What is the difference between steroids and enzymes

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Nucleic Acids Res. Georget, S. Trafficking of the androgen receptor in living cells with fused green fluorescent protein-androgen receptor. Download references. You can also search for this author in PubMed Google Scholar. Correspondence to Shogo Haraguchi or Kazuyoshi Tsutsui. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Reprints and Permissions.

Nozaki, M. Expression of steroidogenic enzymes and metabolism of steroids in COS-7 cells known as non-steroidogenic cells. It also was reported that CYP11B2 does not utilize corticosterone efficiently as a substrate for aldosterone synthesis, thus providing additional evidence that the biosynthesis of aldosterone occurs with deoxycorticosterone as substrate and the catalysis is solely mediated by CYP11B2 and does not involve the sequential action of CYP11B1 followed by CYP11B2 The reactions catalyzed by B1 and B2 are the same as described above for the human and mouse enzymes.

B3 can convert deoxycorticosterone to hydroxycorticosterone, but lacks 18 oxidase activity and thus cannot synthesize aldosterone Enzymatic reaction catalyzed by CYP11B1. This enzyme uses the mitochondrial electron transfer system. Enzymatic reaction catalyzed by CYP11B2. The enzyme catalyzes three sequential reactions, each requiring one molecule of oxygen and one molecule of NADPH. These two genes are closely linked, separated by approximately 40 kb The two genes in mouse found on chromosome 15 are separated by approximately 8 kb Each of the genes consists of nine exons and comprises about 7 kb , Interestingly, the location of the introns in human genes is identical to the location of the introns of the CYP11A gene that encodes the CYP11A protein and accounts for the inclusion of these three CYP genes as members of the same P gene superfamily, i.

In mouse and human genes, the sequence in the three regions—the heme binding domain, the aromatic region, and the region comprising the ozol peptide, which are highly conserved in all P steroidogenic enzymes—is essentially identical B1 , B2 , and B3 have similar structures consisting of nine exons, the same as human and mouse genes The location of the introns in each of these three genes is identical. The B4 gene lacks the exon 3 sequence and part of the exon 4 sequence found in other rat CYP11B genes, and thus, is believed to be a pseudogene The proteins are located in the inner mitochondrial membrane and thus are synthesized including a leader sequence of 24 aa that is cleaved in the mitochondria to yield a protein of aa in human and aa in mouse.

Expression of CYP11B1 appears to be severalfold greater than expression of B2 in both human and rat adrenal glands 10 , In contrast, Domalik et al. The study did not differentiate between the expression of the B1 and B2 proteins due to the unavailability of an antibody that can distinguish between these two enzymes. Coulter and Jaffe examined human fetal adrenal glands between 13 and 24 wk gestation and fetal adrenal glands from rhesus monkeys from d gestation to term.

This pattern of expression was found in adrenal glands until postnatal d 18 with no differences observed in expression in glands from male and female pups. In adrenal glands from mature rats, B3 expression is considerably less than B1.

A major nuclear factor that determines cell-specific expression of P steroidogenic enzymes in gonads and adrenal glands was identified in two laboratories in Although SF-1 is essential for cell-specific gonadal and adrenal expression, other factors are necessary for determining both maximal and cell-specific expression of these enzymes.

Adrenal-specific expression of the CYP21 genes in both human and mouse is mediated by cell-specific elements located within the corresponding C4B and C4A genes. Chronic, but not acute, stimulation by pituitary peptide hormones ACTH in the adrenal zona reticularis and zona fasciculata; LH in ovarian theca, corpus lutea, and testicular Leydig cells; and FSH in ovarian granulosa cells , acting via G protein-coupled receptors, activates adenylate cyclase thereby increasing cAMP, which in turn, leads to increased synthesis of the steroidogenic P enzymes specific for these cells [reviewed for bovine P enzymes by Waterman and Waterman and Keeney ].

Although, hormone-stimulated increases in cAMP enhance the expression of all of the steroidogenic P enzymes, additional factors are involved in maintaining maximal expression, with the exception of CYP17 whose expression appears to be entirely dependent on cAMP stimulation , These studies would indicate that the protein kinase C PKC pathway is not involved in mediating aldosterone-stimulated increases in CYP11B2 transcription.

In a recent study, Bassett et al. The placental-specific expression of these enzymes is dependent on factors distinct from those regulating expression in gonadal and adrenal cells.

