Anti Mullerian Hormones in Polycystic ovarian Syndrome Pati - PowerPoint Presentation

Slide1

Anti Mullerian Hormones in Polycystic ovarian Syndrome Patients

Moustafa Eissa MD FRCOG

Cyberjaya University College of Medical Sciences, MalaysiaSlide2

In this subject facts are disperse and

hypotheses

and

speculations

are the majoritySlide3

Anti Mullerian Hormone (AMH) is a dimeric glycoprotein. It is secreted from granulosa cells of antral and preantral

follicles.

(Pepinsky et al 1988).

Its

expression in females starts as early as 32 weeks of gestational age

(

Rajpert-DeMeyts et al 1999)Slide4

It is secreted from granulosa cells of antral and preantral follicles before selection for dominance. It's secretion declines in preovulatory follicles

(

Durlinger et al 2002).Slide5

This is a widely accepted fact. However, in a study done by our group comparing AMH level in follicular fluid (FF) and serum in a study group of dysfunctional ovulation cysts and a control group of mature graffian follicles, we found high levels of AMH and it was not declining (Table 1). There was a strong correlation between follicular and serum AMH in the study group and inverse significant correlation between AMH (FF) and serum FSH (Figure 1).

(Eissa et al 2013)Slide6

Table (1): Hormonal profile in Control and Cyst formation groups.*FF: follicular fluid (means follicular fluid in group 1 and cyst fluid in group 2).

Hormone

Group 1

Control

(n= 10)

Group 2

Study (Cyst)

(n= 25)

P value

Mean ± SD

Mean ± SD

Serum FSH(

ng

\ml)

4.65±1.5

5.41±1.9

0.2 (NS)

Serum AMH(ng\ml)

5.9±2.02

14.6±3.3

0.0001(S)

FF* AMH (ng\ml)

29.5±25.7

440.7±182.9

0.0001(S)

FF

*

Testosterones(ng\ml)

5.8±4.2

5.2±3

.7

0.6(NS)

FF

*

Estradiol

(ng\ml)

21.2±0.6

20.4±6.8

0.7(NS)

 Slide7

Figure (1) correlation between serum and follicular fluid concentration of AMH in cyst groupSlide8

Polycystic Ovarian Syndrome (PCOS) is one of the most common endocrinopathies affecting 5-10% of women of reproductive age.

(Amer 2006)

PCOS

is a multifactorial complex characterized by chronic

anovulation, polycystic

ovarian appearance, biochemical and clinical manifestations of

hyperandrogenism

. Figure (2 and 3).

(

Rotterdam Consensus 2004). Slide9

Figure 2 Slide10

Figure 3Slide11

The cause of anovulation in PCOS patients

Stein &

Leventhal

(1935)

: the

sclerocystic

thickened capsule is the primary cause of anovulation

Amer

(2006):

chronic anovulation is the result of abnormal

folliculogenesis

and

steroidogenesis

.

Homburg et al (2009):

the basic lesion is excessive secretion of androgens.

Hyperinsulinaemia

and high LH exacerbate the

problem.

La

Marca

et al

(2009):

The

failure to find a causative gene, although its familial

nature,

suggested a developmental theory based on Barker

theory. Slide12

The excessive exposure to androgens in utero of rhesus monkeys programs

the offending

genes. This

theory is not proved in human yet

.

(Abbott et al 2002).Slide13

So

i

t

is now known that the main pathology of PCOS lies in the ovaries itself and the excessive production of androgens by the ovaries is the main endocrinological disturbance. However, insulin resistance and hyperinsulinaemia and increased LH secretion play a role in the pathogenesis of PCOS

. Figure (4)

(Homburg and Crawford 2014)Slide14

Figure 4Slide15

Laparoscopic PCOS drilling

Figure 5Slide16

Figure 6 Slide17

Laparoscopic ovarian drilling

Figure 7Slide18

Numerous theories of the aetiology of the associated anovulation have been speculated as hyperandrogenaemia, hyperinsulinaemia and dysfunctional feedback mechanismSlide19

However, there is no clear evidence that excessive insulin or androgen has a direct inhibitory effect on ovulation. While there is a good correlation between severity of hyperandrogenemia and anovulation, there is no clear evidence that excessive androgen inhibit

ovulation.

