Editing Steroid (section)

== Biosynthesis and metabolism ==
<!-- Diagram illustrating a metabolic pathway and important for the understanding of the section, therefore prominently placed -->
[[File:Sterol synthesis.svg|thumb|300px|alt=Chemical-diagram flow chart|class=skin-invert-image|Simplification of the end of the steroid synthesis pathway, where the intermediates [[isopentenyl pyrophosphate]] (PP or IPP) and [[dimethylallyl pyrophosphate]] (DMAPP) form [[geranyl pyrophosphate]] (GPP), [[squalene]] and [[lanosterol]] (the first steroid in the pathway)]]
The hundreds of steroids found in animals, fungi, and [[plant]]s are made from [[lanosterol]] (in animals and fungi; see examples above) or [[cycloartenol]] (in other eukaryotes). Both lanosterol and cycloartenol derive from [[Cyclic compound|cyclization]] of the [[triterpene|triterpenoid]] [[squalene]].<ref name="urlLanosterol biosynthesis"/> Lanosterol and cycloartenol are sometimes called protosterols because they serve as the starting compounds for all other steroids.

Steroid biosynthesis is an [[anabolism|anabolic]] pathway which produces steroids from simple precursors. A unique biosynthetic pathway is followed in animals (compared to many other [[organism]]s), making the pathway a common target for [[antibiotic]]s and other anti-infection drugs. Steroid metabolism in humans is also the target of cholesterol-lowering drugs, such as [[statin]]s. In humans and other animals the biosynthesis of steroids follows the mevalonate pathway, which uses [[acetyl-CoA]] as building blocks for [[dimethylallyl pyrophosphate|dimethylallyl diphosphate]] (DMAPP) and [[isopentenyl pyrophosphate|isopentenyl diphosphate]] (IPP).<ref name="pmid16621811">{{cite journal | vauthors = Grochowski LL, Xu H, White RH | title = Methanocaldococcus jannaschii uses a modified mevalonate pathway for biosynthesis of isopentenyl diphosphate | journal = Journal of Bacteriology | volume = 188 | issue = 9 | pages = 3192–8 | date = May 2006 | pmid = 16621811 | pmc = 1447442 | doi = 10.1128/JB.188.9.3192-3198.2006 }}</ref>{{better source needed|date=July 2014}}

In subsequent steps DMAPP and IPP conjugate to form [[Farnesyl pyrophosphate|farnesyl diphosphate]] (FPP), which further conjugates with each other to form the linear triterpenoid squalene. Squalene biosynthesis is catalyzed by [[Farnesyl-diphosphate farnesyltransferase|squalene synthase]], which belongs to the [[squalene/phytoene synthase family]]. Subsequent [[Epoxide|epoxidation]] and cyclization of squalene generate lanosterol, which is the starting point for additional modifications into other steroids (steroidogenesis).<ref name="pmid30258364">{{cite journal| vauthors = Chatuphonprasert W, Jarukamjorn K, Ellinger I |date=12 September 2018|title=Physiology and Pathophysiology of Steroid Biosynthesis, Transport and Metabolism in the Human Placenta|journal=Frontiers in Pharmacology|volume=9|pages=1027|doi=10.3389/fphar.2018.01027|issn=1663-9812|pmc=6144938|pmid=30258364|doi-access=free}}</ref> In other eukaryotes, the cyclization product of epoxidized squalene (oxidosqualene) is cycloartenol.

=== Mevalonate pathway ===
<!-- Diagram illustrating a metabolic pathway and important for the understanding of the section, therefore prominently placed -->
[[File:Mevalonate pathway.svg|thumb|300px|alt=Chemical flow chart|class=skin-invert-image|Mevalonate pathway]]
{{Main|Mevalonate pathway}}
The mevalonate pathway (also called HMG-CoA reductase pathway) begins with [[acetyl-CoA]] and ends with [[dimethylallyl pyrophosphate|dimethylallyl diphosphate]] (DMAPP) and [[isopentenyl pyrophosphate|isopentenyl diphosphate]] (IPP).