SF-1, which is essential for expression of these enzymes in adrenal and gonadal cells, is not present in human placenta Identification of factors regulating the placental-specific expression of human CYP11A has long been sought. Hum et al. However, this nuclear protein also was found in other nonsteroidogenic cells that do not express CYP11A A recent study reported the isolation of a placental-specific nuclear protein that specifically binds to a conserved proximal region, SCC1, in the promoter of the human, rat, mouse, ovine, bovine, and porcine CYP11A gene This placental nuclear protein turned out to be activating protein 2 AP Interestingly, the AP-2 binding sequence overlaps with the previously identified SF-1 sequence that determines the gonadal- and adrenal-specific expression of CYP11A.

Placental expression of CYP19 in human and nonhuman primates, ungulates, and rabbits is under the control of a placental-specific exon 1 The placental-specific exon for human has been described above.

CYP19 is not expressed in the placenta of either mouse or rat Relatively little is known regarding the transcription factors that determine placental-specific expression of CYP Kamat et al.

From their studies, they conclude that this region contains both placental-specific positive elements and specific sequences that bind inhibitory transcription factors in nontrophoblast cells. Yamada et al. The number of isoforms or isozymes varies in different species, in tissue distribution, catalytic activity whether they function predominantly as dehydrogenases or reductases , substrate and cofactor specificity, and subcellular localization. The different isoforms are numbered in the order in which they were identified; therefore, the same numeral in different species does not indicate that they are orthologous see Table 2 for human and mouse isoforms.

The largest number of isoforms six was identified in mouse. These isoforms are highly homologous in their aa sequence, but fall into two distinct functional groups. This reaction is catalyzed by a single dimeric protein without the release of the intermediate or coenzyme Each of these isoforms is the product of a distinct gene. Mouse Hsd3b genes are located in a cluster on mouse chromosome 3 close to the centromeric region that shows conservation of gene order and physical distance with the centromeric region of human chromosome 1 4 , Human HSD3B genes are found on chromosome 1p All of the HSD3B genes isolated to date consist of four exons, with the start site of translation found in exon 2 The two human genes are approximately 7.

The size of the mouse Hsd3b genes varies due to differences in the size of their introns , The greatest difference in the mouse genes was found in the size of intron 1 of the mouse Hsd3b6 gene that was determined to be 3. The aa sequences among the isoforms and between the mouse and human isoforms show a high degree of identity.

The cofactor binding site is found in the amino-terminal sequence. Immunolabeling was detected mostly in the endoplasmic reticulum, but also over the vesicular crista membranes of the mitochondria According to studies by Pelletier et al. High expression was seen in interstitial and luteal cells. Immunoreactivity was detected mostly in the endoplasmic reticulum, with some labeling in the crista membranes of the mitochondria In their investigations examining fetal human adrenal glands during midgestation by immunohistochemistry and in situ hybridization, Mesiano et al.

However, expression was detected during late gestation in the monkey fetal adrenal gland. Narasaka et al. Leers-Sucheta et al. In addition, these authors reported that this SF-1 response element also was found to be essential for mediating phorbal ester-induced transcriptional activity. An earlier study on the analysis of the mouse Hsd3b1 promoter identified three potential SF-1 consensus binding sites in the proximal promoter In a subsequent study, it was shown that SF-1 also was required for the expression of mouse Hsd3b1 These two isoforms are essential for the biosynthesis of progesterone in human placenta and in mouse giant trophoblast cells, respectively.

As described above, SF-1 is not expressed in either human or mouse placenta , These transcription factors are also expressed in human placenta. These enzymes catalyze the final step in the biosynthesis of active gonadal steroid hormones, estradiol, and testosterone, and unlike other steroidogenic enzymes described in this review, 17HSDs are not involved in the biosynthesis of adrenal steroids.

Although in in vitro studies these enzymes can function as either reductases or oxidases of the keto group, in intact cells they function in a unidirectional manner The 17HSDs are found as either membrane-bound or soluble enzymes Table 2.

To date, 11 different 17HSDs have been identified. So far, in human, nine different 17HSDs have been cloned, 1—5, 7, 8, 10, and 11 9. The 17HSDs differ in tissue distribution, catalytic preferences, substrate specificity, subcellular localization, and mechanisms of regulation. Among the many different forms of 17HSDs, three forms participate in the final step of biosynthesis of active steroid hormones in gonads, types 1, 3, and 7, and therefore will be the only types discussed in this review.

