Challenges in managing disorders of sex development associated with adrenal dysfunction

ABSTRACT

Introduction

Disorders of Sex Development (DSD) associated with adrenal dysfunction occur due to different defects in the proteins involved in gonadal and adrenal steroidogenesis.

Areas covered

The deficiencies in 21-hydroxylase and 11β-hydroxylase lead to DSD in 46,XX patients, defects in StAR, P450scc, 17α-hydroxylase and 17,20-lyase lead to 46,XY DSD, and 3β-HSD2 and POR deficiencies cause both 46,XX and 46,XY DSD. Challenges in diagnosis arise from the low prevalence and the variability in serum steroid profiles. Replacement therapy with hydrocortisone and fludrocortisone helps to minimize life-threatening adrenal crises; however, availability is still an unresolved problem in many countries. Adverse health outcomes, due to the disease or its treatment, are common and include adult short stature, hypertension, osteoporosis, obesity, cardiometabolic risk, and reproductive health issues. Potential biomarkers to improve monitoring and novel treatment options that have been developed with the primary aim to decrease adrenal androgen production are promising tools to help improve the health and quality of life of these patients.

Expert opinion

Steroid profiling by mass spectrometry and next-generation sequencing technologies represent useful tools for establishing an etiologic diagnosis and drive personalized management. Nonetheless, access to health care still remains an issue requiring urgent solutions in many resource-limited settings.

KEYWORDS:

• Adrenal insufficiency
• aldosterone
• congenital adrenal hyperplasia
• cortisol
• DSD
• glucocorticoid
• mineralocorticoid

Article highlights

• Congenital disorders of steroidogenesis due to 21-hydroxylase and 11β-hydroxylase deficiencies result in adrenal dysfunction with excess virilization in 46,XX individuals, while defects in StAR, P450scc, 17α-hydroxylase and 17,20-lyase lead to adrenal dysfunction with undervirilization in 46,XY individuals. Deficiencies in 3β-HSD2 and POR result in adrenal dysfunction and altered virilization in both 46,XX and 46,XY individuals.

• Novel biomarkers have improved monitoring. Steroid profiling by mass spectrometry and next-generation sequencing are useful tools for establishing an etiologic diagnosis and drive personalized management.

• Replacement therapy with hydrocortisone and fludrocortisone helps minimize life-threatening adrenal crises, but treatment availability remains an unresolved issue in many regions of the world.

• Long-term adverse health outcomes include short stature, hypertension, osteoporosis, obesity, cardiometabolic risk, and reproductive health issues in adults.

• Novel treatment options have been developed aiming to decrease adrenal androgen production without overtreating with corticoids.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this paper was a Director of Diurnal developing new therapies for CAH. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper received no funding.