Male Pseudohermaphroditism
`
`Due to l7a—Hydroxylase Deficiency
`
`MARIA I. NEW with the technical assistance of LADDAWAN SUVANNAKUL
`
`From the Department of Pediatrics, The New York Hospital-Cornell Medical
`Center, New York, New York 10021
`
`ABSTRACT This is the first report of a male with
`1704-hydroxylase deficiency resulting in male pseudo-
`hermaphroditism, ambiguous external genitalia, absence
`of male secondary sexual characteristics, and gyneco-
`mastia at puberty. Diagnosis was based on extensive
`studies of steroid metabolism including the following:
`low urinary excretion of l7-ketosteroids and 17-hydroxy-
`corticoids which did not increase after ACTH; no re-
`sponse of very low plasma testosterone and dehydroepi-
`androsterone to adrenocorticotropin (ACTH) or cho-
`rionic gonadotropin; and low urinary aldosterone and
`plasma renin which increased after dexamethasone. Se-
`cretion rates of 17-hydroxylated steroids, cortisol (F)
`and 11-desoxycortisol
`(S), were very low while de-
`soxycorticosterone (DOC) and corticosterone (B) se-
`cretion rates were increased sevenfold. Results expressed
`as milligrams per meter
`squared per day were as
`follows: F, 1.3; S, 0.023; DOC, 0.35; and B, 16 (mean
`normal values were F, 7.5; S, 0.26; DOC, 0.055, and
`B, 2.2). Plasma gonadotropins were markedly increased
`(FSH, 106; LH, 364 mIU/ml). Testicular biopsies re-
`vealed interstitial—ce1l hyperplasia and early spermato-
`genesis. Karyotype was 46/XY. Pedigree showed no
`other affected member. At laparotomy ovaries, uterus,
`and fallopian tubes were absent, vas deferens was in-
`complete, and prostate was present. External genitalia
`consisted of small phallus, bifid scrotum,
`third-degree
`hypospadias, and small vagina. At puberty there was no
`growth of body hair or phallic enlargement. Biopsy of
`marked gynecomastia showed both ducts and acini. Tes-
`tosterone administration produced virilization. Sexual
`ambiguity demonstrates strong dependence of external
`genitalia on androgens for male differentiation. Sup-
`pression of Miillerian structures occurred despite fe-
`male levels of testosterone indicating this step in male
`
`Dr. New was the recipient of Career Scientist Award of
`the Health Research Council of the City of New York under
`Contract I 481.
`Received for publication 19 February 1970 and in revised
`form 26 May 1970.
`
`testosterone dependent. Pubertal
`differentiation is not
`breast development in this male supports the concept of
`femaleness during ontogeny unless counteracted by
`male factors. Diagnosis of other adrenocortical enzymatic
`deficiencies is excluded by the steroidal studies. The
`clinical response to testosterone excludes testicular femini-
`zation. Deficiency of 17-hydroxylation must be added to
`the cause of male pseudohermaphroditism.
`
`INTRODUCTION
`
`Since the report by Biglieri, Herron, and Brust of 170:-
`hydroxylase deficiency in a female (1), there have been
`three subsequent females described with the syndrome
`of hypertension, primary amenorrhea, and sexual
`in-
`fantilism due to defective 17-hydroxylation (2, 3) of
`steroids.
`
`This is the first report of a male with 17o:-hydroxylase
`deficiency which resulted in male pseudohermaphroditism,
`ambiguous external genitalia, absence of male secondary
`sexual characteristics, and prominent breast development
`at puberty. Unlike the previously reported females, this
`male did not manifest severe hypertension or hypoka-
`lemia. Deficiency of an enzyme necessary for synthesis
`of testosterone and estrogen in the female resulted in a
`normal phenotype while in the male the phenotype was
`markedly altered. The role of estrogens and androgens
`in embryological differentiation of the human male ex-
`ternal and internal genitalia and in the production of
`secondary sexual characteristics is elucidated by this
`case.
`
`METHODS
`
`(S),‘
`(F), 11-desoxycortisol
`Secretion rates of cortisol
`corticosterone
`(B),
`and ll-dcsoxycorticosterone
`(DOC)
`
`‘The following compounds and their trivial names and
`abbreviations are used: 17,21-dihydroxy—pregn—4—ene 3, 20
`dione
`(ll-desoxycortisol;
`compound S); 3a,l7,20-trihy-
`droxy—5B—pregnane
`(pregnanetriol);
`and
`9a-fluoro—l6a-
`methyl—1113,l7a,2l—trihydroxypregn-1,4-diene-3,20-dione (dex-
`amethasone; Decadron).