For discussion of the other types of 17HSDs, see reviews in Refs. The recently introduced nomenclature for 17HSD is based on the genetic identity of the enzymes and their functionality. Furthermore, the 17HSDs were numbered chronologically as they were identified.

Among species, orthologs are assigned the same number; for example, type 4 17HSDs in human, rodent, guinea pig, pig, or chicken are all orthologs of the same enzyme. However, several recently discovered 17HSDs initially were assigned other gene names because a different functionality was studied 9.

It was cloned originally from a human placental library and subsequently found to be expressed in ovary and the mammary gland Human 17HSD1 has substrate specificity for estrogens, whereas the rodent enzyme can utilize both estrogens and androgens; NADPH is the preferred cofactor for conversion of estrone to estradiol Fig.

Whereas human 17HSD1 predominantly catalyzes the conversion of estrone to estradiol, mouse and rat 17HSD1 also efficiently convert androstenedione to testosterone Enzymatic reaction catalyzed by 17HSD isozymes.

Human type I uses estrone as substrate and acts predominantly as a reductase, whereas the rat type I can use estrone and androstenedione equally as substrate Type III acts predominantly as a reductase and preferentially uses androstenedione as substrate Type VII acts predominantly as a reductase and preferentially uses estrone as substrate , The human gene, HSD17B1 , maps to chromosome 17qq21 and encodes a aa protein having a calculated molecular mass of The mouse gene, mHsd17b1 , maps to chromosome 11 and encodes a aa protein with a predicted molecular mass of Only the expression of the shorter transcript is correlated with changes in 17HSD1 protein levels , The three-dimensional structure was solved in The 17HSD1 protein exists as a homodimer, consisting of noncovalently bound but tightly associated subunits; stable dimerization of the enzyme is required for its enzymatic activity The x-ray structure of the dimer indicates that there are two dimerization helices in each monomer forming a four-helix bundle Disruption of the helices by site-directed mutagenesis of specific aa results in improper folding and aggregation Despite the limited sequence homology, the crystal structure of 17HSD1 revealed a fold characteristic of other SDRs Together, the conserved pentapeptide and the cofactor and substrate binding sites comprise the catalytic triad of all members of the SDR The tyrosine residue plays a critical role in the catalytic reaction as a proton donor.

The lysine residue is postulated to stabilize cofactor binding by interacting with the hydroxyl groups of the nicotinamide ribose The inserted helices, which are located at one end of the substrate-binding cleft away from the catalytic triad, restrict access to the active site and appear to influence substrate specificity , When estradiol is docked in the substrate-binding site with the hydroxyl oriented toward the catalytic triad, the steroid molecule fits properly in the pocket.

The histidine on the helical insert of residues to can form a hydrogen bond to oxygen at position 3 of the steroid A-ring, thus creating specific binding of estranes and androstanes , Site-directed mutagenesis of His demonstrated that this residue is essential for catalytic activity The insertions reduce the openness of the binding pocket to introduce substrate-binding specificity.

By analyzing various rat and human chimeric proteins, together with site-directed mutation analysis, the difference in substrate specificity between human and rat 17HSD1 was revealed to be due to several aa variations at the recognition end of the catalytic cleft that alters the preference for neutral vs. The current model predicts that the hydroxyl groups of the conserved serine and tyrosine in the active site form a triangular hydrogen bond network enabling hydride transfer and reduction of estrone Furthermore, the three-dimensional structure revealed not only the position of the catalytic triad as well as the molecular mechanism of inhibition and the basis for substrate selectivity, but also a possible mechanism of keto-hydroxyl interconversion , Immunoreactive 17HSD1 protein has been confirmed in the syncytiotrophoblast of human placenta and in granulosa cells of human ovary.

In ovarian granulosa cells of developing follicles in cycling humans and rodents, 17HSD1 converts estrone to estradiol. Upon ovulation, follicles luteinize and transform into corpora lutea and continue to secrete estradiol at high concentrations although, upon luteinization, 17HSD1 expression declines precipitously in the ovary. The discovery of 17HSD7 explained the apparent paradoxical conversion of estrone to estradiol in the absence of 17HSD1. During the luteal phase of the ovarian cycle, estradiol is secreted mainly from the corpus luteum, where 17HSD7, not 17HSD1, is responsible for the final step in estradiol synthesis — The human and rodent forms of the enzyme efficiently catalyze the conversion of estrone to estradiol , The human gene, HSD17B7 , consists of nine exons and eight introns, spanning The mouse gene, mHsd17b7 , maps to chromosome 1.