DMAPP and IPP donate [[isoprene]] units, which are assembled and modified to form [[terpene]]s and [[terpenoid|isoprenoids]]<ref name="pmid12735695">{{cite journal | vauthors = Kuzuyama T, Seto H | title = Diversity of the biosynthesis of the isoprene units | journal = Natural Product Reports | volume = 20 | issue = 2 | pages = 171–83 | date = Apr 2003 | pmid = 12735695 | doi = 10.1039/b109860h }}</ref> (a large class of lipids, which include the [[carotenoid]]s and form the largest class of plant [[natural product]]s).<ref name="pmid14517367">{{cite journal | vauthors = Dubey VS, Bhalla R, Luthra R | title = An overview of the non-mevalonate pathway for terpenoid biosynthesis in plants | journal = Journal of Biosciences | volume = 28 | issue = 5 | pages = 637–46 | date = Sep 2003 | pmid = 14517367 | doi = 10.1007/BF02703339 | s2cid = 27523830 | url = http://www.ias.ac.in/jbiosci/sep2003/637.pdf | url-status = dead | archive-url = https://web.archive.org/web/20070415213325/http://www.ias.ac.in/jbiosci/sep2003/637.pdf | archive-date = 15 April 2007 }}</ref> Here, the activated isoprene units are joined to make [[squalene]] and folded into a set of rings to make [[lanosterol]].<ref name="pmid7023367">{{cite journal | vauthors = Schroepfer GJ | title = Sterol biosynthesis | journal = Annual Review of Biochemistry | volume = 50 | pages = 585–621 | year = 1981 | pmid = 7023367 | doi = 10.1146/annurev.bi.50.070181.003101 }}</ref> Lanosterol can then be converted into other steroids, such as cholesterol and [[ergosterol]].<ref name="pmid7023367"/><ref name="pmid7791529">{{cite journal | vauthors = Lees ND, Skaggs B, Kirsch DR, Bard M | title = Cloning of the late genes in the ergosterol biosynthetic pathway of Saccharomyces cerevisiae—a review | journal = Lipids | volume = 30 | issue = 3 | pages = 221–6 | date = Mar 1995 | pmid = 7791529 | doi = 10.1007/BF02537824 | s2cid = 4019443 }}</ref>

{{anchor|Pharmacological actions}}
Two classes of [[medication|drugs]] target the [[mevalonate pathway]]: [[statin]]s (like [[rosuvastatin]]), which are used to reduce [[hypercholesterolemia|elevated cholesterol levels]],<ref name="pmid21267417">{{cite journal | vauthors = Kones R | title = Rosuvastatin, inflammation, C-reactive protein, JUPITER, and primary prevention of cardiovascular disease—a perspective | journal = Drug Design, Development and Therapy | volume = 4 | pages = 383–413 | date = December 2010 | pmid = 21267417 | pmc = 3023269 | doi = 10.2147/DDDT.S10812 | doi-access = free }}</ref> and [[bisphosphonate]]s (like [[zoledronate]]), which are used to treat a number of bone-degenerative diseases.<ref name="pmid17062705">{{cite journal | vauthors = Roelofs AJ, Thompson K, Gordon S, Rogers MJ | title = Molecular mechanisms of action of bisphosphonates: current status | journal = Clinical Cancer Research | volume = 12 | issue = 20 Pt 2 | pages = 6222s–6230s | date = October 2006 | pmid = 17062705 | doi = 10.1158/1078-0432.CCR-06-0843 | s2cid = 9734002 | doi-access =  }}</ref>

