Why IVF does not affect ovarian reserves

Recently the 'reality' television star Kourtney Kardashian claimed that the IVF treatment she received had 'put her into the menopause' in the trailer for a new series of 'Meet the Kardashians'. What is not clear, however, is whether she is referring to the short-term use of gonadotrophin releasing hormone (GnRH) agonist medication, which induces a temporary (and fully reversible) suppression of ovarian activity, with its associated side effects – referred by some as a 'medical menopause', or if she has actually developed a permanent premature ovarian insufficiency (known in the past as 'premature menopause'). If the latter then this would be a devastating life changing situation, yet we do not believe it likely that this would have been caused by the drugs used to stimulate the ovaries during IVF, which contain follicle stimulating hormone (FSH) as the main active component. Clinically, there certainly isn't strong evidence to support this notion.

Studies in Current Opinion in Obstetric Gynecology and Reproductive Biomedicine Online that have looked at whether repeated cycles of IVF hasten the menopause or reduce ovarian reserve are reassuring in this regard and suggest no effect. A recent small study published in International Journal of Women's Health reported in the media following Kardashian's announcement, however, found that 50 women who had undergone IVF had a slightly earlier onset of menopause compared with a control group (mean age 49.84y vs 50.66y, respectively, p<0.05) – with less than a year's difference between the two groups. We must take into account that some women undergo IVF who already have a diminished ovarian reserve, which in turn predisposes to an earlier menopause than those with normal ovarian reserve and is unrelated to the treatment, as outlined in a paper published in Human Reproduction.

Furthermore, biologically, it does not seem plausible that IVF drugs would hasten the menopause. Women are born with a finite number of egg cells (oocytes) that do not undergo further cell division until just after fertilisation. Of the one to two million oocytes within both ovaries at birth, only about 450 or so are destined to ovulate – that is assuming ovulation occurs every month for the 38 years from menarche at age 13 through to the average age of menopause at 51. The remaining oocytes are progressively lost by atresia (cellular degeneration) and apoptosis (programmed cell death) at a maximum rate of up to 37 per day (1100 per month) in young women. This loss occurs irrespective of whether a woman is ovulating, pregnant, breastfeeding or taking medication to suppress ovulation such as the contraceptive pill.

Despite extensive research on the processes involved in follicular maturation and recruitment, it has not yet been possible to slow the rate of ovarian ageing – perhaps the 'holy grail' of reproductive medicine. Indeed, the control of ovarian ageing is still one of the biggest enigmas in reproductive biology. The function of the ovary depends upon the total number of oocytes contained within primordial follicles, which are formed during fetal life. The maximum number of germ cells during gestation is approximately seven million, and this number is achieved at 20 weeks' gestation (data that has been derived historically from a relatively small number of post-mortems on fetuses). By birth, this number has already reduced to between one and two million.

The age at which women reach menopause is affected by the size of the initial follicle pool, which in turn is influenced by a combination of genetic and environmental factors, including maternal nutrition and health during the in utero development of the female fetus. While nothing has been found that slows the rate of ovarian ageing, certain 'poisons' may hasten it, such as smoking and the use of cytotoxic drugs used for the treatment of some cancer. Poor diet and lifestyle can affect fertility and may, over time, impact reproductive ageing, and some studies have found a link between anorexia, chronic undernutrition and an earlier menopause. So there are many confounding factors at play which need to be considered when exploring the suggestion that IVF may hasten the menopause too.

The processes that prepare a primordial follicle for development and eventual ovulation are believed to start at least eight to nine months prior to ovulation itself, when dormant follicles are triggered from their inactive state into a growth cycle that culminates in the release of an egg. The size of the total primordial follicle store is not directly related to the rate of ovulation but instead to the daily fraction recruited into the growing phase, which changes with age. At the age of 25, approximately 37 follicles leave the human ovary by either growth or atresia daily (thus, approximately 1100 per month), whereas at the age of 45 this number has reduced to approximately two per day. The fraction of primordial follicles triggered into growth appears to be up-regulated when the total numbers are reduced, thereby explaining the increased rate of loss in humans with age. The accelerated rate of depletion in older ovaries is due more to the initiation of growth than to atresia, although the control mechanisms are still to be fully elucidated. From birth to puberty, approximately 75 percent of the follicle store is lost. At puberty there are approximately 250,000 follicles and menopause occurs when there are about 1000 follicles. Post-menopausally, therefore, some follicles do remain, but they do not grow to maturity.

Recruitment of primordial follicles into the growth cycle occurs throughout life and is initially independent of FSH, indeed the FSH receptor is expressed on the follicle only at the primary follicle stage – that is two weeks or so prior to ovulation. The cellular mechanisms that are involved in the recruitment of the primordial follicles, are only partly understood. Drugs used to stimulate the ovaries during fertility treatment capture those follicles that are ready to grow in that particular month, all but one of which were 'destined to die' – therefore fertility treatment should not hasten the onset of the menopause but simply enable follicles to grow that otherwise would have been lost. Low doses of ovulation inducing medication are aimed at mimicking the physiological environment and recruiting a single follicle, whereas higher, supra-physiological doses of FSH used for IVF treatments may capture the additional follicles that in a natural cycle would otherwise die away. It has been hypothesised that in women with low ovarian reserve, the rate at which follicles are selected to mature each month is upregulated and the follicle store is exhausted earlier, so these women would naturally reach menopause at a slightly younger age, but it is unclear whether IVF would further hasten this process.

With current success rates it is uncommon for women to undergo more than three stimulated cycles of IVF and so any putative effect is likely to be relatively small – and certainly, we would suggest, outweighed by the prospects of having a baby. Overall, given that the trajectory for follicle recruitment commences several months before the follicle becomes sensitive to FSH, there does not appear to be a plausible mechanism whereby ovarian stimulation should hasten the onset of menopause for the vast majority of women who undergo IVF and associated treatments. The clinical and biological evidence is therefore reassuring for women undergoing IVF.