(Homburg

and Crawford 2014).Slide20

Also, there is no convincing evidence that insulin has an inhibitory effect on ovulation. The dysfunctional feedback mechanisms are widely thought to be secondary to the primary pathophysiological change in the ovary itself

(

Franks et al 2006).Slide21

AMH and anovulation in PCOS patients

In PCOS patients,

ovaries have large number of pre-antral and small antral follicles compared to normal ovary, the concentration of AMH is markedly increased

compared

to the

control.

(

Pigny et al 2006).Slide22

Since in vivo and in vitro studies showed that growth of the primordial follicles to growing follicles occurs in absence of AMH (Durlinger 2001), so this is may be the main role of AMH to prevent the growth of primordial follicles and prevent exhaustion of primordial follicle pool. Hence ovarian aging may be delayed in women with PCOS since high AMH levels may inhibit the selection and growth of primordial follicles

(

Mulders et al 2004).Slide23

This may be the initial step of understanding the causative relationship of AMH to anovulation in PCOS patients. On the other hand and in normal ovary, the growing follicles (>10mm) are deprived of AMH, so they become more responsive to circulating FSH and follicle selection occurs.

(

Pellatt et al 2007).Slide24

In studies of McGee and Hsueh (2000) and Durlinger et al (1999),

it was found that AMH decreases the sensitivity of growing follicles to the secreted

FSH.

These studies are not proved in humans and further studies are needed.

Slide25

Kevenaar et al (2007) suggested a role of AMH in FSH induced steriodogenesis in human. This may explain the high oestradiol and the normal or relatively subnormal level of FSH in PCOS patients.Slide26

The main pathophysiological disturbance of failure of ovulation in PCOS patients leads to accumulation of pre-antral and antral follicles and increased secretion of AMH. So, this in a vicious circle, leads to further anovulation.

(

Wang et al 2007).Slide27

Level of AMH, although, high in PCOS patients, it depends on the severity of the condition. T

he density of pre-antral follicles is six times in amenorrheic PCOS patients compared with the normal ovary

(Webber et al, 2003).

It’s concentration in amenorrheic PCOS is high compared to oligomenorrheic and regularly menstruating patients

(La Marca et al 2009)Slide28

Also, it is higher in insulin resistant PCOS patients than insulin sensitive patients. These findings may strengthen the role of AMH in causing anovulation in PCOS patients.

(

Fleming et al 2006). Slide29

Role of AMH in diagnosis and monitoring treatment of PCOS patientsAMH

measurement is useful in diagnosis and monitoring treatment in PCOS patients with high sensitivity and

specificity.

. In absence of ultrasound

diagnosis,

measurement of AMH might be used accurately in diagnosis of

PCOS.

(Pigny et al 2006)Slide30

PCOS women with high circulating AMH (≥ 3.4 ng/mL) seem to be resistant to CC and may require a higher starting dose

(

Mahran

et

al

2013

).

PCOS

women with markedly raised circulating AMH seem to be resistant to HMG ovulation induction and may require a higher starting

dose. The

good response seems to be inversely proportional to AMH level (Figure

6).

(

Amer

et al 2013). Slide31

Figure (8) Good response rates in 34 cycles of HMG ovarian stimulation in PCOS women with different serum AMH

levels

Amer

et al 2013

.Slide32

Conclusion

Further

studies are needed to know if this high AMH in PCOS patients is a result of the accumulation of small antral follicles because of the failure of ovulation or it is a cause of disruption of folliculogenesis. If this proved in humans an AMH antagonist may be the key treatment.Slide33

The use of AMH measurement in evaluation of PCOS patients need a large and well designed trial. More studies are needed to evaluate the role of measuring AMH in adolescent girls to identify those at high risk for developing PCOS. Also, further studies are needed to identify those who may respond to treatment as weight loss, clomiphene citrate and insulin desensitizers. Slide34

Thank you