Journal of Steroid Biochemistry & Molecular Biology 165 (2017) 71–78
`
`Contents lists available at ScienceDirect
`
`Journal of Steroid Biochemistry & Molecular Biology
`
`j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / j s b m b
`
`Review
`
`Steroid 17-hydroxylase and 17,20-lyase deficiencies, genetic and
`pharmacologic
`
`Richard J. Auchus*
`
`Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine and Department of Pharmacology, University of Michigan, Rm. 5560A
`MSRBII, 1150 W Medical Center Drive, Ann Arbor, MI 48109, United States
`
`A R T I C L E
`
`I N F O
`
`A B S T R A C T
`
`Article history:
`Received 7 December 2015
`Received in revised form 22 January 2016
`Accepted 3 February 2016
`Available online 6 February 2016
`
`Keywords:
`Hypertension
`Androgen
`Mineralocorticoid
`17-Hydroxylase/17,20-lyase
`46XY DSD
`Infertility
`Primary amenorrhea
`
`Contents
`
`Steroid 17-hydroxylase 17,20-lyase (cytochrome P450c17, P450 17A1, CYP17A1) catalyzes two major
`reactions: steroid 17-hydroxylation followed by the 17,20-lyase reactions. The most severe mutations in
`the cognate CYP17A1 gene abrogate all activities and cause combined 17-hydroxylase/17,20-lyase
`is replicated by treatment with the potent
`deficiency (17OHD), a biochemical phenotype that
`CYP17A1
`inhibitor abiraterone acetate. The adrenals of patients with 17OHD
`synthesize
`11-deoxycorticosterone (DOC) and corticosterone but no 19-carbon steroids, similar to the rodent
`adrenal, and DOC causes hypertension and hypokalemia. Loss of 17,20-lyase activity precludes sex steroid
`synthesis and
`leads to sexual
`infantilism. Rare missense CYP17A1 mutations minimally disrupt
`17-hydroxylase activity but cause isolated 17,20-lyase deficiency (ILD), Mutations in the POR gene
`encoding the required cofactor protein cytochrome P450-oxidoreductase causes a spectrum of disease
`from ILD to 17OHD combined with 21-hydroxylase and aromatase deficiencies, sometimes including
`skeletal malformations. Mutations in the CYB5A gene encoding a second cofactor protein cytochrome b5
`also selectively disrupt 17,20-lyase activity and cause the purest form of ILD. The clinical manifestations
`of these conditions are best understood in the context of the biochemistry of CYP17A1.
` 2016 Elsevier Ltd. All rights reserved.
`ã
`
`1.
`
`2.
`
`3.
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
`Physiology, genetics, and biochemistry of CYP17A1
`Physiology
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
`1.1.
`1.2.
`Genetics
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
`Biochemistry
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
`1.3.
`Clinical presentation and diagnosis
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
`Clinical presentation
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
`2.1.
`Diagnosis
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
`2.2.
`Abiraterone acetate and pharmacologic induction of 17OHD
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
`2.3.
`Treatment
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
`Glucocorticoids
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
`3.1.
`3.2. Mineralocorticoid receptor antagonists and antihypertensives
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
`3.3.
`Estrogen replacement, progestin withdrawal, androgen supplementation, and surgery
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
`Acknowledgements
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
`References
`
`* Fax: +1 7349366684.
`E-mail address: rauchus@med.umich.edu (R.J. Auchus).
`
`http://dx.doi.org/10.1016/j.jsbmb.2016.02.002
`0960-0760/ã
` 2016 Elsevier Ltd. All rights reserved.
`
`1. Physiology, genetics, and biochemistry of CYP17A1
`
`1.1. Physiology
`
`All vertebrates that exhibit sexual dimorphism and reproduc-
`tion require the 17,20-lyase activity of CYP17A1 to synthesize
`
`Amerigen Exhibit 1168
`Amerigen v. Janssen IPR2016-00286
`
`

`
`72
`
`R.J. Auchus / Journal of Steroid Biochemistry & Molecular Biology 165 (2017) 71–78
`
`deficiency is really only the gonadal component, lack of androgens
`infantilism and pubertal
`and estrogens, which causes sexual
`failure. The absence of 17,20-lyase activity in the adrenal results in
`its sulfate
`deficiency of dehydroepiandrosterone (DHEA) and
`(DHEAS), which prevents adrenarche and the development of
`pubic and axillary hair—not a significant matter in health and
`bodily function.
