Page not availableVarious chemicals found in the human and wildlife environments have the potential to disrupt endocrine functions in exposed organisms. Increasingly, the enzymes involved in the steroid biosynthesis pathway are being recognized as important targets for the actions of various endocrine-disrupting chemicals. Interferences with steroid biosynthesis may steroidogenic pathway of hormones in impaired reproduction, alterations in sexual differentiation, growth, and development and the development of certain cancers. Steroid hormone synthesis is controlled by the activity of several highly substrate-selective cytochrome P enzymes and a number of steroid dehydrogenases and reductases. Particularly aromatase CYP19the enzyme that converts androgens steroidogenic pathway of hormones estrogens, has been the subject of studies into the mechanisms by which chemicals interfere with sex steroid hormone homeostasis and function, often related to de feminization and de masculinazation processes. Studies in vivo and in vitro have focussed on ovarian and testicular function, with less attention steroidogenic pathway of hormones to other steroidogenic organs, such as the how does trenbolone e work cortex. This review aims to provide a comprehensive overview of the state of knowledge regarding the mechanisms by which chemicals interfere with the function of steroidogenic enzymes in various tissues and organisms.
Page not available
In humans, HSD3B2 is the isoform expressed specifically in the adrenals and gonads. Inactivating mutations of the gene frequently produce combined enzyme deficiencies, displaying hypertension, hypokalemia, and sexual infantilism. Isolated 17,lyase deficiency also occurs when lyase activity is selectively impaired by mutations of amino acid residues such as p. R that are crucial to the interaction between CYP17A1 and its redox partners P oxidoreductase and cytochrome b5 in the Pelectron donor complex.
Life-threatening mineralocorticoid and glucocorticoid deficiencies are common in infants and children. Male infants are undervirilized, and puberty is delayed in both sexes. The adrenals and gonads are enlarged and filled with lipid globules. The majority of cases of LCAH is derived from defective cholesterol transport into the mitochondria by inactivating mutation of StAR , and to a lower extent, defective pregnenolone conversion from cholesterol by inactivating mutation of Pscc.
The lack of substrate leads to adrenal steroid deficiency and absence of feedback for ACTH suppression. The elevated level of ACTH excessively stimulates cholesterol uptake and adrenal cell growth, resulting in adrenal hyperplasia. Wai-Yee Chan, in Molecular Pathology , At least 36 inactivating HSD3B2 mutations, mostly missense mutations, have been reported. Aside from complete loss of enzymatic activity, some of the mutated enzymes display impaired stability [ , ].
Most of the reported mutations alter the enzyme structure or generate truncated products and thus completely abolish both enzymatic activities. The enlarged adrenals are filled with lipid globules. Similar damage is observed in the gonads. LCAH results from defective cholesterol to pregnenolone conversion, the first step in steroidogenesis, mediated by Pscc. So far only 5 CYP11A1 mutations have been described [ ].
Most of the genetic lesions actually stem from defective cholesterol transport into the mitochondria by inactivating mutation of StAR. At least 48 inactivating mutations of StAR , most of which are missense and frameshift mutations, are known [ ]. In all cases, the activity of the mutated StARs, in terms of ligand binding and cholesterol-to-pregnenolone conversion, is severely impaired or totally lost. The general patterns for steroid hormone biosynthesis in humans and many other species are seen in Fig.
Briefly, endocrine amounts of aldosterone mineralocorticoid , corticosterone, and cortisol glucocorticoids are produced in the adrenal cortex; testosterone male sex hormone in the testis; and estrogen female sex hormone in the ovary. Progesterone, another important steroid hormone, is produced in the ovary and placenta. The placenta is also a factory for the production of steroid hormones; however, it appears that placental steroidogenesis is not regulated by peptide hormones through PKA in all species Hum and Miller, ; Yamamoto et al.
Each of the steroidogenic pathways begins in the mitochondrion, where cholesterol is converted to pregnenolone by cholesterol side chain cleavage cytochrome P P scc , an integral protein of the inner mitochondrial membrane Simpson, Mitochondrial membranes in all cells contain cholesterol as a structural component. Mitochondria in steroidogenic cells of the adrenal, testis, and ovary also contain a second pool of cholesterol that serves as substrate for P scc.
