Mild androgen insensitivity syndrome presenting as male infertility with azoospermia

Androgen insensitivity syndrome results from a mutation in androgen receptor gene. It has wide spectrum of phenotypic presentations. Mild androgen insensitivity syndrome (MAIS) is the milder form, present as undervirilized male syndrome. In some instances, the only observed abnormality appears to be male infertility; therefore, MAIS could explain some cases of idiopathic male infertility. Here we describe a case of MAIS in a 38 years old male who presented with azoospermia and infertility. Mild androgen insensitivity syndrome presenting as male infertility with azoospermia 1Diabetes and Endocrine unit, Teaching Hospital, Batticaloa This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution and reproduction in any medium provided the original author and source are credited


Introduction
Androgen insensitivity syndrome (AIS) is typically characterized by evidence of under-masculization of the external genitalia at birth, abnormal secondary sexual development in puberty and infertility in individuals with a 46 XY karyotype (1). AIS results from a mutation in androgen receptor gene (Xq11-12). It is an inherited in an X linked recessive fashion, but 40% patients have negative family history. Incidence is estimated to be 1:20000-1:64000 male births (2). AIS can be subdivided in to 3 broad phenotypes: complete androgen insensitivity syndrome (CAIS) with typical female genitalia, partial androgen insensitivity (PAIS) with predominantly female, predominantly male or ambigous genitalia; mild androgen insensitivity syndrome (MAIS) with typical male genitalia. MAIS is the rarest form and diagnosis may be delayed or even missed. This could explain some cases of male infertility. Here we describe a case of MAIS in a 38 years old male who presented with azoospermia and infertility.

Case
A 38-year old man was referred to the Endocrinology department of Teaching Hospital Batticaloa for evaluation of subfertility. He was married for 3 years and unsuccessful in attempting to father a pregnancy. He had no significant medical or surgical history, was not on any long-term medications. He did not smoke or consumes alcohol. He was short with a height of 146 cm and weighing 45.5kg. He was under-virilized with reduced body hair, but he had male pattern facial hair and there was no gynaecomastia. Genital examination revealed low testicular volume of 4ml, penile shaft of 7cm and Tanner stage iii pubic hair distribution ( figure  1).
Semen analysis performed on several occasions revealed very low volume ejaculate with azoospermia. His testosterone level drawn at 8 am was 6.132ng/ml (normal, 3.4 -8.7ng/mL). Repeat morning serum testosterone done at medical research institute was 27.62nmol/l (normal, 8.4-28.7nmol/l). Serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were elevated and prolactin levels were within the normal range (table 1). Transrectal sonographic imaging of the prostate and surrounding structures revealed no evidence of ejaculatory duct obstruction or other abnormality. His karyotyping was 46XY.
The patient's wife was a 31-year-old woman with no known fertility concerns. She had regular menses, and her past medical history was negative for any surgical or medical conditions that might affect her fertility status.  There are no formal diagnostic criteria available due to large variance seen at the molecular, biochemical, and morphologic levels with the various AIS phenotypes. But AIS should be suspected in an individual with a 46 XY karyotype who has following characteristics; undermasculinization of the external genitalia, impaired spermatogenesis with otherwise normal testes, absent or rudimentary mullerian structures, evidence of normal or increased synthesis of testosterone and its normal or increased luteinizing hormone and/ or by the identification of a hemizygous pathogenic variant in AR (1).
MAIS, present as undervirilized male syndrome. The external genitalia of affected individuals are unambiguously male. They usually present with gynecomastia at puberty. They may have undermasculinization that includes sparse facial and body hair and small penis. Erectile dysfunction may be a complaint. Spermatogenesis may or may not be impaired. In some instances, the only observed abnormality appears to be male infertility; therefore, MAIS could explain some cases of idiopathic male infertility (1). MAIS caused by singlenucleotide variants of AR (5) may be clinically indistinguishable from MAIS caused by expansion of the polymorphic CAG repeat in AR (6). Pathogenic expansion of this triplet repeat is the cause of spinal and bulbar muscular atrophy, also known as Kennedy disease. Some cancers show somatic alterations in AR. These, however, appear to result in a gain of function rather than the loss of function seen in AIS.
The present case is compatible with MAIS, though the mutation in AR gene was not confirmed. MAIS is a condition that results in a mild impairment of the cell's ability to respond to androgens. The degree of impairment is sufficient to impair spermatogenesis and/or the development of secondary sexual characteristics at Management of MAIS is currently limited to symptomatic management. This includes surgical correction of mild gynaecomastia, and minor hypospadias repair. Patients may be treated with testosterone or dihydrotestosterone (DHT). The advantage of DHT is that it cannot be aromatized to estrogen. No medical consensus has been reached about this therapy, and no dosage schedules have been established (4). High dose testosterone therapy has been shown to improve virilization in men with MAIS (7). Managing infertility in MAIS is difficult when spermatogenesis is severely impaired. Normal . spermatogenesis is dependent on appropriate signaling from the hypothalamic pituitary gonadal axis. The use of exogenous androgens can influence the axis by exerting negative feedback, and ultimately decrease or complete cessation of spermatogenesis. But, there are reports of high dose testosterone therapy associated with reversing infertility due to low sperm count (8). In addition, psychological support is probably the most important aspect of medical care.
Our patient declined high dose testosterone treatment. Following discussion, he and his wife decided for assisted reproduction with sperm donation.

Conclusion
MAIS often goes unnoticed and untreated due to its mild presentation. Patient will be benefited by testosterone supplementation and other symptomatic management. This case sheds light on the need for screening for mild androgen insensitivity when a patient presents with unexplained infertility and mild hypoandrogenic features.