`The lack of adrenal 17-hydroxylase activity, however, forces
`steroidogenesis
`to corticosterone
`rather
`than
`cortisol via
`11-deoxycorticosterone (DOC), which in human beings is normally
`a very minor adrenal product. DOC, however, is a mineralocorti-
`coid, which is slightly less potent than aldosterone. In the face of
`complete 17-hydroxylase deficiency (17OHD), nascent pregneno-
`is converted
`to progesterone and
`then
`to DOC and
`lone
`corticosterone. Circulating corticosterone rises from typical con-
`(10 nM)
`to nearly 40,000 ng/dL
`centrations of <400 ng/dL
`(1 mM), which adequately substitutes for cortisol for supplying
`glucocorticoid activity, even if >90% is protein-bound (Table 1). In
`parallel, circulating DOC concentrations rise
`from <20 ng/dL
`(0.6 nM) to >300 ng/dL (10 nM), which saturates the mineralo-
`corticoid receptor under most circumstances. Consequently,
`adrenal 17OHD does not really result in glucocorticoid deficiency
`despite the lack of cortisol synthesis, but the important physiologic
`disturbance is low-renin hypertension from DOC excess.
`
`1.2. Genetics
`
`The human CYP17A1 gene is located on chromosome 10q24.3
`[3], spans 6.6 kb, and contains eight exons [4]. An identical 2.1 kb
`mRNA is transcribed from this gene in the both the adrenals and
`gonads [5]. From the 1.6 kb coding region, a 57 kDa polypeptide is
`in
`the smooth endoplasmic
`translated. The protein resides
`reticulum with the
`flavoprotein cofactor P450-oxidoreductase
`(POR). The enzyme system of CYP17A1 and POR catalyzes both the
`17-hydroxylase and 17,20-lyase activities [6]. In cells with high
`17,20-lyase activity, cytochrome b5 (b5)
`is also present with
`CYP17A1 and POR in the endoplasmic reticulum [7]. Collectively,
`POR and b5 are known as
`
`“redox partners,” since both are electron-
`transfer proteins. The importance of b5 in activating maximal
`17,20-lyase activity will be discussed later.
`Over 100 mutations in the CYP17A1 gene have been associated
`with combined 17-hydroxylase/17,20-lyase deficiency
`(OMIM
`202110), including point mutations, small insertions or deletions,
`splice site alterations, and rarely large deletions (Fig. 2A). Although
`these mutations can be found throughout the gene, many occur
`near the C-terminus, emphasizing the importance of even the last
`
`Table 1
`Steroid changes in combined 17-hydroxylase/17,20-lyase deficiency.
`
`Steroid
`
`Normal adult range
`
`17OHD
`
`Progesterone (ng/mL, follicular phase)
`17-Hydroxyprogesterone (ng/dL)
`11-Deoxycorticosterone (ng/dL)
`Corticosterone (ng/dL)
`11-Deoxycortisol (ng/dL)
`Cortisol (mg/dL)
`DHEAS (mg/dL, young adult)
`Aldosterone (ng/dL)
`Androstenedione (ng/dL)
`
`Testosterone (ng/dL)
`46,XX
`46,XY young adult
`
`Estradiol (pg/mL)
`46,XX follicular phase
`46,XY
`
`<0.2
`50–200
`<20
`100–800
`10–160
`2–25
`100–400
`2–10
`25–250
`
`10–50
`400–900
`
`40–100
`10–40
`
`2–40
`10–100
`100–1000
`4000–40,000
`<5
`<2
`<10
`<5
`<50
`
`<20
`<20
`
`<20
`<20
`
`Fig. 1. Major pathways of human adrenal steroid biosynthesis. Panel (A) shows the
`pathways in the normal adrenal, and panel (B) shows altered pathways in 17OHD.
`Dashed arrows show minor or reduced pathways, and size of text indicates relative
`abundance for cortisol, aldosterone, androgens and estrogens, corticosterone, and
`DOC (11-deoxycorticosterone).