It has long been known that peptide hormones can activate steroidogenesis via cAMP in a matter of minutes and that this process is inhibited by the protein synthesis inhibitor cycloheximide Garren et al. It is presumed that a newly synthesized protein plays a key role in making available steroidogenic cholesterol in adrenals and gonads. Through the action of PKA, cholesterol ester hydrolase is activated by phosphorylation.
This enzyme cleaves the ester function from cholesterol esters, producing free cholesterol, which is the substrate for P scc Jefcoate et al. However, the next step, the transport of cholesterol within cells, is not at all well understood. It has been proposed that sterol carrier protein 2 SCP2 participates in bringing free cholesterol from the lipid droplets, where it is produced in response to cAMP, to the mitochondrion Chanderbhan et al.
However, proof of this carrier role of SCP2 remains to be established. An alternative transport pathway for cholesterol from lipid droplets to mitochondria is through intermediate filaments of the cytoskeleton.
The filaments are found by electron microscopy to be attached to both organelles Almahbobi et al. Once cholesterol arrives at the mitochondrion, it must find its way across the outer mitochondrial membrane and across the intermembrane space to the inner mitochondrial membrane where P scc is located. Details of this movement of cholesterol from the surface of the mitochondrion to the vicinity of P scc in the inner mitochondrial membrane are better understood than are the mechanisms of transport to the mitochondrial surface.
Action of cAMP leads to accumulation of cholesterol in mitochondria in steroidogenic cells. In the presence of cycloheximide, this accumulation occurs only in the outer mitochondrial membrane Privalle et al. Thus a newly synthesized, labile protein factor is required for the movement of cholesterol from the outer to the inner mitochondrial membrane.
This labile protein is thought to be present in the cells that serve as factories for the production of steroid hormones the adrenal cortex and the gonads but not in other cells where cholesterol transport occurs, such as the liver Sugawara et al. Two-dimensional gel electrophoresis of proteins from Leydig cells has revealed proteins that appear rapidly following stimulation by cAMP Epstein and Orme-Johnson, ; Stocco and Sodeman, Only recently, however, has such a protein been identified by molecular cloning so that its biochemical function can be elucidated.
Clark and Stocco cloned a protein from Leydig cells that they have named st eroidogenic a cute r egulatory protein StAR Clark et al. Overexpression of StAR in steroidogenic cells enhances production of the C21 steroid pregnenolone from the cholesterol, providing evidence for the role of StAR in enhancing steroidogenic activity King et al.
Further evidence for the role of StAR in making cholesterol available to P scc in the inner membrane of mitochondria in steroidogenic cells comes from the study of congenital adrenal hyperplasia.
The congenital adrenal hyperplasias are a group of genetic diseases involving many of the genes encoding the steroidogenic enzymes shown in Fig. The form known as congenital lipoid adrenal hyperplasia has also been called cholesterol side chain cleavage deficiency, and was thought until recently to result from mutations in the CYP11A P scc gene.
However, unlike other forms of congenital adrenal hyperplasia that result from mutations in the exonic sequences of steroid hydroxylase genes, no such mutation has been found in the CYP11A gene in individuals suffering from congenital lipoid adrenal hyperplasia Lin et al.
Also, mitochondria from Leydig cells of an affected individual show functional P scc activity Sakai et al. Thus, the defect in congenital lipoid adrenal hyperplasia does not directly result from aberrant P scc. It has now been shown that congenital lipoid adrenal hyperplasia is associated with mutations in StAR, providing irrefutable evidence that this protein is essential for transport of cholesterol to P scc Lin et al.
The question remains, however, by what mechanism does StAR participate in the movement of cholesterol from the outer to the inner mitochondrial membrane?
StAR could bind cholesterol or it could participate in formation of contact points between the outer and inner membranes that facilitate the passive flow of cholesterol down a gradient from outside to inside.
This important mechanism remains to be established. In summary, peptide hormones acting through cAMP provide for the rapid mobilization of cholesterol from cellular stores to the site of the first step in all steroidogenic pathways. This acute action of peptide hormones in the factories for steroid hormone production is an essential step in the overall scheme for peptide hormone action presented in Fig.
Ursula Kaiser, Ken K. FSH and LH function to regulate gonadal steroid hormone biosynthesis and initiate and maintain germ cell development in concert with peripheral hormones and paracrine soluble factors.