The mouse cDNA is 1. Recently, Torn et al. They also identified and localized a pseudogene to 1q In this more recent report, Torn et al. In addition, m17HSD7 contains the three critical residues, Ser , Tyr , and Lys , of the catalytic triad as well as the glycine pattern, Gly 9 -X-X-X-Gly 13 -X-Gly 15 , all of which are involved in cofactor binding, required for catalytic activity and characteristic of SDR enzymes , , , , Expression is most abundant around E In the uterus, 17HSD7 is first detected on E5.

By E In contrast to rodent enzymes, the physiological significance of human 17HSD7 and its presumed function in reproduction are not well understood.

In human, the placenta develops as the major source of estradiol, and 17HSD1 is highly expressed throughout pregnancy for estradiol synthesis in syncytiotrophoblasts. Human 17HSD7 is strongly expressed in the ovaries of nonpregnant women.

However, in contrast to rodent enzymes, human 17HSD7 is not detected in the ovaries of pregnant women The human gene HSD17B3 , which maps to chromosome 9q22, is 60 kb in length and contains 11 exons. The cDNA encodes a protein of aa with a molecular mass of The molecular mass of mouse protein is Four of these aa are missing at the N terminus, and the other is Val of the human sequence. The overall aa identity of mouse protein to human protein is The mouse gene, mHsd17b3 , maps to chromosome 13 As mentioned previously, the different 17HSDs, all members of the SDR superfamily, show little homology to each other.

Structure-function relationships have been deduced from genetic analysis of the 17HSDB3 gene from male pseudohermaphrodite patients with compromised testosterone synthesis. One of the causes of pseudohermaphroditism in male patients was identified as a point mutation in the open reading frame of exon 9 resulting in a loss of catalytic activity of 17HSD3 , Other mutations have been identified that map to exon 3 leading to decreased cofactor NADPH binding , The mutations that caused decreased cofactor binding were shown to involve the tyrosine residue at position Site-directed mutational analysis targeted at Tyr 80 demonstrated that this tyrosine is critical for cofactor binding and that substitution with different aa results in alterations in cofactor preference, switching from NADPH to NADH Its expression is restricted to the adult Leydig cell population and thus serves as a specific marker for Leydig cell development They reported that 17HSD3 was expressed in seminiferous tubules until neonatal d 10, with little or no expression observed between d 10 and 20 followed by increased expression between d 20 and 30 in interstitial tissue.

In situ hybridization confirmed exclusive expression of 17HSD3 in seminiferous tubules of fetal testes and in interstitial tissue of adult testes.

The expression of 17HSD1 exhibits species-specific differences, which may be due to distinct mechanisms that control cell- and tissue-specific regulation. Luteinizing agents cause a significant drop in 17HSD1 expression, and thus, 17HSD1 is not expressed in the corpus luteum The high levels of 17HSD1 that are maintained in syncytiotrophoblasts during pregnancy are thus likely due to the contribution of several factors Three functional regulatory elements have been described for the human gene, hHSD17B1 : a retinoic acid response element; adjacent and competing AP-2, Sp1, and Sp3 elements, which act as transcription enhancers; and a GATA element, which acts as a transcriptional repressor.

Deletion of the retinoic acid response element results in loss of response to retinoic acid, which has been shown to enhance 17HSD1 expression in both JEG-3 choriocarcinoma cells and T54D breast cancer cells.

Sp1 and Sp3 are widely distributed transcription factors both of which bind to the same GC-rich Sp motif. Sp1 activates a significant number of promoters and has been shown to compete with Sp3 for binding to the shared sequence, thus limiting its activity. Combinatorial transcriptional regulation of the hHSD17B1 gene by the retinoic acid response element, competing Sp and AP-2 sites, and GATA repressor elements are likely to participate in the expression of the gene and may guide its cell- and tissue-specific expression During the luteal phase of the rodent ovarian cycle, estradiol is secreted mainly from the corpus luteum, where 17HSD7, not 17HSD1, is responsible for the final step in estradiol synthesis — If fertilization occurs, the corpora lutea continue to secrete progesterone and estradiol.

