Inhibition of the glucocorticoid‐activating enzyme 11β‐hydroxysteroid dehydrogenase type 1 drives concurrent 11‐oxygenated androgen excess

Aldo‐keto reductase 1C3 (AKR1C3) is a key enzyme in the activation of both classic and 11‐oxygenated androgens. In adipose tissue, AKR1C3 is co‐expressed with 11β‐hydroxysteroid dehydrogenase type 1 (HSD11B1), which catalyzes not only the local activation of glucocorticoids but also the inactivation of 11‐oxygenated androgens, and thus has the potential to counteract AKR1C3. Using a combination of in vitro assays and in silico modeling we show that HSD11B1 attenuates the biosynthesis of the potent 11‐oxygenated androgen, 11‐ketotestosterone (11KT), by AKR1C3. Employing ex vivo incubations of human female adipose tissue samples we show that inhibition of HSD11B1 results in the increased peripheral biosynthesis of 11KT. Moreover, circulating 11KT increased 2–3 fold in individuals with type 2 diabetes after receiving the selective oral HSD11B1 inhibitor AZD4017 for 35 days, thus confirming that HSD11B1 inhibition results in systemic increases in 11KT concentrations. Our findings show that HSD11B1 protects against excess 11KT production by adipose tissue, a finding of particular significance when considering the evidence for adverse metabolic effects of androgens in women. Therefore, when targeting glucocorticoid activation by HSD11B1 inhibitor treatment in women, the consequently increased generation of 11KT may offset beneficial effects of decreased glucocorticoid activation

Impaired 11β-hydroxysteroid dehydrogenase type 2 activity in chronic kidney disease disrupts 11-oxygenated androgen biosynthesis

Context: 11-oxygenated androgens are a group of adrenal-derived steroids that require peripheral activation. In vitro data highlight a putative role for 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) in 11-oxygenated androgen biosynthesis, converting 11β-hydroxyandrostenedione (11OHA4) to 11-ketoandrostenedione (11KA4), the direct precursor of the potent androgen 11-ketotestosterone (11KT). As the kidney is the major site of HSD11B2 expression, we hypothesized that patients with chronic kidney disease (CKD) would have reduced 11-oxygenated androgen biosynthesis due to impaired HSD11B2 activity.Objective: To determine the role of HSD11B2 in 11-oxygenated androgen biosynthesis using a human CKD cohort alongside complementary cell culture and computational modeling approaches.Design: Cross-sectional observational study of patients with CKD (n=85) and healthy controls (n=46) measuring serum and urinary concentrations of glucocorticoids, classic and 11-oxygenated androgens by liquid chromatography-tandem mass spectrometry. A computational model of peripheral 11-oxygenated androgen biosynthesis was fitted to the serum data to calculate relative HSD11B2 expression levels for each participant.Results: HSD11B2 activity declined with eGFR, evidenced by higher cortisol (F)/cortisone (E) ratios in CKD patients compared to controls (p&lt;0.0001). Serum concentrations of E, 11KA4, 11KT and 11β-hydroxytestosterone were lower in patients with CKD compared to controls (p&lt;0.0001 for each). A computational model based on enzyme kinetic parameters of HSD11B2, 11β-hydroxysteroid dehydrogenase type 1, 17β-hydroxysteroid dehydrogenase type 2 and aldo-keto reductase 1C3 confirmed HSD11B2 as the key enzyme responsible for reduced 11-oxygenated androgen biosynthesis in CKD. Predicted HSD11B2 expression correlated with eGFR.Conclusion: This is the first in vivo study to confirm a central role for renal HSD11B2 in 11-oxygenated androgen biosynthesis. Determining the clinical implications of this observation for patients with CKD requires further research.<br/

Association of Spermatogenic Failure with the b2/b3 Partial AZFc Deletion

Infertility affects around 1 in 10 men and in most cases the cause is unknown. The Y chromosome plays an important role in spermatogenesis and specific deletions of this chromosome, the AZF deletions, are associated with spermatogenic failure. Recently partial AZF deletions have been described but their association with spermatogenic failure is unclear. Here we screened a total of 339 men with idiopathic spermatogenic failure, and 256 normozoospermic ancestry-matched men for chromosome microdeletions including AZFa, AZFb, AZFc, and the AZFc partial deletions (gr/gr, b1/b3 and b2/b3)