=== <span class="anchor" id="Regulation">Steroidogenesis</span> ===
<!-- Diagram illustrating a metabolic pathway and important for the understanding of the section, therefore prominently placed -->
[[File:Steroidogenesis.svg|thumb|300px|alt=Chemical-diagram flow chart|class=skin-invert-image|Human steroidogenesis, with the major classes of steroid hormones, individual steroids and [[Enzyme|enzymatic]] pathways.<ref name="HäggströmRichfield2014">{{cite journal | vauthors= Häggström M, Richfield D |year=2014|title=Diagram of the pathways of human steroidogenesis|journal=WikiJournal of Medicine|volume=1|issue=1|doi=10.15347/wjm/2014.005|issn=2002-4436 |doi-access=free}}</ref> Changes in molecular structure from a precursor are highlighted in white.]]
{{See also|Steroidogenic enzyme}}

Steroidogenesis is the biological process by which steroids are generated from cholesterol and changed into other steroids.<ref name="pmid22217824">{{cite journal | vauthors = Hanukoglu I | title = Steroidogenic enzymes: structure, function, and role in regulation of steroid hormone biosynthesis | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 43 | issue = 8 | pages = 779–804 | date = Dec 1992 | pmid = 22217824 | doi = 10.1016/0960-0760(92)90307-5 | s2cid = 112729 | url = https://zenodo.org/record/890723 | access-date = 20 April 2018 | archive-date = 26 April 2021 | archive-url = https://web.archive.org/web/20210426210129/https://zenodo.org/record/890723 | url-status = live }}</ref> The [[metabolic pathway|pathways]] of steroidogenesis differ among species. The major classes of steroid hormones, as noted above (with their prominent members and functions), are the [[progestogen]]s, [[corticosteroid]]s (corticoids), [[androgen]]s, and [[estrogen]]s.<ref name="pmid21051590"/><ref name="pmid38035948"/> Human steroidogenesis of these classes occurs in a number of locations:
* Progestogens are the precursors of all other human steroids, and all human tissues which produce steroids must first convert cholesterol to [[pregnenolone]]. This conversion is the rate-limiting step of steroid synthesis, which occurs inside the [[mitochondrion]] of the respective tissue. It is catalyzed by the mitochondrial P450scc system.<ref name="1980-Hanukoglu">{{cite journal |vauthors=Hanukoglu I, Jefcoate CR |title=Mitochondrial cytochrome P-450scc. Mechanism of electron transport by adrenodoxin |journal=J Biol Chem |volume=255 |issue=7 |pages=3057–61 |date=April 1980 |pmid=6766943 |doi=10.1016/S0021-9258(19)85851-9 |url=|doi-access=free }}</ref><ref name="1981-Hanukoglu">{{cite journal |vauthors=Hanukoglu I, Privalle CT, Jefcoate CR |title=Mechanisms of ionic activation of adrenal mitochondrial cytochromes P-450scc and P-45011 beta |journal=J Biol Chem |volume=256 |issue=9 |pages=4329–35 |date=May 1981 |pmid=6783659 |doi=10.1016/S0021-9258(19)69437-8 |url=|doi-access=free }}</ref>
* Cortisol, [[corticosterone]], aldosterone are produced in the [[adrenal cortex]].<ref name="pmid21051590" /><ref name="pmid38035948"/>
* Estradiol, [[estrone]] and progesterone are made primarily in the [[ovary]], estriol in [[placenta]] during pregnancy, and [[testosterone]] primarily in the [[testes]]<ref name="pmid21051590" /><ref name="endocrine-poster">{{cite web | url=https://www.endocrine.org/patient-engagement/endocrine-library/hormones-and-endocrine-function/reproductive-hormones | title=Reproductive Hormones | date=24 January 2022 | access-date=12 February 2024 | archive-date=10 February 2024 | archive-url=https://web.archive.org/web/20240210160236/https://www.endocrine.org/patient-engagement/endocrine-library/hormones-and-endocrine-function/reproductive-hormones | url-status=live }}</ref><ref name="hpa">{{cite book | chapter-url=https://link.springer.com/chapter/10.1007/978-3-319-44558-8_1%22 | doi=10.1007/978-3-319-44558-8_1 | chapter=The Hypothalamic–Pituitary–Ovarian Axis and Oral Contraceptives: Regulation and Function | title=Sex Hormones, Exercise and Women | date=2017 | pages=1–17 | isbn=978-3-319-44557-1 | vauthors = Davis HC, Hackney AC }}</ref><ref>{{cite encyclopedia|url=https://www.britannica.com/science/androgen|title=androgen|date=19 January 2024|access-date=12 February 2024|archive-date=29 January 2024|archive-url=https://web.archive.org/web/20240129083600/https://www.britannica.com/science/androgen|url-status=live}}</ref> (some testosterone may also be produced in the adrenal cortex).<ref name="pmid21051590" /><ref name="pmid38035948">{{cite journal |vauthors=Oestlund I, Snoep J, Schiffer L, Wabitsch M, Arlt W, Storbeck KH |title=The glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 catalyzes the activation of testosterone |journal=J Steroid Biochem Mol Biol |volume=236 |issue= |pages=106436 |date=February 2024 |pmid=38035948 |doi=10.1016/j.jsbmb.2023.106436|doi-access=free |hdl=10044/1/108335 |hdl-access=free }}</ref>
* Estradiol is converted from testosterone directly (in males), or via the primary pathway DHEA – androstenedione – estrone and secondarily via testosterone (in females).<ref name="pmid21051590" />
* [[Stromal cells]] have been shown to produce steroids in response to signaling produced by androgen-starved [[prostate cancer]] cells.<ref name="pmid27672740"/>{{primary source inline|date=March 2017}}{{better source needed|date=March 2017}}
* Some [[neurons]] and [[glia]] in the [[central nervous system]] (CNS) express the [[enzymes]] required for the local synthesis of pregnenolone, progesterone, DHEA and DHEAS, [[de novo synthesis|''de novo'']] or from peripheral sources.<ref name="pmid21051590" />{{citation needed|date=March 2017}}

