Approaching Hyperprolactinemia an treatment

Approach to hyperprolactinema

1. App r oaching Hype r p r olactinemia P r epa r ed b y: Ahmed Hegab Registrar Endocrinology Adan Hospital

2. Pr e- test

3. Ca s e (1): • A 3 4 - y ea r -o l d wo m an p r es e n t s with g ala c t o rr h ea, a m en o rr h ea, headaches, fati g ue, and weig h t g ain. Her Labs s h ow t h e f o ll o win g : • Pr o lactin: 1230 n g / m L ( nl , 50 – 5 50 ), • Free T4 5 11 n g / d L ( nl , 7 – 14 ) , and TSH g r eat e r t h an 6 m U/L (nl , . 5 – 5 . ) . • MRI s c an: Enla r ged pit u itary glan d .

4. What is the m ost app r opria t e a c tion? a. b. c. d. Re f er t o Neurosu r gery Sta r t Sta r t Start T re a t m ent T re a t m ent T rea t m ent with with with Cabe r gol i ne Thyrox i ne Cabe r goline and Thyroxine

5. Case (2 ) : • An 18 - y e a r -old wo m an pres e nts with p ri m ary a m enorr h ea b u t ot h er w ise nor m al p r i o r g r o wth and de v elo p m ent. S h e has also been experie n cing h eadaches and decrea s ed v i sual acuit y . • On p h y sic a l exa m i n atio n , her hei g ht is 1 5 4 .9 cm and weig h t is 6 3 . 6 kg (BMI =2 6 .4 k g / m 2 ) . Bl o od p r es s u r e is n o r m al. S h e has galacto r r h ea with T an n er stage 3 b r ea s t and p u b i c hair de v elo p m ent. La b or a t o ry t e st r esults: Karyot y pe, 4 6 ,XX LH = 3 . 8 m I U / m L FSH = <2 . m I U / m L Estradiol = 34 p g / m L Free T4 = 12 TS H = 2 . 5 Cortisol (8 AM) = 280 P r olac t in: 1100 Pre g na n cy t e s t , ne g a t ive • • • • • • • • • • •

6. The f o ll o wi n g MRI P i t u itary is p r o v i d ed:

7. • What is the m ost app r opria t e next a c tion? A. B. C. D. Sta r t Dopa m ine Agonist the r ap y . Su r gic a l exc i sion via t r an s - spheno i dal app r oach. Su r gic a l exc i sion via t r an s - cr a nial app r oach. Repeat se r um pro l ac t in after ser i al di l ut i ons.

8. Ca s e (3): • A 2 9- yea r - old m an pr e sen t s with dec r ea s ed l i bido, er e ct i le dysfunct i on, and heada c hes. His p r ola c tin concen t rat i on is 2904 ng/ m L (126.3 n m ol / L). MRI shows a 2. 4 - cm m acroadeno m a with la t eral, int r asell a r , and suprase l lar extens i on. His tes t osterone concen t rat i on is bo r de r l i ne low at 250 ng/dL (8.7 n m ol / L), and the rest of his pi t ui t a ry function is nor m al. • Cabe r gol i ne is i ni t ia t ed, and the dosage is g r adua l ly inc r ea s ed to 3.5 m g weekl y . As a re s ul t , his prol a ctin lev e l nor m al i ze s , and MRI shows m ar k ed tu m or s ize re d uct i on. His l ib i do and er e ct i le function nor m al i ze, and his heada c hes dis a ppea r . • At a r ecent cl i nic vis i t, his w ife asks whe t her his cabe r gol i ne dosage could be re d uced.

