Partial androgen insensitivity syndrome with predominantly male phenotype – clinical, endocrine, and genetic findings in 37 cases

Mutations of the X-chromosomal androgen receptor (AR) gene are associated with androgen insensitivity syndrome (AIS). The majority of patients described have a severe virilisation deficit and are raised as females. However, little is known about patients with partial AIS raised as males.

Methods: 37 male patients with minimal or partial androgen insensitivity were investigated. 25 patients were prepubertal whereas 12 patients were investigated after puberty. Molecular genetic analysis of the AR-gene was performed from blood leukocyte DNA. In 9 prepubertal patients, hCG stimulation had been performed. In postpubertal patients, LH and testosterone (T) were obtained. Treatment modalities were evaluated if available.

Results: The phenotype was variable, ranging from a slight virilisation deficit without genital malformation to severe hypospadias requiring extensive surgery. All patients had mutations within the coding region of the AR, mostly amino acid substitutions. Within the prepubertal patients hCG stimulation demonstrated a good response with marked rise in T values in most patients, especially in the young age group<1 year (increment >10 nmol/L). In older children, the increment to T was lower. LH was inconclusive in prepubertal children. The postpubertal group showed predominantly high T (4.6–72.1 nmol/L and LH levels (4.9–22.3 U/L). Thus the androgen sensitivity index (LH x T) was above the normal range (>130 nmol x U/L) in 6/8 patients. We could not find a correlation between T levels and clinical outcome after puberty. Therapeutic interventions ranged from transcutaneous application of androgens to high dose intramuscular treatment in different concentrations. Only few patients had a benefit from high dose androgen therapy. Gynecomastia occurred in all postpubertal patients and got worse after androgen treatment.

Discussion: Partial AIS with male phenotype comprises a very heterogeneous patient group. To date it is not possible to predict the clinical response to androgen treatment on account of endocrine and genetic parameters.