Namasthe. These are my powerpoint slides at the just concluded ESICON 2018 in Bhubaneshwar. I thought of sharing my effort to my medical colleagues. Topic: Place of Mineralocorticoid replacement in CAH Alternate Link : https://uploadfiles.io/ba0cw Valid till Jan 4, 2019 Hope you find it useful for clinical purpose. Regards Mohan Shenoy

1. Dr MOHAN T SHENOY MD DM
CONSULTANT ENDOCRINOLOGIST
SREE GOKULAM MEDICAL COLLEGE & RESEARCH
FOUNDATION VENJARAMOODU,TRIVANDRUM
PLACE OF
MINERALOCORTICOID REPLACEMENT
IN CONGENITAL ADRENAL HYPERPLASIA
drmohanshenoy@gmail.com

2. CAH : Case capsule01
Mineralocorticoid principles02
Indications and Implications03
Literature : Basic and Advanced
04
07
CONTENTS
Endocrine Society guidelines (2018)
05
Transition Care Issues
06
Positioning of Fludrocortisone

3. 1
CASE CAPSULE
45 days baby
3rd born of non-consanguinous parents
FTLSCS, Ind: Previous LSCS
Birthweight: 2.85 kg
Found to have hyponatremia and hyperkalaemia
Na: 121.3 mEQ/L K: 8.1mEq/L
Cortisol: 3.4
17-OHP: 9040 ng/ml stimulated
Testo: 1.08ng/ml
Karyotype: 46 XX
Admitted and evaluated
Child active and alert
Weight: 3.8 kg Length 50 cm BSA: 0.2297 m2 (Mosteller)
Absent gonads; No inguinal swelling
Phallus 2 cm; Urethral opening in phallus base
Posterior labial fusion (Prader Stage 2)
NIBP: 74/62 mmHg and 84/74 mm Hg
Current meds
Hydrocortisone 1 mg -1mg- 1mg
Fludrocortisone 100 mcg 1-0-1/2
Salt 2.5 gm/day

5. 5
Approx 75%–80% of CAH fail to
synthesize sufficient aldosterone
to maintain salt balance

6. Treatment and health outcomes in adults with congenital adrenal hyperplasia Han, T. S. et al. Nat. Rev. Endocrinol. 10, 115–124 (2014;
3
Adrenal Crisis
Salt-Wasters
DSD
Failure to thrive
Hot – Humid regions
INDICATIONS
Salt loss crises classically manifest
at the end of the first week of life

7. A HISTORICAL PERSPECTIVE
Øksnes M, et al., Optimal glucocorticoid replacement in adrenal insufficiency, Best Practice & Research Clinical Endocrinology & Metabolism
(2014)
Novel glucocorticoid
preparations
Wilkins L, Lewis RA, Klein R, et al: Treatment of congenital adrenal hyperplasia with cortisone. JCEM 1951; 11:1–25

8. 8

9. PHYSIOLOGY OF
ALDOSTERONE RENIN
AX
9

10. REPLACEMENT REGIMENS
5
Don’t forget salt (first 6months)
2 to 5g/day
Post-weaning: may lose their
salt-wasting tendencies and usually
scavenge adequate salt for their needs
20 mg Hydrocortisone has Mineralocorticoid potency 50 μg of 9α-fludrocortisone
100 µg of Fludrocortisone 1.2 mg Hydrocortisone equivalent
Thrice daily

11. FLUDROCORTISONE ACETATE
Renal tubule – promote Na+ retention: exchange for K+ or H+ ion
Neonatal Accumulation of Anti-Aldosterone metabolites => intravascular & extracellular volume
9-α fludrocortisone : Longer duration of action – once daily:
Highest Requirement : neonatal period and childhood ; begin declining adolescence & early adulthood
With age, Improved renal sensitivity to MCs ; Usual dose varied between 50μg and 300μg per day
Median fludrocortisone doses : 200 μg at 0-6 months, 150 μg at 7-18 mo and 125 μg at 19-24 months
Clinical : edema, blood pressure
Biochemical : electrolytes, PRA
Hypertension :indication to reduce/stop
Susceptibility to oedema increases with age
Minimal drug interactions at usual dose.
Drugs via RAAS pathway: Sympathomimetics - Beta2 agonist; Theophylline
Max Upto 400ug for salt wasters ; FLUDRO dose may be reduced or stopped
Generally, lower dose fludrocortisone in those treated with Hydrocort than Pred or Dexa

