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The Effect of Aging on Ovarian Volume Measurements in Infertile Women

From the Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland.

Address reprint requests to: Fady I. Sharara, MD, 405 West Redwood Street, Baltimore, MD 21201, E-mail: fsharara{at}ummc001.ummc.ab.umd.edu

	Abstract

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Objective: To test the hypothesis that aging is associated with a decrease in ovarian volume, and that the FSH level and volume are correlated inversely.

Methods: One hundred nine women who had 73 in vitro fertilization cycles and 36 ovulation induction cycles were analyzed. Basal FSH and estradiol (E2) levels were measured on cycle day 3, and ovarian volume was measured and antral follicles were counted on the day of starting gonadotropin.

Results: The mean age (± standard deviation) was 32.6 ± 4.7 years. The mean FSH was 6.9 ± 2.4 IU/L. The mean ovarian volume was 6.0 ± 4.7 cm³. There were no significant differences between the median volumes of the left and right ovaries in individual subjects (4.6 and 4.8 cm³, respectively; interquartile range 3.0–7.3 and 3.1–7.9; P = .79). There was a significant positive correlation between age and FSH level (R = .372, P < .001), but not between age and ovarian volume (R = .039, P = .69). A significant relation was noted between FSH and the number of follicles (H = 20.8, P < .001), but not between FSH and volume (R = .102, P = .29). There was a significant decrease in the number of follicles and a higher cycle cancellation rate in women with volume smaller than 3 cm³ compared with those with volume greater than 3 cm³.

Conclusion: Women with small ovarian volumes, low number of antral follicles, and normal basal FSH and E2 levels may have diminished ovarian reserve.

Ovarian volume measurements were first used as a screening tool for ovarian cancer.^1–4 Using abdominal ultrasound in 1015 postmenopausal women, Goswamy et al¹ found a sharp decrease in ovarian volume with aging. Andolf et al² evaluated 377 women aged 40–70 years, about one-third of whom were postmenopausal, and found a nearly linear decrease in mean ovarian volume (± standard deviation [SD]) from 4.8 ± 2.8 cm³ in those 50–55 years old to 1.9 ± 2.0 cm³ in the oldest age group. Expanding on their earlier work, Goswamy et al⁴ evaluated 2221 postmenopausal women from the general population and confirmed again a nearly linear decrease in mean ovarian volume with increasing time since the onset of menopause. Using vaginal ultrasound, Higgins et al³ found a sharp decrease in mean ovarian volumes from 6.2 ± 3.9 cm³ in premenopausal women (aged 40–54 years) to 2.9 ± 2.2 cm³ in post-menopausal women (aged 41–86 years). Few investigations in infertile reproductive-age women have been done, and none have been done in fertile women.

In infertile women, age, basal FSH, and basal estradiol (E2) are used routinely as outcome predictors for in vitro fertilization (IVF) cycles, mainly by predicting ovarian responsiveness to stimulation with gonadotropins.⁵ However, these tests are far from perfect in predicting ovarian response, cancellation rates, and ultimately who will or will not conceive.^6,7 Recently, the measurement of ovarian volume before ovarian stimulation has predicted follicular response in IVF; specifically, higher cancellation rates, higher gonadotropin requirements, lower peak E2, lower number of retrieved oocytes, and lower pregnancy rates in women with ovarian volumes up to 3 cm³.^8–10 Larger ovarian volumes at baseline also predicted the occurrence of ovarian hyperstimulation syndrome¹¹ and correlated with the number of small antral follicles before stimulation,^9,12 which implies that small ovarian volumes (with low numbers of small antral follicles) may represent an earlier test of diminished ovarian reserve than basal FSH and E2.^8,10,12 Ovarian volume measurements also are reproducible among examiners, with very low interobserver and intraobserver variations in measurements (4–7%).^8,13

Little information is available on the effect of aging on ovarian volume in reproductive-age women.^8–10 Some authors have found inverse correlations, whereas others could not detect any association. This prospective study investigated whether aging in infertile women is associated with a decrease in ovarian volumes and whether FSH and ovarian volume are correlated inversely. We also evaluated the distribution of small antral follicles and its effect on ovarian volume and FSH.

	Materials and Methods

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Between April 1997 and April 1998, we prospectively evaluated 109 women who underwent 73 IVF and 36 ovulation induction and intrauterine insemination cycles. One treatment cycle per subject was analyzed. Sixty-two percent of the subjects were white, 30% were black, 6% were Hispanic, and 2% were Asian. Ninety percent were married. Each woman had both of her ovaries, and women with previous ovarian surgery, endometriomas, or follicles measuring at least 8 mm on baseline ultrasound were excluded from the study. All women had their ovarian volumes measured on the day of gonadotropin initiation.

