Pakistan Journal of Medical Sciences

Published by : PROFESSIONAL MEDICAL PUBLICATIONS

ISSN 1681-715X

HOME   |   SEARCH   |   CURRENT ISSUE   |   PAST ISSUES

-

REVIEW ARTICLE

-

Volume 23

April - June 2007 (Part-II)

Number 3


 

Abstract
PDF of this Article

Ovarian reserve and reproductive age

Shahida Zaidi1, Ambreen Usmani2, Ishrat S. Shokh3
 

SUMMARY
Ovarian reserve is an estimate of the primordial follicle pool in the ovaries and is indicative of the reproductive age of a woman. This estimate helps in assessing a woman’s reproductive potential, in predicting her possible response in assisted conception, and in screening women for “early ovarian ageing” as a possible cause for subfertility.
Over the years, several methods have been used for its determination. These include biochemical parameters such as estradiol, FSH/LH levels and ratio, inhibin-B and anti-mullerian hormone levels, sonographic measurement of ovarian volume, antral follicle count and follicular volume, dynamic tests of ovarian function, and ovarian biopsy.
In this paper these methods are briefly described, and their advantages and disadvantantages are discussed with a view to finding accurate, available and easily reproducible methods for assessing ovarian reserve.
This article is a review of several articles obtained from the Internet, www.pubmed.com, Pakistan scientific and technological information centre (PASTIC) and several authors via e-mail.

KEY WORDS: Ovarian reserve, Reproductive age.

Pak J Med Sci   May - June 2007   Vol. 23 No. 3    449-453


1. Shahida Zaidi, FCPS
Professor of Obstetrics & Gynaecology,
2. Ambreen Usmani,
Post-graduate student, Department of Anatomy,
3. Ishrat S. Shokh,
Professor of Anatomy,
1-3: Ziauddin Medical University,
Clifton, Karachi – Pakistan.

Correspondence

Dr. Ambreen Usmani,
44/B, Shahar-e-Ghalib, Block-6, Clifton,
Karachi - Pakistan.
E-mail: ambreenusmani1@yahoo.com
            ambreen_home@hotmail.com

* Received for Publication: August 3, 2006
* Revision Accepted: May 28, 2006


INTRODUCTION

Ovarian reserve is an estimate of the primordial follicle pool in the ovaries. It is an indication of reproductive age, as opposed to chronological age, and is a parameter for calculating reproductive potential and the remaining reproductive life span of a woman.1,2
The human ovary contains a fixed pool of primordial follicles, maximal at five months of intrauterine life, and numbering around 701,000 at the time of birth.3 From this number, the pool reduces to 250,000-300,000 at the time of menarche,4 and then declines with increasing age.5 At 37-38 years, it contains about 25,000 follicles; and at this number, the follicular depletion accelerates, and menopause is estimated be about 12-14 years away (occurring at a mean age of 50-51 years)3, when only a few hundred or thousand follicles remain. This age may vary in different populations, and according to a study conducted in Lahore, it was found to be 49±43.6 years in Pakistani women.6 This model of decline has, however, been modified to one which assumes a single exponential decline, which is more biologically plausible.5,7
Follicular depletion occurs largely due to atresia,8 and is accompanied by a reduction in ovarian volume, which is thus also related to age. In an ‘Ovarian Cancer Screening’ programme9 conducted at the University of Kentucky, involving 13,963 women who underwent transvaginal sonography annually, a statistically significant decrease in ovarian volume was shown with each decade of life from 30 to 70 years.
Follicular depletion and reduction in ovarian volume leading to decrease in fertility apply both to spontaneous as well as assisted conceptions.4,10 The decreased fertility with increasing female age appears to involve several factors besides attrition and utilization of follicles, such as diminution in quality of existing oocytes (partly due to increased aneuploidy because of factors such as changes in spindle integrity), and a reduction in the frequency of intercourse.7
A mathematical model of decline constructed by Faddy and Gosden5 provides an estimate of the follicle pool at any age; it can be used to assess a woman’s chances of spontaneous conception and possible outcome in assisted conception; it also offers the possibility of screening women for ‘early ovarian ageing’ which currently affects 10% of the general population,3 and may be an important cause of infertility in these individuals. It would also assist in predicting the possibility of a pregnancy in women who have survived childhood leukaemias,11,12 and in counseling those considering delaying childbearing for any reason.3

