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17-Hydroxyprogesterone in children, adolescents and adults John W Honour Ann Clin Biochem 2014 51: 424 originally published online 7 April 2014 DOI: 10.1177/0004563214529748 The online version of this article can be found at: http://acb.sagepub.com/content/51/4/424

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Review Article Annals of Clinical Biochemistry 2014, Vol. 51(4) 424–440 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0004563214529748 acb.sagepub.com

17-Hydroxyprogesterone in children, adolescents and adults John W Honour

Abstract 17-Hydroxyprogesterone (17-OHP) is an intermediate steroid in the adrenal biosynthetic pathway from cholesterol to cortisol and is the substrate for steroid 21-hydroxylase. An inherited deficiency of 21-hydroxylase leads to greatly increased serum concentrations of 17-OHP, while the absence of cortisol synthesis causes an increase in adrenocorticotrophic hormone. The classical congenital adrenal hyperplasia (CAH) presents usually with virilisation of a girl at birth. Affected boys and girls can have renal salt loss within a few days if aldosterone production is also compromised. Diagnosis can be delayed in boys. A non-classical form of congenital adrenal hyperplasia (NC-CAH) presents later in life usually with androgen excess. Moderately raised or normal 17-OHP concentrations can be seen basally but, if normal and clinical suspicion is high, an ACTH stimulation test will show 17-OHP concentrations (typically >30 nmol/L) above the normal response. NC-CAH is more likely to be detected clinically in females and may be asymptomatic particularly in males until families are investigated. The prevalence of NC-CAH in women with androgen excess can be up to 9% according to ethnic background and genotype. Mutations in the 21-hydroxylase genes in NC-CAH can be found that have less deleterious effects on enzyme activity. Other less-common defects in enzymes of cortisol synthesis can be associated with moderately elevated 17-OHP. Precocious puberty, acne, hirsutism and subfertility are the commonest features of hyperandrogenism. 17-OHP is a diagnostic marker for CAH but opinions differ on the role of 17OHP or androstenedione in monitoring treatment with renin in the salt losing form. This review considers the utility of 17-OHP measurements in children, adolescents and adults.

Keywords Steroid hormones, evaluation of new methods, endocrinology Accepted: 5th March 2014

Introduction 17-Hydroxyprogesterone (17-OHP) in serum is a critical diagnostic test for congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency which is amongst the commonest genetic disorders in man. The clinical features of CAH have been known for some time, even as far back as 1865, in an autopsy account of a patient described by Luigi de Crecchio. The basis for the problems could not be ascribed at that time. Bongiovanni published a partial translation

of the original account.1 ‘The cadaver of a ‘‘man’’ having a large penis with first degree hypospadias and without externally visable or palpable gonads. On dissection a vagina, uterus, fallopian tubes and ovaries were found within the abdomen’. Unusual steroids in the urine of Institute of Women’s Health, University College London, London, UK Corresponding author: John W Honour, Institute of Women’s Health, University College London, 74 Hunter Street, London WC1E 6AU, UK. Email: [email protected]

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such patients with adrenal virilism and ambiguous genitalia were first chemically characterised in 1937.2 The nature of the steroid hormones and their link with cholesterol, sex steroids, cortisol and aldosterone became apparent over the next 20 years.3 A biosynthetic pathway was defined and generally accepted, although deviations to the route are possible.4 Prior to 1968, excess androgen production in CAH was defined by analysis of 17-ketosteroids (androgens) in urine, an obsolete colorimetric test since specific steroids can now be measured in blood. Pregnanetriol was known to be elevated in urine of patients with virilism before this was accepted as the main metabolite of 17-OHP. CAH due to 21-hydroxylase deficiency was first accepted in 19555 and now constitutes a spectrum of disease with varying severity and biochemical features consistent with expression of mutations in the CYP21A2 gene. The laboratory often gets requests for 17-OHP during investigations of patients with androgen excess.6 This review addresses the utility of measuring 17-OHP concentrations when investigating children, adolescent and adult patients with androgen excess. The information herein will help a clinical biochemist answer questions raised by clinicians. The scientist can help with interpreting steroid/biochemical data and suggest protocols for further investigations of patients according to the clinical presentation.