In the rat, estradiol continues to be produced from ovarian and placental precursors throughout pregnancy as the corpus luteum of pregnancy further matures as a result of prolactin stimulation In the first half of rat pregnancy, steroidogenesis in the corpus luteum is stimulated by prolactin and LH, and estradiol is synthesized from ovarian androgen precursors. At midpregnancy, LH and prolactin are down-regulated, and the luteal-placental shift takes place, at which time the placenta begins to produce the androgen precursors needed for increased estradiol synthesis by the ovaries.

They studied the expression of 17HSD3 mRNA in hpg mice, which lack gonadotropins, and Tfm mice, which lack functional androgen receptors. From these studies, it was concluded that during early postnatal development, 17HSD3 expression is independent of gonadotropin stimulation, but after puberty becomes dependent upon testicular descent, gonadotropins, and especially, androgen action Although this review emphasizes the enzymes involved in the biosynthesis of active steroid hormones from cholesterol in gonads, adrenal cells, and placenta, in recent years, evidence has been obtained for the de novo synthesis of some steroid hormones in the nervous system 13 , 14 , and more recently, in cardiac tissue 15 — Steroids synthesized in the nervous system are referred to as neurosteroids.

Neurosteroids act as paracrine factors within the nervous system, unlike steroid hormones synthesized in gonads and adrenal glands that are carried in the circulation to their target sites where they initiate action. The specific enzymes and their sites of expression in the nervous system are described in the recent review by Mellon and Griffin All of the studies on the expression of enzymes in the nervous system are based on studies in rodents.

To date, there is no evidence for the expression of CYP21 indicating that de novo synthesis of adrenal steroid hormones does not take place in the nervous system However, this does not rule out the possibility that circulating deoxycortisone or deoxycortisol could function as substrate for neural CYP11B1 or B2.

The biological responses of neurosteroids are mediated via either nuclear receptors or neuroreceptors Evidence for the expression of steroidogenic enzyme mRNAs in cardiac tissue obtained from human normal and failing hearts as well as cardiac tissue from mice and rats has been reported recently 15 , Kayes-Wandover and White 15 examined the expression of steroidogenic enzyme mRNA in samples from various regions of the adult human heart as well as samples obtained from whole adult and fetal heart.

CYP11B2 was detected in the aorta and fetal heart, but not in any of the other regions of the adult heart. CYP17 was not detected in any of the cardiac samples. These results suggest that the normal adult heart has the potential for synthesizing corticosterone and deoxycorticosterone, but not cortisol or aldosterone. The relative amount of mRNA detected was approximately 0. Young et al. In general, their findings were in agreement with those reported by Kayes-Wandover and White, with the exception that Young et al.

These studies by Kayes-Wandover and White 15 and by Young et al. Additional studies are needed to establish the relevancy of cardiac expression of steroidogenic enzymes. The expression of these enzymes in target tissues is of particular importance in humans where adrenal glands secrete high amounts of DHEA and DHEA sulfate.

The synthesis of active steroid hormones from adrenal secreted precursors allows for the local production of specific steroid hormones within the target cell. Nagata et al. In these tissues, 17HSD1 catalyzes the conversion of estrone derived from the circulation to the more potent estrogen, estradiol The expression of 17HSD 5 in prostate glands is important for the synthesis of the active androgen, dihydrotestosterone, from adrenal DHEA The peripheral expression of aromatase is critical, especially in men and postmenopausal women.

Peripheral expression of aromatase is determined by tissue-specific promoters of the aromatase gene as discussed in the section on CYP A major site of peripheral expression of aromatase is in adipose tissues of both men and women 12 , The conversion of C19 androgens to estrogens in adipose tissue increases with age in postmenopausal women and in elderly men 12 , The primary site of expression in adipose tissue is in stromal mesenchymal cells Although the major source of estrogen for proper epiphyseal closure is derived from peripheral aromatization in adipose tissue, aromatase also is expressed in both osteoblasts and chondrocytes of human males and females Sasano et al.

Brain is another major site of peripheral expression of aromatase. Aromatase is primarily expressed in the hypothalamus and limbic regions of the brain. Early studies on aromatization in the hypothalamus of male and female rats were reported by Naftolin et al. More recent studies describing the expression of CYP19 in various areas of the brain and retina are reviewed in Simpson et al.