`
`1930
`
`The Journal of Clinical Investigation Volume 49
`
`1970
`
`Amerigen Exhibit 1169
`Amerigen Exhibit 1169
`Amerigen v. Janssen IPR2016-00286
`Amerigen v. Janssen IPR20 l 6-00286
`
`

`
`were measured by the method of New, Seaman, and Peter-
`son (4). Urinary 17-ketosteroids, 17—hydroxycorticosteroids,
`pregnanetriol, aldosterone, and plasma 17—hydroxycorticoids
`were measured by previously reported methods (5). Plasma
`androgens were determined by a double isotope dilution
`derivative technique (6). Urinary estrogens were determined
`by the method of Brown, Bulbrook, and Greenwood (7), as
`modified by Beling (8) and urinary pregnanediol by the
`method of Klopper, Michie, and Brown (9). Plasma lutein-
`izing hormone
`(LH)
`and
`follicle-stimulating hormone
`(FSH) were determined by a radioimmunoassay (10). The
`urinary 17-ketosteroids were partitioned by a single isotope
`dilution technique utilizing hot acid hydrolysis, separation
`of steroids by paper chromatography, and quantitation of
`the separate eluates by the Zimmermann reaction (5).
`The various periods of study described in the results were
`as follows: base line—no medications; i.v. ACTH—40 U of
`ACTH intravenously daily; metyrapone—3 g of metyrapone
`p.o. daily for 3 days; Decadron—8 mg of dexamethasone p.o.
`daily for 3 days; Decadron + CGT—8 mg of dexamethasone
`p.o.+human chorionic gonadotropin, 5000 U intramuscu-
`larly, daily for 3 days; and testosterone—injection of 400
`mg of testosterone enanthate intramuscularly once.
`Case report. This 24 yr old male pseudohermaphrodite
`was admitted for mastectomy. He was born with ambiguous
`genitalia and the sex assignment was uncertain until his
`first medical
`investigation at age 20 months when he was
`definitely considered male. At that age his height
`(90 cm)
`and weight
`(14.5 kg) and blood pressure were normal.
`His genitalia were described as follows: “the labia majora
`or bifid scrotum contain oval shaped bodies (testes); that
`on the right
`is descended and on the left is at the upper
`pole of labium. There is a large prepuce and rudimentary
`penis. A urethral groove is visible on the under surface
`which is divided into two halves. At the posterior end of
`this groove is an opening leading to the bladder.” His bone
`age and urinary 17-ketosteroid excretion were normal. Upon
`cystoscopy at 21 months, a 1.5 cm vagina was visualized.
`The urethral meatus was located in the vagina. No cervix
`was observed. The urethra was described as female in type.
`Exploratory laparotomy at 22 months reported “no female
`adnexa.” The diagnosis was male pseudohermaphroditism.
`He was thereafter reared as a male.
`At 3% yr of age he weighed 18.7 kg and his height was 103
`cm. A biopsy of the right testicle revealed an infantile testis
`and a normal epididymis. Exploration of
`the left inguinal
`canal did not locate the left testicle. Microscopic examination
`of
`the right
`testicular biopsy showed tubules
`lined by
`columnar epithelium which appeared to be inactive. There
`were no mitotic figures, spermatocytes, or sperm seen. The
`interstitial tissue was minimally increased and consisted of
`closely packed fibrous tissue but no increase in Leydig cells.
`At the age of 3% he was treated with methyl testosterone
`5 mg p.o. daily and 5 mg/g of
`testosterone ointment by
`inunction to the genital area for 2 months. The penis in-
`creased from 2.5 to 3.2 cm in length. An intravenous pyelo-
`gram at
`this time demonstrated normal renal function but
`an unusual bladder neck. Over the next 5 yr he had multiple
`urologic operations
`to release the chordee,
`lengthen the
`penis, and bring the urethra to the mid-shaft of the penis.
`He next presented himself at the age of 16 because he had
`developed marked gynecomastia over
`the previous 2 yr.
`At that time he manifested no secondary sex characteristics
`except gynecomastia. He had no pubic, axillary, or
`facial
`
`hair. A prostate was palpated. A small right testis was in
`the scrotum and a mass was felt in the left inguinal canal.
`Urinary 17—ketosteroid excretion was 14 mg/24 hr (normal
`for outside laboratory 15-20) ; 17-hydroxycorticoid excretion
`was 2.3 mg/24 hr
`(normal
`for outside laboratory 2-4).
`Karyotype was reported as 46/XY and a male chromatin
`pattern was observed on buccal smear. Serum electrolytes
`were normal
`(K, 4.1 mEq/liter). Repeat testicular biopsies
`were performed at age 16 which revealed the same micro-
`scopic findings bilaterally. There was mild tubular atrophy
`with increased space between tubules and basement mem-
`brane thickening. Tubules
`showed decreased spermatozoa
`and were lined almost completely with Sertoli cells. There
`was a relative increase in Leydig cells. The microscopic
`diagnosis was atrophy of
`the right and left testes. When
`the patient was 20 yr of age, a prostate was palpated and
`the patient claimed to have normal libido but no ejaculation
`or orgasm. His voice was high-pitched, he still had no
`facial, axillary, or body hair, no temporal hair recession,
`and gynecomastia was marked. Height was 68 inches (pubis
`to crown, 31:} inches, and pubis to floor, 36% inches). A
`bone age was normal and the proximal epiphyses of
`the
`fibulae were fused.