METHODS IN USE FOR THE
ASSESSMENT OF OVARIAN RESERVE

Various methods have been proposed and are currently used for the assessment of ovarian reserve.10 These include biochemical markers such as basal follicle stimulating hormone (FSH), luteinizing hormone (LH),13 ratio of FSH/LH,14 oestradiol (E2),15 inhibin–B16 and anti-Mullerian hormone (AMH);17,18 ultrasound measurements such as ovarian volume, antral follicle count19,20 and ovarian stroma blood flow;21 dynamic tests of ovarian function such as clomiphene citrate challenge test (CCCT),22,23 exogenous FSH ovarian reserve test (EFORT)24,25 and GnRH agonist stimulation (GAST).26 Finally, an ovarian biopsy to determine follicular density directly assesses ovarian reserve.27
Some of the commonly used methods are described below.
a) Biochemical Parameters: With ovarian ageing, levels of oestradiol (E2) and inhibin B decline, while those of FSH rise.28 These markers constituting the classical hypothalamus–pituitary-gonadal feedback loop are interdependent.29 The levels of serum AMH, a recently added marker,17,18,30-34 also decline with age, with the decrease occurring earlier than changes in FSH or inhibin-B levels.
b) Ultrasound: During the past three decades, ultrasound (especially transvaginal scanning) has proved a valuable imaging technique, allowing visualization of the pelvic structures, including an assessment of their size and an evaluation of morphology.35
The sonographic variables used for assessing ovarian function include ovarian volume,36-38 antral follicle count (AFC)19,20,39, follicular volume,2 and size of uterus and thickness of endometrium.40 Ovarian volume, and the antral follicle count in the early follicular phase give an indication of ovarian reserve, whereas the size of the uterus and thickness of endometrium provide an indirect estimate of circulating ovarian hormones.
Total ovarian volume (calculated for each ovary by applying the formula for an ellipsoid) is a sum of the volumes of the two ovaries, AFC is a sum of follicles measuring 2-10mm in diameter in both ovaries; the total follicular volume is a sum of the volumes of all the follicles up to 10mm in diameter in both ovaries.2 The total ovarian volume and AFC have been negatively correlated with age and decrease linearly with advancing age;4,35,39 the total follicular volume also decreases with age (due to follicular atresia), though the mean follicular volume increases in later years.2
c) Histological Assessment: An ovarian biopsy provides a direct assessment of follicular density.27,41,42 However the distribution of follicles in ovarian tissue has been found to be extremely uneven, differing from patient to patient and from sample to sample from the same ovary.42 Thus, while the presence of follicles is reassuring, their low density does not necessarily indicate a low reserve. In addition, the procedure carries the risk of later adhesion formation.