Among the women having IVF, 24 (32.8%) had tubal disease, 19 (26.0%) had male-factor infertility, 12 (16.4%) had diminished ovarian reserve (defined as having an FSH level greater than 8.5 IU/L), 12 (13.7%) had endometriosis, four (5.5%) had ovulatory dysfunction, and four (5.5%) were oocyte donors. Some women had more than one infertility factor. For the ovulation induction group, nine (25.0%) had ovulatory dysfunction, nine (25.0%) had diminished ovarian reserve, seven (19.4%) had unexplained infertility, seven (19.4%) had male factor, and four (11.1%) had endometriosis. Overall, 57% of our subjects were nulligravid and 43% were multigravid.

All ultrasound measurements used a 6.5-MHz vaginal probe (Performa, Acoustic Imaging; Dornier Medical Systems, Phoenix, AZ). Ovarian volumes were calculated according to the formula for an ellipsoid (0.526 x length x height x width).^3,8–10 Mean ovarian volume was the mean volume calculated for both ovaries in the same individual. Women with ovarian follicles of at least 8 mm were excluded from the study because their volumes would not be measured accurately. The number of small antral follicles (2–7 mm) was also recorded and grouped as less than five, five to 15, and more than 15.⁹

For serum FSH, we used a microparticle enzyme immunoassay calibrated against the World Health Organization (WHO) Second International Reference Preparation for human FSH (78/549) (Abbott Axsym system; Abbott Pharmaceuticals, Abbott Park, IL). The interassay and intra-assay coefficients of variation were 3.48% and 4.52%, respectively. The upper limit of normal for FSH in our laboratory is 10 IU/L (conversion factor to SI units, 1.0), which is equivalent to 18 IU/L by radioimmunoassay (RIA) (Leeco assay; Leeco Diagnostics, Southfield, MI). For E2, an RIA was used (Coat-a-count; Diagnostic Products Corporation, Los Angeles, CA). The interassay and intra-assay coefficients of variation were 7.8% and 5.8%, respectively.

Data are expressed as mean ± SD. Linear regression, Student t test, Mann-Whitney rank-sum test, ², and Fisher exact test were used as appropriate. Kruskal-Wallis one-way analysis of variance on ranks with pairwise multiple comparison using the Dunn method was used to evaluate FSH levels and the number of small antral follicles. P < .05 was considered significant.

	Results

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The mean age was 32.6 ± 4.7 years (range 23–43). Mean basal FSH was 6.9 ± 2.4 IU/L (range 1.2–19.9). Basal E2 was less than 50 pg/mL in all subjects. The mean ovarian volume was 6.0 ± 4.7 cm³ (range 0.9–32.1). There were no significant differences between the median volumes of the left and right ovaries in individual subjects (4.6 and 4.8 cm³, interquartile range 3.0–7.3 and 3.1–7.9, respectively; P = .79). There was a linear correlation between age and FSH (R = .372, P < .001), but no significant correlation between ovarian volume and age (R = .039, P = .69). There was also no significant correlation between FSH and ovarian volume (R = .102, P = .29). These results were unchanged when the ovulation induction group was excluded from the analysis, and also after excluding the two outliers with ovarian volumes greater than 25 cm³. Small ovarian volumes were noted in some women with normal basal FSH and E2 levels. Two women in the IVF group (2.7%) developed moderate ovarian hyperstimulation syndrome with mean ovarian volumes of 8 and 13.8 cm³, respectively, and both had more than 15 follicles in each ovary.

Twenty-six of 109 women (23.8%) had mean ovarian volumes of at most 3 cm³ (23 in the IVF group and three in the ovulation induction group) with a mean age of 32.4 ± 3.7 years, mean FSH of 6.7 ± 2.0 IU/L, and mean ovarian volume of 2.3 ± 0.6 cm³. Fifteen of 26 (57.7%) had fewer than five preantral follicles in both ovaries, 11 (42.3%) had fewer than five follicles in one ovary and five to 15 in the other ovary, and none had more than 15 follicles in either ovary. In contrast, among the 83 women with a mean ovarian volume exceeding 3 cm³, only 14 (16.9%) had fewer than five small antral follicles in both ovaries (P < .001), 12 (14.5%) had fewer than five follicles in one ovary and five to 15 in the other ovary (P = .006), and 57 (68.6%) had five to 15 or more than 15 follicles in each ovary (P < .001).

Thirty-one subjects had fewer than five follicles in each ovary (group 1), 13 had more than 15 follicles in each ovary (group 2), and 65 had five to 15 follicles or more than 15 follicles per ovary (group 3). There was a significant difference in median FSH levels between groups 1 and 2 (8.3 and 5.3 IU/L, interquartile range 6.5–9.5 and 4.1–6.3, respectively; P < .001) and between groups 1 and 3 (8.3 and 6.6 IU/L, interquartile range 6.5–9.5 and 5.7–7.5, respectively; P < .001), but not between groups 2 and 3.

