File:Diagram of the pathways of human steroidogenesis.pdfSteroid hormones are made from cholesterol, primarily derived from lipoproteins that enter cells via receptor-mediated endocytosis. These diseases are characterized by accumulated cholesterol and steroidogenesis pdf esters in most cell steroidogenesis pdf. Mechanisms for trans-cytoplasmic cholesterol transport, membrane insertion, and retrieval from membranes are decay definition clear. Cholesterol transport to the cholesterol-poor outer mitochondrial membrane OMM appears to steroidogenesis pdf cholesterol transport proteins. Chronic steroidogenic capacity is determined by CYP11A1 gene transcription. StAR mutations cause congenital lipoid adrenal hyperplasia, with absent steroidogenesis, potentially lethal salt loss, and 46,XY sex reversal. StAR mutations initially destroy most, but not all steroidogenesis; low levels of StAR-independent steroidogenesis are lost later due to cellular damage, explaining the clinical findings.
File:Diagram of the pathways of human omosironews.info - Wikiversity
Adrenal steroidogenesis is a dynamic process, reliant on de novo synthesis from cholesterol, under the stimulation of ACTH and other regulators. The syntheses of mineralocorticoids, glucocorticoids and adrenal androgens occur in separate adrenal cortical zones, each expressing specific enzymes.
Congenital adrenal hyperplasia CAH encompasses a group of autosomal recessive enzymatic defects in cortisol biosynthesis. This review discusses in detail the epidemiology, genetics, diagnostic, clinical aspects and management of 21OHD. Adrenal steroidogenesis is a dynamic process, reliant on de novo synthesis, with no pre-synthesized hormones stored for immediate release.
Cholesterol is the common precursor for all steroids and is efficiently converted along a series of steps to the final product. To initiate steroidogenesis, cholesterol is mobilized from a pool in the outer mitochondrial membrane OMM 1 , which is replenished from cytosolic storage droplets of cholesterol esters.
Major adrenal steroid synthesis pathways. Adrenal zonation and enzyme expression pattern. Mineralocorticoid synthesis occurs in the zona glomerulosa ZG , and requires the subsequent action of three enzymes: The ZG is optimized for aldosterone synthesis: Angiotensin 2 and high extracellular potassium are the main stimulators of aldosterone synthesis, via increased intracellular calcium 6.
The glucocorticoid cortisol is synthesized in the zona fasciculata ZF under the regulation of adrenocorticotropin ACTH. Both reactions occur in a single active site, but with different regulation, as described below. With the activities of HDS3B2 and CYP21A2, which perform reactions similar to those on the mineralocorticoid pathway, hydroxysteroids are converted to deoxycortisol.
Adrenal C 19 steroids are synthesized in the zona reticularis ZR. Additional growth factors have been postulated to regulate adrenal androgen synthesis and to control the development of the ZR, but these remain poorly understood.
The ZR resembles the fetal adrenal, which provides the C 19 substrate for estrogen synthesis during pregnancy but involutes at birth. The ZR is only few cells thick at birth but expands during childhood, leading to a rise in circulating DHEAS and the phenomenon of adrenarche, which manifests as the development of axillary and pubic hair.
ZR function and serum DHEAS peak about age 25 and then gradually decline, falling to childhood values in the seventh or eighth decade of life. Congenital adrenal hyperplasia CAH refers to a group of inherited enzymatic defects in cortisol biosynthesis. Impaired cortisol production relieves negative feedback to the hypothalamus and the pituitary gland, which in response amplify the secretion of corticotropin-releasing hormone CRH and ACTH, respectively, resulting in hyperplasia of the adrenal cortex.
The spectrum of enzymatic deficiencies ranges from mild to complete and from a single activity to several activities. Conventionally, 21OHD is dichotomized into classic and nonclassic forms, based on the presence or absence of cortisol insufficiency.
Other forms of CAH are summarized in Table 1. This review will further expand the discussion of 21OHD. Classic 21OHD occurs in 1 of 16, live births worldwide Nonclassic 21OHD is much more frequent, occurring in approximately 1 of 1, Caucasians and more commonly in certain ethnic groups, such as Ashkenazi Jews 1: All forms of CAH are inherited in a monogenic, autosomal-recessive pattern. Human hydroxylase is encoded by CYP21A2 gene, on chromosome 6p Only 30 kb away resides the non-functional CYP21A1P pseudogene, which encodes a truncated, inactive enzyme.