`time to The New York
`He was admitted for the first
`Hospital at 24 yr of age for mastectomy. At this time he
`had marked gynecomastia (see Fig. 1), hypospadias, chordee,
`hypoplasia. of the scrotum, empty left scrotum, and a small
`right gonad. His height was 68 inches and weight 206 lb.
`The blood pressure was only slightly elevate.‘
`(150—l30/
`90-60). He was markedly obese and had a eunuchoid
`habitus. He claimed to have erections and sexual
`inter-
`course but no ejaculation. Enuresis was common. His voice
`was high-pitched,
`there was no recession of temporal hair
`line, skin was very smooth, and there was no facial hair,
`seborrhea, or acne. He never had shaved. Repeated cystos-
`copy confirmed the presence of a vaginal utricle 1.5 cm
`from the bladder neck in the floor of the urethra. The 2 X 3
`cm utricle could be filled with water and readily emptied
`with pressure via a 2 mm opening into the = rgieally con-
`structed urcthra. A retrograde and voiding cystogram
`demonstrated an irregular distal urethra. and a bulbous
`dilation of
`the mid—portion of
`the urethra. Bone age was
`normal
`(Fig. 2).
`At this point he was studied extensively from an endo-
`crine viewpoint as indicated below. Random fasting growth
`hormone level was 1.9 mug/ml (normal 0-8). A mastectomy
`was performed and the microscopic sections
`showed an
`unusual
`lobular pattern of
`acini
`(Fig. 3). He had a
`smooth operative and postoperative course without steroid
`treatment. Postoperatively he was
`treated
`with testos-
`terone
`enanthate
`400 mg
`intramuscularly
`and
`subse-
`quently testosterone propionate 25 mg intramuscularly every
`2 wk. Within 6 wk he manifested the following signs
`of virilization: deepening of voice,
`seborrhea and very
`slight acne, pubic hair and facial hair
`requiring him to
`shave weekly. He claimed improved muscular strength. In
`addition body hair on arms and legs increased. The Size
`of the phallus after 2 months of treatment with testosterone
`had not changed. Family history revealed no other affected
`member.
`
`Review of testicular biopsies confirmed histological diag-
`nosis of infantile testes at age 2. At age 16 the presence of
`spermatocytes and marked interstitial-cell hyperplasia was
`confirmed (Fig. 4). A repeat karyotype was 46/XY.
`
`Male Pseudohermaphroditism Due to 17a-Hydroxylase Deficiency
`
`1931
`
`

`
`RESULTS
`
`Urinary excretion of metabolites of steroidal hor-
`mones
`(Table I ).
`The daily urinary 17—ketosteroid
`excretion was low for an adult male and the response to
`ACTH was minimal. The 17-hydroxycorticoid excretion
`doubled with ACTH but showed no greater increase with
`metyrapone. At no period before treatment with testos-
`terone did the urinary 17-ketosteroid excretion or the
`17-hydroxycorticoid excretion rise to adult male levels.
`
`Although the urinary 17-hydroxycorticoids suppressed
`briskly with 2 mg of dexamethasone, the 17-ketosteroid
`values decreased only slightly. With the maintenance of
`adrenal suppression, chorionic gonadotropin did not in-
`crease the 17-ketosteroid excretion. Treatment with tes-
`tosterone increased 17-ketosteroid excretion while 17-
`
`hydroxycorticoid excretion remained low. A partition of
`the urinary 17-ketosteroid on the day of ACTH adminis-
`tration showed an etiocholanolone excretion of 2.1 mg,
`
`17-Hydroxylase defect resulting in male pseudohermaphroditism with
`FIGURE 1
`prominent breast development and absence of virilizing signs at puberty. Note
`eunuchoid habitus, absence of recession of hairline, and hairlessness.
`
`1932
`
`M. I. New
`
`

`
`film demonstrating fusion of all epiphyses of
`FIGURE 2 Wrist
`metacarpals and distal ulna and radius, despite marked deficiency
`of androgens and estrogens.
`
`androsterone 2.5 mg, and dehydroepiandrosterone of
`1.9 mg. The total 17-ketosteroid excretion on that day
`was 6.6 mg.
`Pregnanetriol excretion was slightly increased. This
`was determined by an unpublished single isotope dilu-
`tion technique and then rechecked by a double isotope
`dilution derivative technique (11). The level of preg-
`nanetriol excretion varied very little with either stimula-
`
`tion by ACTH or chorionic gonadotropin or with sup-
`pression by dexamethasone or testosterone (see Table I).
