Fertility in patients with 5 alpha-reductase-2 deficiency

23 03 2011

To the Editor:

The case report by Matsubara et al. (1) is very interesting and an extensive study for the diagnosis of 5 alpha-reductase-2 deficiency.

The authors reported the successful birth of a healthy male child through intracytoplasmic sperm injection (ICSI). It is imperative to test the genotype of the newborn, since there was a strong familial aggregation (both grandparents were heterozygous, father was homozygous for p.R246Q mutation on exon 5) of SRD5A2 gene mutations in this family.

We also reported two unrelated families with male pseudohermaphroditism that were homozygous for p.R246Q mutation on exon 5 of SRD5A2 gene (2). One of our patients was reared as a girl until puberty, then opted for a male gender identity. After several interviews (by a psychiatrist and an endocrinologist) it was decided that the child should be reared as a boy. We observed in this patient a progressive reduction of sperm counts from puberty until age 25 years (3).

In another large kindred, we detected a heterozygous SRD5A2 gene mutation on exon four, p.G196S in two brothers. These two had a normal fertility, but their offspring had abnormal genotypes. It interesting note that one male child with hypospadias had a hemizygous mutation in the third exon of the AR gene p.A596T and a heterozygous SRD5A2 gene mutation on exon four, p.G196S (4).

Steroid 5 α- reductase-2 is an important enzyme involved in testosterone (T) metabolism that converts testosterone into the more active metabolite, dihydrotestosterone (DHT). T plays a major role in the virilization of Wolffian ducts and DHT in the normal development of external genitalia, urethra, and prostate in the male fetus. The 5 α- reductase-2 deficiency is an autosomal recessive disorder caused by mutations in the 5 α- reductase-2 gene (SRD5A2). Previous functional studies have revealed that the R246Q mutation affects the ability of the enzyme to bind testosterone substrate and decreases the affinity for the NADPH cofactor (5). This mutation not only affects the cofactor binding directly by disrupting this domain of the enzyme, but also diminishes the activity and changes the pH.

Several studies have shown that the missense mutations in SRD5A2 gene affect the enzymatic activity and further cause the deficient virilization of male external genitalia (6). Genital ambiguity at birth with progressive virilization at puberty with a gender role change is the best-characterized clinical presentation of this disorder.

Most of the affected individuals are oligospermic or azoospermic. Patients with 5 alpha- reductase-2 deficiency are frequently infertile. The commonly described semen abnormalities include reduced sperm counts and a low semen volume with high viscosity. This is mainly attributed to rudimentary prostate glands and small seminal vesicles as a direct consequence of a deficient DHT action. The differentiation of external genitalia and prostate is governed by DHT (7). Normal fertility has also been reported in men without cryptorchidism (8).

Therefore the early diagnosis and the establishment of sperm banking at an early age for patients with 5 alpha- reductase -2 deficiency can reduce the psychological trauma.

Marumudi Eunice, Ph.D.
Ariachery C. Ammini, M.D, D.M.
Department of Endocrinology & Metabolism
All India Institute of Medical Sciences
New Delhi, India

1. Matsubara K, Iwamoto H, Yoshida A, Ogata T. Semen analysis and successful paternity by intracytoplasmic sperm injection in a man with steroid 5 α- reductase-2 deficiency. Fert Steril. 2010; 94:2770.e7-e10.

2. Eunice M, Philibert P, Kulshreshtha B, Audran F, Paris F, Khurana ML et al. Molecular diagnosis of 5 α -reductase-2 gene mutation in two Indian families with male pseudohermaphroditism. Asian J Androl. 2008; 10:815–818.

3. Ammini AC, Eunice M, Kulshreshtha B, Francoise Audran, Pascal Phillibert , ML Khurana et al. Progressive post pubertal loss of gonadal function in an Indian male pseudophrodite with 5 alpha- reductase 2 gene mutation. Hormone Res. 2007; Vol. 68, Suppl. 1; PO3-655: pp203.

