH), prolactin (PRL), cortisol and sex hormones i.e. estradiol (E2) and progesterone (P4) in women and testosterone (T) in men were simultaneously performed to establish normal range data of hormone secretions in Thai subjects. Values of hormonal profiles in the females during the normal menstrual cycles or in 118 healthy males of reproductive age were similar to data described for Thai and other nationalities by previous investigators. Data obtained in the present study may be useful as a guide for interpretation of normal and abnormal hormone secretions in Thai subjects, although minor inter-laboratory discrepancies in results may exist.