`
`19-carbon androgens and subsequently 18-carbon estrogens
`(Fig. 1A). CYP17A1 genes are expressed in the gonads of all these
`organisms for this purpose. Zebrafish [1] and trout [2] contain 2
`CYP17A1 genes, which are both expressed under different
`regulation, and 1 enzyme has only 17-hydroxylase activity while
`the other also has 17,20-lyase activity. Based on its location in the
`steroidogenic pathways, CYP17A1 is the exclusive gateway to sex
`steroid production. As will be explored below, the substrates for
`the 17,20-lyase reaction are 17-hydroxysteroids—the products of
`the 17-hydroxylase reaction, which CYP17A1 also catalyzes. In fact,
`the 17-hydroxylase activity is only required in animal physiology to
`generate intermediates for subsequent conversion to androgens.
`For example, rodents express CYP17A1 only in the gonads but not
`in the adrenal glands. Rats and mice produce corticosterone as
`their dominant glucocorticoid rather than cortisol for this reason
`(Fig. 1B). Thus, the 17-hydroxylase reaction would be completely
`dispensable if CYP17A1 could generate 17-ketosteroids directly
`from 17-deoxypregnanes such as pregnenolone.
`Nevertheless, the balance of enzyme activities and substrate
`preferences
`in
`the adrenal varies amongst species, as do
`sensitivities of their nuclear hormone receptors
`for various
`steroids, plasma steroid binding capacities, and pathways of
`steroid catabolism. As a result, human beings need adrenal
`17-hydroxylase activity to produce cortisol and to maintain
`glucocorticoid and mineralocorticoid homeostasis. Based on this
`analysis, complete deficiency of CYP17A1,
`like all
`forms of
`congenital adrenal hyperplasia, features both consequences of
`hormone deficiency—what is lacking after the block—and hormone
`excess—what accumulates upstream of the block. The hormone
`
`

`
`R.J. Auchus / Journal of Steroid Biochemistry & Molecular Biology 165 (2017) 71–78
`
`73
`
`activity largely unaffected. Mutations R347H or C and R358Q map
`to the enzyme surface, and these mutations impair interactions of
`CYP17A1 with POR and more importantly with b5 [18–21], thus
`explaining a selective deficiency of 17,20-lyase activity. Mutation
`E305G is located in the active site and also preferentially impairs
`the 17,20-lyase activity [22], yet homozygous patients bearing this
`mutation show some biochemical but not clinical evidence of
`17-hydroxylase impairment, with increased excretion of DOC and
`corticosterone metabolites [23]. POR mutation G539R causes ILD,
`which is clinically and biochemically a phenocopy of ILD caused by
`CYP17A1 mutations [24,25].
`
`1.3. Biochemistry
`
`Like all cytochrome P450 enzymes, CYP17A1 follows a catalytic
`cycle, including 2 one-electron transfers from reduced nicotin-
`amide adenine dinucleotide phosphate (NADPH) via POR, binding
`of substrate and oxygen, formation of the reactive heme-iron
`complex with oxygen in concert with OO bond scission and
`water release, and
`finally substrate oxidation [26]. The co-
`existence of two major activities
`in one enzyme was
`first
`demonstrated with the co-purification of 17-hydroxylase and
`17,20-lyase activities from neonatal porcine testes [27]. Purified
`CYP17A1 disproportionately
`loses 17,20-lyase activity during
`purification as b5 is removed from the system, and addition of a
`stoichiometric amount of b5 restores the lost 17,20-lyase activity
`[28–30]. The effect of b5 is not subtle—a 10-fold increase in 17,20-
`activity
`for
`17-hydroxypregnenolone
`(17 Preg)
`and
`lyase
`17-hydroxyprogesterone (17OHP) substrates [31] or a 3-fold
`stimulation with 5a-pregnane-3a,17a-diol-20-one,
`the best
`17,20-lyase substrate for human CYP17A1 [32]. The importance
`of the b5 effect is illustrated in patients with mutations in the
`CYB5A gene, which causes the purest form of ILD [33,34].