Clinical presentation of hyperandrogenism In a newborn female infant, clitoromegaly is a sign of androgen excess in utero. In some cases, virilisation is so profound that without careful inspection, the child can get male gender assignment. Ambiguous genitalia can also reflect a failing of 46XY male development, so karyotyping is important. Androgen excess in a child and adult can cause changes in body hair, growth patterns and apocrine sweat gland function. Bone age may be advanced by excess androgen exposure in children although before the end of puberty the normal growth spurt is aborted by epiphyseal fusion and the adult patient will be short. Adrenarche needs to be considered. This is a period of development characterised by the appearance of pubic and axillary hair and increase in body odour in girls around 8 years of age and boys around 9 years of age.7 Early adrenarche (premature adrenarche/pubarche) is a condition reflecting early development of the zona reticularis in the adrenal gland between the cortex and medulla secreting androgen.8 CAH and adrenal tumours need to be excluded. Imaging will be needed in some patients. Premature adrenarche, once characterised, is usually a benign diagnosis. The hair growth pattern in adrenarche in the pubic and axillary areas is different to the general hair growth (hypertrichosis) with use of certain drugs

such as cyclosporin, diazoxide, minoxidil and phenytoin. The hair pattern is also different to the androgenic pattern seen in adrenal tumours, polycystic ovary syndrome (PCOS) and other states where hair is on the arms, legs, back and chin. Puberty results when pulsatile secretion of gonadotrophins activates the gonads. In precocious puberty, the secondary sex characteristics develop prematurely. This can include breast development in girls (oestrogen exposure) and growth of penis, facial hair and musculature in boys from androgen excess without the normal pubertal changes in ovaries seen on ultrasound and size of the testes. Hirsutism is defined as excess body or coarse facial hair in females in a male-like pattern. Hair growth should be assessed on chin, face, chest, abdomen, back, thighs and upper arms. A scoring system by Ferriman and Gallwey in 19619 is a visual assessment and a recent version with patient photographs is a useful reference point.10 A polycystic ovarian appearance is inevitable in any of these clinical situations.11,12 PCOS is also often associated with insulin resistance and hyperinsulinemia. Insulin resistance may also develop through the metabolic effects of androgens.7,13,14 The precise mechanism for cardiovascular risk is still unclear. In the adolescent and adult, androgen excess may be due to peripheral or central defects and tend to be rarer in origin. Anovulation, menstrual irregularity and infertility in CAH are also linked with the androgen and progesterone excess.15 The hypothalamic-pituitary ovarian axis is disrupted and gonadotrophin releasing hormone (GnRH) pulse frequency is rapid, favouring LH secretion. Disorders of dihydrotestosterone (DHT) production may also manifest for the first time at 12–15 years of age through symptoms of androgen excess. In rare cases, there may be additional dysmorphic features. Exogenous steroid use needs to be questioned. A dialogue between clinician and the laboratory is important in the diagnosis of an ever broadening field. A multidisciplinary team meeting should assemble clinical and laboratory experts to debate issues around difficult cases.16

Steroid synthesis Adrenal steroid synthesis of cortisol and aldosterone from cholesterol (Figure 1) starts with the uptake of cholesterol into mitochondria through the action of steroidogenic acute regulatory protein (StAR) followed by side chain cleavage (a cytochrome P-450 enzyme, now called CYP11A1), to liberate pregnenolone.17 Cholesterol and pregnenolone have -hydroxyl groups at carbon 3 (C3) and double bonds at C5 to C6 (5-ene). In the smooth endoplasmic reticulum of the adrenal zona fasciculata, pregnenolone can be hydroxylated at

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Figure 1. Biosynthesis of steroids, including alternative path to DHT from 17-OHP via androsterone and 5a-androstane-3a,17-diol.

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C17 by 17a-hydroxylase (CYP17A1) to produce 17-hydroxypregnenolone which is converted to the steroid hormone 17-OHP (17-hydroxy 4-pregnene-3,20dione) with carbonyl at C-3 and C4 to C5 double bond (4-ene) by the action of 3-hydroxysteroid dehydrogenase and 5,4-isomerase (HSD3B2). 17-OHP is converted to 11 deoxycortisol by C-21 hydroxylase (CYP21A2). 11-deoxycortisol has to migrate to the mitochondria for 11-hydroxylation by 11 beta hydroxylase (CYP11B1) to produce cortisol in the fasciculata zone. 17-OHP is thus an intermediate steroid in the adrenal pathway from cholesterol to cortisol but not significantly for androgens because 17-OHP is a poor substrate for CYP17A1. Cortisol and cortisone are interconverted by oxidase and reductase activities of two 11-hydroxysteroid dehydrogenases (HSD11B2 and B1 respectively). The electron transfer of the reductase is coupled with hexose-6-phosphate dehydrogenase.18 In the outer zona glomerulosa, pregnenolone is converted to progesterone, deoxycorticosterone, corticosterone and aldosterone through the actions of HSD3B2, CYP21A2, and then CYP11B2 that has 18-hydroxylase and aldosterone synthetase activity. In the human adrenal cortex, CYP17A1 can efficiently convert pregnenolone to dehydroepiandrosterone (DHA) but cannot convert progesterone to androstenedione. DHA is conjugated with sulphuric acid through the action of sulphotransferase to the sulphate (DHAS). In adults, DHAS is the main steroid secreted by the adrenal cortex from the inner zona reticularis leading to circulating concentrations of 2–10 micromoles per litre. The adrenals secrete small amounts of testosterone but greater amounts of androstenedione through the action of CYP11A1, HSD3B2 and 17-hydroxysteroid dehydrogenase (an aldo-keto reductase, AKR1C3).19 The gonads also produce 17OHP and high concentrations of 17-OHP can be found for example in ovarian follicles.20 17-OHP may also be converted to DHT through a ‘backdoor path’.21,22 This may provide a more efficient route to DHT under conditions of high 17-OHP accumulation as in CAH due to 21-hydroxylase deficiency.23 In the past decade, other aspects of steroid synthesis have attracted clinical interest. A cytochrome P450-oxidoreductase (POR) is part of the electron transport system for CYP21A2 and CYP17 (and other enzymes).24