Complete deletions, large gene conversions, and non-sense or frame-shift mutations that completely ablate hydroxylase activity typically result in salt-wasting forms of CAH. Nonclassic 21OHD patients may be either compound heterozygotes with one classic allele and one nonclassic allele or heterozygotes with two nonclassic alleles. While the most severe and mildest forms of the disease tend to maintain some genotype-phenotype correlation, the intermediate forms are often poorly linked with specific gene defects, suggesting other contributors genetic or environmental to the phenotypical expression As a result of hydroxylase dysfunction, upstream steroid precursors accumulate and are diverted towards accessible pathways to form potent androgens Figure 2.
In the normal pathways to aldosterone and cortisol, progesterone and 17OHP are first hydroxylated at position 21 by CYP21A2, and subsequently at other positions.
Pathways of steroid hormone synthesis in hydroxylase deficiency, including backdoor pathway and oxygenated androgens. This pathway might contribute to the virilization of female fetuses with CAH The 17OHP levels are reflective of disease severity. Screening decreases the time to diagnosis and improves morbidity and mortality 30 - 33 , particularly by preventing salt wasting crises.
Males with CAH are more likely to not be diagnosed early clinically, as they do not exhibit genital ambiguity at birth. False-positive results, however, are common in premature and severely ill infants 34 , Thus, weight and gestational age adjusted cutoffs for 17OHP improve the positive predictive value of screening 36 - Although false negative results are reportedly more common in girls 40 , it is possible that missed males remained unidentified, while the diagnosis was more likely to be pursued in girls, who are born with ambiguous genitalia.
Patients evaluated for clinical evidence of inappropriate androgen excess initially undergo testing of 17OHP in an early morning serum sample The gold standard for diagnosing any form of CAH in patients with indeterminate values is a cosyntropin stimulation test, which maximizes the ratio between the steroids upstream and downstream the enzymatic blockage Because other forms of CAH are not tested, the cost is high and management is rarely changed, genetic testing is not routinely recommended.
Approximately three-quarters of patients with classic 21OHD have aldosterone deficiency and thus are prone to volume depletion and hyperkalemia Where neonatal screening is not performed, undiagnosed male infants might present with failure to thrive and dehydration in the first 2 weeks of life, which can lead to death if not appropriately recognized and treated. Girls with classic 21OHD of all severities are born with varying degrees of genital ambiguity. Prenatal exposure to adrenal androgens activates the androgen receptors in genital skin, favors clitoral enlargement and labial fusion, and interferes with the urogenital sinus septation, which normally occurs at 7 weeks of gestation in girls.
The degree of virilization is classified according to the 5-point Prader scale Figure 4. If virilization is severe Prader , assignment to male sex of rearing might inadvertently occur, and in rare cases, parents choose to raise the child as a boy knowing the diagnosis. Prader scale, female external genitalia viewed from above top and in cross-section bottom. Boys with classic 21OHD typically have normal male genitalia Prader 5.
Subtle findings, such as hyperpigmentation of the scrotum and enlarged phallus, might be present at birth. In inadequately treated classic 21OHD, the adrenal androgen excess promotes further clitoral growth in girls and phallus enlargement in boys. Children with nonclassic 21OHD may exhibit evidence of androgen excess at various ages, such as premature pubarche and oily skin, but not genital virilization. Poorly controlled adolescent girls might experience hirsutism, acne, and irregular menses, similarly with polycystic ovarian syndrome patients Both male and female infants with classic 21OHD are longer than average at birth Increased circulating levels of sex steroids promote accelerated linear growth and bone maturation early in life, which results in below average final height, due to premature epiphiseal closure.
Additionally, glucocorticoid treatment, especially when excessive, suppresses growth. A meta-analysis of data from 35 centers concluded that the near-final height of patients with classic 21OHD was A multitude of factors influence adult height, including severity of disease 51 , age at diagnosis 49 , treatment regimen 52 , 53 and compliance. These known factors, however, failed to prove significant individually in pooled data, possibly because of heterogeneity and inconsistent reporting between studies.