`CYP17A1 from various species all appear to 17-hydroxylate both
`pregnenolone and progesterone with comparable efficiencies, and
`this property is true for the human enzyme [30,31]. Human
`CYP17A1 also 16a-hydroxylates 20–25% of progesterone but not
`pregnenolone [35], and the presence of A rather than L at residue
`105 allow for this high proportion of 16a-hydroxylation [36]. With
`progesterone substrate, human CYP17A1 also affords <1% DOC—
`the 21-hydroxylation product, and this fraction can be increased by
`deuterium incorporation at C-17 [37]. The X-ray crystal structures
`of modified wild-type human CYP17A1 with bound inhibitors [38]
`and mutation A105L with bound substrates [39] help to explain the
`
`Fig. 2. Cartoon of CYP17A1 gene showing the location of common mutations and
`mutations causing isolated 17,20-lyase deficiency. Exons are shown as numbered
`rectangles connected by introns as solid horizontal line and are approximately
`drawn to scale. Mutations found in isolated 17,20-lyase deficiency are shown below
`the gene cartoon.
`
`!
`
`14 amino acids for enzyme activity. Splice site mutations can lead
`“exon skipping”
` and truncated, inactive protein [8,9]. Some
`to
`frameshift mutations introduce premature stop codons, which also
`yield truncated proteins. The most commonly mutated residues
`include Y329 (to D, X, or frameshift TAC
` AA with 418X), R362 (to
`C or H), and H373 (to L, N, or D) in exon 6; W406 (to R) in exon 7;
`and deletion of D487-S488-F489 or a CATC duplication within
`D487-S488 in exon 8. For some patients with a clinical and
`hormonal diagnosis of 17OHD, no CYP17A1 mutations have been
`identified [10]. Cases of incomplete 17-hydroxylase deficiency
`combined with partial 21-hydroxylase deficiency can result from
`mutations in POR, but the biochemical and phenotypic spectrum of
`POR deficiency can be quite variable [11,12].
`In Brazil, CYP17A1 deficiency appears to be the second most
`common cause of congenital adrenal hyperplasia, due to founder
`mutations R362C and W406R [13]. In a large series from China, the
`aforementioned Y329
`frameshift and D487-F489 deletions
`accounted for >80% of the affected alleles in 26 affected individuals
`[14]. These positions appear to be mutational
`“hot spots,”
` as the
`same mutations have been identified in other ethnic groups in Asia
`[15] and elsewhere. A duplication of four nucleotides at amino acid
`478, which induces a frameshift and premature stop codon, has
`been found in Dutch Frieslanders and in Canadian Mennonites
`[16], and a phenylalanine 53 deletion has been identified in Japan
`and elsewhere [17].
`A special case of CYP17A1 dysfunction is isolated 17,20-lyase
`deficiency (ILD, Fig. 2B). In these rare cases, missense mutations
`preferentially impair 17,20-lyase activity and leave 17-hydroxylase
`
`Fig. 3. Steroid-binding pocket in human CYP17A1. Images demonstrate proximity of hydrogen atoms at C-16, C-17, and C-21 of progesterone to heme ring (A) and hydrogen
`bonding (arrows) of A-ring oxygen to side-chain of N202 in 17-hydroxypregnenolone (B) or 17-hydroxyprogesterone (C). Images were generated from the X-ray crystal
`structures of CYP17A1 mutation A105L with bound steroids (pdbid numbers 4NKX, 4NKY, 4NKZ) with program PyMol.
`
`

`
`74
`
`R.J. Auchus / Journal of Steroid Biochemistry & Molecular Biology 165 (2017) 71–78
`
`diverse chemistry in this enzyme. The steroid rests against the I-
`helix perpendicular to the heme ring with the steroid D-ring
`closest to the heme iron and the A-ring pointing away to the center
`of the enzyme (Fig. 3A). In this orientation, the hydrogen atoms on
`carbon atoms 16, 17, and 21 are all within the minimum distance to
`react with the iron-oxygen species, and the order of reactivity
`parallels the stability of carbon-centered radicals formed during
`catalysis [26,40].
