Anti-Mullerian Hormone in the pathophysiology of PCOS Roy Homburg Homerton University Hospital,...

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Anti-Mullerian Anti-Mullerian Hormone in the Hormone in the pathophysiology of pathophysiology of PCOS PCOS Roy Homburg Roy Homburg Homerton University Hospital, Homerton University Hospital, London London & Barzilai Medical Centre, & Barzilai Medical Centre, Ashkelon, Israel. Ashkelon, Israel.

Transcript of Anti-Mullerian Hormone in the pathophysiology of PCOS Roy Homburg Homerton University Hospital,...

Anti-Mullerian Hormone Anti-Mullerian Hormone in the pathophysiology in the pathophysiology

of PCOSof PCOS

Roy HomburgRoy Homburg

Homerton University Hospital, LondonHomerton University Hospital, London& Barzilai Medical Centre, Ashkelon, & Barzilai Medical Centre, Ashkelon,

Israel.Israel.

Anti-Müllerian hormoneAnti-Müllerian hormone((TGF-TGF-ββ superfamily: Müllerian duct regression in male embryos) superfamily: Müllerian duct regression in male embryos)

Maximal expression occurs in preantral and small antral follicles1,2

Expression disappears in maturing pre-ovulatory follicles (expression restricted to GCs of the cumulus)2

1. Laven et al. J Clin Endocrinol Metab 2004; 89: 318–323; 2. Weenen et al. Mol Hum Reprod 2004;10: 77–83; 3. Cook et al. Fertil Steril 2000; 73: 859–861; 4. La Marca et al. Hum Reprod 2004; 19: 2738–2741; 5. La Marca et al. Hum Reprod 2006; 21: 3103–3107

AMHAMH

AMH is expressed in pre- AMH is expressed in pre-

antral and small antral follicles.antral and small antral follicles.

AMH is thus a good indicator AMH is thus a good indicator

of the size of the ovarian of the size of the ovarian antral follicle pool.antral follicle pool.

PCOS morphologyPCOS morphology

x6 the density of pre-antral x6 the density of pre-antral follicles compared with follicles compared with normal ovary. normal ovary. Webber et al, 2003Webber et al, 2003

AMH serum AMH serum

concentrations in concentrations in PCOS are highPCOS are high

PCOSPCOS PCOS – individual follicles PCOS – individual follicles

produce more AMH produce more AMH

Intrinsic property of PCOS Intrinsic property of PCOS granulosa cells or ? Due to A’s granulosa cells or ? Due to A’s or insulinor insulin

Individual cell dysfunction in Individual cell dysfunction in PCOSPCOS

AMH concentrations in size-matched AMH concentrations in size-matched granulosa cells granulosa cells

Anovulatory PCOS Anovulatory PCOS

Ovulatory PCOSOvulatory PCOS

Normal ovaries Normal ovaries

X 75

X 4-18

(Pigny et al, 2003; Pellatt et al, 2007)

Antral follicle dysfunctionAntral follicle dysfunction- Arrest of growth/anovulation- Arrest of growth/anovulation

Dewailly et al, 2007Dewailly et al, 2007

The size of the 2-5mm follicle pool is an The size of the 2-5mm follicle pool is an independent and important contributor to independent and important contributor to the follicular arrest of PCOS.the follicular arrest of PCOS.

R. Homburg, A. Ray, P. Bhide, A. Gudi, R. Homburg, A. Ray, P. Bhide, A. Gudi, A.Shah, A.Shah,

P. Timms and K. GraysonP. Timms and K. Grayson

Homerton University Hospital, Homerton University Hospital, LondonLondon

Hum Reprod, 2013Hum Reprod, 2013

PCOS & AMHPCOS & AMH Pre- antral and small antral follicles produce AMHPre- antral and small antral follicles produce AMH

x6 the density of pre-antral follicles compared with the x6 the density of pre-antral follicles compared with the normal ovary in PCOS. (normal ovary in PCOS. (Webber et al, 2003)Webber et al, 2003)

High AMH levels in PCOS also due to increased High AMH levels in PCOS also due to increased

production by individual follicles (production by individual follicles (Pellatt et al, 2007)Pellatt et al, 2007)

Some have suggested that asymptomatic polycystic Some have suggested that asymptomatic polycystic morphology (PCOM) is not an entity but a mild variation of morphology (PCOM) is not an entity but a mild variation of normal. normal.

Study aimsStudy aims

1. To define the place of polycystic ovarian 1. To define the place of polycystic ovarian morphology (PCOM) in the hierarchy of morphology (PCOM) in the hierarchy of polycystic ovary syndrome (PCOS).polycystic ovary syndrome (PCOS).