{{Production rates, secretion rates, clearance rates, and blood levels of major sex hormones}}

=== Alternative pathways ===
In plants and bacteria, the [[non-mevalonate pathway]] (MEP pathway) uses [[Pyruvic acid|pyruvate]] and [[glyceraldehyde 3-phosphate]] as substrates to produce IPP and DMAPP.<ref name="pmid12735695"/><ref name="pmid15012203">{{cite journal | vauthors = Lichtenthaler HK | title = The 1-deoxy-d-xylulose-5-phosphate pathway of isoprenoid biosynthesis in plants | journal = Annual Review of Plant Physiology and Plant Molecular Biology | volume = 50 | pages = 47–65 | date = Jun 1999 | pmid = 15012203 | doi = 10.1146/annurev.arplant.50.1.47 }}</ref>

During diseases pathways otherwise not significant in healthy humans can become utilized. For example, in one form of [[congenital adrenal hyperplasia]] a [[congenital adrenal hyperplasia due to 21-hydroxylase deficiency|deficiency in the 21-hydroxylase enzymatic pathway]] leads to an excess of [[17α-Hydroxyprogesterone]] (17-OHP) – this pathological excess of 17-OHP in turn may be converted to [[dihydrotestosterone]] (DHT, a potent androgen) through among others [[CYP17A1|17,20 Lyase]] (a member of the [[cytochrome P450]] family of enzymes), [[5α-Reductase]] and [[3α-Hydroxysteroid dehydrogenase]].<ref name="pmid20671993">{{cite journal | pmc = 2910408 | pmid=20671993 | doi=10.1155/2010/625105 | volume=2010 | title=Nonclassic congenital adrenal hyperplasia | journal= International Journal of Pediatric Endocrinology| pages=1–11 | vauthors=Witchel SF, Azziz R| year=2010 | doi-access=free }}</ref>