For the IVF subjects, five were canceled (4.6%) because of poor follicular development. The mean ovarian volume in women with canceled cycles was 2.9 cm³ (four had fewer than five follicles in each ovary at baseline scan, and one had seven follicles in each ovary). When grouped according to ovarian volumes, four women in the group with ovarian volumes less than 3 cm³ were canceled (four of 26, 15.4%), compared with one cancellation when mean ovarian volumes exceeded 3 cm³ (one of 83, 1.2%; P < .001). The latter woman had a mean ovarian volume of 3.1 cm³ with fewer than five follicles in both ovaries.

	Discussion

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Women who received hormone replacement therapy (HRT) did not have decreased ovarian volumes, and in those not receiving HRT, the most important factor for ovarian size was age.² Parity, age at menopause, or day of the menstrual cycle when the examination was done did not affect ovarian volumes.² In contrast to the results of Andolf et al,² Goswamy et al⁴ evaluated 2221 postmenopausal women over the age of 45 years and showed that significant predictors of ovarian volume were years since menopause, weight, parity, age at menopause, a history of HRT, and previously diagnosed breast cancer. These investigators found that one delivery enlarged the ovaries by 6% and two deliveries increased ovarian volume by approximately 12%. There was no effect of further deliveries.⁴ The cause of the discrepancy between the results of Goswamy et al⁴ and those of Andolf et al² is not clear. But the women evaluated by Andolf et al² were from a referral population, rather than the general population evaluated by Goswamy et al. In those studies, cystic spaces less than 20 mm in size were considered normal and therefore were included in the calculation of ovarian volumes,² or no exclusion criteria were given,^1,3 leading to erroneously large ovarian volumes. Our study excluded women with follicles or cysts larger than 8 mm, making it more stringent with ovarian volume calculations.

Using vaginal ultrasound in 446 asymptomatic women aged 40 years and older with normal scans, Higgins et al³ confirmed the sharp decrease in mean ovarian volumes, from 6.2 ± 3.9 cm³ in perimenopausal women (aged 40–54 years) to 2.9 ± 2.2 cm³ in post-menopausal women (aged 41–86 years). The number of small antral follicles was not addressed in these studies, and no reports correlated ovarian volumes with basal FSH or E2 levels. Reuss et al¹⁴ performed vaginal ultrasound on days 4–6 of the cycle in 31 healthy volunteers aged 22–42 years and found a 60% decrease in small antral follicles between ages 22 and 42 years. We did not find a similar correlation in our infertile women, possibly because the volunteers evaluated by Reuss et al¹⁴ were not infertile, none were smokers, and all had regular menstrual cycles. We did find a marked decrease in the number of small antral follicles in women with ovarian volumes of no more than 3 cm³ at any age group (23–35 or 36–43 years). Unfortunately, Reuss et al¹⁴ did not measure ovarian volumes, so they could not confirm whether the decrease in follicle count was mirrored by a decrease in ovarian volumes.

Syrop et al⁸ evaluated the ovarian volumes of 188 infertile women undergoing IVF. Total ovarian volume (the sum of both ovarian volumes) did not change significantly across age groups (23–45 years). They also found that cigarette smoking was associated with smaller ovarian volumes, with a 22% reduction in total volume that could not be accounted for by differences in age or body mass index (BMI).⁸ More recently, Tomas et al⁹ could not find an association between age and mean ovarian volume in 166 infertile women undergoing IVF. Unlike these results and ours, Lass et al¹⁰ found a significant negative correlation between age and ovarian volume in 140 infertile women aged 24–46 years having IVF. The reason for this discrepancy is unclear, but could stem from the relatively small sample in the study by Lass et al.¹⁰ In our study, elevated FSH did not correlate significantly with low ovarian volume, but there were small ovarian volumes in women with normal basal FSH and in all age groups, confirming recent results.^8–10 Levels of FSH reflected the number of preantral follicles, also confirming previous results.¹² We did not analyze the effect of smoking on ovarian volume because only ten women were active smokers, but 40% had ovarian volumes of no more than 3 cm³. Smokers have an accelerated onset of diminished ovarian reserve and undergo menopause 1–4 years earlier than age-matched nonsmokers.¹⁵

Cancellation rates of IVF cycles in women with small ovarian volumes have been reported.^8,10 Syrop et al⁸ reported a cancellation rate of 22% in women whose smallest ovarian volume was less than 3 cm³, compared with 14% and 0% in women whose volumes were 3–9 or greater than 9 cm³, respectively. Lass et al¹⁰ reported a cancellation rate of 52.9% in women with a mean volume of less than 3 cm³, compared with 8.9% in those with a volume exceeding 3 cm³. Our results confirm higher cancellation rates in these women.

