Not all of us are Japanese, but there is definitely some interesting info to be gleamed from this study.
Micropenis and the 5-Reductase-2 (SRD5A2) Gene: Mutation and V89L Polymorphism Analysis in 81 Japanese Patients
jcem.endojournals.org/cgi/content/full/88/7/3431
Selected bits:
INTRO
… MICROPENIS IS A HETEROGENEOUS condition defined as significantly small penis that is free from associated external genital ambiguity such as hypospadias (1, 2). It is a quantitative character and can occur either as a single gene disorder or as a multifactorial disorder subject to various genetic and environmental factors (1, 2). Because the development of male external genitalia including penile growth is primarily caused by the biological effects of gonadal androgens, genes involved in the gonadal androgen production and in the peripheral androgen action could be relevant to the development of micropenis (1, 2, 3).
[b]The 5-reductase-2 is encoded by the SRD5A2 gene on chromosome 2p23 /b. The SRD5A2 gene consists of five exons and is expressed in the 5DHT-dependent genital tissues as well as in other organs/tissues, including liver (9, 10). To date, multiple mutations distributed throughout the coding region of the SRD5A2 gene have been identified in patients with 5-reductase-2 deficiency, and phenotypic spectrum in such patients is known to range widely from nearly female external genitalia to apparently male external genitalia (4, 9). Indeed, micropenis phenotype has been reported in a boy with a mutant SRD5A2 gene (11). Furthermore, a polymorphism in the SRD5A2 gene may also be relevant to the development of micropenis by raising the susceptibility to undermasculinization. In this regard, the most frequent polymorphism V89L (ValLeu substitution at the 89th codon) at exon 1 has been shown to decrease 5-reductase-2 activity by approximately 30% (12, 13), and previous studies have suggested that this polymorphism may reduce the susceptibility to androgen-dependent prostate cancer (13, 14). Thus, V89L polymorphism may be more prevalent in patients with micropenis than in normal males.
RESULTS
…Human chorionic gonadotropin (hCG) tests (3000 IU/m2 per dose im for 3 consecutive days; blood sampling on d 1 and 4) showed markedly elevated T/5DHT ratios, together with poor T response in case 3. GnRH tests (100 µg/m2 bolus iv; blood sampling at 0, 30, 60, 90, and 120 min) resulted in normal FSH and LH responses, except for a mild FSH hyperresponse in case 3. Analyses of steroid hormone metabolites for random urine samples by a gas chromatograph-mass spectrometry revealed markedly increased ratios of 5ß to 5a metabolites, especially for tetrahydrocortisol (THF) derived from cortisol.
Because cases 1–3 and/or their parents hoped to receive therapy immediately, 25 mg of testosterone enanthate (TE) was administrated im two or three times with an interval of more than 4 wk, resulting in subnormal penile length responses. After establishing the diagnosis of 5-reductase-2 deficiency, 12.5 or 25 mg of 5DHT (Andractim gel, Laboratories Besins Iscovesco, Paris, France) was transdermally applied to the genital region once per day for 8 or 16 wk according to the method of Choi et al. (23), increasing the penile length to nearly the average of age-matched Japanese boys
DISCUSSION
… Mutation analysis showed two missense mutations (G34R and R227Q) and one nonsense mutation (Y26X) of the SRD5A2 gene in three patients with micropenis. The two missense mutations have previously been reported in patients with 5-reductase-2 deficiency (8, 11), and functional studies have indicated that both mutations severely compromise the enzyme activity
… Furthermore, several matters appear to be worth pointing out for the diagnostic and therapeutic findings of cases 1–3. First, the hCG stimulated T/5DHT ratio was unequivocally elevated in cases 1–3. This suggests that 5-reductase-2 deficiency can be diagnosed by standard endocrine studies, even in boys with micropenis only phenotype. Second, case 3 showed low T response in the hCG test and slightly high FSH response in the GnRH test, as has occasionally been described in 5-reductase-2 deficiency (11, 27).
Although this would be ascribed to secondary testicular dysfunction resulting from cryptorchidism (11, 27), such endocrine data may lead to misdiagnosis of defective testicular steroidogenesis unless the hCG stimulated T/5DHT ratio is examined.
Third, urinary steroid hormone profile analysis revealed markedly elevated ratios of 5ß to 5a metabolites, as has been reported previously (28, 29). [u]Although this would primarily be due to defective 5-reductase-2 activity in the liver, which would mainly catalyze adrenal rather than testicular steroid hormone[/u]s (6, 10, 30), urinary steroid hormone profile analysis is a highly sensitive and noninvasive test and, therefore, appears to be more advantageous than serum androgen measurement for the diagnosis of 5-reductase-2 deficiency. In addition, it can often identify heterozygotes (this study and Ref. 31).
Lastly, TE therapy with a standard dosage showed a subnormal effect, and 5DHT gel treatment caused sufficient penile growth. This is consistent with impaired activity of 5-reductase-2 that converts exogenous as well as endogenous T into 5DHT, and it implies that early diagnosis of 5-reductase-2 deficiency enables application of appropriate therapy with 5DHT gel and prevention of adverse effects such as skeletal maturation of TE therapy