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Research Article

Effect of obesity on ovarian reserve parameters in mid-reproductive age women

[version 1; peer review: 1 approved, 1 approved with reservations]
PUBLISHED 06 Nov 2012
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Abstract

Background: The initiation and maintenance of reproductive functions are related to an optimal body weight in women. Body weight affects the ovarian reserve, which is basically an estimate of how many oocytes (eggs) are left in the ovaries.
Objective: To study the relationship between obesity and serum and ultrasound markers of ovarian reserve in mid-reproductive age women (21–35 years old).
Patients and methods: Twenty participants (“obese”) had a body mass index (BMI) of 30 to 35 kg/m2 and another 20 participants (“non-obese”) had a BMI 20–29 kg/m2. The obese women had a mean age of 27.9 years and the non-obese women had a mean age of 29.5 years. Blood samples were collected from all participants, anthropometric measurements were calculated, and transvaginal ultrasonography was performed to measure the antral follicle count (AFC) during the early follicular phase. The blood samples were assayed for antimüllerian hormone (AMH), follicle-stimulating hormone (FSH) and estradiol (E2).
Results: There was no significant difference between the two groups regarding ovarian reserve markers and there is no significant correlation between these markers and BMI, except for serum E2 in the obese group.
Conclusion: Obesity has no effect on the levels of serum FSH, AMH, or AFC indicating that obesity is unlikely to affect ovarian reserve in the mid-reproductive age group.

Introduction

The initiation and maintenance of reproductive functions are related to an optimal body weight in women. Underweight (BMI under 19 kg/m2), as well as overweight (BMI over 25 kg/m2) and obesity (BMI over 30 kg/m2) are associated with an increased risk of certain disorders1. In addition to conditions such as diabetes mellitus, hypertension, cardiovascular disease, pancreatitis, and musculoskeletal diseases, obese women are more likely to experience reproductive problems2,3, which include menstrual disorders, infertility, and maternal complications during pregnancy4,5. Overweight women, as distinct from obese women, are known to be at higher risk of menstrual dysfunction and anovulation. The mechanisms by which obesity causes or exacerbates subfertility are manifold, one suggested theory that Hyperandrogenemia results in granulosa cell apoptosis, while peripheral conversion of androgens to estrogen in adipose tissue inhibits gonadotrophin secretion6, or possibly due to altered secretion of pulsatile GnRH7. Obesity is also associated with polycystic ovary syndrome (PCOS), which is a heterogeneous condition characterized by oligo or anovulation, hyperandrogenism, menstrual irregularities and subfertility8,9. Overweight and obese subfertile women have a reduced probability of successful fertility treatment and their pregnancies are associated with more complications and higher costs10. Weight loss regularizes menstrual cycles and increases the chance of spontaneous ovulation and conception in anovulatory overweight and obese women. In women undergoing assisted reproductive technology, being obese or overweight has been associated with a need for higher doses of gonadotropins, increased cycle cancellation rates, and fewer oocytes retrieved than in women of normal weight11. Lower rates of embryo transfer, pregnancy, and live birth have also been reported in these women, as well as higher miscarriage rates12.

The term “ovarian reserve” refers to the quantity and quality of a woman’s current reservoir of oocytes, and is closely associated with reproductive potential. It is an indirect measure of a woman’s reproductive age13. Over the past two decades, a number of tests of ovarian reserve have been used to determine follicle number and quality and to predict the outcome of assisted reproduction procedures14. The woman’s age and assays of serum FSH in the early follicular phase were among the earliest and most useful parameters used for evaluation of ovarian reserve15,16. Several ultrasound parameters have been used for evaluation of ovarian reserve, including ovarian volume17,18 and the antral follicle count (AFC), with varying degrees of reliability19. Recently, serum antimüllerian hormone (AMH) levels have been introduced as a novel measure of ovarian reserve. AMH is a product of the granulosa cells in preantral and antral follicles20. Serum AMH levels decline with age and are correlated with the number of antral follicles and the ovarian response to hyperstimulation21.

Few studies have evaluated the effect of obesity on ovarian reserve. The present study was conducted to examine the effect of obesity on ovarian reserve in women in the mid-reproductive age group. We assessed the effect of obesity on accepted markers of ovarian reserve, specifically levels of basal FSH, E2 and AMH, as well as the ultrasound marker of AFC.

Patients and methods

This study was conducted in the fertility center of Al-Sader Medical City, in Al Najaf province/Iraq, from December 2010 to March 2011. All participating women gave written informed consent before beginning the study. We performed a cross-sectional comparative study of two age-matched groups of 20 participants (group A, obese women) had a BMI of 30–35 kg/m2, with mean age 27.9 years, and the other 20 participants (group B, non-obese women) BMI of 20–29 kg/m2 with mean age of 29.5 years, these serve as a control group. Blood samples were collected from all participants, and transvaginal ultrasonography was performed to measure the AFC during the early follicular phase. The blood samples were assayed for AMH, follicle-stimulating hormone (FSH) and estradiol (E2). Thyroid function test and serum testosterone as well as dehydroepiandrosterone serum levels were assessed as well. The women were seeking treatment for infertility because of tubal factor proved by hysterosalpingiography or laparoscopy.