With newly available techniques such as microarray analysis, we predict that many more peripheral sites of expression of steroidogenic enzymes will be found that will lead to the discovery of previously unknown sites of action of steroid hormones. It belongs to the aldo-ketosteroid reductase superfamily Miller WL Molecular biology of steroid hormone synthesis. Endocr Rev 9 : — Google Scholar.

Mol Endocrinol 5 : — Endocrinology : — Genomics 16 : — Mol Endocrinol 7 : — Mol Endocrinol 9 : — J Biol Chem : — Mol Cell Endocrinol : 1 — 4. Annu Rev Physiol 64 : 93 — Baulieu EE Neurosteroids: a novel function of the brain. Psychoneuroendocrinology 23 : — Trends Endocrinol Metab 13 : 35 — J Clin Endocrinol Metab 85 : — J Clin Endocrinol Metab 86 : — White PC Aldosterone: direct effects on and production by the heart.

J Clin Endocrinol Metab 88 : — Endocr Rev 18 : — Mol Endocrinol 6 : — Steroids can be divided into different groups of parent compounds, based on the number of carbons that they contain Fig. In addition to gonanes, which consist of 17 carbons, estranes consist of 18 carbons C18 steroids and include estrogens.

Androstanes have 19 carbons C19 steroids and include androgens. Pregnanes contain 21 carbons C21 steroids and include progesterone and corticosteroids. This chapter focuses primarily on C18, C19, and C21 steroids.

Cholanes have 24 carbons and include bile acids, and cholestanes have 27 carbons and include cholesterol as well as cholesterol-like compounds.

The compounds in this group are also referred to as sterols. Figure 2. Classification of steroids, based on the number of carbons in the molecule. In each group of parent steroids, compounds differ in their characteristics because of the presence of different functional groups on the molecules. Common functional groups include the ketone group, hydroxyl group, and double bond, as shown in the chemical structure of the cortisol molecule in Figure 3.

Other functional groups include the carboxyl and aldehyde groups, which are present in the molecules of bile acids and aldosterone, respectively see Fig. An important characteristic of the C18 steroids is the presence of an aromatic ring that is found in estrogens e.

Figure 3. Functional groups present in chemical structures of steroids. Sources of steroid hormone formation in the body can be divided into two types Table 1. One source is the endocrine glands. In women, they include the adrenals, ovaries, and placenta, which is an incomplete endocrine gland. In men, the endocrine glands include the adrenals and testes. A second source of steroid hormones in the body is peripheral tissues.

These are nonendocrine tissues such as the liver, intestine, fat, skin, kidneys, and brain. The first steroidal precursor for biosynthesis of steroid hormones in the adrenals, ovaries, and testes is cholesterol. In these endocrine glands, cholesterol can be synthesized de novo from acetate by a complex series of reactions.

Alternatively, it can be obtained directly from circulating low-density lipoprotein LDL cholesterol. Cholesterol can be converted to a variety of steroid hormones in the endocrine glands through the action of specific enzymes, encoded by different genes. The first and rate-limiting reaction in the formation of steroid hormones is the conversion of cholesterol to pregnenolone, which is stimulated by adrenocorticotropin hormone ACTH in the adrenals and by LH in the ovaries and testes.

This reaction is complex and occurs in the mitochondria. It is catalyzed by the enzyme Clyase also referred to as Cdesmolase , which is encoded by the CYP11A gene.

A key step in the reaction is the transport of cholesterol from extracellular sources to the inner mitochondrial membrane, and subsequent loading of the precursor into the active site of the enzyme.

Intramitochondrial cholesterol movement appears to involve coordinated activation of the steroidogenic acute regulatory StAR protein and peripheral-type benzodiazepine receptor. Once pregnenolone is formed, it can then be converted to progesterone, androgens, estrogens, and corticosteroids.

Although the adrenals, ovaries, and testes can all synthesize androgens, only the adrenals produce corticosteroids. The ovaries and testes, but not the adrenals, can form estrogens. This does not mean that the adrenals, ovaries, and testes lack the enzymes to synthesize estrogens, or corticosteroids. This is evident in feminizing adrenal tumors, which produce estrone and estradiol in high amounts, and in testicular and ovarian tumors that produce certain corticosteroids.

Thus, it appears that the activity of certain steroidogenic enzymes in the adrenals, ovaries, and testes are suppressed by mechanisms that are not yet understood. The placenta also does not express certain steroidogenic enzymes and, as mentioned previously, is an incomplete endocrine organ.