`By the method used,
`the total excretion of estrone
`(E1), estradiol (E2), and estriol (E3) is 5-10 ,ug in nor-
`mal males. Estrogen excretion in this patient was very
`low. E2 was 1.1 ,ug/day. E1 and E3 were undetectable.
`This patient excreted 0.29 mg of pregnanediol in 24
`hr. Although few determinations of pregnanediol
`in
`
`Male Pseudohermaphroditism Due to 17a-Hydroxylase Deficiency
`
`1933
`
`

`
`FIGURE 3 Histology of breast tissue demonstrating both ductal and
`acinar development.
`
`male urine have been reported, this level does not appear
`to be elevated. Excretion rates in males have been previ-
`ously reported as 0.32-0.88 mg/day (12); 1.1 mg/day
`(13), and 0.7 mg/day (14).
`Plasma hormones (Table I ). The plasma 17-hydroxy-
`corticoids were initially at
`the lower limit of normal
`and showed no diurnal variation. There was no rise of
`
`plasma 17-hydroxycorticoids with ACTH administra-
`tion; however, the pre-ACTH concentration was higher
`than previous values. The plasma testosterone levels
`were repeatedly in the female range and below the nor-
`mal adult male range (6). Neither ACTH nor chorionic
`gonadotropin administration caused an increase in the
`plasma testosterone. Dexamethasone did not suppress
`the already low levels of testosterone. The plasma de-
`hydroepiandrosterone (DEA) was below normal female
`or male levels
`(6). Plasma gonadotropins were very
`high (FSH 106, LH 364). Normals for this laboratory
`are FSH 3.9-42, LH 2.5—32 mIU/ml (10). Plasma renin
`initially was very low, 0.1 mug/ml per hr. Normal
`values in this laboratory are 2-7 rung of angiotensin gen-
`
`erated per ml per hr. Plasma progesterone was 0.020
`pg/100 ml? Normal values for a female in the follicular
`phase are 0.020—0.l00 Mg/100 ml. Normal male levels are
`very low. Plasma 17-hydroxyprogesterone was 0.091
`ug/100 ml’ and 17-hydroxy-A-5-pregnenolone was 0.200
`pg/100 ml.’ Both values were considered to be within the
`normal range.
`Secretion rates of cortisol (F), corticosterone (B),
`desoxycorticosterone (DOC), desoxycortisol (S), and
`aldosterone (aldo)
`(Table II). The secretion rates of
`F, S, and aldo were very low whereas the secretion rates
`of B and DOC were 7-8 times normal (4).
`Metabolic balance studies (Fig. 5). The sodium and
`potassium balance as determined by dietary intake and
`urinary excretion are depicted in Fig. 5. The blood pres-
`sure was never very elevated. The highest diastolic blood
`pressure was 100 mm. No single period of study produced
`a consistent change in blood pressure; rather the values
`
`to Dr. Mortimer Lipsett for carrying
`2We are grateful
`out these determinations. Normal values are those given by
`Dr. Lipsett for his laboratory.
`
`1934
`
`M. I. New
`
`

`
`were erratic throughout. ACTH administration induced
`the expected acute rise in aldosterone excretion but no
`other significant change. Metyrapone produced a marked
`sodium retention but no kaliuresis while aldosterone
`
`excretion returned to low control levels. This suggested
`that a hormone other than aldosterone was responsible
`for
`the sodium retention.
`In contrast dexamethasone
`
`caused a marked natriuresis without significant kaliure-
`sis, while the aldosterone excretion remained at
`the
`previously low level. Toward the end of the period of
`the treatment with dexamethasone when human chorionic
`
`gonadotropin was added to the therapy, aldosterone ex-
`cretion began to increase and continued to increase even
`after dexamethasone treatment was discontinued and one
`dose of
`testosterone enanthate was administered. As
`
`sodium balance was
`aldosterone excretion increased,
`gradually restored and potassium excretion increased
`to meet intake levels. The serum Na and K were normal
`
`at the beginning and end of the study.
`The 17-ketosteroid excretion remained low throughout
`except for the period after testosterone therapy.
`
`DISCUSSION
`
`A. Laboratory data. The low urinary excretion of 17-
`ketosteroids, 17-hydroxycorticoids, aldosterone, and es-
`trogens and the low plasma testosterone and high plasma
`gonadotropins present in this patient are similar to the
`findings in the females reported with 17a-hydroxylase de-
`ficiency (l-3). The low plasma 17-hydroxycorticoids
`and the lack of response to ACTH were reported by
`Goldsmith, Solomon, and Horton (2) (Table III).