Small ovarian volumes may be an earlier sign of diminished ovarian reserve than elevated basal FSH or E2, but whether these women enter the perimenopause earlier is unclear. We believe this group of women may be at risk for early perimenopausal transition, with resultant hypoestrogenism. In our study and the referenced reports, only infertile women were evaluated, many of whom had diminished ovarian reserve; therefore, extrapolation of our data to the population at large may be misleading. Mehta et al¹⁶ found recently that the mean ovarian volume of 17 women with premature ovarian failure was equal to that of 20 menopausal women and significantly less than the mean volume of 19 volunteers taking an oral contraceptive. Although these numbers are limiting, small ovarian volumes may predict impending ovarian failure. Farhi et al¹⁷ recently reported on 12 infertile women aged 34–43 years with normal basal hormonal characteristics who did not respond to gonadotropin stimulation in two consecutive ovulation induction cycles. All 12 developed premature ovarian failure 3–19 months from their initial evaluations.¹⁷ Larger population studies are needed to determine the relations between reproductive aging and ovarian volume, whether women with small ovarian volumes have occult evidence of estrogen deficiency, and whether they enter the climacteric sooner than age-matched and FSH-matched women with larger ovarian volumes. The effects of smoking, BMI, years since menopause, age at menopause, and parity as independent variables should be addressed in such prospective studies.

	Footnotes

 
PII S0029-7844(99)00242-2

Received September 21, 1998. Received in revised form December 10, 1998. Accepted January 7, 1999.

	References

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2. Andolf E, Jorgensen C, Svalenius E, Sunden B. Ultrasound measurement of the ovarian volume. Acta Obstet Gynecol Scand 1987;66:387–9.[Medline]

3. Higgins RV, van Nagell JR Jr, Donaldson ES, Gallion HH, Pavlik EJ, Endicott B, et al. Transvaginal sonography as a screening method for ovarian cancer. Gynecol Oncol 1989;34:402–6.[Medline]

4. Goswamy RK, Campbell S, Royston JP, Bhan V, Battersby RH, Hall VJ, et al. Ovarian size in postmenopausal women. Br J Obstet Gynaecol 1988;95:795–801.[Medline]

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7. Scott RT Jr, Hofmann GE, Oehninger S, Muasher SJ. Intercycle variability of day 3 follicle-stimulating hormone levels and its effect on stimulation quality in in vitro fertilization. Fertil Steril 1990;54:297–302.[Medline]

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9. Tomas C, Nuojua-Huttunen S, Martikainen H. Pretreatment transvaginal ultrasound examination predicts ovarian responsiveness to gonadotrophins in in-vitro fertilization. Hum Reprod 1997;12: 220–3.[Abstract/Free Full Text]

10. Lass A, Skull J, McVeigh E, Margara R, Winston RM. Measurement of ovarian volume by transvaginal sonography before ovulation induction with human menopausal gonadotrophin for in-vitro fertilization can predict poor response. Hum Reprod 1997;12: 294–7.[Abstract/Free Full Text]

11. Danninger B, Brunner M, Obruca A, Feichtinger W. Prediction of ovarian hyperstimulation syndrome of baseline ovarian volume prior to stimulation. Hum Reprod 1996;11:1597–9.[Abstract/Free Full Text]

12. Chang MY, Chiang CH, Hsieh TT, Soong YK, Hsu KH. Use of the antral follicle count to predict the outcome of assisted reproductive technologies. Fertil Steril 1998;69:505–10.[Medline]

13. Higgins RV, van Nagell JR Jr, Woods CH, Thompson EA, Kryscio RJ. Interobserver variation in ovarian measurements using transvaginal sonography. Gynecol Oncol 1990;39:69–71.[Medline]

14. Reuss ML, Kline J, Santos R, Levin B, Timor-Tritsch I. Age and the ovarian follicle pool assessed with transvaginal ultrasonography. Am J Obstet Gynecol 1996;174:624–7.[Medline]

15. Sharara FI, Beatse SN, Leonardi MR, Navot D, Scott RT. Cigarette smoking accelerates the development of diminished ovarian reserve as evidenced by the clomiphene citrate challenge test. Fertil Steril 1994;62:257–62.[Medline]

16. Mehta AE, Matwijiw I, Lyons EA, Faiman C. Noninvasive diagnosis of resistant ovary syndrome by ultrasonography. Fertil Steril 1992;57:61–5.

17. Farhi J, Homburg R, Ferber A, Orvieto R, Ben Rafael Z. Non-response to ovarian stimulation in normogonadotrophic, nor-mogonadal women: A clinical sign of impending onset of ovarian failure pre-empting the rise in basal follicle stimulating hormone levels. Hum Reprod 1997;12:241–3.[Abstract/Free Full Text]

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