`In contrast to the similar activities with 17-deoxypregnanes for
`the 17-hydroxylase reaction, CYP17A1 from various species often
`show strong preferences among 17-hydroxysteroid substrates for
`the 17,20-lyase reaction. Human CYP17A1 catalyzes the 17,20-lyase
`reaction approximately 50-times more efficiently with 17Preg
`substrate than with 17OHP, and b5 markedly stimulates both
`reactions [30,31]. As a consequence, the human adrenal zona
`reticularis produces large amounts of DHEA, which is sulfated and
`circulates as DHEAS [41]. In the X-ray crystal structures of CYP17A1
`mutation A105L with 17Preg (Fig. 3B) or 17OHP (Fig. 3C), the A-ring
`hydroxyl- or keto-group form a hydrogen bond with the carbonyl
`oxygen or amide hydrogen of N202, respectively [39]. Despite
`slightly different positioning of
`the steroid D-rings,
`these
`structures alone do not explain the difference in reactivity [26].
`
`2. Clinical presentation and diagnosis
`
`2.1. Clinical presentation
`
`Severe mutations of CYP17A1 cause complete 17OHD, which
`disrupts steroidogenesis in both the adrenals and the gonads. The
`
`Table 2
`Differential diagnosis and distinguishing features.
`
`production of both androgens and estrogens
`the
`requires
`the availability of 17-
`17,20-lyase activity of CYP17A1 and
`hydroxysteroid substrates for this reaction, which are exclusive
`products of CYP17A1 as well. Thus, pubertal failure is one of the
`major features of 17OHD. In addition, individuals with both 46,XX
`and 46,XY karyotypes will have female external genitalia from
`absent testosterone (T) and dihydrotestosterone (DHT) synthesis in
`fetal life, but the 46,XY individuals will not have internal Müllerian
`structure, due to preservation of anti-Müllerian hormone from the
`testes. Occasionally, the 46,XY children are identified due to
`inguinal hernia or discrepancy between external (female) genitalia
`and chromosomal sex obtained from amniocentesis, performed for
`other reasons.
`The second major feature of 17OHD derives from the adrenal
`enzyme deficiency. Unlike all other forms of congenital adrenal
`hyperplasia, infants are not glucocorticoid deficient, even though
`their cortisol production
`is
`low.
`In the absence of adrenal
`17-hydroxylase activity, corticosterone accumulates and substi-
`tutes for cortisol, similar to the physiology of the rodent adrenal.
`Consequently, adrenal crisis is very rare in 17OHD, and children
`escape diagnosis until adolescence for this reason. Instead, the
`precursor DOC accumulates, but manifestations of mineralocorti-
`coid excess tend not to occur in infancy because the newborn
`kidney is rather insensitive to mineralocorticoids. Gradually and
`typically in adolescence, DOC excess causes hypertension and
`hypokalemia. Thus, the most common presentation of 17OHD is an
`adolescent girl without secondary sexual characteristics or menses
`and low-renin hypertension [42,43]. The hypokalemia can be
`severe and cause muscle cramps or frank tetany, which can be the
`
`Infant
`
`46,XX/45,X
`
`Turner stigmata
`Skeletal anomolies
`Genitalia
`Gonadotropins
`17OHP
`
`Infant
`
`46,XY
`
`Skeletal anomolies
`Genitalia
`17OHP
`Testosterone
`Androstenedione
`Cortisol
`DOC
`Corticosterone
`
`Adolescent and adult
`
`46,XX/45,X
`
`Blood pressure
`Stature
`Estradiol
`Cortisol
`DOC
`
`Adolescent and adult
`
`46,XY
`
`Blood pressure
`Pubertal virilization
`Testosterone
`Cortisol
`DOC
`
`17OHD
`
`Absent
`Absent
`Prader 1
`High
`Low/Nl
`
`Turner
`
`Present
`Absent
`Prader 1
`High
`Nl
`
`17OHD
`
`Absent
`Prader 1–3
`Low/Nl
`Low
`Low
`Low
`High
`High
`
`AIS/5aRD
`
`Absent
`Prader 1–2
`Nl
`Nl male
`Nl male
`Nl
`Nl
`Nl
`
`PORD
`
`Present
`Prader 2–4
`High
`Low
`Low
`Low
`Nl
`Nl or high
`
`17bHSD3D
`
`Absent
`Prader 1–3
`Nl
`Low
`High
`Nl
`Nl
`Nl
`
`17OHD
`
`High
`Nl or tall
`Low
`Low
`High
`
`Turner/Gon dys
`
`Nl or high
`Short or Nl
`Low
`Nl
`Nl
`
`17OHD
`
`High
`Absent
`Low
`Low
`High
`
`AIS
`
`Nl
`Absent/partial
`Nl male
`Nl
`Nl
`
`17bHSD3D/5aRD
`
`Nl
`Present
`Low/low Nl
`Nl
`Nl
`
`PORD
`
`Absent
`Present
`Prader 1–4
`High
`High
`
`Gon dys
`
`Absent
`Prader 1–2
`Nl
`Low
`Low
`Nl
`Nl
`Nl
`
`PORD
`
`Nl
`Nl
`Low
`Low
`Nl
`
`Gon dys
`
`Nl
`Absent
`Low
`Nl
`Nl
`
`Gonadal dysgenesis; gon dys, AIS; androgen insensitivity syndrome, 5aRD; 5a-reductase deficiency, 17bHSD3D; 17bHSD3 deficiency.