`
`is sur-
`The slightly elevated urinary pregnanetriol
`prising since other l7—hydroxylated precursors of corti-
`sol are markedly decreased. The presence rather than
`absence of plasma 17-hydroxyprogesterone and 17-hy-
`droxy-A-5-pregnenolone suggests that the 17-hydroxylase
`deficiency is partial. The pregnanediol and plasma pro-
`gesterone were curiously not
`increased despite an in-
`creased production of other aldosterone precursors,
`e.g., DOC and B. Perhaps the adrenal precursor pro-
`gesterone is rapidly utilized for synthesis of B and DOC
`in this patient and is not secreted freely into the cir-
`culation. In the patient of Biglieri et al. (1) the urinary
`pregnanediol and plasma progesterone were not
`in-
`creased while in the case of Goldsmith et al. (2) they
`were markedly increased (Table III).
`Unlike the data on the patient of Biglieri et al. (1) in
`whom the 17a-hydroxylase defect was very severe, the
`laboratory data on this male patient suggest a partial
`l7oz—hydroxylase deficiency. The degree of defect is com-
`parable to that in patients reported by Goldsmith et al.
`(2) and Mallin (3). This statement is based on a simi-
`lar elevation of the secretion rates of B and DOC and a
`
`similar depression in the secretion of F, S. and aldo-
`sterone (Table III). The impairment in androgen syn-
`thesis appears to be more marked than that in cortisol
`synthesis. The plasma testosterone did not respond either
`to ACTH or to chorionic gonadotropin which suggests
`that both testis and adrenal are deficient in 17-hydroxyla-
`tion. In the other form of male pseudohermaphroditism
`caused by an enzymatic defect, the 33-01-dehydrogenase
`deficiency, the defect occurs in the gonad and adrenal as
`well (15). The low plasma DEA and high DOC and
`
`Q
`
`435 .
`V
`
`,.
`
`£
`
`testicular biopsy at age 16. Note Leydig cell
`FIGURE 4 Histological section of
`hyperplasia and early spermatogenesis.
`
`Male Pseudohermaphroditimn Due to 17a-Hydroxylase Deficiency
`
`

`
`Laboratory Studies in a Male Pseudohermaphrodite with 17a-Hydroxylase Defect
`
`TABLE 1
`
`Condition
`
`Urinary
`
`17KS
`
`17OH
`
`mg/day
`
`mg/day
`
`p’—triol
`mg/day
`
`aldo
`
`pg/day
`
`testosterone
`
`pg/I00 ml
`
`17-OH-
`corticoids
`
`a.m. 5.0
`p.m. 4.9
`
`Base line
`Base line
`Base line
`
`ACTH
`
`M etyrapone
`M etyrapone
`M etyrapone
`
`Dexamethasone (2 mg)
`Dexamethasone (2 mg)
`
`Dexamethasone (8 mg)
`Dexamethasone (8 mg)
`
`Dexamethasone + chorionic gonado-
`tropin 5000 U intramuscularly
`Dexamethasone + chorionic gonada-
`tropin 5000 U intramnscularly
`Dexamethasone + chorionic gonad0-
`tropin 5000 U intramuscularly
`
`Testosterone enanthate (400 mg)
`No treatment
`
`Testosterone propionate
`
`Normal values-adult male
`
`Normal values-adult female
`
`5.9
`6.0
`3.4
`
`6.6
`
`7.2
`4.2
`
`3.4
`3.7
`
`3.0
`
`3.7
`
`4.0
`
`5.9
`
`9.7
`11.0
`10.0
`9.2
`13.0
`12.0
`14.0
`13.0
`14.0
`10.1
`
`3.7
`
`8.4
`12.0
`9.4
`10.2
`
`8-25
`
`4-14
`
`2.7
`3.7
`2.3
`
`5.9
`
`4.0
`5.1
`6.1
`
`2.9
`
`3.5
`0.84
`
`1.3
`1.3
`
`1.0
`
`1.6
`
`2.3
`
`1.1
`4.0
`0.82
`1.7
`4.2
`2.4
`1.6
`3.2
`1.2
`2.2
`
`3.4
`
`3.8
`2.1
`4.1
`3.7
`
`1.9
`1.3
`1.5
`
`1.5
`
`1.8
`2.0
`1.5
`
`2.9
`
`3.0
`2.0
`
`1.8
`1.6
`
`0.54
`
`2.0
`
`2.1
`
`3.3
`
`2.1
`2.3
`
`0.75
`1.8
`1.4
`1.2
`1.3
`1.7
`1.2
`
`1.3
`0.98
`3.0
`
`11.0
`
`7.0
`1.62
`0.86
`
`1.1
`
`1.1
`
`6.9
`
`7.1
`
`5.1
`
`8.6
`13.0
`25.0
`10.0
`20.0
`8.6
`6.0
`7.7
`
`4.3
`
`0.55
`
`0.67
`0.53
`0.68
`0.69
`
`4-14
`
`0.5-1.0
`
`5-20
`
`5-25
`
`0.28—1.4
`
`0.13-1.0
`
`0.004-0.07
`
`0.14-1.0
`
`B secretion rates eliminate a 3/3-ol-dehydrogenase de-
`feet as the cause of low androgen production. The over-
`production of DOC is less than that reported by others,
`an observation which is compatible with the absence of
`hypokalemia or severe hypertension. Yet aldosterone
`secretion is largely suppressed presumably via the same
`
`mechanism proposed for the patient of Biglieri et al. (1),
`i.e.,
`the excess DOC causes Na retention which sup-
`presses renin and secondarily aldosterone production.