4. Kulshreshtha B, Philibert P, Eunice M, Audran F, Paris F, Khurana ML et al, Phenotype, hormonal profile and genotype of subjects with partial androgen insensitivity syndrome: report of a family with four adult males and one child with disorder of sexual differentiation. Andrologia. 2009; 41(4):257-63.

5. Russell, DW and Wilson,JD.,. Steroid 5 alpha – reductase: two genes/ two enzymes. Ann.Rev. Biochem. 1994; 63, 25-61.

6. Maimoun L, Philibert P, Cammas B, Audran F, Bouchard P, Fenichel P, et al. Phenotypical, Biological, and Molecular Heterogeneity of 5{alpha}-Reductase Deficiency: An Extensive International Experience of 55 Patients. J Clin Endocrinol Metab. 2010 Dec 8.

7. Grumbach MM, Conte FA Disorders of sexual differentiation In : Wilson JD, Foster DW, Krokenberg HM, Larsen PR,EDS Williams textbook of endocrinology ed 9 . Philadelphia W.B Saunders .1998; 1303-1425.

8. Imperato-McGinley J, Zhu YS. Androgens and male physiology the syndrome of 5alpha-reductase-2 deficiency. Mol Cell Endocrinol. 2002 Dec 30; 198(1-2):51-9.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.03.076

The Authors Respond:

We read the letter from Drs. Marumudi and Ammini with great interest.

Steroid 5 alpha-reductase-2 deficiency is a unique disorder in which 46,XY patients reared as females frequently exhibit gender identity disturbance and change social sex to males (1). Thus, it may be suggested to raise 46,XY patients as males, even with rather feminized external genitalia (1). In this case, as Drs. Marumudi and Ammini claimed, it may be recommended to store sperms at an early age, since semen quality deterioirates with age in this condition. Indeed, considering the remarkable progress in the artificial reproductive technology (ART), such management will reduce the psychological impact in patients who hope to have a child.

However, several points should be made with regard to the sperm banking in 5 alpha-reductase-2 deficiency. First, precise diagnosis is required for appropriate gender assignment and prevention of gonadectomy in early life. Thus, a genetic diagnosis system should be established, because endocrine diagnosis is difficult in early infancy primarily due to interference by unknown steroid metabolites of fetal adrenal origin.

Second, further studies are mandatory to improve our knowledge about brain sex development. In particular, while gender role disturbance is described in patients with complete deficiency (2), the effects of residual enzyme activities (amorphic mutations vs. hypomorphic mutations) on brain sex development remain to be elucidated.

Similarly, while “tomboy” behavior is observed in patients who underwent gonadectomy during infancy (3), the effects of early gonadectomy on brain sex development at a later age remain to be examined.

Third, while sperm banking should be performed at an early age, it would be difficult to discuss sperm banking before adulthood. At present, appropriate timing of sperm collection remains unknown and would be variable among patients according to their environmental background.

Finally, although ART is required to produce a child using stored sperms, ART may have a genetic risk to exaggerate the development of pathologic conditions such as imprinting disorders (4). Further careful studies of these issues will serve to provide evidence-based, personalized patient care and establish the sperm banking system for patients with this condition.

Tsutomu Ogata, M.D.
Keiko Matsubara, M.D.
Department of Molecular Endocrinology
National Research Institute for Child Health and Development
Tokyo, Japan

1. Houk CP, Lee PA. Disorders of sex development: making ambiguity less ambiguous. Growth, Genetics, & Hormones 2007;23:33–39.

2. Sasaki G, Nakagawa K, Hashiguchi A, Hasegawa T, Ogata T, Murai M. Giant seminoma in a patient with 5 alpha-reductase type 2 deficiency. J Urol 2003;169:1080–1081.

3. Dati E, Baldinotti F, Conidi ME, Simi P, Baroncelli GI, Bertelloni S. A girl with tomboy behavior: lesson from misdiagnosis in a baby with ambiguous genitalia. Sex Dev 2010;4:150–154.

4. Niemitz EL, Feinberg AP. Epigenetics and assisted reproductive technology: a call for investigation. Am J Hum Genet 2004;74:599–609.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.03.077




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