Transitioning to Adulthood & Beyond

Richard J. Auchus, MD, PhD Division of Metabolism, Endocrinology & Diabetes Departments of Internal Medicine & Pharmacology

University of Michigan

Disclosures •  Contracted Research:

– Neurocrine Biosciences – Millendo Pharmaceuticals

•  Consulting – Diurnal LTD – Spruce Biosciences – Alder Biopharmaceuticals

Pregnenolone

17-hydroxy-pregnenolone

Progesterone

17-hydroxy-progesterone

Dehydroepi-androsterone

11-deoxy-corticosterone

11-deoxy-cortisol

Cortico-sterone

Cortisol

18-hydroxy-corticosterone Aldosterone

CYP11B1

CYP11B2 CYP11B2 CYP11B2

Cholesterol

CYP11A1 StAR

Andro-stenedione Testosterone

AKR1C3

zona fasciculata

zona glomerulosa

zona reticularis

Dehydroepi-androsterone

Sulfate

CYP17A1 CYP17A1

CYP17A1 Cyt b5

CYP17A1 Cyt b5

SULT2A1

Renin/Ang-II CYP21A2

CYP21A2

3βHSD2

3βHSD2

3βHSD2

periphery

21-Hydroxylase Deficiency (21OHD)ACTH

Androgen Excess Variable Glucocorticoid & Mineralocorticoid Deficiency

21OHD Rx Goals: Children •  Prevent Adrenal Crisis

– Hydrocortisone <17 mg/m2/d TID-QID •  Maintain Volume Status

– Fludrocortisone 0.1-0.4 mg/d + Salt •  Minimize Androgen Excess •  Prevent Early Puberty •  Maximize Height •  Nonclassic Similar, Less Treatment

Speiser et al 2010 JCEM 95: 4133

•  Replace the Adrenal Insufficiency – Daytime Glucocorticoid + Fludrocortisone – Adrenal Crises Uncommon in Adults

•  Control the Androgen Excess – Compliance is the Key – Often Requires Extra or Odd Dosing

•  Prevent and Detect Neoplasms •  Preserve or Restore Fertility •  Mitigate Consequences of Chronic Rx

– Bones, CV Risk, Cognition, Etc

CAH Treatment Goals: Adults

The Transition Process •  Start Early, Phase In Gradually

– Demonstrate Self-Management Skills – Motivation & Understanding of Care – Parents Role Shifts to ‘Consultant’

•  Healthcare System(s) •  Specific Conditions & Providers •  Huge Spectrum of Individuals •  In USA, This Rarely Happens •  For CAH, Will Not Happen Without Help

– Cystic Fibrosis Centers vs CAH Care

CRH

ACTH

Cortisol Androgens

Hypothalamus

Men With 21OHD & Androgens

Pituitary

Adrenal

LH

GnRH

Testis Testosterone

Testicular Adrenal Rests - Sono

Adrenal Rests: Treatment •  High-Dose Glucocorticoids

– Often Shrinks Rest Tissue – Variable Effect on Testosterone, Sperm – Side Effects of Long-Term Use

•  Testis-Sparing Surgery –  Improves Mass Effect – Little Benefit For Testosterone, Sperm

•  Up To 3-4 Years’ Rx Intensification •  TART, FSH > 35 IU/L Poor Prognosis

Claahsen-van der Grinten et al 2007 JCEM 92:612 King et al 2016 Clin Endocrinol 84:830

Fertility: 21OHD Women •  High Androgens •  High Progesterone •  Anovulation •  Inadequate introitus •  Vaginal Stenosis/Restenosis

Pregnancy & Classic CAH •  Few Attempt Pregnancy (<25%) •  Pregnancy Rate Normal (>90%) •  Salt Wasting Less Likely to Attempt •  Suppress AM Progesterone <0.6 ng/mL

– Chronic ‘Luteal Phase’ from Adrenal Prog •  Discuss Genotyping Partner •  Androgens & 17OHP Rise; Placenta

Protects Fetus From Maternal Androgens •  Unilateral/Bilateral Adrenalectomy?