9. Which of the following adv e rse eff e cts of cabe r g o li n e is she most l i kely c o nce r ned about? A. Di f ficul t y ur i nat i ng B. Hypers e xual i ty C. Sleep apnea D. Rest l ess legs

10. First, L ets start with some basics Pi t uitary is a s m a l l o v al gland ( .5 g m ) s i tuat e d at the base of the s k ull in the Sel l a T u r c i ca within the s p he n oid b o ne. It co n sis t s of A n t e rior and P o st e rior Pi t uitar y . Blood supply: Hyp o p h ys e al arteri e s f r om the c i rcle of W i l l i s Rela t ions: A n t e rio r : T u b erc u lum Sel l ae. Posterio r : D o rs u m Se l l a e and b r a i n s t e m . S u pe r io r : Diap h ra g m a Sel l ae, O p t i c Chias m a and Hyp o thal a m us La t eral: C a ve r n o us Sin u s. Pi t uitary gland is ab o ut the si z e of a Pea.

11. Regul a ti o n o f P r o l actin Se c r etio n : • Do p a m i n e (DA) is t h e p r i n cipal P r o lactin I n h i b i t o ry Factor (PI F ) (Maj o r E f fect). • T h y r o tr o p i n -rele a sing h o r m o n e ( TRH), Estr o gen and vas o active i n testinal pe p ti d e (VIP) are Pr o lactin Rele a sing Factors (Mi n or E f fe c t). • Pr o lactin is u n d er co n ti n u o us i n h i b i ti o n. Funct i o n s: 1 - Breast de v e l o p m ent d u ring p r eg n a n c y . 2- Lac t a t io n . 3 - Role in de v e l o p m ent of fetal lu n g.

12. Hype r p r olactinemia

13. Di f f e r e n t c a us es o f H y p e r p r ol a ctin e mi a : • Hypo t hala m ic Sti m ula t ion: ( h i g h TRH) • Phy s i o l o g i cal: Lact a tion, Pregn a ncy ( m ost c o mm on caus e ) , Coitus, str e ss A. B. C. Pri m ary h y p o t h y r o idism Adre n al I n su f ficiency A c ro m egaly (1/3 o f ca s e s ) • Dec r eased P r olac t in Eli m ina t ion: A. B. Renal Failure Li v er cell Fail u re • Medi c at i ons: (I n h i b i t d o p a m i n e rele a se) • Inc r eased P r olac t in P r oduct i on: 1. Ant i -e m etics: m etocl o p r a m i d e , Do m perid o ne. Anti u lcer: H2 Anta g o n ists, o m eprazole Ant i -H y perte n sive: C C B and m eth y l d o pa Ant i -Ps y ch o tics: Risperi d o n e Ps y ch o tr o p i cs: SSRI, TCA Neur o lept i cs: P h en o t h iazine s , H alo p erid o l , S u l p iri d e COC A. B. PCO Pit u itary T u m ors: Pro l a c tin o m as or H y p o t h ala m ic Stalk co m p r es s i o n. 2. 3. 4. 5. 6. • Neu r ogeni c : A. B. C. Chest wall i n j u ry Suc k ling E p ilep t ic Fi t s ( h i g h serum p r o l actin i s an i n d i cator o f a tr u e fit). 7.

14. Pa t hophysio l ogy (T h eory) For P r ola c tin o ma: • In p r olac t in secret i ng pitui t ary ade n o m as, a m o n oclo n al p o p u l a t i on of p r olac t i n - p r odu c ing ce l ls escapes n o r m al p h ys i ol o g i c in p ut of d o pa m ine f r om the hyp o thal a m u s , ap p arent l y by acquiring a perip h e ral blo o d su p pl y . • In a l m o s t a l l cases, res p o n s i veness to a p h ar m acolo g ic d o se of d o pa m ine is m a i ntained. Etiolo g y: • H y perpr o la c tine m ia in fe m al e s in c hil d bearing age is m ore co mm on d u e to m icroaden o m a (causing Galactorr h ea, A m en o rr h ea, I n fertilit y ) • H y per p r o lactine m ia in p o st m en o pa u sal fe m ales or m ales is m o r e m ost l y d ue to m acroade n o m a causing p r es s u r e s y m p t o m s.