2. To investigate the relationship of AMH to 2. To investigate the relationship of AMH to gonadotrophin concentrations. gonadotrophin concentrations.

Homburg et al, Hum Reprod,2013 Homburg et al, Hum Reprod,2013

Homburg et al, Hum Reprod,2013 Homburg et al, Hum Reprod,2013

Data was collected prospectively from three groups of Data was collected prospectively from three groups of women before undergoing fertility treatment:women before undergoing fertility treatment:

PCOS (Rotterdam criteria) n=90PCOS (Rotterdam criteria) n=90

Polycystic ovarian morphology but no symptoms Polycystic ovarian morphology but no symptoms (PCOM) n=35(PCOM) n=35

Normal ovaries – controls matched for age and Normal ovaries – controls matched for age and BMI n=90 BMI n=90

Matched for age and BMIMatched for age and BMI

Homburg et al, Hum Reprod,2013 Homburg et al, Hum Reprod,2013

Groups Groups NoNo AgeAge BMIBMI

ControlsControls 9090 32.5 32.5

(3.3)(3.3) 24.8 24.8

(2.6)(2.6) PCOMPCOM 3535 32.1 32.1

(4.2)(4.2) 24.7 24.7

(2.6)(2.6) PCOSPCOS 9090 31.6 31.6

(4.4)(4.4) 24.9 24.9 (2.4)(2.4)

PP NS NS NSNS

AMH concentrationsAMH concentrations

AMH measured by Beckman-Coulter Gen II assayAMH measured by Beckman-Coulter Gen II assay

Groups Groups NoNo AMH (pmol/l)AMH (pmol/l)

ControlsControls 9090 23.6 (15.0)*23.6 (15.0)*

PCOMPCOM 3535 52.2 (35.0)**52.2 (35.0)**

PCOSPCOS 9090 77.6 (61.0)***77.6 (61.0)***

P<0.05P<0.05

P<0.001P<0.001

PCOM vs PCOSPCOM vs PCOS

Controls vs PCOMControls vs PCOM

Controls vs PCOSControls vs PCOS

Mean values and 95% confidence intervals for Mean values and 95% confidence intervals for AMH AMH (pmol/l) in the group of controls (N), PCOM and PCOS.(pmol/l) in the group of controls (N), PCOM and PCOS.

Conclusion Conclusion

Serum AMH concentrations are Serum AMH concentrations are capable of differentiating between capable of differentiating between normal ovaries, PCOM and PCOS.normal ovaries, PCOM and PCOS.

Suggests that the number of small Suggests that the number of small follicles determines the severity of follicles determines the severity of the syndrome.the syndrome.

Homburg et al, Hum Homburg et al, Hum Reprod,2013 Reprod,2013

AMH levels in PCOS according to the menstrual AMH levels in PCOS according to the menstrual statusstatus

9944441818Number of Number of patientspatients

120.4120.4( ( 50.850.8))83.683.6( ( 60.360.3))58.458.4( ( 31.931.9))AMH AMH (pmol/L)(pmol/L)

AmenorrAmenorrhehe

OligomenOligomen-orrhea-orrhea

Regular Regular cyclescycles

MenstruaMenstrual statusl status

Pigny et al., 2006

Higher AMH values in oligo - amenorrheic womenHigher AMH values in oligo - amenorrheic women

and in women with hyperandrogenismand in women with hyperandrogenism

Kolhapur PCOS study – ‘MAPIN’ study

2007 – 2011

1257 women with PCOS – Rotterdam CriteriaAnalysis ready for 492

ClinicalEndocrinology and MetabolismUltrasound

(Kulkarni, Gudi, Homburg and Conway)

Kolhapur PCOS study – BMI distribution

11 22 33 44 55nn 9696 8989 105105 9292 9393ageage 2323 2424 25*25* 2525 27*27*BMIBMI 17.417.4 20.9*20.9* 23.3*23.3* 26.1**26.1** 30.9**30.9**TSHTSH 2.42.4 2.12.1 2.82.8 2.72.7 3.3*3.3*TestoTesto 4242 53*53* 58*58* 62*62* 67*67*InsulinInsulin 6.16.1 9.79.7 12.2*12.2* 12.9*12.9* 15.0**15.0**AMHAMH 3.653.65 3.673.67 4.01*4.01* 4.33*4.33* 4.88*4.88*

