1. Endocrine Nurse’s Conference Cushing’s Disease Veronica Kieffer MA BSc (Hons) RGN Endocrine Nurse Specialist Leicester Royal Infirmary, Leicester

2. History October 1997 Miss A 16 year old girl Moon face Hirsutism Central obesity Purple striae Proximal myopathy Primary amenorrhoea

3. Investigations Urea and Electrolytes (U&E) Liver Function Test (LFT) Thyroid function tests (TFTs) LH/FSH Oestrogen Prolactin Growth hormone Cortisol Adrenocorticotrophic hormone (ACTH) 24 hour Urinary Free Cortisol (UFC)

4. Results LFTs, U&Es, TFTs –all normal LH 0.9iu/L FSH 2.8iu/L Prolactin 120iu/L ( 50-400 iu/L) Oestradiol <50pmol/L Cortisol 568nmol/L UFC 257 nmol/24hours ( 28-221nmol/24hrs) ACTH 60ng/L (0-50ng/L)

5. Further Investigations Circadian rhythm cortisol Midnight cortisol Low dose Dexamethasone suppression test CRH test MRI Pituitary gland CT Adrenal glands Petrosal Sinus Catheter

6. RESULTS Circadian rhythm  0930 --- 556nmol/L  1200 --- 663nmol/L  1700 --- 635nmol/L  Mean --- 618nmol/L  Midnight cortisol --- 490nmol/L Low Dose Dexamethasone Test Dex 2+0 --- 568nmol/L Dex 2+48--- 246nmol/L

7. Results CRH Test No change in cortisol levels so not useful in diagnosing cause MRI Pituitary ?Right Pituitary microadenoma CT Adrenals No lesion found

8. Petrosal Sinus Catheter SampleRightLeftPeripheralGradient:Gradient Right:PeriLeft:PeriRight:Left ACTH: Basal9868871.10.81.4 ACTH: 5min1,4243,62012311.629.40.4 ACTH: 10min2104,3881591.327.60.0

9. Treatment Metyrapone 19/11/1997 Cortisol levels on Metyrapone 750mg stat  0900 – 554nmol/l  1200 – 79 nmol/l  1700 – 107nmol/l 18/12/1997 Cortisol levels on Metyrapone 250mg t.d.s  0900 – 120nmol/l  1200 – 135nmol/l  1430 – 89nmol/l  1700 – 109nmol/l  Mean 113nmol/l

10. Treatment 9 th January 1998 0900 cortisol – 656 nmol/l 19/1/1998 Cortisol levels on Metyrapone 250mg nocte  0900 – 514nmol/l  1200 – 674nmol/l  1430 – 620nmol/l  1700 – 493nmol/l  Mean -- 575nmol/l Block and Replace  Metyrapone 250mg t.d.s / Hydrocortisone10mg o.d.

11. Treatments for Cushing’s Disease. Trans-sphenoidal removal of tumour.  Remission in 75-80% cases External pituitary radiation  Slow acting. Effective in 50-60% cases. Medical Therapy to reduce ACTH (Bromocriptine )  Rarely effective Bilateral Adrenalectomy  Effective last resort

12. Surgery Trans-sphenoidal hypophysectomy 10/03/1998  18/03 - 0900 cortisol --- 768nmol/l  19/03 - 0900 cortisol --- 992nmol/l Trans-sphenoidal hypophysectomy 17/04/1998  22/04 - 0900 cortisol --- 738nmol/l  23/04- 0900 cortisol --- 624nmol/l  25/04 -0900 cortisol --- 596nmol/l Pan hypopituitarism with diabetes insipidus Restart ‘Block and Replace’

13. Block and Replace 16/11/1998 Metyrapone 250mg t.d.s/ Hydrocortisone 10mg o.d.  0930 --- 555nmol/l  1200 --- 273nmol/l  1430 --- 103nmol/l  1700 --- 101nmol/l  Mean 258nmol/l  24 hour UFC 63nmol/24hours

14. Options Tablets - such as Metyrapone Radiotherapy to the pituitary gland. An operation to remove both adrenal glands.

15. Options Not easily controlled tablets Tablets would be necessary several years after radiotherapy Recommend bilateral adrenalectomy– refer to surgeon Miss A and family agreed.

16. Treatment 23/12/1998 Bilateral adrenalectomy -  Hydrocortisone 10mg,5mg,5mg  Fludrocortisone 100mcg o.d.  Pigmentation knuckles and palmar creases  Close watch on ACTH  TFTs normal on Thyroxine  Desmopressin still for Diabetes Insipidus  Gonadotrophin deficiency

17. February 1999 Day curve – levels cortisol good  mean 392 nmol/l No features Cushing’s Suppressed Renin levels (Fludrocortisone) ACTH 602ng/l Oestrogen replacement (Mercilon) ?Nelson’s syndrome

18. Nelson’s Syndrome Rapid enlargement of a pituitary adenoma following bilateral adrenalectomy Lack of negative feedback from cortisol  Mass effects  Increased production ACTH  Increased production melanocyte stimulating hormone. Muscle weakness Hyperpigmentation

19. June 1999 Progressive darkening skin Increase Hydrocortisone 10mg/10mg/5mg Repeat Hydrocortisone day curve Repeat ACTH levels

20. September 1999 Blood Cortisol levels and UFC at day curve top end acceptable level  mean bloods 559nmol/L  UFC 552nmol/24hrs ACTH lower 181ng/L (increased suppression corticotroph adenoma) Weight gain Stretch marks Balancing act MRI

21. March 2000 DNA MRI appointment October 1999 February 2000 MRI reported as:  Macroadenoma on left pituitary fossa extending into cavernous sinus.Not visible on previous MRIs or at surgery.  Increasing pigmentation Pituitary radiotherapy –June 2000

22. September 2000 Pigmentation less Continues Hydrocortisone 10mg/10mg/5mg ACTH still elevated  9000ng/L pre morning Hydrocortisone  640ng/L 2 hours after  Weight gain but risk of enhancing growth adenoma if dose Hydrocortisone reduced.

23. ACTH levels

24. Follow Up 2003-2005 Continued to be stable and no changes in pigmentation MRI July 2003 – adenoma stable ACTH level lower in 2003 Gynae problems GH deficient but declined treatment.

25. 2006 Well No changes in pigmentation ACTH before and after Hydrocortisone  Higher than previously (post 808ng/l)  Hydrocortisone increased  Monitor

26. 2007 Increased pigmentation ACTH pre and 2 hours post Hydrocortisone  Post 4,760nmols/l MRI pituitary  Significant Lt lateral extension passing through cavernous sinus Significant enlargement compared to previous films mostly laterally but now filling fossa.

27. Treatment MDT discussion  Further de-bulking surgery –but unlikely to be completely resectable as wrapped around carotid and ocular motor nerves  Possible gamma knife therapy  Cabergoline –no effect

28. Trans-sphenoidal Hypophysectomy December 2007 Post op MRI – encouraging but many ‘scars of battle’ Plan further MRI June ACTH 2 hour post hydrocortisone  133ng/L June MRI – Good clearance but possible small amount residual tissue. Continue monitoring ACTH and MRI

29. June 2008 ACTH Pre and post Hydrocortisone levels  Pre >1250ng/L  Post 423ng/L

30. Conclusion Cushing’s syndrome 2 transsphenoidal hypophysectomies Bilateral adrenalectomy Nelson’s syndrome Radiotherapy 3 rd transsphenoidal hypophysectomy ? Nelson’s recurring

31. The Future? Watchful wait Gamma knife therapy No further radiotherapy after that Repeated de-bulking surgery Careful monitoring