Androgen receptor mutations in familial androgen insensitivity syndrome: A metabolic reprogramming pathway to type 2 diabetes susceptibility

Table 1 Overview of the hormonal milieu, metabolic phenotypes, and key management points across developmental stages in androgen insensitivity syndrome

Stage /subtype	Hormonal exposure and treatment strategy	Dominant metabolic phenotype	Key risk/protective factors	Management priorities
Adolescence - CAIS (testes retained)	High circulating testosterone → aromatized to estradiol; no hormonereplacement therapy (HRT)	Generally, normal body weight and lipid profile; feminine fat distribution; low lean (muscle) mass	Endogenous estradiol confers metabolic protection	Monitor bone mass and body composition; determine optimal timing of gonadectomy
Adolescence - PAIS (reared male + androgen supplementation)	Residual AR activity plus exogenous testosterone	↑ Muscle mass; possible improvement in insulin sensitivity	Partial restoration of androgen action	Tailor testosterone dose individually; guard against excess weight gain
Adulthood - CAIS (early gonadectomy + absent/insufficient HRT)	Prolonged deficiency of both estrogen and androgen	Central obesity, insulin resistance, dyslipidemia	“Silent” hypoestrogenic state	Initiate and maintain adequatedose estradiol as early as feasible
Adulthood - CAIS (postpubertal gonadectomy + standard HRT)	Physiological aromatization peak achieved, followed by lifelong estradiol therapy	Relatively low metabolic risk	Timely and sustained estrogen replacement	Regular monitoring of BMI, lipid profile, and bonemineral density
Adulthood - PAIS (individualized androgen/estrogen regimen)	Lowdose testosterone or estradiol	Body composition and metabolic status depend on residual AR function and treatment adherence	Optimal HRT regimen remains unsettled	Maintain hormones within physiological range; reassess dynamically
Reference: PCOS (hyperandrogenism)	Excess endogenous androgens	Visceral obesity, insulin resistance, metabolic syndrome	AR overactivation	Weight control, insulinsensitizing agents, antiandrogen therapy

HRT: Hormone-replacement therapy; PAIS: Partial androgen insensitivity syndrome; AR: Androgen receptor; CAIS: Complete androgen insensitivity syndrome; PCOS: Polycystic ovary syndrome; BMI: Body mass index.