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This version published online on April 11, 2006
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-2460
A more recent version of this article appeared on July 1, 2006
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Submitted on November 10, 2005
Accepted on April 3, 2006

Urine Steroid Hormone Profile Analysis in Cytochrome P450 Oxidoreductase Deficiency: Implication for the Backdoor Pathway to Dihydrotestosterone

KEIKO HOMMA, TOMONOBU HASEGAWA, TOSHIRO NAGAI, MASANORI ADACHI, REIKO HORIKAWA, IKUMA FU JIWARA, TOSHIHIRO TAJIMA, RYOUJUN TAKEDA, MAKI FUKAMI, and TSUTOMU OGATA*

Departments of Laboratory Medicine (K.H.) and Pediatrics (T.H.), Keio University School of Medicine, Tokyo 160-8582; Department of Pediatrics, Dokkyo University School of Medicine Koshigaya Hospital (T.N.), Koshigaya 343-8555; Division of Endocrinology and Metabolism, Kanagawa Children's Medical Center (M.A.), Yokohama 232-8555; Division of Endocrinology and Metabolism, National Center for Child Health and Development (R.H.), Tokyo 157-8535; Department of Pediatrics, Tohoku University School of Medicine (I.F.), Sendai 980-0878; Department of Pediatrics, Hokkaido University School of Medicine (T.T.) Sapporo 060-8638; Department of Pediatrics, Shirakawa Kousei General Hospital (R.T.), Shirakawa 961-0907; and Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development (M.F., T.O.), Tokyo 157-8535, Japan

* To whom correspondence should be addressed. E-mail: tomogata{at}nch.go.jp.

Context: Although the "backdoor" pathway to dihydrotestosterone has been postulated in the fetal to early infantile period of patients with cytochrome P450 oxidoreductase deficiency (PORD), clinical data in support of this pathway remain limited.

Objective: To obtain clinical evidence for the presence of the "backdoor" pathway in PORD.

Setting: Collaboration study between laboratories and hospitals.

Subjects: Twenty-two Japanese patients with molecularly confirmed PORD and 1,763 control subjects.

Intervention: Urine steroid profile analysis was performed by gas chromatography/mass spectrometry. In five patients and 776 control subjects, urine samples were obtained before 12 months of age.

Main Outcome Measure: Identification of a urine steroid(s) indicating the "backdoor" pathway.

Results: In the PORD patients, pregnanediol, pregnanetriolone, and pregnanetriol were obviously elevated, and the urine steroid ratios reflecting CYP17A1 and CYP21A2 activities were decreased throughout the examined ages. Furthermore, etiocholanolone and 11-hydroxyandrosterone, which should originate almost exclusively from androstenedione in the conventional "frontdoor" pathway, were grossly normal or somewhat decreased since early infancy, whereas androsterone, which can be derived not only from androstenedione and dihydrotestosterone in the conventional "frontdoor" pathway but also from 5{alpha}-pregnane-3{alpha},17{alpha}-diol-20-one in the "backdoor" pathway, was increased during early infancy and remained grossly normal thereafter. Thus, the androsterone/etiocholanolone ratio was increased during early infancy and remained grossly normal thereafter. 5{alpha}-pregnane-3{alpha},17{alpha}-diol-20-one was elevated throughout the examined ages.

Conclusions: The increased androsterone excretion during early infancy, as compared with the etiocholanolone and 11-hydroxyandrosterone excretions in the same period, suggests the presence of the "backdoor" pathway in PORD.
Key words: abnormal genitalia • androsterone • backdoor pathway • cytochrome P450 oxidoreductase deficiency • urine steroid profile analysis




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