`This is supported by the return to normal or even in-
`creased levels of aldosterone after dexamethasone ad-
`ministration. With this treatment, DOC secretion is
`
`1936
`
`M. I. New
`
`

`
`TABLE II
`Secretion Rate Studies
`
`Cortisol
`
`Corticosterone
`
`mg/day
`
`mg/mi
`per day
`
`mg/day
`
`mg/m2
`per day
`
`Desoxycorticosterone
`mg/mi
`mg/day
`per day
`
`Desoxycortisol
`mg/day
`me/m’
`per day
`
`Aldosterone
`mg/m‘
`mg/day
`per day
`
`Urinary
`excretion
`aldo pH 1
`1413/W!‘
`Mg/day
`per day
`
`9.4
`12.0
`12.0
`16.0
`—
`7.4
`
`7.3
`9.2
`7.5
`
`10.1
`
`Normal subjects
`K.McG.
`14
`H.McG.
`41
`M.H.
`16
`C.M.
`3
`C.P.
`8
`C.B.
`14
`_I.P.
`22
`T.W.
`20
`T.W.’
`21
`M.McG.
`13
`R.W.
`0.5
`Mean of normals
`
`8.3
`15.5
`25.0
`4.9
`5.8
`19.0
`6.7
`17.2
`14.5
`5.7
`3.4
`11.5
`
`5.2
`7.8
`14.0
`7.0
`5.8
`11.0
`3.5
`8.5
`7.3
`3.6
`8.5
`7.5
`
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`
`1.4
`2.2
`2.4
`1.2
`1.5
`3.5
`2.9
`3.7
`2.2
`1.1
`
`2.2
`
`0.23
`0.31
`0.5
`0.3
`0.48
`0.28
`0.51
`0.3
`0.42
`0.45
`
`0.38
`
`0.14
`0.15
`0.28
`0.43
`0.48
`0.16
`0.27
`0.15
`0.21
`0.28
`
`0.26
`
`——
`—
`
`0.18
`
`0.13
`
`0.029
`0.06
`0.067
`0.06
`0.079
`0.06
`0.019
`0.06
`0.037
`0.075
`
`0.055
`
`0.35
`
`Male with 17 a-hydroxylase deficiency
`13.5.
`24
`2.8
`1.3
`
`0.051
`
`0.023
`
`0.075
`
`0.034
`
`.
`
`2.2
`
`renin suppression ceases, and aldosterone
`diminished,
`stimulation is permitted. If the adrenal cortex were con-
`sidered as two glands—the fasciculata and the glomeru-
`losa—such feedback effects assume a more logical se-
`quence. The fasciculata which suffers from the 17-hy-
`droxylase defect produces excessive DOC which is re-
`leased into the circulation and causes excessive renal
`
`tubular resorption of sodium which in turn suppresses
`renal renin production. Thus the glomerulosa does not
`receive the required renin stimulation for aldosterone
`synthesis, and low aldosterone secretion results. Upon
`administration of dexamethasone, ACTH stimulation of
`the fasciculata is suppressed and DOC secretion di-
`minishes permitting renin stimulation of the glomerulosa
`to secrete aldosterone. That DOC secretion is responsible
`for sodium balance is deduced from (a) the positive Na
`balance with very low aldosterone excretion and low
`plasma renin,
`(b)
`the failure to observe Na diuresis
`with metyrapone despite a low aldosterone excretion,
`and (C) when dexamethasone is administered there is
`profound sodium loss 5 days before a change in aldo-
`sterone. Later after prolonged treatment with dexametha-
`methasone,
`the aldosterone increases, possibly via the
`mechanism described above. This increase persists for
`some time after dexamethasone treatment is discontinued
`
`and then vanishes as evidenced by the return to a low
`value on 4/28. (Fig. 5).
`this man sus-
`Like the patients reported previously,
`tained repeated anaesthesia and major surgery despite
`impaired cortisol secretion. Apparently, corticosterone
`has suflicient glucocorticoid effect to obviate the need for
`cortisol administration during surgery.
`The absence of hypokalemia may indicate that DOC
`secretion is not sufficient to produce K” wasting or that
`
`an escape from the kaliuretic effect of endogenous DOC
`secretion has occurred. Patients with hyperaldosteronism,
`however, rarely show an “escape” phenomenon from the
`kaliuretic effect of aldosterone but commonly show es-
`cape from sodium retention effects.