Lo et al 1999 JCEM 84:930 Casteràs et al 2009 Clin Endocrinol 70:833

Adrenal Rests After ADX

Crocker et al 2012 JCEM 97: E2084

CAH Patients Get Other Stuff! •  Endometriosis •  Blocked Fallopian Tubes •  Carpal Tunnel Syndrome •  Broken Bones •  Migraine Headaches •  Endogenous Obesity & Diabetes •  Hypothyroidism •  Asthma •  Crohn’s Disease •  Rheumatoid Arthritis

Glucocorticoid Options •  Hydrocortisone

–  Generally Need 3 Doses of 5-10 mg –  CANNOT Control AM ACTH With PM Hydrocortisone

•  Prednisone: Once Daily Works Sometimes –  More Side Effects, Unreliable At Small Doses –  Prednisolone, Methylprednisolone More Reliable

•  Dexamethasone: Effective, Toxic, Titration Hard •  Combination: Day Hydrocortisone, PM Other

–  15/5 mg Hydrocortisone + 1 mg Prednisolone QHS

Glucocorticoid Step Therapy Step Drug(s) Frequency Total daily dose 1 Hydrocortisone TID or BID 15-30 mg 2 Hydrocortisone BID-TID 15-25 mg

+ Prednisolone HS 1-2.5 mg + Dexamethasone HS 0.1-0.375 mg

3 Prednisolone BID or TID 5-15 mg 4 Dexamethasone QD or BID 0.5-2 mg

PM Hydrocortisone & AM 17OHP Rise

Charmandari 2001 JCEM 86:4679

Long-Acting Corticosteroid

Long-Acting Corticosteroid

Laboratory Monitoring Analyte Physiology Goals & Comments Plasma renin Volume status Low to normal

unless hypertension Sodium Glucocorticoid Goal is normal Potassium Mineralocorticoid Goal is normal Testosterone (T) Total androgens Adrenal + gonadal Androstenedione Mostly adrenal Assess with T SHBG T binding protein Estrogen raises DHEAS Major adrenal Should be low 17OHP Highly variable Should not be low

Laboratory Monitoring Analyte Physiology Goals & Comments Men Gonadotropins Gonadal axis Low if adrenal

androgen excess Androstenedione Adrenal vs Ratio should be <0.5 & Testosterone gonadal androgen Semen analysis Fertility Normal is ideal Women Progesterone Adrenal Normalize for fertility

& corpus luteum (<0.6 ng/mL) during follicular phase

Nonclassic 21OHD & Fertility •  Ascertainment Rate is Low •  <15% Present For Infertility •  83% Pregnant in 1 Year +/- Treatment •  High Rate of Miscarriage

– 26% Without Rx, 6.5% With Hydrocortisone •  No Data For Infertility or TART in Men

– Often Stop Rx After Puberty •  Consider Genotyping Patient, Partner •  Stress Dosing Only If Suppressed

Bidet et al 2010 JCEM 95:1182

Management Of NCAH •  Women If Hirsute, Oligomenorrhea

– Birth Control Pill, Anti-Androgen is OK! – “Severe NCAH” (P30L Hemizygotes) Hardest

•  Glucocorticoid If Infertility – Hydrocortisone 10-20 mg/d Thru Pregnancy – Dexamethasone LOW DOSE; 0.25-0.5 mg MWF

•  Genetic Counseling! – Up to 70% Carry 1 Classic CAH Allele

•  Stress Dosing? Based on CST •  Males Rarely Ascertained (3 in CaHASE!)

Potential Therapies for CAH •  Modified-Release Hydrocortisone •  Hydrocortisone sc Infusion Pump •  Super-Androgen Receptor Antagonists Ø Abiraterone Acetate (CYP17A1 Inhibitor) Ø CRH Receptor Antagonist: NBI77860 Ø ACAT1 (SOAT1) Inhibitor: ATR-101

What Do They Have in Common?

CAH Patient

More Steroid Pathways in 21OHD

Turcu et al 2016 Eur J Endocrinol 174:601