To meet the inclusion criteria, women had to be in the mid-reproductive age (20–35 years) according to Stages of Reproductive Aging Workshop (STRAW)22, with an intact uterus and ovaries and to have a regular menstrual cycles for the previous three months, normal thyroid function and no evidence of hyperandrogenism by examination or hormonal assessment. Exclusion criteria were: current use of hormones or drugs that may affect ovarian function, smoking, pregnancy, lactation, previous ovarian surgery, clinical or ultrasound criteria suggesting polycystic ovarian syndrome or endometriosis, or any medical condition that might affect ovarian function. All participating women underwent a comprehensive history and thorough physical examination, calculation of BMI, assays of serum FSH, E2 and AMH, and had a transvaginal ultrasound examination for assessment of AFC. For calculation of BMI, height and weight were measured using the same scale for all participants. BMI was determined by the ratio of weight in kg divided by the height squared in metric units. Blood samples were withdrawn from the antecubital vein on cycle day 2, 3 of the menstrual cycle in all women. All samples were centrifuged at 2000 g for 15 minutes. Serum was separated and stored at -20°C until assayed. Measurement of serum FSH was performed using Mini VIDAS method (bioMérieux® France). Inter-assay Coefficient of Variance% (CV%) 4.7; Intra-assay CV% 5.9, lower limit of detection ≤ 0.1 mIU/ml within 95% probability. For E2 the kit we used (bioMérieux® France) with Mini VIDAS technique Inter-assay CV% 4.6; Intra-assay CV% 3.2. Lower limit of detection 9 pg/ml within 95% probability. Serum levels of AMH were determined by enzyme-linked immunosorbent assays (ELISA) using (Beckman coulter inc., USA) kit. The assays were done according to the manufacturer’s instructions. The detection limits of this assay were 0.08 ng/ml within 95% probability, and its intra-assay and inter-assay coefficients of variation were 5.6% and 4.5% respectively.

Transvaginal ultrasound was performed during the early follicular phase (cycle day 2 or 3), by means of a transvaginal ultrasound scanner (Philips 11*E), with a 5 MHz probe. In each ovary, the total number of small follicles (2–8 mm) was counted. The total follicle count was the sum of the follicle counts in each ovary.

Statistical analysis: descriptive statistics were expressed as mean and standard deviation. Student’s t-test was used to compare groups. Significant relationships between study parameters were evaluated by Pearson’s correlation coefficient. P-values < 0.05 were considered to be significant. Statistical analysis was performed using SPSS version 17.

Results

The 20 women in group A (obese women) had a mean BMI of 32.45 kg/m2, with a range of 30 to 35 kg/m2, and the 20 non-obese women (group B) had a mean BMI of 24.9 kg/m2, with a range of 20 to 29 kg/m2. The mean age in the obese group was 27.9 years; with a range of 22 to 35 years. The mean age in the non-obese group was 29.5 years; with a range of 21 to 35 years. The mean BMI in the obese group (32.45 ± 1.57) was significantly higher than that of the non-obese group (24.9 ± 2.57) (P < 0.05). There was no significant difference between the two groups regarding age, serum levels of AMH or FSH, E2, or AFC. These data are shown in the (Table 1). There was no significant correlation between BMI and serum AMH, serum FSH and AFC in both groups; but significant positive correlation at P < 0.05 level was found between BMI and serum E2 in group A only, these results are shown in (Table 2).

Table 1. The studied parameters in the two groups.

ParameterGroup A
(obese women)
Group B
(non-obese women)
P-value
Age (years)27.9 ± 4.2929.50 ± 4.76NS
BMI (kg/m2)32.45 ± 1.5724.9 ± 2.57P<0.05
AMH (ng/ml)3.06 ± 1.492. 83 ± 3.51NS
FSH (mIU/ml)5.56 ± 2.125.63 ± 2.53NS
E2 (pg/ml)40.64 ± 16.1640.11 ± 19.53NS
AFC7.5 ± 1.617.3 ± 3.61NS

The values are expressed as mean ± SD.

Table 2. Correlation of BMI with FSH, E2, AMH and AFC in group A and B.

ParameterGroup AGroup B
FSH (mIU/ml)0.3590.387
E2 (pg/ml)0.469*0.260
AMH (ng/ml)-0.2440.075
AFC0.1980.098

* P less than 0.05.

Discussion

Obesity is an increasingly prevalent health hazard and causes many disorders of female reproduction23,24. In fact, overweight women have a higher incidence of menstrual dysfunction, anovulation, and infertility than other women of reproductive age25, even though altered pulsatile gonadotropin secretion is a well-defined mechanism in obese patients26.

This study was performed in obese and non-obese women20 with normal menstrual cycles who were referred to fertility center because of tubal factor infertility. Our aim was to examine the possible effects of body mass on some ovarian reserve markers, namely FSH, E2, AMH plasma levels and the number of ovarian follicles in the early follicular phase. The women included were normally ovulating obese and non-obese, with regular menstrual cycles and with neither clinical nor hormonal signs of hyperandrogenism in their mid-reproductive age.