DISCUSSION

The determination of ovarian reserve is a relatively new concept and has important applications in assessing reproduction potential, including prediction of success in assisted conception. Numerous tests and markers have been proposed for its assessment, their very number indicating that no satisfactory method for its assessment is available yet. In fact, a comprehensive systematic review of literature by Kwee et al43 concluded that the ovarian reserve tests known to date have “only modest-to-poor predictive properties.”
Of the biochemical variables, serum FSH, LH and E2 levels are in common use for investigating subfertility and monitoring ovarian stimulation cycles. Raised FSH levels indicate a low ovarian reserve, but are a late finding, after considerable follicular depletion has occurred. Elevated day 3 FSH/LH ratios (>3) due to low LH concentration predict a reduced ovarian response.14 Serum AMH is valuable; expressed in granulosa cells of growing follicles, its expression is strongest in small antral follicles, and is lost in large antral follicles.31 Its level reflects the follicle population and is not influenced by the gonadotropic status.17,24,44 It correlates strongly with the AFC,17,33 and in contrast with other serum markers, remains relatively constant during the menstrual cycle.33-35 Its level declines earlier than that of FSH and inhibin B;26 it may, therefore, be more useful than other parameters in detecting ovarian ageing early.
A difficulty with all these biochemical variables is that they test the number of developing follicles which may not reflect the number of primordial follicles.7
Of the ultrasound variables, the two important ones are ovarian volume and AFC; both have been found to correlate negatively with advancing age.2,9,39 They have also been found to be reduced in subfertile women in comparison with fertile women of the same age. They may also be decreased in young females of reproductive age due to early ovarian ageing, this being a possible cause for their subfertility3,35
In the “Ovarian cancer screening” programme conducted at the University of Kentucky,9 the mean ovarian volume was 6.6 ml in women <30 years of age, 6.1ml in women 30-39 years, 4.8 ml in those aged 40-49 years, 2.6ml in the group 50-59 years old and 2.1ml in women aged 60-69 years. Overall, the mean ovarian volume was 4.9ml in premenopausal women and 2.2ml in postmenopausal women.
Scheffer et al2 compared the mean values and ranges of several endocrine and sonographic parameters for 3 age groups: young (25 – 34 years), middle (35- 40 years) and old (41 – 46 years). They found that values of all endocrine variables (with the exception of inhibin B) in the old age group differed significantly from those in the young group. Ovarian volume also decreased with age (being 7.4, 7.0 and 5.2ml respectively in the three age groups), that in the oldest women differing significantly from those in the two younger groups. Importantly, the number of antral follicles showed a significant difference in all three groups (being 15, 9 and 4 respectively). In addition, total follicular volume decreased with increasing age (0.71, 0.58 and 0.39 ml), though this was less steep than the fall in AFC.2 Ruess et al45 too, reported a significant reduction in AFC with age in a group of women 22 – 42 years of age. These differences were independent of the stage of the menstrual cycle. The AFC, therefore, may be a sensitive parameter for assessing ovarian reserve, and its use as a single test for predicting response to controlled ovarian stimulation seems rational.37,42
Another notable finding in Scheffer’s study2 was an increase in mean follicular volume with increasing age, being almost double in the old group as compared with the younger groups (0.05, 0.06 and 0.09 ml). Values of E2 also correlated positively with age, being 195 and 206 pmol/l in the younger women, and 278 pmol/l in the older women. Thus, while the number of antral follicles and total follicular volume decreased in the older women, the mean follicular volume increased and E2 production also increased. This phenomenon suggests accelerated growth of antral follicles,44 or more advanced follicular growth2 in older women.
The size of the uterus and the thickness of the endometrium, measured sonographically, give an indirect estimate of oestradiol secretion, and can be used as a bio-assay of follicular oestradiol production.46 Ovarian biopsy47 as a test of ovarian reserve is no longer recommended as the distribution of follicles in ovarian tissue was found to be extremely uneven,42 and quantitative counting of primary follicles did not provide information about the quality of the oocytes embedded in them,42,48 which is an important factor in predicting reproductive potential. The value of this procedure has therefore been questioned49 and it is now no longer carried out for these reasons, and because of its invasive nature and the risk of later adhesion formation.

CONCLUSION

Several methods are available for assessing ovarian reserve. Of the biochemical tests, inhibin–B and AMH levels are valuable, but are expensive and performed by only a few laboratories in Pakistan. The gonadotropins FSH and LH, and the ovarian hormone oestrogen indirectly determine the adequacy of hypothalamic-pituitary-gondal axis (and hence ovarian reserve) and may be used in conjunction with other techniques, such as ultrasound. Sonographic measurement of ovarian volume and antral follicle count is an accurate direct method, which is easily performed, reproducible, readily available, besides being non-invasive.