`This patient clearly virilized in response to testosterone
`treatment ruling out any suggestion of testicular femini-
`zation.
`
`B. Male difierentiation. Because the previously re-
`ported cases (1-3) of 17a-hydroxylase deficiency have
`been females with absence of secondary sexual charac-
`teristics, it is of interest that the male with this enzyme
`deficiency manifests male pseudohermaphroditism.
`In-
`deed the enzyme defect must be added to the list of
`considerations
`in the differential diagnosis of male
`pseudohermaphroditism.
`Federman (16) divides male differentiation into the
`following four steps: (a) inhibition of Miillerian primor-
`dia; (b) stimulation of Wolffian ducts; (c) posterior mi-
`gration of labioscrotal folds; and (d) elongation of geni-
`tal tubercle and midline fusion of the genital folds and
`swellings to form the penis and scrotal sacs.
`Jost (17) adds the important initial step of differenti-
`ation of the gonadal primordium into testis. It would
`seem worthwhile to add male secondary sex character-
`istics at puberty to the list of
`steps
`in total male
`differentiation.
`
`Familial causes of male pseudohermaphroditism have
`included testicular feminization and other gradations of
`incomplete masculine development as reported by Prader
`(18), Lubs, Vilar, and Bergenstal (19), Gilbert-Drey-
`fus, Savoie, Sébaoun, Alexandre, and Belaisch (20), and
`Reifenstein (21). In all of these cases the first step in
`masculinization was accomplished,
`i.e. Miillerian duct
`
`Male Pseudohermaphroditism Due to 17a-Hydroxylase Deficiency
`
`1937
`
`

`
`suppression, while there were varying degrees of incom-
`plete Wolffian development, phallic growth, and labio-
`scrotal and urethral development. There is ample evi-
`dence to support the theory of Jost
`(22-24)
`that the
`testis plays an inducer role in the Miillerian suppression
`and that this inducer is not testosterone (25). Further,
`the development of the Wolffian system apparently re-
`quires both inducer
`substance and androgen while
`external genitalia are largely dependent on androgen.
`This case of 17a-hydroxylase deficiency in the male
`provides confirmation to the proposal that the male in-
`ducer substance which causes Miillerian suppression is
`not testosterone. The patient did not have a uterus or
`fallopian tubes despite a marked incapacity to synthesize
`androgens. The presence of the epididymis suggests that
`some Wolffian development occurred in this patient but
`it was incomplete. The lack of ejaculation suggests an
`absence of vas deferens. External genitalia showed the
`
`least virilization and therefore give evidence for the
`strongest dependence on androgens for development.
`The histology of
`the breast
`tissue, which was the
`only manifestation of puberty, demonstrated acini and
`ducts as in the female. The breasts cannot, therefore, be
`regarded as adolescent glynecomastia which only shows
`periductal fibrous stroma and ductal hypertrophy (26,
`27). The control of breast development
`is not entirely
`understood but most data suggests that pituitary gonado-
`tropins, prolactin, and estrogen combine in some way
`to cause breast development in the female. Except for
`adolescent gynecomastia, breast development in the male
`suggests a pathological disorder
`in which there is
`gonadal deficiency and increased gonadotropin produc-
`tion (28). Both conditions were present in this patient.
`Federman (16) suggests the possibility that in the male
`there is a substance produced by the fetal testis which
`inhibits the breast anlage. Thus the abnormal testis in
`
`LS. AGE 24 VEARS
`MALE PSEUDCMERMAPHRODITE
`
`§§o§§c-338$8
`
`BLOOD
`PRESSURE
`mm Hg
`
`non c----3
`17KS (--I
`mql day
`
`ALDOSTERONE
`EXCRETION
`H9/day
`
`POTASSIUM
`INTAKE (—)
`
`URINARY
`OUTPUT (-----l
`mEq I day
`
`SODIUM
`INTAKE (——l
`URINARY
`OUTPUT (-----I
`
`TESTOSTERONE
`ENANTHATE
`
`L.) -‘
`
`L1'
`I
`
`..
`
`I.
`...
`1
`
`--
`
`.
`
`3I2lZ325Z7293l4I24 68101214161820
`
`28
`
`sodium and potassium correlated
`FIGURE 5 Metabolic balance of
`with various periods of
`therapy and hormonal measurements.
