Congenital Adrenal Hyperplasia @ Dr. Shyam Kalavalapalli and Team of Best Endocrinologist in...
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Transcript of Congenital Adrenal Hyperplasia @ Dr. Shyam Kalavalapalli and Team of Best Endocrinologist in...
A Confusing Case of Congenital Adrenal Hyperplasia
S Kalavalapalli, K Kaushal, FC WuDepartment of EndocrinologyManchester Royal Infirmary
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38 year old man Presented with dehydration at 10 days of age
Salt losing classic congenital adrenal hyperplasia (21-hydroxylase deficiency)
Commenced on cortisone acetate and fludrocortisone
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At age 15 presented with bilateral gynaecomastia and haematuria On cortisone acetate 25mg bd, fludrocortisone 100mcg od, salt tablets
Examination findings: Short stature (<3rd centile) Absent testes Normal sized penis Gynaecomastia with markedly pigmented nipples Mass palpable on rectal examination
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Investigations 46XX karyotype
Laparoscopy: small uterus with normal fallopian tubes and ovaries
Psychologically entirely male orientated
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Interpretation Genetically female
Extensive virilisation in utero
Typically male external genitalia, with normal penis, normal urethral opening from glans tip, normally formed but empty scrotum
Led to incorrect assignment of male gender at birth
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Subsequent management
Hysterectomy and BSO, with insertion of testicular prostheses
Commenced on monthly sustanon injections
Dose of glucocorticoids reduced
Bilateral mastectomy age 16
Satisfactory sexual function on sustanon, normal male sexual orientation
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Glucocorticoid therapy (1) Hypertensive from age 20
Poorly suppressed 17 OHP levels on CA then HC
Started on dexamethasone 0.5mg mane (age 29), fludrocortisone decreased to 50 mcg od
17 OHP levels <5nmol/l
Unsuccessful attempt at dose reductionhttp://[email protected]
Glucocorticoid therapy (2) Subsequently converted to prednisolone 5/2.5mg
?Wedge fracture of T12 (age 32)
DEXA ?osteoporosis
Subsequent DEXA 4 y later normal
At present on Prednisolone 2.5/2 mg, 17 OHP 69 nmol/l
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Glucocorticoid therapy and androgens
1995: Sustanon stopped whilst on HC (age 28)
4/95 (HC)
8/95 (Dex 0.5)
8/97 (Dex 0.5)
8/04 (Pred 2.5/2)
Mean 17 0HP (nmol/l)
236 6 5 69
T (nmol/l) 30.5(Trough)
2.1(off
Sustanon)
18.5(25 mg
Testogel)
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Summary
Extreme example of overwhelming effects of prenatal androgen exposure
Absence of testes was missed at birth therefore raised as male
Onset of normal female puberty Gonads (ovaries) removed Excessive glucocorticoids may have contributed
to hypertension and possibly osteoporosis
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Treatment of classic 21-hydroxylase deficiency
Glucocorticoids Minimise adverse effects of cortisol deficiency Suppress excessive CRH and ACTH Reduce adrenal sex steroid levels Avoid glucocorticoid excess Optimise growth and BMD
Mineralocorticoids Sodium chloride supplements
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What is the optimal steroid dose for CAH?
(what is an acceptable 17 OH Progesterone level)
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Glucocorticoids in CAH
Physiological doses of glucocorticoids will prevent adrenal insufficiency – both sexes
Higher doses required to suppress androgens -in women
Complete adrenal suppression should be avoided – represents overtreatment
Higher doses may be needed in men with testicular adrenal rest tumours
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Choice of glucocorticoids
Hydrocortisone first choice in childhood 10-20mg/m2/day – 2 to 3 divided doses
Prednisolone/dexamethasone after completion of linear growth Dose of prednisolone 5-7.5mg/d Dose of dexamethasone 0.25-0.5mg/day
Insufficient data to recommend higher morning or evening doses
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Height and BMD in CAH
Mean final adult height known to be lower than target height Excessive glucocorticoids Excessive androgens
Effects on bone mineral density Negative effects of glucocorticoids may be balanced by positive
androgen effect – especially lower doses
Fludrocortisone may lower glucocorticoid requirement
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Learning points
Full examination of external genitalia is essential in CAH
Karyotype should be checked if any doubt
Good control of 17-OHP is less important in males as compared to females
Good control of 17-OHP is unnecessary and undesirable in the agonadal male
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Learning points
Polycythaemia due to sustanon may be treated by stopping treatment and switching to transdermal preparation
Could glucocorticoid therapy have been reduced or even stopped?
Would this have reduced the requirement for testosterone replacement therapy?
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Other treatments Bilateral adrenalectomy
Decreases adrenal androgens Reduces likelihood of iatrogenic hypercortisolism
NIH trial of low dose glucocorticoid, androgen-receptor antagonist (flutamide), aromatase inhibitor (testolactone) and fludrocortisone
CRH receptor antagonist
Gene therapy
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Date 24/2/04 4/6/04 23/7/04 24/8/04 23/11/04
Haemoglobin (g/dl)
20 16.3 15.2 16.7 17.1
Haematocrit 0.57 0.46 0.44 0.47 0.49
Testosterone(nmol/l)
38.7 3.1 0.7 18.5 24.9
Sustanon stopped
Testogel (25mg)
commenced
Resolution of polycythaemia
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Testosterone and polycythaemia
Erythropoiesis androgen-dependent Increased erythropoietin Direct effect on stem-cells
Intramuscular testosterone preparations more commonly associated with polycythaemia than transdermal Supraphysiological levels of testosterone with i.m Dobs et al (JCEM, 1999): 43.8% elevated haematocrit with i.m
vs 15.4% with transdermal testosterone
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Testosterone and polycythaemia
Men with higher haematocrit experience greater cardiovascular mortality
No testosterone-associated thromboembolic events reported to date
Reversible following cessation of therapy
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Androgen replacement
2000 (Age 34): Frequency of sustanon injections increased to fortnightly as trough testosterone 8.8 nmol/l
2004 (Age 38): Developed polycythaemia Hb normalised when sustanon stopped Commenced on Testogel Currently remains well with normal Hb and trough
testosterone level of 24.9 nmol/l
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