Bone Mineral Density in Women Living with Complete Androgen Insensitivity Syndrome and Intact Testes or Removed Gonads

Abstract

Complete androgen insensitivity syndrome (CAIS) is due to complete androgen resistance in androgen-dependent tissues. Since androgens are involved in growth, development, and mass maintenance of the skeleton, bone health may be a relevant clinical issue for improving quality of life of women living with CAIS. Bone mineral density (BMD) in women with CAIS and intact gonads has been reported in a normal range, although exceptions are known showing a low BMD mainly at the lumbar level. In women with CAIS and removed gonads, BMD is usually reduced at both the lumbar spine and femoral neck. However, the fracture risk remains largely unknown. In women with CAIS, hormonal replacement therapy may improve BMD, but it does not normalize it. Several factors may be operative (e.g., loss of AR signaling at the bone level, gonadal removal, and age at surgery [before or after attainment of the peak bone mass], inadequate sex steroid replacement therapy, poor compliance with hormonal treatment, high serum FSH levels, lack of testicular protein hormones after gonadal removal), but they are poorly evaluated. In conclusion, the maintenance of testes may represent a strategy to improve bone health in women with CAIS, but a strict follow-up to monitor the cancer risk is mandatory mainly from their 20s onwards. Optimal sex steroid substitutive therapy in adolescence and adulthood is a key factor to improve BMD status in women with CAIS and removed gonads, but conclusive data on optimal management are lacking.

Management of Gonads in Adults with Androgen Insensitivity: An International Survey

“…In line with this observation, it has been found that only few in situ lesions progress to invasiveness in individuals who have AIS [20]. A small number of studies report a positive effect of retained gonads on bone mineral density in women with CAIS, which cannot always be obtained by hormone replacement therapy (HRT) [21, 22]. For men and women with PAIS, recommendations for the management of gonads at risk have been proposed only recently, but the evidence remains weak and partly based on extrapolations from other conditions such as testosterone biosynthesis defects [9].…”

Caring for individuals with a difference of sex development (DSD): a Consensus Statement

“…Only a handful of small-scale studies have investigated bone health in individuals with 46,XY DSD. Women with the complete form of androgen insensitivity syndrome (CAIS) who had gonadectomy have a notable decrease in BMD in comparison with male and female reference values, whereas BMD seems to be less compromised in women with CAIS who have retained testes 111,112 . Both the lack of androgenic effects at the bone level and subnormal oestrogen levels contribute to reduced bone health 110,113 .…”

Different Clinical Presentations and Management in Complete Androgen Insensitivity Syndrome (CAIS)

“…As previously assessed, androgens are involved in physiological body development, including achievement of bone mass peak and maintenance of bone mineral density (BMD) [127,128]. The presence of AR in osteoclasts, osteoblasts, osteocytes, and chondrocytes in the general male population confirms the pivotal role of androgens in bone homeostasis [128,129,130,131,132] Indeed, CAIS disorder seems to be associated with a reduced BMD on dual-energy X-ray absorptiometry (DXA) and an increased risk of osteoporosis in adulthood due to a lack of androgen function [78,133]; bilateral gonadectomy may also play an important role [134]. Certainly, the early identification of bone mineral density alterations could prevent comorbidity and improve the quality of life of these subjects.…”

“…Some studies reported an increased fracture risk in patients with CAIS and removed gonads [136,138], but they involved only a small number of subjects, and often, there was substantial bias (i.e., reference values used for DXA), so the data are still inconclusive; there are no consistent data about fracture rate in patients with CAIS with intact gonads [134]. Additionally, patients with CAIS seem to also have a specific body composition; indeed, several animal studies have reported altered body fat mass with earlier development of obesity, an abnormal lipid profile, alterations in adipose tissue related hormones and decreased insulin sensitivity due to the resistance or absence of androgen activity [147,148,149,150].…”