`
`

`
`TABLE II I
`
`Comparison of Cases with 17a-Hydroxylase Deficiency
`
`Biglieri (1)
`
`Goldsmith (2)
`
`Mallin (3)
`
`Female
`
`26
`
`Female
`
`35
`
`75
`
`Sibling
`
`Female
`
`17
`
`164
`
`44.5
`
`Present
`report
`
`Male
`
`24
`
`172
`
`106
`
`445
`
`43
`
`220/140
`
`140/100
`
`150/100
`
`140/100
`
`180/100
`
`150/90
`
`Absent
`
`Absent
`
`Absent
`
`Absent
`
`Present
`
`Present
`
`50
`00
`2.0-11.0
`-—
`<1.0
`<0.2
`
`8.0
`10
`21.0
`0
`
`1.0
`
`1.5
`0.7
`
`0
`(THS 0)
`4
`112-124
`0.010—0.018
`
`3.0
`(THS 0)
`1.4
`44.0
`0.029
`
`(THDOCOJW)
`(THB20)
`
`1%
`
`0.9-2.8
`1.8-3.4
`17, 3.8
`0.2, 0.1
`
`23.0
`
`3.0-3.6
`
`5.9
`2.7
`0.29
`1.9
`1.3
`0.11
`
`4.3
`
`5, 4.9
`0.04
`0.02
`0.02—0.1
`106
`364
`1.9
`
`0.1
`
`28
`
`Sex
`
`Age, yr
`
`Height, cm
`
`Vl/eight, kg
`
`Blood pressure
`
`Female secondary sex
`characteristics
`
`Urine
`
`17KS, mg/day
`l7OH, mg/day
`Pregnanediol, mg/day
`Pregnanetriol, mg/day
`Aldosterone, pg/day
`Estrogen (E2), pg/day
`
`Serum K, mEg/liter
`Plasma*
`
`17OH,pg/100 ml
`Testosterone, pg/I00 ml
`Progesterone, ;1g/ 100 ml
`Normal value
`FSH, ml U/ml
`LH, mI U/ml
`GH, mpg/ml
`Renin (mpg of angiotensin
`generated per ml per hr)
`
`Secretion rates,1 mg/day
`F
`S
`DOC
`B
`Aldo
`
`* See text (Discussion, section B) and Table I for normal values.
`I Results in parentheses represent excretion rates rather than secretion rates.
`
`male pseudohermaphroditism fails to cause this inhibition.
`Recent experiments lend support to Federman’s hypothe-
`sis. Male rats treated in utero with an adrogen antag-
`onist (cyproterone acetate) show female postnatal breast
`development (29). In our patient, estrogen excretion was
`very low, despite the prominent breast development.
`This would imply that hormonal factors at puberty other
`than estrogens promoted breast development or that the
`breast primordia were very sensitive to the small quan-
`tity of estrogen available. Neumann’s experiments (29)
`also imply that estrogens may not play a major role in
`breast organogenesis since cyproterone acetate is not
`
`estrogenic. In addition there have been reports of breast
`hypertrophy upon DOC administration (30). Although
`it is an unlikely cause, this patient was exposed to high
`endogenous DOC secretion. The puzzling contrast to the
`females with 17a-hydroxylase deficiency with virtual lack
`of breast development and this male with the same en-
`zyme defect and prominent breasts is unexplained.
`Other features of maturation in the male, i.e., bone age,
`height age, appear
`to have progressed normally de-
`spite the very low levels of androgens and estrogens.
`The failure of body hair to grow, also noted in the
`patient of Biglieri et al. (1) must be in part attributable
`
`Male Pseudohermaphroditism Due to 17a-Hydroxylase Deficiency
`
`1939
`
`

`
`to the low androgens since the response to administered
`testosterone has been a prompt growth of body hair as
`well as facial and pubic hair.
`The other enzyme deficiencies of steroidogenesis as-
`sociated with male pseudohermaphroditism are 319-01-
`dehydrogenase ( 15) and desmolase deficiency (31, 32).
`However there are no reports of the type of puberty
`these children manifested largely because they have not
`survived into puberty. The suggestion by New and
`Peterson (33) that a phenotypic and genetic male with
`dexamethasone suppressible hyperaldosteronism might
`have suffered from a partial 17-hydroxylation defect
`has subsequently been revised. Further studies do not
`reveal any enzyme defect (34). In 1968 Miura et al. (35)
`described a young girl with hypertension which the
`authors attributed to a partial 17a-hydroxylase defect.
`However, this patient had regular menstrual periods, ex-
`creted normal quantities of estrogens, had hyperaldos-
`teronism and secreted normal levels of F, DOC and S.
`The similarities to the cases reported by Biglieri et al.
`(1), Goldsmith et al. (2), and Mallin (3) are a high B
`secretion rate,
`low urinary 17-ketosteroids,
`l7-hydroxy-
`corticoids and pregnanetriol. The patient of Goldsmith
`et al. (2) also had a partial 17a-hydroxylase deficiency
`as evidenced from this laboratory data. (Table III). Yet
`his patient manifested primary amenorrhea. Therefore
`it seems unlikely that the girl described by Miura et al.
`(35) falls into the same category of hypogonadism and
`hypermineralocorticoidism as
`the other
`females with
`17a-hydroxylase deficiency (1-3)