12. 12
 Cortisol + aldosterone def : hyponatremic dehydration and shock
 Exacerbated by deficiency of catecholamines
 Additional MC replacement during stress & elective surgery
unclear
 9α-fludrocortisone should be given If oral intake possible
 Stress regimen of double/triple dose IV hydrocort is sufficient
ADRENAL CRISIS

13. IMPLICATIONS
4
Supraphysiologic hydrocortisone
doses often necessary to adequately
suppress androgen production

14. ROLE OF FLU
14
HYPERCORTISOLISMHYPERANDROGENISM
Fludrocortisone
Mineralocorticoids in Saltwasters
hypovolemic drive for ACTH secretion
Lower Glucocorticoid dose

15.  Sodium /potassium values
 PRA values (treatment goal: <18 ng/ml/h until 6 months of age
<5.5 ng/ml/h above the age of 6 months)
 17-OH P just prior to 1st dose 7:30-8:30am( 1-10ng/ml)(target 18 nmol/l): 3-4monthly in growing years
 Testosterone /androstenedione
 Plasma ACTH concentrations are of little help in adjusting doses
 Cohen et al. suggested PRA is of value in determining MC underreplacement
Plasma ANP is a more sensitive index of Fludro overreplacement
 Regular monitoring of blood pressure and measurement of plasma electrolytes and renin activity are
required to prevent complications of under or over dosage
7
FOLLOWUP PARAMETERS

16. 16

17. AS TIME PROGRESSES . . .
Merke DP, Chrousos GP, Esenhofer G et al. Adrenomedullary
dysplasia and hypofunction in patients with classic 21-
hydroxylase deficiency. N Eng J Med 2000; 343: 1362–1368
8
Hypertension is
frequent . May need
antihypertensives
Mineralocorticoids:
may not be needed
(esp Simple Virilising)
Insulin resistance and
DM, Increased intima
media thickness
(Sartorato et al)
Vulnerable to all
other diseases that
an adult encountersAdrenal medullary
dysfunction?
Timing of diagnosis
Age at onset of therapy
Adequacy of metabolic control
Quality of therapy
Patient compliance
Experience of the treating physician
INFLUENCE ON GROWTH

18. PUBERTY-INCREASED CORTISOL
TURNOVER
European Journal of Endocrinology 151 U77–
U82
18

19. Issues
• Salt wasting
• Adrenal crisis
• Gender
• Linear growth
• Pubertal issues
Issues
•Adrenal insufficiency
•Androgen excess
•Ectopic adrenal rests
•Steroid adverse effects
•Psychosocial issues
•Infertility
•Care during pregnancy
10
Insulin resistance and DM, Increased intima media thickness (Sartorato et al)

20. 6
• LINEAR GROWTH: Der Kamp and Jansen et al. (Archives of Disease in Childhood 2002;87:139-144)
Benefit of reducing mean dose of hydrocortisone from 26 mg/m2/day to 17.6 mg/m2/day by institution of
mineralocorticoid in 60 Dutch CAH patients. Authors added that due consideration should be given to treating
both SW and SV forms of CAH with 9α-fludrocortisone
• META-ANALYSIS FROM MAYO CLINIC USA : To aid The Endocrine Society’s expert task force
Kalpana Muthusamy et al (JCEM Sept 2010) : 1088 publications and 35 eligible studies with sufficient data:
treatment outcomes (P =0.02) in CAH who received long-term treatment with mineralocorticoids achieved
significantly better adult heights compared with those who were prescribed glucocorticoids alone.
LITERATURE
BASIC AND ADVANCED
Shrikant Tamhane et al (JCEM November 2018) :14 studies (12 longitudinal, two cross-sectional):
Cardiovascular and Metabolic Outcomes for 437 patients (300 children/adolescents and 137 adults, aged 14

21. MINERALOCORTICOIDS AND HYPERTENSION
Children with classic CAH : higher prevalence of
raised systolic blood pressure than general
population.
US cohort aged 8–17 years : 2/3rd with
salt-wasting CAH were hypertensive, as compared
to the 3% estimate in general population
33 CAH patients followed from birth to 4 years of age
No association was found between hypertension and raised BMI or fludrocortisone dose
Hypertension was associated with suppressed plasma renin activity
Clinical Endocrinology (2014) 81, 871–875
Bajpai et al. noted a positive effect of laboratory monitoring (0.91; 95% CI 0.41–1.41; P 0.001) and
simple virilizing form (1.07; 95% CI 0.54–1.61; P 0.001) on age specific height SDS.
Indian Pediatrics 2007; 44:771–773
CaHASE study : UK cohort: 203 total - 138 women, 65 men - median age 34 yrs (range 18–69).
Increased blood pressure in women with CAH: raised plasma renin in more than 50% of all patients
Insufficiently treated with mineralocorticoids and and suggestion of glucocorticoid overtreatment
Reassessment of requirement for mineralocorticoid replacement during early adulthood
J Clin Endocrinol Metab. 2010 Nov;95(11):5110-21

