Androgen biosynthesis during minipuberty favors the backdoor pathway over the classic pathway: Insights into enzyme activities and steroid fluxes in healthy infants during the first year of life from the urinary steroid metabolome

Abstract

during minipuberty favors the backdoor pathway over the classic pathway: insights into enzyme activities and steroid fluxes in healthy infants during the first year of life from the urinary steroid metabolome, Journal of Steroid Biochemistry and Molecular Biology http://dx.doi.org/10. 1016/j.jsbmb.2016.07.009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Highlights-Male androgen biosynthesis shows a significant peak at week 7 during minipuberty -Androgens in minipuberty are (at least in part) produced through the backdoor pathway -Steroid enzyme activities in the first year of life are all age-, some sex-specific -Steroid enzyme ratios obtained from urine GC-MS are comparable between laboratories AbstractThe steroid profile changes dramatically from prenatal to postnatal life. Recently, a novel backdoor pathway for androgen biosynthesis has been discovered. However, its role remains elusive. Therefore, we investigated androgen production from birth to one year of life with a focus on minipuberty and on production of androgens through the backdoor pathway. Additionally, we assessed the development of the specific steroid enzyme activities in early life. To do so, we collected urine specimens from diapers in 43 healthy newborns (22 females) at 13 time points from birth to one year of age in an ambulatory setting, and performed in house GC/MS steroid profiling for 67 steroid metabolites. Data were analyzed for androgen production through the classic and backdoor pathway and calculations of diagnostic ratios for steroid enzyme activities were performed. Analysis revealed that during minipuberty androgen production is much higher in boys than in girls (e.g. androsterone (An)), originates largely from the testis (An boysAn girls ), and uses predominantly the alternative backdoor pathway (An/Et; Δ5<Δ4 lyase activity).Modelling of steroid enzyme activities showed age-related effects for 21-, 11-, 17-hydroxylase and P450 oxidoreductase activities as well as 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase type 1/2 and 5α-reductase activities. Sex-related characteristics were found for 21-hydroxylase and 5α-reductase activities.Overall, our study shows that androgen biosynthesis during minipuberty favors the backdoor pathway over the classic pathway. Calculations of specific diagnostic ratios for enzyme activities seem to allow the diagnosis of specific steroid disorders from the urinary steroid metabolome.

Is There a Dysregulation of Backdoor Pathway of Androgen Synthesis in Autistic Disorders?

“…It is currently accepted that steroid profile changes prenatal to postnatal and androgen biosynthesis during minipuberty favors the backdoor pathway over the classic pathway with several pathologic associations (21-Hydroxylase Deficiency, Fragile-X-Syndrome or an altered sexual development. [16,20,21,22,23,24,25] Despite limited by a relatively small sample size especially for girls a significant increase for boys but not girls of the two androgens Androsterone and Eticholanolone during puberty persists. The increased androgens during this sensitive period of development might additionally promote autistic regression.…”

“…[20,21,22,23,24,25,26,31,32,33] We therefore suggested that a dysregulation of backdoor pathway (normally mainly active during mini puberty in the first year of life) might persist in autistic individuals up to puberty yielding to altered androgen production through activation of this respective pathway. [16,17] We suggested a dysregulation and stated as hypothesis with potential falsification, that there is no difference of A/E ratios respectively activity of backdoor pathway in affected autistic pubertal children compared to healthy controls. [34]…”

“…[1,2] When focusing on biochemical pathways of androgen synthesis two major pathways are to mention: the classic and the backdoor pathway. [16,17,18,19] In short, human steroidogenic enzymes efficiently catalyze all the required steps in a route to Dihydrotestosterone (DHT) that does not involve the Testosterone intermediate, called the backdoor pathway. [19] The backdoor pathway provides a (more) efficient route to DHT.…”

Dihydrotestosterone levels at birth associate positively with higher proportions of circulating immature/naïve CD5+ B cells in boys

“…The reason for these differences can only be speculated upon, but DHT, which is converted by 5α-reductase from testosterone, is a more potent agonist to the androgen receptor than testosterone 45 . Moreover, a “non-classical” pathway leading to DHT synthesis from progesterone that does not pass the testosterone step has been described, and this pathway is particularly active in the fetus and early infancy in male sex 46 , 47 . Finally, testosterone, but not DHT, can be converted to estradiol by aromatase, which thereby diversifies its androgen action by activating estrogen receptors 48 .…”

The role of miRNAs in regulating adrenal and gonadal steroidogenesis

“…Journal of Molecular Endocrinology this pathway plays an important role in hyperandrogenic disorders (Miller & Auchus 2019) such as 21-hydroxylase deficiency-linked congenital adrenal hyperplasia (Kamrath et al 2012), polycystic ovary syndrome (PCOS) (Martin et al 2017), some virilized female newborns with P450 oxidoreductase deficiency (Shackleton et al 2004, Homma et al 2006, Krone et al 2012) and physiologic 'minipuberty of infancy' (Dhayat et al 2017). Furthermore, AKR1C2 and AKR1C4 gene mutation studies (Flück & Pandey 2014) led to the conclusion that both 'classic' pathways of androgen synthesis and 'backdoor' are required for normal male genital development (Biason-Lauber et al 2013).…”