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

http://www.ideaclinics.cominfo@ideacentres.com

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

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

Investigations 46XX karyotype

Laparoscopy: small uterus with normal fallopian tubes and ovaries

Psychologically entirely male orientated

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

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

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://www.ideaclinics.cominfo@ideacentres.com

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

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)

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

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

What is the optimal steroid dose for CAH?

(what is an acceptable 17 OH Progesterone level)

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

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

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

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

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?

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

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

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

Testosterone and polycythaemia

Men with higher haematocrit experience greater cardiovascular mortality

No testosterone-associated thromboembolic events reported to date

Reversible following cessation of therapy

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

Thank YouContact Us:

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~ Phone:040 4004 2000~ Phone: 80081 66166

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