Steroid biosynthesis

About: Steroid biosynthesis is a research topic. Over the lifetime, 1721 publications have been published within this topic receiving 58977 citations.

CHAPTER 20 – Physiology of Testicular Steroidogenesis

Abstract: Testosterone represents the major circulating androgen in the male and is synthesized by a sequence of enzymatic reactions that converts the substrate for all steroid biosynthesis, cholesterol, initially to the first steroid produced, pregnenolone, and then through a number of steroid intermediates to testosterone. This chapter discusses the specific enzymatic reactions and the products so formed. Cholesterol synthesis involves the formation of mevalonic acid, squalene, lanosterol, and finally cholesterol. The uptake of cholesterol from the serum requires the interaction of circulating lipoproteins with specific cell surface receptors designed to interact with these lipoproteins and internalize them either in whole or in part. The initial enzymatic reaction in the biosynthesis of all steroids in all steroidogenic tissues is the conversion of cholesterol to pregnenolone. This reaction occurs through the activity of the cytochrome P450 side-chain cleavage enzyme. In the testis, testosterone is the major androgen produced by the Leydig cells and is responsible for the normal maintenance of spermatogenesis. However, testosterone can also be converted to the more potent androgen, dihydrotestosterone (DHT), through the action of the enzyme 5α-reductase.

Differential Regulation of Human 3β-Hydroxysteroid Dehydrogenase Type 2 for Steroid Hormone Biosynthesis by Starvation and Cyclic Amp Stimulation: Studies in the Human Adrenal NCI-H295R Cell Model

Abstract: Human steroid biosynthesis depends on a specifically regulated cascade of enzymes including 3β-hydroxysteroid dehydrogenases (HSD3Bs). Type 2 HSD3B catalyzes the conversion of pregnenolone, 17α-hydroxypregnenolone and dehydroepiandrosterone to progesterone, 17α-hydroxyprogesterone and androstenedione in the human adrenal cortex and the gonads but the exact regulation of this enzyme is unknown. Therefore, specific downregulation of HSD3B2 at adrenarche around age 6–8 years and characteristic upregulation of HSD3B2 in the ovaries of women suffering from the polycystic ovary syndrome remain unexplained prompting us to study the regulation of HSD3B2 in adrenal NCI-H295R cells. Our studies confirm that the HSD3B2 promoter is regulated by transcription factors GATA, Nur77 and SF1/LRH1 in concert and that the NBRE/Nur77 site is crucial for hormonal stimulation with cAMP. In fact, these three transcription factors together were able to transactivate the HSD3B2 promoter in placental JEG3 cells which normally do not express HSD3B2. By contrast, epigenetic mechanisms such as methylation and acetylation seem not involved in controlling HSD3B2 expression. Cyclic AMP was found to exert differential effects on HSD3B2 when comparing short (acute) versus long-term (chronic) stimulation. Short cAMP stimulation inhibited HSD3B2 activity directly possibly due to regulation at co-factor or substrate level or posttranslational modification of the protein. Long cAMP stimulation attenuated HSD3B2 inhibition and increased HSD3B2 expression through transcriptional regulation. Although PKA and MAPK pathways are obvious candidates for possibly transmitting the cAMP signal to HSD3B2, our studies using PKA and MEK1/2 inhibitors revealed no such downstream signaling of cAMP. However, both signaling pathways were clearly regulating HSD3B2 expression.

The levels of plasma cholesterol in the human fetus throughout gestation.

Abstract: Summary: The present study was undertaken to define the umbilical cord plasma concentrations of cholesterol throughout human gestation. Mixed arterial and venous cord plasma samples obtained from abortuses of women undergoing elective abortion or from infants of women who underwent spontaneous premature vaginal delivery, and from infants of women who delivered vaginally at term were assayed for cholesterol by a micro-enzymatic method. No cases that involved any maternal or fetal complications (other than prematurity) were included in this study. Early in gestation (10–16 weeks post-conception), the total cholesterol level in cord plasma was 85.4 ± 30.7 mg/dl (mean ± SD), n = 68, with the cholesterol levels in some samples falling within the range of those of adults. Between 16.5 and 20 weeks post-conception, the umbilical cord plasma cholesterol level declined to 39.9 ± 21.0 mg/dl, n = 19 (P < 0.001). The cholesterol concentration in umbilical cord plasma then rose to 67.8 ± 24.0 mg/dl, n = 17, (P < 0.001) between 26.5 and 32 weeks of gestation. Thereafter, a second decline in the umbilical cord plasma cholesterol level occurred, with the values at 32.5–36 weeks being 58.4 ± 13.6 mg/dl (n = 16), and at 36.5 to 40 weeks post-conception (term) being 51.4 ± 11.5 mg/dl, n = 44 (P < 0.01 vs. 26.5–32 wks). We suggest that the observed changes in fetal cholesterol levels could be related to alterations during development in the rates of lipoprotein-cholesterol biosynthesis and subsequent clearance from plasma by the fetal adrenals wherein cholesterol is used as substrate for steroid biosynthesis.

The Role of Dafachronic Acid Signaling in Development and Longevity in Caenorhabditis elegans: Digging Deeper Using Cutting-Edge Analytical Chemistry

Abstract: Steroid hormones regulate physiological processes in species ranging from plants to humans. A wide range of steroid hormones exist, and their contributions to processes such as growth, reproduction, development, and aging, is almost always complex. Understanding the biosynthetic pathways that generate steroid hormones and the signaling pathways that mediate their effects is thus of fundamental importance. In this work, we review recent advances in (i) the biological role of steroid hormones in the roundworm Caenorhabditis elegans and (ii) the development of novel methods to facilitate the detection and identification of these molecules. Our current understanding of steroid signaling in this simple organism serves to illustrate the challenges we face moving forward. First, it seems clear that we have not yet identified all of the enzymes responsible for steroid biosynthesis and/or degradation. Second, perturbation of steroid signaling affects a wide range of phenotypes, and subtly different steroid molecules can have distinct effects. Finally, steroid hormone levels are critically important, and minute variations in quantity can profoundly impact a phenotype. Thus, it is imperative that we develop innovative analytical tools and combine them with cutting-edge approaches such as comprehensive and highly selective liquid chromatography coupled to mass spectrometry (LC-MS) based or new methods such as supercritical fluid chromatography coupled to mass spectrometry (SFC-MS) if we are to obtain a better understanding of the biological functions of steroid signaling.