Although both the homologous LH and FSH molecules are cosecreted by gonadotrophs, their regulatory mechanisms are not uniformly concordant. The heterodimeric structure of the common—and unique—subunit of LH and FSH is essential for biologic activity. Disulfide linkages within each subunit result in a tertiary structure that enables and maintains noncovalent heterodimerization, which also determines the ultrastucture of the mature folded molecule to facilitate specific ligand-receptor interaction.
Unlike LH, hCG is present only in primate and equine species and is expressed primarily in the placenta. Rey, Nathalie Josso, in Endocrinology: Adult and Pediatric Seventh Edition , Inheritance is autosomal recessive. It is common among the Japanese, Korean, and Palestinian Arab populations but is rare elsewhere.
Symptoms are those of complete adrenal insufficiency: The age of onset is variable, from 1 day to 3 months of age, but it usually occurs later than in hydroxylase deficiency. Affected 46,XY individuals exhibit complete phenotypic sex reversal and lack of pubertal development, whereas affected 46,XX patients develop normally until puberty but subsequently develop polycystic ovaries without hyperandrogenism.
Successful pregnancies have been reported after hormonal treatment. Radiologic examination usually shows massive adrenal enlargement resulting from accumulation of cholesterol and cholesterol esters in the adrenal cortex and sometimes also in Leydig cells. Darbre, in Endocrine Disruption and Human Health , EDCs can also act though interfering with activities of different metabolic enzymes.
Some EDCs can alter the activity of enzymes involved in steroid hormone biosynthesis or degradation. This has resulting consequences to the levels of hormones secreted, thereby perturbing the homeostatic balance between the concentrations of different hormones, with inevitable physiological consequences.
Phytoestrogens have been shown to have diverse actions on a range of enzymes  , including the inhibition of protein tyrosine kinases  , inhibition of enzymes involved in regulating cell cycle progression  , inhibition of DNA topoisomerase [42,43] , and inhibition of enzymes regulating angiogenesis [44,45]. Karen Lin-Su, Maria I. Virilization of an XX infant is most commonly caused by CAH, although other virilizing conditions can be involved see Figure Occasionally, the presence of excess androgens of maternal origin can result in virilization of the female fetus Grumbach and Conte, A unique cause of both maternal and fetal masculinization is placental aromatase deficiency Conte et al, Most patients with SRY-positive 46,XX male sex reversal syndrome have normal male external genitalia, but occasionally the genitalia are ambiguous Ergun-Longmire et al, ; Wang et al, LDs are compartments which store metabolic energy as neutral lipids covered by a monolayer of phospholipids and pertinent proteins.
Besides their central role in retaining the cellular energy, LDs are multifunctional organelles involved in steroid hormone biosynthesis , membrane trafficking, and signaling Gross and Silver, LDs depend on extensive co-operation with the ER for their functionality, since the ER is the central compartment responsible for the cellular lipid syntheses.
Certain lipid metabolic enzymes are suggested to shift from the ER to LD under conditions favoring lipogenesis Soni et al. On the contrary, overexpression of ORP2 enhanced the transport of newly synthesized cholesterol to the PM Hynynen et al. Recent evidence suggests that frameshift mutations in the OSBPL2 gene encoding ORP2 causes in humans an autosomal dominant form of hearing loss, and that the protein localizes to inner and outer hair cell stereocilia Thoenes et al.
This puzzling observation suggests that ORP2 could in the inner ear hair cells perform a yet unidentified lipid metabolic task necessary for function of the stereocilia. Polycystic ovary syndrome PCOS is a common heterogeneous endocrine disorder associated with amenorrhea, hyperandrogenism, hirsutism, insulin resistance, obesity, and a 5—fold increased risk of type 2 diabetes mellitus.
It is a leading cause of female infertility. The inherited basis of this disease was established by epidemiologic studies demonstrating an increased prevalence of PCOS, hyperandrogenemia, insulin resistance, and altered insulin secretion in relatives of women diagnosed with PCOS.
PCOS appears to be associated with the absence of the four-repeat-units allele in a polymorphic region of the CYP11A gene, which encodes cytochrome Pscc. Alteration of serine phosphorylation also seems to be involved in the post-translational regulation of 17,lyase activity CYP About 50 genes have been demonstrated to have association with PCOS. Linkage and association studies identified a hotspot of candidate genes on chromosome 19p Further confirmatory and functional studies are needed to identify key genes in the pathogenesis of PCOS.