REFERENCES

1. Scheffer GJ, Broekmans FJ. Antral follicles counts by transvaginal ultrasound are related to age in women with proven natural fertility. Fertil Steril 1999;72:845-51.
2. Scheffer GJ, Broekmans FJ, Looman CWN. The number of antral follicles in normal women with proven fertility is the best reflection of reproductive age. Human Reproduction. 2003;18:700-6.
3. Wallace WH, Kelsey TW. Ovarian reserve and reproduction age may be determined from measurement of ovarian volume by transvaginal sonography. Human Reproduction 2004;l9:1612-7.
4. Ng EH, Chan CC, Yeung WS. Effect of Age on Ovarian Stromal flow measured by Three Dimensional Ultrasound with Power Doppler in Chinese women with Proven Fertility. Human Reproduction 2004;19:2132-7.
5. Faddy MJ, Gosden RG.A mathematical model of follicle dynamics in the human ovary. Human Reproduction 1995;10:770-5.
6. Yahya S, Rehan N. Perception of menopause among rural women of Lahore. J Coll Phys Surg Pak 2003;13:252-4.
7. ESHRE Capri Working Group. Fertility and ageing. Human Reproduction Update 2005:11(3)261-76.
8. Santoro N, Isaac B, Neal-Perry G. Impaired folliculogenesis and ovulation in older reproductive aged women. J Clin Endocrin Metab 2003;88:5502-9.
9. Pavlic EJ, De Priest PD, Gallion HH. Ovarian volume related to age. Gynaecol Oncol 2000;80:333-4.
10. Bukulmez O, Arici A. Assessment of ovarian reserve. Curr opin Obstet Gynaecol 2004;16:231-7.
11. Bath LE, Wallace WHB, Shaw MP, Fitzpatrick C, Anderson RA. Depletion of ovarian reserve in young women after treatment for cancer in childhood: Detection by anti-Mullerian hormone, inhibin–B and ovarian ultrasound. Human Reproduction 2003;18:2368-74.
12. Larsen EC, Muller J, Schmiegelow K, ReChnitzer C, Andersen AN. Reduced ovarian function in long term survivors of radiation-and chemotherapy–treated childhood cancer. J Clin Endocrinology Metab 2003;88:5307-14.
13. Scott RT, Hoffman GE. Prognostic assessment of ovarian reserve. Fertil Steril 1995;63:1-11.
14. Shrim A, Elizur SE, Seidman DS, Rabinovici J, Wiser A, Dor J. Elevated day 3 FSH/LH ratio due to low LH concentrations predicts reduced ovarian response. Reprod Biomed Online 2006;12(4):418-22.
15. Licciardi FL, Hung Ching L, Rosenwaks Z. Day 3 estradiol serum concentrations as prognosticators of ovarian stimulation response and pregnancy outcome in patients undergoing in vitro fertilization. Fertil Steril 1992;64:991-4.
16. Seifer DB, Scott RT, Bergh PA. Women with declining ovarian reserve may demonstrate a decrease in Day 3 serum inhibin-B before a rise in day 3 follicle stimulating hormone. Fertil Steril 1999;72:63-5.
17. VanRooij IAJ, Broekmans FJM, Te Velde ER, Fauser BC. Serum anti-Mullerian hormone levels: a novel measure of ovarian reserve. Human Reproduction 2002; 17:3065-71.
18. Visser JA, de Jong FH, Laven JSE, Themmen APN. Anti-Müllerian hormone: a new marker for ovarian function. Reproduction 2006;131:1-9.
19. Lass A, Skull J, McVeigh E. Measurement of ovarian volume by transvaginal sonography prior to human menopausal gonadotropin hyperstimulation can predict poor response of infertile patients in an IVF programme. Human Reproduction 1997;12:294-7.
20. Tomas C, Nuojua HS, Martikainen H. Pretreatment transvaginal ultrasound examination predicts ovarian responsiveness to gonadotrophins in in vitro fertilization. Human Reproduction 1997;12:220-3.
21. Engmann L, Sladkevicius P, Argwal R. Value of ovarian stromal blood flow velocity measurement after pituitary suppression in the prediction of ovarian responsivness and outcomes of in vitro fertilization treatment. Fertil Steril 1999;71:22-9.
22. Navot D, Rosenwaks Z, Margalioth E. Prognostic assessment of female fecundity. Lancet 1989;645-7.
23. Bukman A, Heineman MJ. Ovarian reserve testing and the use of prognostic models in patients with subfertility. Human Reproduction Update 2001;7(6):581-90.
24. Fanchin R, de Ziegler D, Olivennes F. Exogenous follicle stimulating hormone ovarian reserve test (EFFORT): A simple and reliable screening test for detecting ‘poor responders’ in in-vitro fertilization. Human Reproduction 1994;9:1607-11.
25. Fanchin R, Schonauer LM, Righini C, Frydman N. Serum anti-Mullerian hormone dynamics during controlled ovarian hyperstimulation. Human Reprod 2003;18:328-32.
26. Winslow KL, Toner JP, Brzyski RG. The gonadotrophin–releasing hormone agonist stimulation test –A sensitive predictor of performance in the flare up in vitro fertilization cycle. Fertil Steril 1991;56:711-7.