`
`

`
`R.J. Auchus / Journal of Steroid Biochemistry & Molecular Biology 165 (2017) 71–78
`
`75
`
`presenting symptom complex. In addition, like other forms of
`mineralocorticoid-mediated hypertension, the blood pressure is
`resistant to common antihypertensive agents yet responds well to
`mineralocorticoid-receptor antagonists (MRA) such as spirono-
`lactone.
`In the differential diagnosis, 17OHD patients with 46,XX
`karyotypes resemble Turner syndrome with Müllerian structures
`and absent secondary sexual characteristics; however, the 17OHD
`patients
`lack the other Turner stigmata (lymphedema, wide
`carrying angle, cardiac defects) and are typically normal height
`or tall rather than short. The 17OHD patients with 46,XY karyotype
`somewhat resemble complete androgen insensitivity syndrome
`due to the blind vaginal pouch without Müllerian structures or
`body hair, but the 17OHD patients fail to feminize spontaneously
`and will respond to androgens
`if administered. Also on the
`differential diagnosis is P450-oxidoreductase deficiency (PORD),
`which itself has partial but variable deficiency of 17-hydroxylase
`and 17,20-lyase activities. Because of overlapping hormonal
`abnormalities in PORD and 17OHD, the two conditions can be
`difficult to distinguish in 46,XY individuals (Table 2). In contrast,
`PORD patients with 46,XX karyotypes often show inappropriate
`masculinization for complex biochemical reasons. Additional clues
`to PORD include elevated 17OHP and 21-deoxycortisol as in 21-
`hydroxylase deficiency, the presence of Antley-Bixler syndrome
`malformations in some but not all cases, and maternal virilization
`during pregnancy.
`Unlike most other forms of congenital adrenal hyperplasia, a
`true nonclassic form of 17OHD has not been well defined—meaning
`normal cortisol production and prenatal sexual development but
`discernable genetic and biochemical abnormalities with subtle
`clinical manifestations. One could speculate that such patients
`low-renin
`“essential”
`might have what would appear to be
`hypertension with low aldosterone, but because DOC is rarely
`measured in clinical practice, a genetic condition would not be
`suspected. The closest case so far described is a child with mild
`undervirilization, normal blood pressure, and biochemical evi-
`dence of partial 17OHD [44]. This child is a compound heterozygote
`for a frameshift mutation in R36, creating a stop codon at residue
`107, and W121R, which shows 60% 17-hydroxylase and 16% 17,20-
`lyase
`activity
`of
`the wild-type
`enzyme.
`Indeed,
`the
`rs1004467 polymorphism in the CYP17A1 gene has been identified
`as a susceptibility allele for hypertension in several studies [45,46],
`but this single-nucleotide polymorphism does not change the
`coding region of the enzyme. Females with mild 17OHD might
`have irregular menses and subfertility, while affected males might
`have low-normal testosterone with slightly elevated gonadotro-
`pins and possibly oligospermia.
