Ovarian Reserve Score Of Assisted Reproductive Therapy Outcome Biology Essay

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The tendency to delay childbirth has increased the importance of ovarian reserve as a determinant of infertility treatment outcome. The ovarian reserve, constituted by the size of the ovarian follicle pool and the quality of the oocytes therein. Various methods have been proposed and are currently used in the assessment of ovarian reserve in order to predict the outcome in assisted reproduction. Patients and methods: This prospective study included 300 patients who had undergone ART in Al-Azhar University Hospitals and International Islamic Center for Population Studies and Research (IICPSR). Measurement of basal FSH, E2 and AMH levels was done on cycle day 3 of the cycle prior to controlled ovarian hyperstimulation. Ultrasound scanning was performed on the same day to ascertain AFC and the ovarian volume. Every patient was given a score according the value of the previous parameters. Induction of ovulation for assisted reproductive therapy using long GnRH protocol was done. Patients with an follicle count of <5 were considered poor responders. Results: The results showed that all patients with ORS < 3 are poor responders. Patient with ORS 3 are borderline (55% are poor responders and 45% optimal responders). Patient with ORS with ORS <3 are good responders. Patient with ORS 9 all are high responders and at high risk for Ovarian Hyperstimulation Syndrome. The most sensitive predictor of poor ovarian response is the ORS followed by AFC and AMH. Conclusion: This study suggests that ORS that used in this study is useful for prediction of poor response to controlled ovarian hyperstimulation (COH) and counseling the couples regarding their performance during ovarian stimulation. Also can be useful in adjustment of the dose of human menopausal gonadotrophins to get the optimum response.

Introduction

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The tendency to delay childbirth has increased the importance of ovarian reserve as a determinant of infertility treatment outcome. In context of assisted reproductive technology, effective strategies to overcome the impact of ovarian aging and diminished ovarian reserve on pregnancy chances remain elusive. Markers of ovarian reserve are increasingly used to aid management and counseling of these patients (Macklon and Fauser, 2005).

Predicting ovarian function before in vitro fertilization (IVF) treatment is particularly important in older patients and in those with poor ovarian response (Baird et al., 2005).

Ovarian reserve is a term used to describe the functional potential of the ovary (Maheshwari et al., 2006). The ovarian reserve, constituted by the size of the ovarian follicle pool and the quality of the oocytes therein, declines with increasing age, resulting in the decrease of a woman’s reproductive function. The size of the follicle pool is established at an early point in life (Visser et al., 2006). During the fourth or fifth week of gestation the primordial germ cells migrate to the gondal region where the gonads will develop, there are about 1000 to 2000 germ cells at that time. At about the seventh month of gestation the number of germ cells reaches its maximum, about seven million. All the germ cells are by then transformed into oocytes. The number of oocytes then drops sharply again to about 2 million at birth (Gougeon 2004). At the onset of puberty only some 400.000 are left. The wasting of follicles continuous throughout reproductive life, reaching a critical number of a few thousand at a mean age of 45 when menstrual cycles become irregular, and falling to clearly below a thousand follicles at the time menstrual cycles cease, the event know as menopause (Kwee et al., 2007).

As a woman ages, her ovarian reserve declines principally due to apoptotic loss of primordial follicles, not ovulation (Faddy et at., 1992). Unfortunately, the rate of apoptotic loss of oocytes is not consistent within the population. Therefore the biological age of the ovary might not reflect its chronological age (Tremellen et al, 2004).

Various methods have been proposed and are currently used in the assessment of ovarian reserve in order to predict the outcome in assisted reproduction. Female age alone is a rough parameter for assessing ovarian reserve. The basal follicle stimulating hormone (FSH) level is not adequately sensitive to predict poor outcome and the same is true for other basal parameters, including basal estradiol (E2), the follicle stimulating hormone/luteinizing hormone (FSH/LH) ratio (Bukulmez and Arici , 2004).