Several studies have suggested a negative effect of obesity on parameters of ovarian reserve. De Pergola and his coworkers suggested that overweight and obese fertile women, in comparison with women of normal weight, have lower serum levels of FSH, LH, inhibin B, and estradiol in the early follicular phase, with a possible direct inhibitory effect of body mass on gonadotropin and estradiol production, independent of age27. The difference between their study and our findings may be attributed to selection of BMI of the control group which was normal (BMI < 25 kg/m2), compared to our control group which included BMI > 25 kg/m2. Other investigators reported lower levels of AMH in obese women compared with normal weight women in the late reproductive age28. However, these studies documented that obesity had no effect on ovarian follicle count. They suggested that lower levels of AMH in obese late-reproductive age women result from physiologic processes other than decreased ovarian reserve27. Our results showed that there are no significant differences in serum levels of FSH, E2, AMH, and AFC between obese and non-obese women. There was no significant correlation between BMI and the serum or ultrasound markers of ovarian reserve. Accordingly, we are suggesting that obesity may have limited effect on ovarian reserve in mid-reproductive age women.

The fact that our results showed no effect of obesity on AMH levels, contrary to other studies, may be related to factors in our study population and limitations in other reports. Our group of obese women was limited to women with a BMI between 30 and 35 kg/m2. We did not include morbidly obese patients because we thought that this specific group of women may have a different endocrine profile that may not apply to women with lesser obesity.

In a study of women with polycystic ovary syndrome by Pigny and his team, they found that AMH levels were lower in obese than non-obese women, but the difference was not statistically significant29. Another study suggested no correlation between BMI and AMH in women with polycystic ovary syndrome and control subjects30. These data may support our findings. We did not find an effect of obesity on AFC, which has been suggested by others27,28. This supports our impression of a limited effect of obesity on ovarian reserve.

Zaidi and his colleagues showed that ovarian volume decreases with an increase in the BMI, indicating the possible decrease in fertility with an increase in a woman’s weight; their study group included normal weight and overweight, and includes a higher-age study group than ours31. This decrease may be due to age effect rather than BMI. They didn’t find any correlation between BMI and AFC, which is in consistent with our study results. In a study conducted in Tehran32 where 115 fertile women were included of a different age group (25–45-years old), they found that BMI had moderate positive correlation with FSH and a moderate negative correlation with estradiol and AFC, but after adjustment of age, BMI as an independent factor had no effect on ovarian reserve markers, a finding which supports our results.

The significant positive correlation of BMI with estrogen in obese women may be attributed to the contribution for estrogen from the conversion of androgens to estrogens by aromatase in adipose tissue, or may be due to subtle undetected lack of insulin that increases the blood cholesterol concentration. These effects are probably caused mainly by changes in the degree of activation of specific enzymes responsible for the metabolism of lipid substances including cholesterol, which is the precursor of estrogen33. The difference between our finding and that found by other researchers may be attributed to ethnic difference or life style factors34,35. The negative correlation between BMI and AMH have been confirmed by Pingy et al. but it doesn’t prove to be significant29.

Conclusion

Obesity doesn’t have an effect on the selected parameters of ovarian reserve among our cohort of mid-reproductive age women. However, this should be verified by larger studies with clear distinctions between normal, overweight, obese, and morbidly obese women, and between groups of different age groups.

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Altaee H, Al-Madfai ZAM and Alkhafaji ZH. Effect of obesity on ovarian reserve parameters in mid-reproductive age women [version 1; peer review: 1 approved, 1 approved with reservations]. F1000Research 2012, 1:43 (https://doi.org/10.12688/f1000research.1-43.v1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
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Reviewer Report 29 Jan 2013
Angelique Goverde, Department of Reproductive Medicine and Gynaecology, University Medical Centre Utrecht, Utrecht, The Netherlands 
Approved with Reservations
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This is a cross-sectional comparative study of two age-matched groups, each of 20 participants, the first being obese (BMI 30-35 kg/m2), the second (control) group with  BMI 20-29 kg/m2, in which the effect of obesity on markers of ovarian reserve ... Continue reading
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Goverde A. Reviewer Report For: Effect of obesity on ovarian reserve parameters in mid-reproductive age women [version 1; peer review: 1 approved, 1 approved with reservations]. F1000Research 2012, 1:43 (https://doi.org/10.5256/f1000research.219.r741)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Reviewer Report 07 Nov 2012
Richard A. Anderson, MRC Human Reproductive Sciences Unit, The Queen's Medical Research Institute, Edinburgh, UK 
Approved
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I confirm that I have read this submission and believe that I have an ... Continue reading
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Anderson RA. Reviewer Report For: Effect of obesity on ovarian reserve parameters in mid-reproductive age women [version 1; peer review: 1 approved, 1 approved with reservations]. F1000Research 2012, 1:43 (https://doi.org/10.5256/f1000research.219.r355)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.

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Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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