15. C l ini c al P i ct u r e

16. Clinical P i c tu r e of Pituita r y Disease hormone d e fic i ency Ex c ess h o rmo n e secr e tion Mass e f fe c t if Macro a denoma Other pitu i ta r y if Macro a denoma

17. S y mp t oms a n d si g ns in Pi t ui t ary Dise a se: Local complications • Hea d ache • Vi sual fie l d de f ect • D i sconnection h y p e rp rolactinae m i a • D i plopia (cave rn ous sinus i n vo l veme nt ) • A cu t e in f arc t ion / expansio n (pitui t ary a p op l exy) Hormone excess Hypopituitarism Growth ho r mone • Letha r gy Hyperpro l acti n aemia • Ga l acto r rhoea • Amen o rr h oea • H ypogo n ad i sm �� A c r om e ga l y Gonado t rop h i ns • • • • L e tha r gy L o ss of l ib i do Hai r l o ss Amenorrho e a • • • Hea d ache Swea t ing Change in shoe and ring s i ze (skeletal changes) AC T H • • • • Letha r gy Postural hypotension P a ll o r Hai r l oss Cushi n g ' s disease • W e i ght ga i n • • • • • Br u ising Myopa t hy Hypertension St ri ae D epres s i o n TS H • L e t h argy Vasopress i n ( A D H ) ( u s ually post-su r g i ca l ) • T h i rst and p o l yuria M icroade no ma ( a rrow) < 1 m m d i a meter

18. In P re- m enopaus a l fe m al e s, Cl i nic a l pic t ure can be Cli n ical Pictu r e of Hype r p r olactin e mia: re l at e d to the level of P r ola c t i n. A. P r e - meno p a u s a l females: A m eno r rh e a, Gala c to r rh e a , infer t i l i t y . Pos t - meno p a u s a l females: dec r ea s ed Lib i do, m ass e f fect. Men: decre a sed l i bido, i m poten c e & m ass e f fect. B. C. ➢ Gal a ctorrhea is t h e d i scha r ge o f m ilk from the b re a st n o t a s sociat e d with p reg n ancy or lactatio n .

19. I n v e s ti g ations: 1. Serum Pro l ac t in N. B . : First test to do w hen inves t igat i ng hyperpro l actin e m ia is Pregnancy test ( m ost co m m on caus e ). 2. Other Pi t ui t ary Profile if C o r t isol 9 AM, T F T) V isu a l Fie l d T es t ing Mac r oadeno m a: (FSH, L H , Est r ogen, T es t ost e ron e , 3. 4. MRI Pi t ui t ary with cont r ast

20. A - P r o l ac t in l e v el co r e l a t es wi t h t he Tumor size ❖ Pr o lactin level a b o v e ( 5 n g / m l ) : d i ag n ost i c of m a c ro p rolactin o m a . ❖ Pr o lactin level a b o v e 2 5 n g / m l: su g gesti v e of m acro p r o lactin o m a . ❖ Pro l a c tin level less t h an 2 50 n g / m l: su g gesti v e of m icro p r o lactin o m a . ❖ If Macroa d en o m a p r es e nt with p r o lactin less than 100 n g / m l: 1. Pituit a ry st a lk comp r essi o n by n o n f unc t i oni n g ade n o m a H o ok ef f ect by h u g e f u nction i ng 2. m acroade n o m a

21. Th r ee I mportant Pit f al l s whi l e asse s s i ng Serum P r olac t in 1- Pi t ui t ary Sta l k Compre s s i on 2- High Dose Hook E f fect 3- Macrop r olac t ine m ia

22. 1 - Pit u it a ry St a lk Comp r essi o n • Caused B y n on -f u ncti o n i ng p i t u itary aden o m a or any t u m or co m p r es s i n g p i t u itary stalk a t h y p o t h ala m us. • Leadi n g to i n cre a sed p r o l actin l evel d ue to d ecr e as e d Do p a m i n e p r o d ucti o n fr o m h y p o t h ala m us. • Pres e nted with m ild h y perpr o la c tine m ia n o t related to size of aden o m a. • Mass e f fect b u t n o G a lactorr h ea.