Dynamic endocrine tests have also been proposed to predict the ovarian capacity, including the clomiphene citrate challenge test (CCCT), the gonadotrophin releasing hormone (GnRH) agonist stimulation test (GAST) and the FSH stimulation test (EFORT). In recent years, direct markers of ovarian potential such as the ovarian volume and the number of antral follicles (AFC) have been widely considered, with the view that a direct assessment of the ovarian reserve may predict assisted reproductive outcomes better than indirect tests such as baseline and ovarian challenge tests (Lorusso et al., 2007).

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Finally, inhibin B and anti-mullerian hormone (AMH) have been introduced as novel markers for ovarian reserve. Both markers provided to be indicative of ovarian response to gonadotrophin stimulation. In particular, inhibin B seems to be an effective marker of follicular development and a useful predictor of embryo quality (Chang et al., 2002). Whereas AMH seems to be a powerful mean for predicting both oocyte number and quality (Ebner et al., 2006).

Despite the number of reports on ovarian reserve, the results are still controversial and there is currently no consensus regarding the best marker of ovarian function (Lorusso et al., 2007).

Patients and methods

This prospective study included 300 patients who had undergone ART in Al-Azhar University Hospitals and International Islamic Center for Population Studies and Research (IICPSR).

Patients were selected according to following criteria: 1) Age 25 - 35 years old; 2) BMI >25 - 30 kg/m2; 3) Have two ovaries; 4) Regular cycles; 5) 1st cycle IVF; 6) No Poly Cystic Ovarian Disease (PCOD); 7) No pelvic masses or diseases (e.g: endometriosis, fibroids, hydro- salpnix, ...); 8) No history of medical disorders (e.g: hypertension, D.M, thyroid dysfunction, liver diseases, renal diseases,...); 9) Non smoker or alcohol consumer; 10) Exclude Residents of areas of pollution; 11) Exclude azoospermia as a cause of male factor infertility.

The study protocol was approved by the Ethics Committee of Obstetrics and Gynecology Department, Faculty of Medicine, Al-Azhar University.

Basal ovarian reserve screening:Measurement of basal FSH, E2 and AMH levels was done on cycle day 3 of the cycle prior to controlled ovarian hyperstimulation. Ultrasound scanning was performed on the same day to ascertain AFC and the ovarian volume.

Every patient was given a score according the following table (Ovarian Reserve Score):

Score

Variable

O

1

2

AMH (ng/ml)

<1

1-5

>5

FSH (mlU/ml)

>10

5-10

<5

E2 (pg/ml)

>50

20-50

<20

AF C (no)

<3

3-9

>9

MOV (Cm3)

< 6

6-10

>10

AMH = anti-mullerian hormone, FSH = follicle stimulating hormone, E2 = estradiol, AFC = antral follicle count, MOV= mean ovarian volume.

Induction of ovulation for assisted reproductive therapy using long GnRH protocol: In the day the 7 day after ovulation, daily s.c injection with triptoreline-acetate (Decapeptyl, 0.1 mg/day; Ferring, Hoofddorp, The Netherlands). Document of down regulation after 14 days by measurement of E2 <50 pg/ml. Ovarian stimulation was started using HMG 3 ampoules/day (Merional 75 I.U/150 I.U, IBSA).

Assessment of ovarian response by transvaginal ultrasound was done, according to which patients fall into three responder groups:

A- poor responders: >5 follicles.

B- Optimal responders: 5-20 follicles.

C- High responders: <20 follicles.

Triggering of ovulation was done by administration of 10000 1U HCG (Choriomon, IBSA) when at least half of follicles measuring 18 - 22 mm.

Oocyte retrieval 34-36 hours later on. The oocytes were placed in culture medium and intracytoplasmic sperm injection (ICSI).

Embryos transfer: It was done 3 days after oocytes retrieval.

followup of the patient after embryo transfer: Serum HCG was estimated 2 weeks after embryo transfer. Clinical pregnancy was defined by the demonstration of a gestational sac on ultrasound.

RESULTS

Clinical characteristics and outcomes of ovarian stimulation in the total group are tabulated in table (1)

Variable

Mean

SD

Age (ys.)

29.66

4.07

BMI

27.83

1.61

Duration of infertility (ys.)

6.74

3.84

FSH (mIU/ml)

6.86

2.31

E2 (pg/ml)

46.37

23.75

AMH (ng/ml)

3.39

1.09

AFC (n.)