27. Massin N, Gougeon A, Meduri G. Significance of ovarian histology in the management of patients presenting a premature ovarian failure. Human Reproduction 2004;19:2555-60.
28. Burger HG, Dudley EC, Hopper JL. The endocrinology of the menopausal transition: a cross sectional study of a population–based sample. J Endocrinol Metab 1995;80:3537-45.
29. Burger HG, Dudley EC, Hopper JL. Prospectively measured levels of serum follicle stimulating hormone, estradiol, and the dimeric inhibins during the menopausal transition in a population based cohart of women. J Endocrinol Metab 1999;84:4025-30.
30. de Vet A, Laven JS, de Jong FH. AntiMullerian hormone serum levels: A putative marker for ovarian ageing. Fertil Steril 2002;77:357-62.
31. Weenen C, Laven JS, Von Bergh AR. Anti-Mullerian hormone expression pattern in the human ovary: Pential implications for initial and cyclic follicle recruitment. Mol Human Reprod 2004;10:77-83.
32. Kevenaar ME, Meerasahib MF, Kramer P, Brigitte MN, Frank H, et al. Serum Anti-Mullerian hormones levels reflect the size of the primordial follicle pool in mice. Endocrinology 2006;7:3228-34.
33. Cook CL, Siow Y, Taylor S, Fallet ME. Serum Mullerian inhibiting substance levels during normal menstrual cycles. Fertil Steril 2000;73:859-61.
34. La Marca A, Malmusi S, Giulini S, Tamaro LF, Orvieto R, Levratti P, et al. Anti-Mullerian hormone plasma levels in spontaneous menstrual cycles and during treatment with FSH to induce ovulation. Human Reproduction 2004;19:2738-41.
35. Tufan E, Eelter K. Assessment of Reproductive Age Patterns by Hormonal and Ultrasonographic Ovarian Reserve Tests. Human Reproduction 2004;19:2484-9.
36. Giacobbe M, Pinto M. The Usefulness of Ovarian Volume, Antral follicle Count and Age a predictor of menopause status. Climateric 2004;7:255-60.
37. Sharara FI, McClamrock HD. The effect of reproductive ageing on ovarian volume measurements in infertile women. Obstet Gynaecol 1999;94:57-60.
38. Raine FNJ, Campbell BK. Interobserver reliability of ovarian volume measurement is improved with three dimensional ultrasound, but dependent upon technique. Ultrasound Med Bio 2003;29:1685-90.
39. Ng EH, Tang OS. The significance of the number of antral follicles prior to stimulation in predicting ovarian responses in an IVF programme. Human Reproduction 2000;15:1937-42.
40. Adams J, Mason WP, Tucker M. Ultrasound assessment of changes in the ovary and the uterus during LHRH therapy. Ups J Med Sci 1984;89:39-42.
41. Kohl J, Dittrich R, Siebzehnrubl E, Wildt L. Determination of follicle numbers in human ovarian biopsy-a method for estimation of outcome of ovarian cryoreservation. Fertil Steril 2000;74:1,212.
42. Schmidt KLT, Byskov A, Nyboe Andersen A, Muller J, Yding AC. Density and distribution of primordial follicles in single pieces of cortex from 21 patients and in individual pieces of cortex from three entire human ovaries. Human Reproduction 2003;18:1158-64.
43. Kwee J, Hendriks DJ, Mol BW. A systematic review of tests predicting ovarian reserve and IVF outcome. Human Reproduction update 2006,12(6):685-718.
44. Klein NA, Battaglia DE, Fujimoto VY, Davis GS, Bremner WJ. Reproductive ageing: Accerelerated ovarian follicular development associated with a monotropic follicle stimulating hormone rise in normal older women. J Clin Endocrinology Metab 1996;81:1038-45.
45. Ruess ML, Santos R, Levin B. Age and the ovarian follicle pool assessed with transvaginal ultrasonography. Am J Obstet Gynecol 1996;174:624-7.
46. Hansen KR, Thver AC, Sluss PM. Reproduction ageing and ovarian function, is the early follicular phase FSH rise necessary to maintain adequate secretory function in older ovulatory women. Human Reproduction 2005;20:89-95.
47. Sharara FI, Scott RT, Jr Seifer DB. Contemporary investigation of ovarian reserve in infertile women. Am J Obstet Gynaecol 1998;179:804-12.
48. te Velde ER, Pearson PL. The variability of female reproduction ageing. Human Reproduction 2002;8:141-54.
49. Sharara FI, Scott RT. Assessment of ovarian reserve. Is there still a role for ovarian biopsy? Human Reprodution 2004;19:470-1.


HOME   |   SEARCH   |   CURRENT ISSUE   |   PAST ISSUES

Professional Medical Publications
Room No. 522, 5th Floor, Panorama Centre
Building No. 2, P.O. Box 8766, Saddar, Karachi - Pakistan.
Phones : 5688791, 5689285 Fax : 5689860
pjms@pjms.com.pk