Mutations in the protamine locus: association with spermatogenic failure?

abstract: The protamine locus consists of a 28.5 kb region with a linear array of the protamine (PRM)1, PRM2, PRM3 and transition nuclear protein (TNP)2 genes. Several studies indicate an abnormal expression pattern of protamine genes associated with male infertility, although the molecular mechanism underlying this observation is unclear. Here, we determined the spectrum of DNA variants present in all four genes in men with unexplained infertility compared with an ancestry-matched fertile/normospermic population. A total of 160 control individuals and at least 125 infertile men with either idiopathic azoospermia or oligozoospermia were sequenced for the open reading frame of PRM1, PRM2, PRM3 and TNP2 genes. All individuals carried an apparently intact Y chromosome. Of the 28 variants identified, 21 were previously described in the literature. The novel variants that were observed only in the infertile cohort included the SNP c.65G.A mutation which resulted in an amino acid change at the codon 22 (p.Ser22Asn) in the PRM1 gene, a mutation in the promoter region of PRM2 (267C.T) and a nonsense mutation in the PRM3 gene. These data are consistent with that of previous studies which have indicated that mutations in the protamine locus may be an infrequent cause of male infertility

Online methods in geography educational research

Online methods in geography educational researc

Parenting gone wired: empowerment of new mothers on the Internet?

The extension of information and communication technologies is purported to provide great opportunities for women, with the potential for empowerment and feminist activism. This paper contributes to the debate about women and cyberspace through a focus on the role of the internet in the lives of a group of technologically proficient, socially advantaged white heterosexual new mothers. The internet played a central role in providing virtual social support and alternative information sources which increased these women’s real sense of empowerment in the transition to motherhood. Simultaneously, however, very traditional stereotypes of mothering and gender roles persisted. A paradox is evident whereby the internet was both liberating and constraining: it played an important social role for some women while at the same time it encouraged restrictive and unequal gender stereotypes in this particular community of practice. An examination of new virtual parenting spaces therefore has a contribution to make in understanding changing parenting practices in the new millennium. L'expansion des technologies de l'information et de la communication est censée pouvoir offrir de multiples possibilités aux femmes susceptibles de renforcer leur autonomie et le militantisme féministe. Cet article apporte un éclairage au débat sur les femmes et le cyberespace en examinant le rôle de l'Internet dans les vies d'un groupe composé de nouvelles mères de race blanche, hétérosexuelle, socialement plus avantagées et maîtrisant les nouvelles technologies. L'Internet a joué un rôle primordial dans le développement d'un milieu de soutien social virtuel et l'offre de sources alternatives d'informations qui ont permis d'accroître leur sentiment réel d'être autonome lors du passage au stade de la maternité. En parallèle, toutefois, les idées stéréotypées traditionnelles du maternage et des rôles sexospécifiques persistent. Un paradoxe émerge entre l'effet libérateur et contraignant de l'Internet: celui-ci a joué un rôle social important pour quelques femmes tandis qu'il a simultanément favorisé des stéréotypes liés au genre restreignants et inégaux au sein de cette communauté de pratique. L'étude des nouveaux espaces virtuels qui encadrent le métier de parent sert donc à mieux comprendre les pratiques des parents au nouveau millénaire. Se sugiere que el aumento de tecnologías de informática y comunicación les ofrece grandes oportunidades a las mujeres, con la posibilidad de empoderamiento y activismo feminista. Este papel contribuye al debate sobre mujeres y el ciberespacio por medio de un estudio del papel del internet en las vidas de un grupo de madres nuevas, blancas y heterosexuales, privilegiadas socialmente y muy competentes en el uso de nuevas tecnologías. El internet jugaba un papel importante al ofrecerles apoyo social virtual y fuentes alternativos de información, lo cual aumentaba el sentido de poder real que tenían estas mujeres en la transición hacia la maternidad. Sin embargo, simultaneamente, persistían estereotipos muy tradicionales de la maternidad y los papeles de los géneros. Existía una paradoja en que el internet les liberaba tanto como les limitaba. Jugaba un papel social importante para algunas mujeres pero, al mismo tiempo, fomentaba estereotipos de género limitantes y desiguales en esta comunidad de práctica. Como consecuencia, este estudio de nuevos espacios virtuales para madres tiene algo que contribuir a nuestro entendimiento de cambios en las prácticas de criar a los hijos en el nuevo milenio