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2 Risk of early menopause following IVF treatment

Sesh Kamal Sunkara

Department of Women’s Health, Faculty of Life Sciences and Medicine, King’s College London, London, UK

Case History 1: A 34‐year‐old woman due to commence ICSI treatment for male factor infertility is concerned about the risk of premature menopause from ovarian stimulation. She has regular menstrual cycles and normal FSH, LH and estradiol levels. A pelvic ultrasound scan showed a normal sized uterus, and both ovaries were of normal morphology and volume with a total antral follicle count of 16. She is fit and well with no significant medical history.

Case History 2: A woman who is now 43 years of age had IVF treatment 5 years ago which was unsuccessful. She had only three oocytes retrieved following ovarian stimulation with gonadotropins. Her periods had become irregular 2 years following the IVF treatment cycle, and they stopped a year ago.

Background

In women, the ovaries age with time and finally lose their function, with menopause marking the definite end of female reproductive life. The ovarian concept of reproductive aging assumes that the age‐related loss in female fertility is dictated by the decline of both the quantity and quality of the follicles [1]. Women with regular menstrual cycles (premenopausal) have ovarian follicle counts 10 times greater than in perimenopausal women of similar age, while follicles are virtually absent in postmenopausal women [2].

Both fertility and the age at menopause vary substantially between women [3]. Results from a large cohort study, the population of which was selected from the Prospect‐EPIC (European Prospective Investigation into Cancer and Nutrition) project that involved a questionnaire survey of women aged 50–69 years from the city of Utrecht in the Netherlands, showed that fertility problems are frequently followed by early menopause [4], supporting the view that both are an expression of accelerated ovarian aging.

Questions have been raised on whether gonadotropin stimulation used in assisted reproductive technology (ART) treatments has an impact on ovarian aging and menopause. A retrospective cohort study investigating whether menopausal age is inversely related to the number of ART cycles found no such correlation [5], supporting the view that gonadotropin stimulation in women does not accelerate follicular depletion, an observation consistent with experimental studies that showed primordial follicle recruitment to be independent of gonadotropin stimulation.

In this context it is also important to address the association between poor ovarian response to gonadotropin stimulation and early menopause. A large questionnaire survey of women selected from participants of a nationwide cohort study (the OMEGA Project) of 19,840 women who underwent IVF treatment in the Netherlands from 1983 to 1995 indicated that a low number of retrieved oocytes at the first IVF treatment was an important predictor of early menopausal transition [6]. The results of this study were in line with an earlier finding that anticipated poor responders are at a greater risk of becoming postmenopausal at the age of 46 years or before than normal responders [7].

Management options

A question not infrequently asked by women embarking on ovarian hyperstimulation for IVF treatment is whether this would lead to a depletion of the primordial follicles in the ovaries and thereby an increased risk of early menopause. It is important to counsel women, explaining the various steps involved in IVF treatment and implications they are likely to have for the woman in the short and long term. Women should be reassured that there is substantial evidence to suggest that gonadotropin stimulation to induce multifollicular recruitment and optimize the outcome of IVF treatment does not result in a depletion of the ovarian primordial follicles.

Women should be informed that those encountering fertility problems may have an increased background risk of reaching early menopause than fertile women, but gonadotropin stimulation during IVF treatment does not increase their risk of attaining early menopause. Women who have responded poorly to controlled ovarian hyperstimulation during IVF treatment indicated by a low number of retrieved oocytes have a compromised ovarian reserve and are at risk of becoming menopausal earlier (Case History 2) than women who have had a normal response. Women should be informed that all procedures involved in the IVF treatment process are generally safe and do not put the woman at risk of premature ovarian failure.

Key points

Challenge: IVF treatment and the risk of early menopause.

Background:

 The question is frequently raised by women undergoing IVF treatment.

 Women with fertility problems have a higher background risk of reaching menopause earlier than fertile women.

 Gonadotropin stimulation does not cause depletion of primordial follicles.

 Women with a compromised ovarian reserve (indicating ovarian aging) are at risk of becoming menopausal earlier than women with a good ovarian reserve.

Management options:

 Reassure women that the procedures involved in the IVF treatment cycle do not put them at a risk of reaching earlier menopause.

 There is no association between the number of attempts at IVF treatment and the age at menopause.

Answers to questions patients ask

1  Q1 Will having ovarian stimulation for IVF make me get early menopause? A1. No, it wouldn’t. Ovarian stimulation is a routine part of IVF, aiming to increase the number of eggs available for treatment, compared with what happens in a spontaneous menstrual cycle. During a menstrual cycle, several follicles start to grow initially, but only one follicle and sometimes two follicles become dominant and release an egg following ovulation. The remaining follicles die out, as they require a higher level of follicle stimulating hormone for their continued growth. During ovarian stimulation, this hormone is given in the form of injections to recruit and mature these follicles so that they do not die out. Therefore, ovarian stimulation is only salvaging follicles that would have otherwise perished in a natural menstrual cycle. Hence, ovarian stimulation for IVF does not lead to early menopause.

2  Q2 I have had seven IVF cycles, and each time they collected about 10 eggs. Does that mean that I will run out of eggs in my ovaries earlier? A2. No, it doesn’t. Studies have shown that the number of IVF cycles and the number of eggs collected do not affect the age of menopause.

References

1 1 Te Velde ER, Pearson PL. The variability of female reproductive ageing. Hum Reprod Update. 2002; 8:141–54.

2 2 Richardson SJ, Senikas V, Nelson JF. Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab. 1987; 65:1231–7.

3 3 Te Velde ER, Dorland M, Broekmans FJ. Age at menopause as a marker of reproductive ageing. Maturitas. 1998: 30:119–25.

4 4 Kok HS, Van Asselt KM, van der Schouw YT, Grobbee DE, te Velde ER, Pearson PL, et al. Subfertility reflects accelerated ovarian ageing. Hum Reprod. 2003; 18:644–8.

5 5 Elder K, Mathews T, Kutner E, Kim E, Espenberg E, Faddy M, et al. Impact of gonadotrophin stimulation for assisted reproductive technology on ovarian ageing and menopause. Reprod Biomed Online. 2008; 16:611–16.

6 6 de Boer EJ, Den Tonkelaar I, Te Velde ER, Burger CW, van Leeuwen FE; OMEGA Project Group. Increased risk of early menopausal transition and natural menopause after poor response at first IVF treatment. Hum Reprod. 2003; 18:1544–52.

7 7 de Boer EJ, Den Tonkelaar I, Te Velde ER, Burger CW, Klip H, van Leeuwen FE. Low number of retrieved oocytes at IVF treatment is predictive of early menopause. Fertil Steril. 2002; 77:978–85.