N.S. Macklon, M.D., Ph.D.; B.C.J.M. Fauser, M.D., Ph.D.


Semin Reprod Med. 2005;23(3):248-256. 

In This Article

Clinical Consequences of Ovarian Aging

As reproductive age advances to the menopause, the menstrual cycle decreases in length predominantly due to a shortening of the luteal phase,[9] and follicle-stimulating hormone (FSH) concentrations gradually increase.[10] This has been considered to result from depletion of the ovarian follicular pool[5] leading to a diminished production of estradiol and inhibin-B.[11] A major individual variability exists in follicle pool depletion within the normal range of menopausal age; complete follicle pool exhaustion may occur between 40 and 60 years.[12]

Poor ovarian response to ovarian hyperstimulation for in vitro fertilization (IVF) is clearly associated with chronological aging. An age-related decline in response to stimulation with gonadotropins and a reduction in the number of oocytes,[13] oocyte quality,[14] fertilization rates,[15,16] and ultimately embryos[17,18,19] have been well documented. Many studies point to 40 years of age as a significant cut-off for effectiveness of IVF.[20,21,22,23] This age-related effect on pregnancy rates is similar to that reported in donor sperm programs[24] and chances for spontaneous pregnancy.[12] A multiple regression analysis of factors influencing IVF outcomes revealed a predicted live birth rate of 17 per cycle at age 30, decreasing to just 7% at 40 years and 2% at 45 years of age.[25] Although age is an important predictor of IVF outcome,[26] chronological age is poorly correlated with ovarian aging.[12]

The most prominent determining factor for IVF outcome is the individual variability in ovarian response to stimulation.[27] Rather than exhibiting the desired response, women can present with either a hyporesponse or a hyper-response to stimulation. The concept of poor response as a feature of chronological and ovarian aging has been supported by recent studies linking poor response to ovarian hyperstimulation to subsequent early menopause.[28,29,30]

Although hyper-response to gonadotropin stimulation can usually be prevented by modification of the stimulation regimen, a poor response to ovarian stimulation is highly resistant to therapeutic intervention.[31] Strategies for stimulating so-called low responders include varying the dose or day of the cycle for initiating stimulation with gonadotropins. Studies undertaken so far have been unable to demonstrate a beneficial effect of gonadotropin dose increase in patients who exhibit a poor response to standard-dose regimens.[31,32,33] Alternative approaches include early cessation or microdose gonadotropin-releasing hormone (GnRH) agonist protocols, and the adjunctive use of aromatase inhibitors, growth hormone, and GnRH antagonists.[34] However, at present no therapeutic intervention has been shown in large randomized studies to offer a solution to poor response to ovarian stimulation in IVF.

In recent years, attention has been given to the identification of sensitive and specific markers of ovarian aging, which may enable prediction of poor or good response to ovarian hyperstimulation. This would open the way to improved counseling and patient selection for IVF.


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