Kolhapur PCOS study – BMI quintiles

) Kulkarni, Gudi, Homburg and Conway (

Kolhapur PCOS study – types of diet

1 Carb1 Carb VegVeg Non Non VegVeg

JunkJunk

nn 5050 219219 170170 5151BMIBMI 17.117.1 22.3*22.3* 25.7*25.7* 30.6**30.6**WHRWHR 0.820.82 0.850.85 0.840.84 0.850.85LHLH 10.510.5 9.39.3 9.39.3 9.99.9TestoTesto 4444 54*54* 64*64* 68*68*AndroAndro 2.742.74 2.842.84 2.612.61 3.153.15SHBGSHBG 3030 4040 3232 3030InsulinInsulin 5.85.8 10.7*10.7* 12.6*12.6* 13.7**13.7**AMHAMH 3.693.69 3.82*3.82* 4.36*4.36* 5.11**5.11**

Kolhapur PCOS study - diet

Kolhapur PCOS study – hirsutism

F-GScore

<8<8 8-98-9 10-1110-11 12-1312-13 >13>13nn 7272 130130 102102 9292 9292ageage 2323 2424 25*25* 26*26* 27*27*BMIBMI 18.418.4 21.0*21.0* 24.1*24.1* 26.4**26.4** 29.0**29.0**TSHTSH 2.62.6 2.32.3 2.8*2.8* 2.7**2.7** 3.2**3.2**TestoTesto 4242 5252 6262 6161 7070InsulinInsulin 7.87.8 9.39.3 12.3*12.3* 11.211.2 15.4**15.4**AMHAMH 3.863.86 3.633.63 4.214.21 4.39*4.39* 4.70*4.70*

Kolhapur PCOS study - hirsutism

Effect of aging on PCOSEffect of aging on PCOSWomen with Women with

PCOS gain regular PCOS gain regular menstrual cycles menstrual cycles when agingwhen aging

Menstrual cycle Menstrual cycle restored in those restored in those with a smaller with a smaller follicle countfollicle count

Elting et al, 2000, 2003Elting et al, 2000, 2003

Lack of influence of endogenous Lack of influence of endogenous FSHFSH

FSH levels generally lower than normal but FSH levels generally lower than normal but within normal limits.within normal limits.

Adding exogenous FSH (CC, low dose FSH) Adding exogenous FSH (CC, low dose FSH) restores normal follicular growth.restores normal follicular growth.

Increased responsiveness to exogenous FSHIncreased responsiveness to exogenous FSH

Suggests an endogenous inhibition of FSH Suggests an endogenous inhibition of FSH action in PCOS.action in PCOS.

Mean values and 95% confidence intervals for Mean values and 95% confidence intervals for FSHFSH (IU) in (IU) in the groups of control (N), PCOM and PCOS.the groups of control (N), PCOM and PCOS.

Possible role of AMH in the Possible role of AMH in the pathophysiology of PCOSpathophysiology of PCOS

•The size of the 2-5mm follicle pool is an independent and important contributor to the follicular arrest of PCOS. (Dewailly et al, 2007)

•AMH concentrations are very high in PCOS. The higher they are, the greater the ovulatory disturbance. (Pigny et al, 2006)

•Action of FSH in promoting follicular growth is counteracted by AMH. (Pigny et al, 2003;Weenen et al, 2004; Durlinger et al, 2001)

AnovulationAnovulationA excess A excess LH +insulin LH +insulin

Multiple small folliclesMultiple small follicles

AMHAMH

FSH actionFSH action

Anovulation progesteroneAnovulation progesterone

TreatmentTreatment Weight loss Weight loss – Lower AMH at start do better if – Lower AMH at start do better if

AMH falls AMH falls ovulation ovulation (Moran et al, 2007)(Moran et al, 2007)

CC in obese & laparoscopic ovarian drilling CC in obese & laparoscopic ovarian drilling – – Response dependent on initial AMH conc.Response dependent on initial AMH conc.

(Amer et al, 2009)(Amer et al, 2009)

MetforminMetformin – Very long time for AMH to fall– Very long time for AMH to fall (Fleming et al, 2005)(Fleming et al, 2005)

FSHFSH – AMH falls with Rx – AMH falls with Rx (Catteau-Jonnard, 2007)(Catteau-Jonnard, 2007)

ConclusionsConclusions

The severity of symptoms of PCOS The severity of symptoms of PCOS is positively related to the number is positively related to the number of small follicles reflected by AMH. of small follicles reflected by AMH.

AMH may play an important part AMH may play an important part in the pathophysiology of PCOS.in the pathophysiology of PCOS.