8.76

4.43

MOV (cm3)

7.99

1.40

ORS (n.)

5.24

1.48

number of Follicle

15.09153

7.647535

number of retrieved oocytes

10.3806

5.322266

number of MII oocytes

6.640927

3.110127

number of embryo

5.817814

3.068859

number of embryo transferred

3.063559

0.835506 Values are given as mean±SD.

The study cases are classified according to their response (number of follicles) to controlled ovarian hyperstimulation into poor response (number <5), optimal responders (number 5 - 20) and high responders (number >20). There are 83women get pregnant with pregnancy rate among the whole study is 27.7%. Correlation between ORS and the study subgroups are tabulated in table (2):

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ORS

Poor Responders(23)

Optimal

Responders(258)

High

Responders (39)

No

%

No

%

No

%

0 (1)

1

100

0

0

0

0

1 (8)

8

100

0

0

0

0

2 (8)

8

100

0

0

0

0

3 (11)

6

55

5

45

0

0

4 (33)

0

0

33

100

5 (114)

0

0

110

96.5

4

3.5

6 (76)

0

0

64

84.21

12

15.79

7 (48)

0

0

35

72.91

13

27.08

8 (6)

0

0

1

17

5 One of them underwent coasting to avoid Ovarian Hyperstimulation Syndrome.

83

9 (5)

0

0

0

0

5 all of them underwent coasting to avoid Ovarian Hyperstimulation Syndrome.

100

This table shows that: Patients with ORS < 3; all are poor responders. Patients with ORS <3; have good response (Optimal responders or High responders). Patients with ORS 3 are border line as regard ovarian response. Patients with ORS 9; all are high responders and at high risk for Ovarian Hyperstimulation Syndrome.

Table (3): Description of baseline hormonal profile (FSH, E2 and AMH), AFC, MOV and ORS among the subgroups.

Poor responders

(23) 7.67%

Optimal responders

(258) 79.33%

High responders

(39) 13%

Mean

SD

Mean

SD

Mean

SD

Age

32

2.69680

30.2269

3.14337

29.33

3.255

FSH

10.5043

1.51852

6.6870

2.17117

5.8026

1.42099

E2

56.2174

22.86513

47.0588

23.93162

30.1026

19.87434

AMH

0.8905

0.24178

3.4361

0.76818

4.5685

0.80664

AFC

1.9130

0.79275

8.3025

3.10588

15.6923

3.65739

MOV

5.8370

0.75228

8.0298

1.20262

8.9913

1.52587

ORS

1.8261

0.88688

5.3109

0.92548

6.8717

1.17383

This table shows the mean and standard deviation of the basal hormonal profile on cycle day three, AFC, MOV and ORS for poor, optimal and poor responders.

There is an obvious statistical difference as regard all variables between the three groups.

Table (4): Performance of different basal ovarian reserve tests and ORS in the prediction of poor response.

Variable

Threshold

prediction of poor response

sensitivity

specificity

Age (year)

>30

0.87

0.45

>32

0.67

0.60

FSH (mIU/ml)

>8

0.96

0.77

>9

0.85

0.88

>10

0.61

0.93

E2 (pg/ml)

>30

0.87

0.20

>50

0.61

0.70

AMH (ng/ml)

<2

0.96

0.96

<2.5

1.00

0.91

<3

1.00

0.88

AFC (no)

<3

0.82

1.00

<4

1.00

0.98

<5

1.00

0.91

MOV (cm3)

<6

0.44

0.99

<7

0.91

0.85

<8

1.00

0.47

ORS (no)

<3

1.00

1.00

<4

1.00

0.98

This table show that:

The most sensitive predictor of poor ovarian response is the ORS (when ORS <3, the sensitivity is 1.00 and the specificity is 1.00).

AFC and AMH are better than other basal ovrian reserve tests as regard prediction of poor response. When AFC <4, the sensitivity is 1.00 and the specificity is 0.98. When AMH <2.5 ng/ml, the sensitivity is 1.00 and the specificity is 0.91.

Table (5): Performance of different basal ovarian reserve tests and ORS in the prediction of occurrence of pregnancy.