Congenital adrenal hyperplasia Increased concentrations of the 17-OHP in the peripheral circulation indicate a deficiency of 21-hydroxylase activity.25 Failure to synthesise cortisol leads to an increase in ACTH through activation of the cortisol negative feedback and is the basis of CAH. Aldosterone synthesis can also be affected, so

progesterone may also be elevated failing its conversion to deoxycorticosterone. There are variable consequences to glucose and electrolyte problems due to steroid deficiencies that need to be characterised. Electrolyte disturbance is the key feature of the male neonate with CAH. The classical form of 21-hydroxylase deficiency presents usually in childhood. Virilisation is the result of hyperandrogenaemia, and in many cases salt loss is the consequence of reduced aldosterone synthesis. The androgen excess in CAH must derive from 17-hydroxypregnenolone to produce DHA through the 17,20-lyase activity of CYP17A1. The non-classical CAH form (NC-CAH) was first called late-onset (sometimes cryptic) because of the time of presentation notably in adolescents and adults. The effects of cortisol and aldosterone deficiency are not usually apparent and the presentation is due to signs of androgen excess. Precocious puberty, acne, hirsutism and subfertility are the commonest presenting features of NC-CAH requiring investigations. The prevalence of NC-CAH in women with androgen excess can be from 0.6 to 9% according to ethnic background and genotype (see reference 26 for survey). The disorder is more common in Ashkenazi Jews, Mediterranean, Middle-Eastern and Indian populations. NC-CAH is more likely to be suspected clinically in females.

Genetic basis of 21-hydroxylase deficiency The gene for steroid 21-hydroxylase was sequenced in 1985,27–29 some 6 years before genetic mutations specific to mild forms of 21-hydroxylase deficiency were described in family studies that included asymptomatic members.30–31 The clinical presentation are usually related to the magnitude of 21-hydroxylase deficiency, being severe in neonates and milder during childhood and adults. Two CYP21 genes are located in chromosome 6 within the coding region for the major histocompatability complex and fourth component of complement, C4. The active 21-hydroxylase gene (CYP21A2) is about 30 kb downstream of a pseudogene (CYP21A1P) that does not encode protein. The genes have 98% nucleotide homology in 10 exons and 9% homology in introns.27 Human leucocyte antigen (HLA) typing has been used to track gene mutations of CYP21A2. HLA-B14 is found in about 40% of NCCAH haplotypes. The common mutations of CYP21A2 are genetic recombinations with CYP21A1P as well as deletions and point mutations. The mutations cause varying degrees of enzyme deficit as shown by in vitro expression studies32 as well as genotype–phenotype correlations.33–34 In the classic defect, more than 95% of enzyme activity is lost through mutations in the CYP21A2 gene coding the

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protein.27 Where the enzyme activity is lost, the phenotype is of salt-wasting disease with virilisation. When 21-hydroxylase activity is as little as 2% of normal, the phenotype is simple virilisation. If the 21-hydroxylase activity is 10–75% of normal, patients have the mild NC-CAH picture. This was recently reviewed.35 Work with molecular models of the enzyme substituted for the absence of crystalline structure of the human 21-hydroxylase protein.36–39 NC-CAH is associated most commonly with homozygous Valine to Leucine conversion at position 281 that alters haem binding. This mutation is found in NC-CAH often as a compound heterozygote with a severe mutation on the other allele. Another mutation commonly found in NC-CAH is Proline to Leucine at position 30 that is at the point for membrane insertion and enzyme stability. The NC-CAH mutations have been found to affect 21-hydroxylase activity at oxidoreductase interactions, salt-bridge and hydrogen bonding networks and non-conserved hydrophobic interactions.40 Multiple copies of the genes are found due to unequal crossover in meiosis at various points in the sequence.41 The approach for genetic analysis of gene deletions, gene conversions, point mutations and small gene alterations has been reviewed recently.42 A reference laboratory skilled in this analysis should be consulted. Different concentrations of service are offered from linkage analysis to complete sequencing of the gene. Analyses are available for detection of deletions, duplications and targetted mutations. The impact of changes in the gene on protein expression may be required in a few cases. CAH is now recognised as a spectrum of clinical presentations from mild androgen excess (NCCAH) to prominent androgen excess with adrenal failure of cortisol (simple virilising form) and often of aldosterone (salt-wasting form) production.

