Deficiency of androgen receptors in male pseudohermaphroditism

DEFICIENCY

OF ANDROGEN

RECEPTORS

IN

MALE PSEUDOHERMAPHRODITISM

ERN=\

MARK.

SAL\‘ADOR

CASTELLS,

KENNETH

GLASSBERG.

SOOK

FRANCISCA

1I.D.

JA CHOI,

1I.D. 11. D.

KAREN CLAUDE

TOLETE-VELCEK,

DAVID,

bl. D

h1.D.

J. MIGEON.

1l.D.

hI.D.

From the Departments of Pediatrics (Unit of Growth and hIetaldism~, Downstate Yledical Center, Urology, Seonatology, and Surgery, State University of New York; Department of Obstetrics and Gynecology (Section of Genetics), The Brooklyn Hospital. Brooklyn, Ne\v York, and the Department of Pediatrics. Baltimore, 1larylancl Johns Hopkins LTni\.ersity,

1lale pseudol~eriiiapliroditisin \vitliout an!. evidence of RIiillerian structures may he clue to iiiadequate testosterone synthesis, inadequate clili~clrotestosterone synthesis, or an aiidrogen receptor (cytoplasinic receptor or nuclear acceptor) deficiency. ’ Fl’lieii an iiifmt is diagnosed with any of the aforemelltionecl ~~l~normalities. the assignment of gender is then dependent on the appearance of the genitalia, and, when the phallus is small, on the ability of the phallus to grow in response to endogenous or esogenous androgens.2 To our knowledge, we describe the first case of androgen receptor deficiency in a patient with aml)iguous genitalia, diagnosed in the newborn period.

A 2,020-Gin infant was born 1)~ cesarean section after a frill-term pregnmc>~ to 311 eighteen-year-old black mother. Prenatal and f:,lmil> history was iioncontril,iito~~-, and tlwre was 110 history of horinoiie therapy during pregnancy. The stretched phallus nleasured 1.7 cm in length and 0.7 cm in diameter. The scrotum ~~1s

not fused and contained normal-sized testes l)ilaterall>~. A pres~lnled urethra opened in the perineum (Fig. 1‘4). The remainder of tht physical exmination mxs unre~narkal~lt~. Bloocl pressure and plasma elec+rolytes \\‘ere nornd. Buccal smwr mxs negative. Chronlosome analysis revealed a iiorinal 46,SY chromosome constitution in white l~lood cells. No uterus was detected 1,~. sonograph~~. The genitograin revealed a vaginal poudi opening 1 cm proximal to the ineatris of the urogenital sinus (Fig. 1B). There \v;ls no cer\.ical impression. These findings were confirn~ecl 1)). q,stoscop!~. At one week of age, intramuscular aclministration of human chorionic gonadotropin (HCG) was initiated at 2,000 units daily for fi1.e clays and continued at 500 units (3.000 units/m”) three times a week for fi\.e weeks to stimulate testosterone prodiiction mid phallus pmvth. There \vas no cletectal,lc increase in the size of the phallus drlriiig the six lveeks of treatment. Plasma testosterone cleteriiiinctl I,>. radioimmiinoassa~~, \vhicli in Ixisal conditions at fi\.c da\-s of age was 119 ng/dl, increased to 1.510 iigicll

DIHYDROTESTOSTERONEBINDING (moles r 10 Ypg DNA)

Lr-AEOUCTASE ACTIVITY (pglhrlpg DNA)

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to ha\.e a deficiency of’cytoplasmic ceptors, it was decided to assign ‘4 clitoral recession fende gender. orchiectomy were perfbrn~ed at six prior to discharge from hospital.

androgen rethe patient a and hilateral weeks of age,

Co111111e11t Anihiguity of the external genitalia at birth ina~. he the consequence of \-irilization of a feinale fetus or incomplete virilization of a male. In our case the presence of palpable scrotal gonads and the nornial ?iT sex ~lii-01ii0soiiie coinplenient indicated a normal male genotype. Incomplete virilization of ii 46,XY fetus can result from almorinalities in fetal prodwtion of anclrogens or in uiiresl’olisi\-eness of the genital organs to androgens. In our patient, lxdi baseline plasnia, concentration of testosterone, and the testosterone response to six weeks of HCG therapy were normal, excluding a deficiency in testosterone sjmthesis but not necessarily an al~norinality in the timing of testosterone secretion in utero. Since testosterone synthesis was normal in 0~11 patient, it was necessary to rule out an al,norniality in clih)-drotestoste~o~ie synthesis” (Fig. 3). A defect in tl ic reduction of testosterone to DHT l,!z a decrease in $5~~reductase

activity has been described in some males \vith anil~iguous genitalia,7m” hut our patient had normal 5a-reductase activity in his genital skin filmd~lasts and normal DHT levels in l~loocl. The next step is the binding of DHT to ;I specific cytoplasniic receptor protein and the subsequent translocation of this coinplex to the nuclear compartment where it l,inds to the acceptor sites of the chromatin (Fig. :3). An absence or sel’ere deficiency of cytoplasniic anclrogen receptors in cultured skin fibroblasts has been associated with the svndrome of consplete androgen insensitivity (CAI, Receptor -), previously designated as testicular feniinization. 4,10-13 In addition , a milder deficiency of receptor binding sites has heeli sliown to he associated with the syndrome of partial anclrogen insensitivity (PAI, Receptor - ) previouslv designated iis incomplete testiculai feminization or Reifenstein syndrome. ‘.I4 It also has heen shown that patients with c’onlplete or partial androgen insensitivit), could have nornial androgen receptor acti\it), (
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