`Additional manifestations of 17OHD include ovarian cysts and
`cyst rupture in 46,XX patients [47,48]. The mechanism of cyst
`formation is thought to be chronically elevated gonadotropins
`without an estrogen-triggered ovulatory surge. Occasionally, 46,
`XX patients with 17OHD have spontaneous but irregular menses
`[49,50]. At this time, there are no published examples conclusively
`documenting a successful pregnancy in which either partner has
`17OHD. Cases of 46,XX women with 17OHD have been described in
`whom embryos were obtained after adrenal-derived progesterone
`suppression with dexamethasone prior to superovulation with
`gonadotropins, oocyte retrieval, and in vitro fertilization, but these
`embryos have not afforded live births [51].
`Boys with ILD are usually ascertained at birth because of
`impaired virilization [18,22,52], and girls with this condition have
`been
`identified as siblings of affected boys [52] or during
`evaluation of primary amenorrhea without hypertension [53].
`The boys show varying degrees of poor genital development with
`hypospadias, bifid scrotum, and micropenis. Both girls and boys
`
`with this condition do not progress normally through puberty and
`are likewise infertile.
`
`2.2. Diagnosis
`
`The two scenarios most commonly encountered in which the
`diagnosis of 17OHD is entertained include the infant with 46,XY
`karyotype and female or ambiguous genitalia and inguinal or
`abdominal testes, or the adolescent girl with primary amenorrhea
`and absent secondary sexual characteristics with hypertension and
`hypokalemia [42]. In the
`first case, the infant will have had the
`karyotype and initial laboratory
`findings of low T with high
`insensitivity and 5a-
`gonadotropins. At that point, androgen
`reductase deficiency are essentially excluded, so the differential
`diagnosis primarily includes various forms of gonadal dysgenesis
`and 17b-hydroxysteroid dehydrogenase type 3 deficiency. Cosyn-
`tropin stimulation testing reveals the adrenal steroidogenic defect:
`low cortisol, DHEA, and 17OHP but high DOC and corticosterone
`[13,54]. As in all cases of enzyme deficiency, the most informative
`tests are the high analytes above the block, particularly cortico-
`sterone. Progesterone is also above the block and is high in 17OHD
`[55] and even higher in PORD [56,57], but low 17OHP and very high
`DOC distinguishes 17OHD from PORD [58]. Finally, the other
`hypertensive
`form of congential adrenal hyperplasia
`is 11-
`hydroxylase deficiency (11OHD), because DOC also accumulates,
`is
`low
`in 17OHD and high
`in 11OHD.
`but 11-deoxycortisol
`Androgens are also elevated in 11OHD but low in 17OHD [13,59].
`For the adolescent girls with primary amenorrhea, the initial
`evaluation will suggest a
`form of gonadal dysgenesis: high
`gonadotropins,
`low T, and
`low estradiol (E2), regardless of
`karyotype. The 46,XY cases will also lack a uterus and might have
`palpable testes in the inguinal regions. While the focus in these
`cases is on the gonads and reproductive development, the critical
`step in making the correct diagnosis is the consideration of a
`simultaneous defect in adrenal steroidogenesis, which is hinted in
`the majority of cases from the presence hypertension and/or
`hypokalemia. Steroid analysis, basal and after cosyntropin
`stimulation, will reveal the biosynthesis defect as described for
`infants.
`The diagnosis of ILD is primarily considered for newborn boys
`with undervirilization. The presumptive diagnosis of gonadal
`dysgenesis will be consistent with initial laboratory tests, which
`show low AD and T and often high gonadotropins. Among the
`distinguishing laboratory features is the elevated 17OHP/AD ratio
`at baseline or with hCG stimulation, which is typically >50 in
`affected cases [18]. A second clue to the diagnosis in the neonate is
`a low DHEAS, which is normally >100 mg/dL but falls sharply after
`birth [41]. The low DHEAS indicates both an adrenal and gonadal
`defect and focuses the differential diagnosis on enzymes common
`to both glands, including CYP17A1. For girls, ILD is a very rare cause
`of pubertal failure but without hypertension as in 17OHD [53].