22. ENDOCRINE SOCIETY GUIDELINES
(UPDATED 2018)
11
• Genotyping is fraught with error complexity of gene duplications, deletions, rearrangements chromosome 6p21.3
• Aim of Newborn screening (NBS) for 21-OHD : avoid early salt-wasting crises, allow early diagnosis of simple-
virilizing CAH in males, and reduce delay in sex assignment in severely virilized females
• Sensitivity to MC varies: Some recover timely from salt-wasting, probably 2o to extra-adrenal 21-hydroxylation
• Psychiatric support should be encouraged for patients with adjustment problems
• Biochemical control only achieved in approx. one-third of patients despite variety in personalized regimens
• Still many existing controversies in diagnosis, management, and treatment

23. ·
01
03 04
02 IMPEDIMENTS =>DISCONTINUATION
Acute consequences of mineralocorticoid excess
volume overload and congestive heart failure
Chronic consequences: Growth impairment caused
by its glucocorticoid properties
EXISTING LITERATURE & GUIDELINES
12
POSITIONING
• Early infancy with salt loss
• Can be fatal if unidentified and treated early
• Dose traditionally calculated based on BSA
• Higher req in neonates and infants
 Current recommendation for mineralocorticoid replacement in SW-21OHD is based on expert opinions
 An initial dose of 100-200 μg/day of 9-α-fludrocortisone, regular dose reassessment & individualized adjustment
ALDOSTERONE DEFICIENCY

24. • Carlson, A.D., et al. “Congenital adrenal hyperplasia: Update on prenatal diagnosis and treatment.
” The Journal of Steroid Biochemistry and Molecular Biology Vol. 69, No. 1–6 (1999): 19–29.
• Merke, D.P., et al. “NIH Conference. Future directions in the study and management of congenital
adrenal hyperplasia due to 21-hydroxylase deficiency.” Annuals of Internal Medicine Vol. 136, No
. 4 (2002): 320–334.
• Trapp, C.M. and S.E. Oberfield. “Recommendations for treatment of nonclassic congenital adrenal
hyperplasia (NCCAH): An update.” Steroids Vol. 77, No. 4 (2012): 342–346.
• Eldar-Geva, T., et al. “Secondary biosynthetic defects in women with late-onset congenital adrenal
hyperplasia.” The New England Journal of Medicine Vol. 323, No. 13 (1990): 855–863.
• Arnaout, M.A. “Late-onset congenital adrenal hyperplasia in women with hirustism.” European Jo
urnal of Clinical Investigation Vol. 22, No. 10 (1992): 651–658.
• Witchel, S.F. and R. Azziz. “Nonclassic congenital adrenal hyperplasia.” International Jounal of Pedi
atric Endocrinology Vol. 2010 (2010): 1–11
• Fanta, M., D. Cibula, and J. Vrbíková. “Prevalence of nonclassic adrenal hyperplasia (NCAH) in hyp
erandrogenic women.” Gynecological Endocrinology Vol. 24, No. 3 (2008): 154–157.
References :

25. THANK YOU 25

26. 26

27. IMPORTANCE OF CAH IN PREGNANCY
 1. High rate of spontaneous miscarriage
 2. Risk of having a fetus with CAH (Cuhaci N. et al. Case Reports in Endocrinology.2015)
In Mother with Classic CAH
Chance of having a child with Classic-CAH is 1 : 120
In Mother with Non-Classic CAH
Chance of having a child with NonClassic-CAH is ~15% & C-CAH ~2.5%
 3. Controversies in treatment
As recommended for the management of other forms of adrenal insufficiency, the glucocorticoid dose might
need to be increased by 25–40% during the last trimester. Mineralocorticoid requirements during pregnancy
cannot be monitored with plasma levels of renin, as it is physiologically increased during gestation. However,
serum and urinary levels of sodium and postural hypotension can be monitored. 27