23. 2 - High Dose H o ok Effect: • V ery high pro l ac t in lev e ls m ay be f ound to be f als e ly nor m al becau s e of t he high - dose hook ef f ect of the assa y ; if cl i nic a l l y ind i ca t e d, the sa m ple s hould be assayed again after dilu t ion. • The La r ge a m ount of ant i gen i n an i m m unoas s ay sys t em i m pair ant i ge n- an ti body binding, re s ul t ing in low ant i gen det e r m ina t i o n. Pat i ent pr e sen t s with t ypic a l • f eatu r es of Galacto r rhea.

24. 3 - Mac r o p r ol a ctinemia • Ap p arent i ncrease in serum p r o l actin with o ut t y pical s y m pt o m s. In t h is co n d i ti o n, serum p r o l actin • m o l ecules p o l y m erize i n to d i m er f o rm and su b seq u ently b i nd to i mm u n o g lo b ulin G (IgG). T h is f o rm of p r o lactin is u na b le to b i nd to p r o l actin r ec e p t o r s and ex h i b its no s y ste m ic resp o nse. So p atient is co m p l etely As y m p t o m atic with elevated PRL • • level.

25. B - V is u al F i e ld T e s t i ng: for Mac r oa d en o m as Bit e mporal visual f i eld def e ct. • Co m pute r iz e d pe r i m et r y prov i des accu r ate det a i l s re g ar d ing visu a l field los s . In th i s pa r t i cul a r pat i ent the r e was a l so loss of the r i ght infer i or nasal field.

26. C - M R I Pi t ui t a r y: See Lat e r ☺ ▪ Pi t ui t ary Mac r oadeno m a : More t han 1 cm ▪ Pi t ui t ary Mi c ro a deno m a: Less than 1 cm

27. Flow diag r am for the diagnos t ic evalua t i on of hyperpro l actin e m ia. MAC, Ma c ro a denoma; MIC, m i c ro a denoma; P R L , prola c t i n.

28. T r eat m ent

29. T r eatment: • S u r gery is n o t t h e first l i n e t h erapy because: 1 . Up to 5 % of p r olac t i n o m as rec u r after s u r ge r y . 2 . Hig h ly res p o n s ive to d o pa m ine ag o nist thera p y in t e r m s of si z e and PRL levels. • Patients who have a m a c roaden o m a or s y m p t o m atic m icroa d en o m a req u ire t h erapy with d o p a m i n e ag o n i sts. T arge t s: A. B. C. Lo w er p r ola c t i n. R e d u ce si z e of M a cr o ade n o m a. R e store g o na d al f u nctions. NB : Pat i ents with asy m pto m at i c m ic r oadeno m as with m odest P R L el e vation re q ui r e just F U P .

30. Do p ami n e Ag o ni s t s : Bro m oc r ip t ine, Cabe r gol i ne, Pe r gol i de ➢ B r om o criptine An e r g o t de r ivat i ve that has b o th D 1 R and D 2 R ag o nist p r o p e r t i e s . Therape u t i c d o ses ran g e f r om 2 . 5 m g/day to 15 m g/day in o n ce to three t i m es dai l y d o ses. R e d u ce PRL l e vel & cause tu m or s h rinkage. ➢ Cabergoline: N o n e r g o t, S u pe r ior to b r o m oc r i p t i ne in re d ucing PRL l e vel & tu m or s h rin k a g e. M o r e ( b ut n o t stri c t l y) se l ec t ive f o r the D 2 R and has a lo n g d u rat i on of ac t io n . The r ape u t i c d o ses ra n ge f r om . 5 m g/week to 2 . m g/week in o n ce or twi c e wee k ly d o ses. ➢ Pergo l ide: R e m o v ed fr o m m ar k et f o l l o w i n g co n cer n s of hi g h incidence of car d i a c valves p r o b l e m s.