`
`2.3. Abiraterone acetate and pharmacologic induction of 17OHD
`
`The prostate gland requires androgens for its formation and
`growth, and prostate cancer likewise demonstrates androgen
`dependence in most cases. For this reason, surgical or medical
`castration has been used for decades to treat this disease, at least in
`the initial stages. Currently, the standard of care in metastatic
`disease is testicular suppression with long-acting gonadotropin-
`releasing hormone agonists or antagonists, which often induces
`remission or stable disease for months to years [60]. When the
`therapy,
`the condition
`is called
`disease progresses despite
`castration-resistant prostate cancer (CRPC), and evidence from
`the past decade has shown that traces of residual androgens are
`primarily responsible for disease progression [61,62]. Because
`
`

`
`76
`
`R.J. Auchus / Journal of Steroid Biochemistry & Molecular Biology 165 (2017) 71–78
`
`CYP17A1 activities are the essential for all biochemical pathways of
`androgen synthesis, CRPC has been treated with additional means
`to suppress these androgens, such as dexamethasone to suppress
`inhibitor of
`adrenal-derived androgens and ketoconazole, an
`multiple cytochrome P450 enzymes including CYP17A1 [63]. To
`specifically target CYP17A1, selective inhibitors of this enzyme
`have been developed, including abiraterone [64], given orally as
`the acetate [65], and galeterone. Abiraterone is a very potent active
`site-directed
`inhibitor, with a binding affinity of 1–3 nM for
`purified CYP17A1 [66].
`Administration of abiraterone to men with CRPC with contin-
`ued medical castration suppresses testosterone from a baseline of
`5–20 ng/dL to <0.1 ng/dL in the majority of cases [65]. In the phase I
`and II trials, abiraterone was given without glucocorticoids, and the
`potent CYP17A1 inhibition caused DOC and corticosterone to rise
`to concentrations
`found
`in 17OHD
`[65]. As a
`dramatically
`consequence, many men developed hypertension and hypokale-
`mia, which was successfully treated with the selective mineralo-
`corticoid-receptor
`antagonist
`eplerenone
`[67]. When
`dexamethasone was added to abiraterone, DOC and corticosterone
`fell back to baseline values. Abiraterone is indicated for use in CRPC
`in combination with glucocorticoids, typically prednisone, pred-
`nisolone, or dexamethasone to prevent the ACTH-driven mineral-
`ocorticoid excess seen in the phase I and II trials [63]. These data
`confirm that the hypertension and hypokalemia of 17OHD is
`from DOC and corticosterone accumulation. More
`derived
`importantly, this pharmacologic cause of 17OHD is now far more
`common than CYP17A1 mutations, and these patients are elderly
`males unlike typical cases of genetic 17OHD.
`
`3. Treatment
`
`3.1. Glucocorticoids
`
`As discussed above, high corticosterone production compen-
`sates for cortisol deficiency, and as a result, patients with 17OHD
`do not experience clinical glucocorticoid insufficiency and rarely if
`ever experienced adrenal crises. Consequently, corticosteroid
`replacement is not essential, and pharmacologic glucocorticoids
`therapy can induce adrenal axis suppression with the risk of failure
`to mount an appropriate augmentation in corticosterone produc-
`tion during acute illness. Furthermore, chronic glucocorticoid
`therapy in Addison’s disease [68] and 21-hydroxylase deficiency
`[69,70] is associated with deleterious impairments in bone health
`factors. Nevertheless, glucocorticoid
`and cardiovascular risk
`administration will lower DOC production and normalize blood
`pressure and potassium as observed in patients taking abiraterone.
`incomplete
`replacement will
`As a compromise, partial or
`substantially reduce but not normalize DOC yet mitigate long-
`term consequences of glucocorticoid therapy. Adjunctive treat-
`ments are likely to be necessary in this case, using mineralocorti-
`coid antagonists as described in the next section, as glucocorticoid
`therapy alone might not achieve good blood pressure control [71].
`
`3.2. Mineralocorticoid receptor antagonists and antihypertensives
`
`All forms of ACTH-dependent mineralocorticoid excess respond
`well to mineralocorticoid receptor antagonist therapy, because a
`rise in renin due to treatment does not enhance production of the
`pathogenic steroid. In 17OHD, spironolactone at 50–200 mg/d
`given in 1 or 2 divided doses is often ideal therapy. Because these
`patients are phenotypically female, the typical side effects seen in
`man, including gynecomastia and erectile dysfunction, are not an
`issue. Breast tenderness can occur with spironolactone, and 46,XX
`individuals might