Girls with classic 21OHD show more male-pattern play, activities, and career preferences 54 , Additionally, some studies have found that affected girls display more aggressive behaviors and lower maternal drive as compared with their unaffected siblings 56 , Exposure to higher than normal androgens prenatally and in childhood is thought to "imprint" the brain, leading to masculine behavior but rarely to male gender identity if treated from birth. Some studies suggest that females with 21OHD, particularly those with more severe forms, undergo male-like cognitive development, with higher visuospatial and logic performance and lower verbal abilities 58 - It has been suggested that salt-wasting 21OHD might result in lower IQs, possibly due to electrolyte imbalances in infancy Conversely, other authors found no overall IQ or cross-gender performance differences between 21OHD patients and unaffected controls Women with 21OHD have lower fertility rates, which correlate inversely with disease severity 63 , Hormonal, anatomical, and psychosocial factors have been suggested to contribute to impaired fertility Adrenal androgen overproduction can inhibit ovarian folliculogenesis and disturb the normal gonadotropin secretion pattern 69 , Elevated adrenal-derived progesterone in the follicular phase interferes with the normal menstrual cycle and impairs sperm penetration 66 , 71 , Non-hormonal contributors to decreased fertility in 21OHD women include distorted genital anatomy, such as vaginal stenosis and reduced clitoral sensitivity, as well as decreased sexual motivation 67 , 76 and lower maternal interest Nevertheless, in women with classic 21OHD who attempt pregnancy under skilled management, fecundity rates are normal In contrast to the frequent development of adrenal rest tumors in the testes of men with 21OHD, ovarian adrenal rest tumors have only sporadically been reported in affected women 78 - This difference could be due to several factors, including more difficult distinction of ectopic adrenal tissue from theca cells in the heterogeneous ovary, the position of the ovaries in the pelvis, and possibly better control in most women, in whom undesirable clinical manifestations of androgen excess might provide motivation for compliance.
Fertility in men with 21OHD has not been studied as extensively as in women. In the absence of newborn screening, boys with simple-virilizing 21OHD might remain undiagnosed, until they present with sexual precocity, accelerated growth, adrenal crisis during an infection, or rarely after fathering an affected girl.
Studies from UK and Finland suggest that male fertility is well below that of the normal population 82 , The two main contributors to male infertility in 21OHD are hypogonadotropic hypogonadism, due to gonadal axis suppression from adrenal-derived androgens, and testicular adrenal rest tumors TARTs 84 , TARTs are typically bilateral masses, arising in the rete testes, thus often non-palpable when small Some, but not all TARTs, regress following intensified glucocorticoid treatment The variable response might be in part due to fibrotic changes 90 and to the number of adrenal-lineage cells, which migrated to the gonad during embryologic development TARTs may lead to obstruction of seminiferous tubules, gonadal dysfunction, and infertility Surgery to remove TARTs give good long-term control of tumor growth and mass effect 92 , 93 , but rarely restores fertility or testicular testosterone production 93 , For this reason, medical therapy is continued as primary treatment as long as the luteinizing hormone LH is in the normal range, the rests are shrinking, and the testosterone is rising, for at least 6 months and longer if tolerated.
A rise in follicle-stimulating hormone FSH and fall in inhibin B indicate loss of Sertoli cell function and poor prognosis for restoration of testicular function. Abrupt resumption of tight disease control in patients with TARTs and suppressed testicular function will lower serum testosterone into the hypogonadal range.
To enhance compliance, the patient should be warned of these changes, and a gradual increase in medication should be considered. Little is known about fertility in men with nonclassic 21OHD, as few are ever diagnosed, and men with unexplained infertility are rarely tested for 21OHD. A high prevalence of benign adrenal masses has been reported in patients with 21OHD.
Most tumors had a diameter of less than 2 cm, but several giant myelolipomas have also been reported, typically in patients who are chronically under-treated 96 - Similar findings have been reported in smaller studies 99 - and have been mostly attributed to glucocorticoid overtreatment. Glucocorticoids and mineralocorticoids are the mainstays of treatment for 21OHD. Glucocorticoids exert two principal actions: Patients with classic 21OHD all require chronic glucocorticoid replacement.