Related enzyme defects Androgen excess can also be the consequence of defects of HSD3B, CYP11B1 and POR. Cases are usually detected after birth because of typical presentations. The markers for these defects are DHAS, 11-deoxycortisol and in the case of POR both 17-OHP and corticosterone. In CAH due to 3-hydroxysteroid dehydrogenase (HSD3B2) deficiency, the aldosterone production may also be blocked and, in the absence of this mineralocorticoid, salt loss leads to stimulation of renin production.43 DHA is the substrate for HSD3B2 and a circulating marker for the defect along with 17-hydroxypregnenolone. In a newborn infant with CAH due to HSD3B2, the 17-OHP can be apparently elevated either through cross reaction in an immunoassay with 17-hydroxypregnenolone (and more so it’s sulphate form) or because 17-OHP

is genuinely raised through the action of other 3-hydroxysteroid dehydrogenase isoenzymes on 17hydroxypregnenolone.44 In CAH due to 11-hydroxylase deficiency, the production of deoxycorticosterone is increased and this potent mineralocorticoid causes renal sodium retention with suppression of renin release form the renal juxtaglomerular apparatus.45 ‘Functional’ deficiency of 21-hydroxylase and 17hydroxylase has been described with POR defects.46,47 17-OHP and corticosterone concentrations in serum are raised although assays for the latter are not generally available. Although POR deficiency is usually detected in neonates with ambiguous genitalia and skeletal abnormalities (Antley-Bixler syndrome), mild forms can present with adrenal insufficiency and later polycystic ovaries. A urinary steroid profile (USP) shows characteristic high excretion of both 17-OHP and corticosterone metabolites.47 Non-classic forms of CAH may also be attributable to mutations leading to mild defects in HSD3B248 and CYP11B149–51, POR52 and StAR.53 The interconversion of cortisol to cortisone can be defective in the reverse reaction by cortisone reductase (HSD11B1) and leads to a need for an increase in ACTH to raise cortisol and androgen production. This condition presents like adrenarche but is best characterised in a USP from the high ratio of cortisone to cortisol metabolites.54 This can be distinguished from apparent cortisone reductase deficiency (ACRD) due to inactivating mutations in hexose-6-phosphate dehydrogenase gene by even lower cortisol metabolites and higher cortisone metabolites. High ACTH also leads to some increased 17-OHP production.

17-OHP analysis The first assay for 17-OHP per se was based on competitive protein binding with radioactive 17-OHP using a crude preparation of cortisol binding globulin as ligand.55,56 Radioimmunoassays were available from 197157 and have remained the prominent test although are now being superceded by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) methods.58,59 Two main analytical methods are thus in use for plasma 17-OHP; immunoassay and chromatographic. Immunoassay (IA) is the most frequently used technique for steroid measurement. 17-OHP is quantitatively displaced from its binding proteins and measured immunometrically using antibodies supposedly specific to 17-OHP. In practice, some crossreactivity, e.g. with 11-deoxycortisol, is inevitable. Commercial assays that use antibody-coated tubes are designed for 17-OHP concentrations up to 100 nmol/L; reflecting the more common requirement, in clinical

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Table 1. 17-OHP results with RIA and GC-MS (Supraregional Assay Service data) basally and after ACTH stimulation.

Infants (unstressed) Infants (stressed) Adult males Adut females – follicular phase Adult females – luteal phase Patients with untreated 21-hydroxylase deficiency Patients with NC- CAH Heterozygote carriers

RIA (serum) nmol/L (60 min ACTH stim

GC-MS (plasma)nmol/L (30 min ACTH stim)

100 (63–470) (6–44)

30 nmol/L indicates non-classic CAH (depending on the assay and reference data). A number of other steroid defects in steroid synthesis and metabolism can be characterised by a USP with, in some cases, further genetic tests for absolute confirmation. All laboratory results should be interpreted using reference ranges for the appropriate assay technology. This is particularly important when steroid assays of greater specificity (for example, LC-MS/MS) are introduced to the laboratory repertoire.

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Acknowledgements The author is grateful to members of the Clinical Science Review Committee, Dr Gill Rumsby and Dr Adel A Ismail for advice and constructive criticism. This article was prepared at the invitation of the Clinical Sciences Reviews Committee of the Association for Clinical Biochemistry and Laboratory Medicine.

Declaration of conflicting interests None.

Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethical approval Not applicable.

Guarantor JWH.

JWH researched the literature and is responsible for the manuscript in full.

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