Variable

Threshold

prediction of poor response

sensitivity

specificity

Age (year)

<30

0.53

0.61

<32

0.65

0.45

FSH (mIU/ml)

<7

0.66

0.45

<8

0.80

0.30

<10

0.94

0.13

E2 (pg/ml)

<30

0.11

0.77

<50

0.68

0.31

AMH (ng/ml)

>2

0.96

0.14

>3

0.74

0.28

>3.5

0.58

0.44

AFC (no)

>3

1.00

0.09

>6

0.92

0.30

>9

0.57

0.56

MOV (cm3)

>6

0.99

0.06

>7

0.81

0.21

>8

0.35

0.53

ORS (no)

>3

1.00

0.08

>5

0.89

0.24

>6

0.47

0.60

This table show that the ORS and basal ovarian reserve tests are of limited value in prediction of occurrence of pregnancy.

Discussion

The results of this prospective study documented the importance of maternal age as one of the good predictors of ovarian reserve. As the maternal age goes beyond thirty years, there was decline in the ovarian reserve with subsequent poor response to gonadotrophin. The probability of occurrence of poor response was increased nearly 5 times (11.7% versus 2.3%) when the age exceeded 30 years. Maroulis et al., 2005 concluded that Fertility in women peaks between the age of 20 to 24 and then steadily decreases, by 4 - 8% for ages 25 - 29, 15 - 19% for ages 30 -34, 26 - 46% for ages 35 -39, and as much as 95% after the age of 40.

Also, there were positive significant correlations between age and basal FSH, basal E2. This was supported by another retrospective study carried on patient undergoing their first cycle of IVF (Chuang et al., 2003). On the other hand, there was negative significant correlation between age and AMH, AFC and MOV. This was supported by results of other investigators (de Vet et al., 2002, Fanchin et al., 2003, Ng et al., 2003).

As regard basal hormonal profile; the study evaluated the role of basal FSH, basal E2 and basal AMH in prediction of ovarian reserve and ovarian response to gonadotrophin ovarian stimulation. In present study, hormonal parameters of ovarian reserve were found to be correlated with either number of follicles and number of retrieved oocytes. And as regard the role of ultrasound in prediction of ovarian reserve and ovarian response to gonadotrophin ovarian stimulation, study evaluated the role of AFC and MOV which were correlated with both number of follicles and number of retrieved oocytes. AFC and AMH are better than other basal ovrian reserve tests as regard prediction of poor response. When AFC <4, the sensitivity is 1.00 and the specificity is 0.98. When AMH <2.5 ng/ml, the sensitivity is 1.00 and the specificity is 0.91. this is noticed by other investigators (Bancsi et al., 2002, Visser et al., 2006).

In the present study every patient was given a score according to the value of FSH, E2, AMH, AFC and MOV as prescribed in patient and method, we called it "Ovarian Reserve Score" [ORS]. The results showed a positive significant correlation with age which was obvious mainly in poor responders subgroup. Also, there were significant positive correlation between ORS and follicle number, number of retrieved oocytes, number of MII oocytes and number of embryo.

The results showed that all patients with ORS < 3 are poor responders. Patient with ORS 3 are borderline (55% are poor responders and 45% optimal responders). Patient with ORS with ORS <3 are good responders. Patient with ORS 9 all are high responders and at high risk for Ovarian Hyperstimulation Syndrome.

This suggests that we can use this ORS for prediction of poor response to controlled ovarian hyperstimulation (COH) and counseling the couples regarding their performance during ovarian stimulation. Also can be used to adjust the dose of human menopausal gonadotrophins to get the optimum response (i.e. increase the dose for the patients with low ORS and decrease the dose for the patient with high ORS).

Conclusion

This study suggests that ORS that used in this study is useful for prediction of poor response to controlled ovarian hyperstimulation (COH) and counseling the couples regarding their performance during ovarian stimulation. Also can be useful in adjustment of the dose of human menopausal gonadotrophins to get the optimum response. Patients with ORS < 3 are poor responders.

We recommend using AFC and AMH as routine markers of ovarian reserve and for prediction of poor responders for COH. Also use of such ORS for prediction of poor responders and for adjustment of the dose of human menopausal gonadotrophins.