transitioning to adulthood & beyond
TRANSCRIPT
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