31. Si d e Effects of Dopamine Ag o nists: Common Side Eff e cts for Dopamine Agonist s : Serious Side Ef f ec t s for Dopamine Agonist s : 1. Pleur o pul m o n a r y cha n ges co n sis t ing of pleu r al e f f u s i o n s , pleural th i ckening, and pare n chy m al lung fib r os i s. Fib r otic valv u l a r hea r t disease as well as co n stri c t i ve pe r i c ard i t i s . 1. 2. 3. Nausea & v o m i t ing ( m ost co mm o n ) Hea d ache. Excessive day t i m e sl e epiness or s u d d en sl e ep a t t a cks. V isual halluc i nati o n s . Co n f u si o n. Leg swe l l i ng and discol o r a t i o n. Dyski n es i a ( n ot as co m m o n ) Co m p u ls i ve be h aviors (s u ch as 2. (B r om o cr i pt i ne> C a berg o l i ne ) 4. 5. 6. 7. 8. 3. N o ns u r g i c al C SF r hin o rr hea has been rep o rted d u ring early trea t m ent of a l a r ge ( o ften giant) m acr o p r olac t i n o m a u s ing e i ther cabe r g o l i ne or b r o m oc r ipt i ne. D u e to partly re m o v ing the “cor k ” that was f o r m ed by the ade n o m a to co v er the tu m o r - ind u ced de f ect in the s k ull base u n co n t r o l l e d s h o p ping, ga m blin g , ea t in g , and sex u al u r ges) N . B.: Estro g en or t e stosterone re p l a ce m ent m ig h t cause resis t ance to DA thera p y & m ig h t theo r e t i c a l ly increase tu m or si z e. So caref u l m o n i t o r ing is nee d ed

32. S u rge r y: 1 st ▪ N o t the Line of m ana g e m ent, m a i n d r aw b ack is recu r re n ce aft e r su r ge r y . ▪ T ra ns- sphe n o i dal A p p r oach ▪ M a inly in pati e nts w h o can n ot tolera t e or d o n ’ t res p o n d to trea t m ent.

33. Monito r ing Therapy: • Pro l ac t in can be m oni t or e d 2 - 4 weeks after st a rt of t he r apy with D A , then every 3 to 4 m onths once pat i ent is stab l e. • For Mic r o a den o ma: MRI Pi t ui t a ry F U P in one yea r , If both Mi c ro a deno m a & P R L a r e st a ble at one yea r , No Further i m aging is need e d. • For Mac r o a den o ma: F U P MRI Pi t ui t ary in 3 m onths then every 6 - 12 m onths once stab i l i t y is co nf i r m ed. • R e - i m aging is ind i ca t e d if P R L lev e ls r i ses despi t e the r ap y .

34. When T o Stop T r ea t ment? • R e m iss i on of hype r p r o l ac t i ne m ia m ay occ u r in ab o ut 2 % of pati e nts in w h om d o p a m ine ag o nis t s are t a pered and then discont i nu ed . Ge n eral l y , with d ra w al s h o u ld o n ly be a t t e m pted after at l e ast 2 y ears of thera p y and in pati e nts with evide n ce of tu m or res o lut i on . • T ape r ing of cabe r g o l i ne d o ses p r ior to co m plete thera p y with d ra w al has been rec o mm en d ed. • P r edictors of achieving norm o- p r olact i nem i a aft e r w i t h d ra w al: inc l u d e lower cabe r g o l i ne d o ses re q uired with evide n t tu m or m ass s h rin k a g e and m ass r esoluti o n. • R e cu r re n ces after with d ra w al are m o r e l i kely to occ u r f o r m acr o ade n o m as and are re p o r t e d in ab o ut 3 % of pati e nt s . •