It lacks the enzymes required to form cholesterol, as well as those required to convert progesterone to androgens, and subsequently estrogens. Figure 4 illustrates the biosynthetic pathways leading to the formation of androgens and estrogens in the ovaries and testes.

The relative importance of the two pathways is poorly understood. Figure 4. Biosynthesis of steroid hormones in the ovaries and testes. As the name oxidoreductase implies, the reaction in which DHEA is converted to androstenediol involves reduction addition of two hydrogens to the ketone group at carbon 17 of DHEA or oxidation removal of two hydrogens from the hydroxyl group at carbon 17 of androstenediol. Thus, the conversion of DHEA to androstenediol is reversible.

The enzymatic reaction involves oxidation, that is, removal of two hydrogens from the hydroxyl group at carbon 3, forming a ketone group. In contrast to the reversible formation of androstenediol from DHEA, this reaction is not reversible to any significant extent. Once the ketone group is formed, the double bond between carbons 5 and 6 is rapidly shifted and becomes located between carbons 4 and 5 through the action of the isomerase enzyme. It is localized predominantly in the ovary granulosa cells and placenta syncytiotrophoblast.

The enzyme is distributed among many extraglandular tissues, such as endometrium, placenta, and liver; however, it is primarily expressed in the endometrium. The activity of the type 2 isoenzyme is increased during the luteal phase of the menstrual cycle in a manner that parallels circulating progesterone levels during the cycle.

It appears that the type 4 isoenzyme catalyzes the oxidation of C18 steroids, for example, estradiol to estrone, whereas the type 5 isoenzyme catalyzes the reduction of C19 steroids, for example, androstenedione to testosterone.

These individuals have testes, wolffian duct-derived male internal genitalia with the exception of a prostate , female external genitalia, and gynecomastia. The two androgens, androstenedione and testosterone, can undergo a series of complex reactions aromatization catalyzed by the aromatase enzyme, forming the estrogens, estrone E 1 and estradiol E 2 , respectively.

This reaction is encoded by the CYP19 gene. Figure 5 shows the biosynthetic pathways of steroid hormone formation, which includes mineralocorticoids, glucocorticoids, and androgens, in the adrenals. Because aromatase activity is not expressed in the adrenals, no estrogens are formed. Instead, the adrenals form corticosteroids. They are formed by the mineralocorticoid and glucocorticoid pathways. Figure 5. Biosynthesis of mineralocorticoids, glucocorticoids, and androgens in the adrenals.

The mineralocorticoid pathway starts with hydroxylation of progesterone to form deoxycorticosterone DOC. The enzyme in this reaction, hydroxylase, is encoded by the CYP21 gene. These two reactions are catalyzed by hydroxylase and hydroxysteroid dehydrogenase, respectively, which are encoded by the same gene, CYP11B2.

Instead, the placenta uses precursors from the mother and fetus to make estrogens see Fig. Subsequently, both androgens are transformed to estrone and estradiol via the enzyme, aromatase. Figure 6. Formation of progesterone, estrone, and estradiol in the placenta.

Because of the fact that the estriol precursor originates predominantly from the fetus, serum estriol levels have been used for many years to monitor fetal well-being. Use of this marker was replaced with nonhormonal types of antepartum testing. Figure 7. Formation of estriol in the placenta. So far, the pathways of steroid hormone biosynthesis that have been discussed occur in the endocrine glands.

Steroid hormones are also formed in peripheral tissues but not de novo , that is, from acetate or cholesterol. Instead, they are synthesized from circulating precursors made in the endocrine glands. Two important steroidogenic reactions that occur in peripheral tissues are the conversion of androgens to estrogens in adipose tissue, and transformation of testosterone to the more potent androgen, dihydrotestosterone DHT in skin.

Adipose tissue has high activity of the enzyme aromatase, which efficiently converts androstenedione to estrone and, to a lesser extent, testosterone to estradiol. This is the mechanism by which estrogens are formed in postmenopausal women. CBG binds with high affinity but low capacity to corticosteroids, progesterone, and hydroxyprogesterone. Table 3 shows the binding distribution of important endogenous steroid hormones in normal women during the menstrual cycle. Free steroids are available for action in target cells and also for metabolism in peripheral tissues.

Table 3. Westphal U. Steroid-Protein Interactions, p