5-Alpha-Reductase Deficiency Workup

Updated: Nov 11, 2016
  • Author: Anna H Isfort, MD; Chief Editor: Robert P Hoffman, MD  more...
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Workup

Laboratory Studies

General laboratory evaluation for all newborns with ambiguous genitalia should begin with the following:

  • Karyotype with specific X and Y probes.

  • 17-hydroxyprogesterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, dihydrotestosterone (DHT), anti-Müllerian hormone (AMH), electrolytes, and urinalysis

  • Abdominopelvic ultrasound to assess for presence of internal male/female structures

Results should be expedited, ideally available within 48-72 hours.

In neonates with Y material (46,XY or fluorescent in situ hybridization [FISH] results positive for sex-determining region [SRY]) and ambiguous genitalia, 5-alpha-reductase type 2 deficiency should be considered.

Elevated serum testosterone-to-DHT ratio (T/DHT) is the hallmark of 5-alpha-reductase type 2 deficiency. Typically, testosterone levels are normal to modestly elevated and DHT levels are low to undetectable. Levels are detectable to diagnostic levels during the physiologic testosterone surge that occurs between birth and age 1-3 months. Basal unstimulated T/DHT levels are not usually high enough to make a definitive diagnosis, especially in a prepubertal patient over 3 months of age.

Human chorionic gonadotropin (hCG) stimulation is needed after the early infant period of minipuberty in order to obtain adequate levels of testosterone and DHT for diagnosis. Multiple protocols, both short-term and long-term, have been established with varying sensitivities. Three common protocols include the following: (1) 1500 IU intermuscularly (IM) on days 1, 3, and 5 (short test); (2) 1500 IU IM every other day for 7 injections (prolonged test); or (3) 5000 IU/m2 IM as a single dose. Baseline laboratory results are established prior to hCG administration, and stimulated laboratory studies are drawn 24 hours after the last dose for the multi-day tests, or 72 hours after the single-dose test. The reference ranges for expected stimulated values were obtained using the short test as described above, and may be applied to the other testing methods, however values have not been validated in these other testing methods.

In normal prepubertal males, the mean T/DHT ratio following hCG stimulation is 10.7, with ranges from 3.5-14. In male infants, the stimulated ratio is somewhat lower and is usually less than 10. The T/DHT ratio in prepubertal patients with 5-alpha-reductase-2 deficiency generally exceeds 30. In adults, the discriminatory value of the post hCG T/DHT ratio is even higher. Normal patients respond with ratios from 8-16, while patients with 5-alpha-reductase-2 deficiency exhibit T/DHT ratios from 35-84. [23]

Mutation analysis of the 5-alpha-reductase type 2 gene (SRD5A2) is now available commercially through GeneDx (www.genedx.com). Testing is performed via exon array comparative genomic hybridization (CGH) or by direct gene sequencing. Utility of this testing includes confirmation of a clinical diagnosis; differentiation of 5-alpha-reductase type 2 deficiency from other causes of 46,XY DSD; prenatal diagnosis for known familial mutations; and carrier testing for at-risk relatives.

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Imaging Studies

Ultrasonography

Although not diagnostic for 5-alpha-reductase type 2 deficiency, ultrasonography of the pelvis is useful.

Ultrasonography can verify the location of the testes and other wolffian structures as well as the absence of müllerian structures, to include the cervix and uterus.

The ultrasonographer, and other members of the radiographic and laboratory evaluation team, should be cognizant of the suspected diagnosis and be trained on how to properly discuss findings with gender-neutral terms.

Genitography

A genitogram (ie. dye introduced into the urogenital (UG) sinus via small catheter or feeding tube) is a useful tool to assess urethral anatomy, UG sinus length, or evidence of müllerian remnants.

This study can verify that no fistulous connections are present between the urinary tract and UG sinus.

CT and MRI

CT or MRI are usually not necessary but may be useful to more accurately assess internal anatomy.

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Histologic Findings

The testes exhibit Leydig cell hyperplasia and decreased spermatogenesis. However, testicular biopsy is not part of the routine evaluation.

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