35. P r o la c tinoma & P r e g nancy • P r olac t ino m as enla r ge in p r eg n a n cy d u e to Lac t otr o p h s hype r plasi a . Pat i ents with m acr o ade n o m as ha v e a sig n ifi c a n t risk of tu m or g r o w th. • M e asu r ing P r olac t in l e vel d u ring p r eg n ancy is m is l eadin g . ❖ If Mi c r o a den o m a: – Stop Dopa m ine agoni s ts. – Monitor clinically onl y . ❖ If Mac r o a deno m a: – Instruct patient to u s e cont r aception ( B a r r ier is pre f er r ed to hor m onal ) . – Su r gical debulking prior to pregnan c y or Dopa m ine agoni s t therapy throughout pregnanc y . – Bro m ocriptine is p r efer r ed in pregnanc y . – Monitor clinically & visu a l field te s ting in each tr i m e s te r . – If heada c hes & visu a l f ield defe c t s : Non contra s t M R I Pituitar y . – Con s ider su r gery if v ision deterio r ates or Hge in a deno m a. – Post pa r tum M R I pituita r y after 6 week s .

36. D r ug I n duced H y pe r p r o l actinemia • Drug in d uced H y perpr o la c tine m ia: t y pically c a use rise 2 5 -1 n g / m l. • NB: Drugs t h at may ca u se s e ve r e h y perp r o l acti n e m ia (> 40 0): Risperi d o n e, P h en o t h iazines & Met o clo p ra m i d e. • Drug W ith d raw a l T est: Hold t h e sus p ect e d o f fen d i n g d r ug f o r 3 d a y s to see if p r o lactin level returns to n or m al. • T r ea t m e nt: 1. 2. 3. 4. S w i t ch to an o ther d r u g . If Asy m pt o m a t i c : No trea t m ent nee d ed. If hyp o g o n a di s m : Estro g en or t e stosterone re p l a ce m ent. D o pa m ine ag o nists TTT is co n trove r si a l as they m ay exacer b a t e p s y c h o sis (E x pe r t B a sed Ju d g m ent).

37. So m e B a sic Im a ging, M R I P i tui t a r y :

38. M R I Pi t u i t a r y : ✓ MRI i s the m ain s tay of i m aging f or pi t ui t a ry m ic r oadeno m as and Mac r oadeno m as. C o ntr a s t - enhan c ed MRIs have a sensi t ivity of 90 % . ✓ ✓ Pos t- cont r ast and espe c ia l ly th i n - sec t i o n dyna m ic co n t r as t - enhan c ed i m aging has sign i fican t ly i m prov e d diagno s t i c accu r acy S m all pi t uitary inc i denta l o m as are re l atively co m m on, with up to 2 - 30% of autop s ies iden t ifying s m all asy m pto m at i c m ic r oadeno m as. ✓

39. ▪ Pi t ui t ary Mac r oadeno m a: M o r e than 1 cm ▪ Pi t ui t ary Mi c ro a deno m a: Less than 1 cm ➢ P o s t - con t r ast and especia l ly thi n- sec t i o n dyna m ic co n tras t- enha n ced i m agin g : is an i m p o rtant pa r t of a p i t uitary M R I a nd has sig n ifi c a n t l y i m p r o v ed diag n o s t i c accuracy f o r M i cr o ade n o m as. ➢ T1 C + ( G d): • D yna m ic se q ue n ces de m o n stra t e a r o u n d e d region of del a y ed en h ance m ent co m pared to the rest of the gland • Dela y ed i m ages are va r i a ble, ra n gi n g f r om hyp o - enha n ce m ent ( m o s t co m m o n ) to i s ointense to the rest of the gland, to hype r inte n se ( r e t a i ned co n tras t )

40. T a k e home messa g es: ✓ In fe m ale chi l dbea r i n g age; the r e is w ide range for pr e sen t ations of h y pe r pro l ac t i n e m ia ra n ging from m ens t ru a l i r re g ula r i t ies up to the clas s ic a l a m eno r rh e a, gal a cto r rhe a . ✓ There are m any di f f erent causes o f hyperpro l act i ne m ia and m any pitfal l s w h i l e in t er p ret i ng se r um pro l ac t i n . ✓ Don ’ t fo r get t o m oni t or side e f fects of D A the r ap y .

41. Thank ☺ y ou