Homerton Fertility Centre, Homerton University Hospital, London, UK
Before any treatment for infertility, some important factors affecting the outcome of this treatment must be taken into account and in particular, female age and body mass index. Advancing female age is probably the single most important factor influencing fertility potential. Physiologically, from the age of about 35 years onwards, there is a steady downward trend in fertility capacity and this is a reflection of the declining number of follicles remaining, biological aging and exposure to many deleterious influences on the ova remaining in the ovaries. As a result, following the age of 42, spontaneous pregnancy becomes quite a rare event and from the mid-thirties onwards, fertility potential decreases considerably. Public awareness of these facts is insufficient. In addition to the delaying of a wish for pregnancy until a later age, obesity is also an undesirable product of modern society and maternal weight seems to have a substantial effect on fertility potential. Obese women are less fertile and have higher rates of miscarriage than their counterparts of normal weight. The successful treatment of obesity is capable of reversing its deleterious effects on fertility potential. Weight loss is notoriously difficult to achieve and maintain, particularly it seems for women with PCOS. It is not enough merely to tell these patients to lose weight and come back in say 3 months time. Referral to a clinic dedicated to instruct in life style changes, diet and exercise is a necessity to achieve the goal.
OvulationFemale ageFertilityPrimordial folliclesOocytesAssisted reproductive technologiesARTOvulation inductionOvarian reservePrimordial folliclesOvarian failureLHPremature ovulationEarly luteinisationOestrogenInhibinAnti-Mullerian hormoneAMHAntral follicleOvumBody mass indexFSHObesityPCOSHyperinsulinaemiaHyperandrogenismHyperandrogenemiaGonadotrophinsHyperstimulationMetformin
Before considering the treatment of anovulation, and indeed any treatment for infertility, some important factors affecting the outcome of this treatment must be taken into account and in particular, female age and body mass index. In addition to these, smoking is said to reduce ovarian reserve and fertility potential of the female and, possibly, the semen quality.
4.1 Influence of Female Age
Advancing female age is probably the single most important factor influencing fertility potential. Physiologically, from the age of about 35 years onwards, there is a steady downward trend in fertility capacity and this is probably a reflection of the declining number of primordial follicles remaining, biological aging and exposure to many deleterious influences on the ova remaining in the ovaries. In addition to the persistently decreasing number of available, potentially fertilizable oocytes, it is also assumed that the best quality ova are preferentially recruited in the earlier stages of the reproductive period. As a result, following the age of 42, a spontaneous pregnancy becomes quite a rare event and from the mid-thirties onwards, fertility potential decreases considerably. Advancing female age not only affects natural conception but also the results of ovulation induction and assisted reproductive technologies.
Public awareness of these facts is insufficient. It is sad that many, in this modern day and age of career women and delayed wish for conception, not only make life difficult for themselves and their physicians but may often “miss the boat” completely. The increasing phenomenon of the single woman who realizes that the prince on a white horse may not arrive after all but wants to conceive and increasing divorce rates followed by second marriages have also pushed up the mean age of women presenting with a problem of infertility. We have not yet succeeded in impressing the general public sufficiently with these facts. An awareness of the declining pregnancy rates with age at least allows an informed consideration of the timing of attempted conception when this is flexible.
In order to fully inform couples of their prognosis regarding fertility potential, especially if the female partner is in the more advanced age group, data on the state of ovarian function is needed. This information should be utilized not only to forecast the chances on conception but, not infrequently, to decide whether treatment should be embarked upon at all.
To answer these questions, information regarding both the number of available oocytes (ovarian reserve) and their quality is needed. Very frequently a dwindling ovarian reserve is accompanied by poor quality oocytes. When these two coincide, prognosis for pregnancy is poor. However, it is now becoming more apparent that these two factors do not always run in parallel and, similarly, the results of the static and dynamic tests available require accurate interpretation of their value before an informed discussion can be undertaken.
4.1.1 Ovarian Reserve
The total number of primordial follicles remaining in the ovary declines with age. Although this decline is a gradual process up to the age of 35, thereafter the slope becomes much steeper. This downward trend can occasionally occur before this age and is then related to an impending premature ovarian failure.
There are several suggestive symptoms and signs of a dwindling ovarian reserve: a shorter cycle on account of a shorter follicular phase, a premature LH surge, premature ovulation and early luteinisation. These are due to decreasing concentrations of inhibin, a consequent increase and even ‘overshoot’ of FSH release by the pituitary producing an accelerated rate of follicular growth and oestrogen concentrations.
The assessment of ovarian function is fully described in the following chapter.
4.1.2 Prognosis for Conception
If these clinical signs of a dwindling ovarian reserve are associated with a high intra-menstrual FSH concentration, low anti-Mullerian hormone (AMH) concentrations or severely reduced antral follicle count, these are gloomy portents not only of ovarian response to stimulation but also, often, of prognosis for pregnancy. In this case, serious consideration of a halt in further investigations and treatment should be made, especially if these have been accompanied by a very poor or non-response to maximal ovarian stimulation. Ovum donation, if acceptable, produces an excellent alternative in these situations. However, poor responders, even with moderately high FSH concentrations and low AMH/antral follicle count, in the younger age groups, have a better chance of conceiving than those with similar signs who are of advanced reproductive age . In other words, age is an independent predictor for quality of oocytes and therefore pregnancy rates, whereas FSH, AMH concentrations and antral follicle count and the dynamic tests are indirect predictors of ovarian reserve. The worst prognosis for pregnancy is therefore predicted by advanced reproductive age, high FSH concentrations, low AMH serum concentrations, a low antral follicle count and a poor response to gonadotrophin stimulation.
4.2 Influence of Obesity and Weight Loss
In addition to the delaying of a wish for pregnancy until a later age, obesity is also an undesirable product of modern society and maternal weight seems to have a substantial effect on fertility potential. Obese women are less fertile in both natural and ovulation induction cycles and have higher rates of miscarriage than their counterparts of normal weight. Induction of ovulation in obese women requires higher doses of ovulation inducing agents.
Although obesity per se seems to be an independent factor in the aetiology of subfertility and the poor outcome of treatment in general, its predominance in women with associated PCOS further complicates the issue as 80 % of these women have insulin resistance and a consequent hyperinsulinaemia. They almost inevitably have the stigmata of hyperandrogenism and irregular or absent ovulation. Insulin stimulates LH and ovarian androgen secretion and decreases sex hormone binding globulin concentrations so increasing circulating free testosterone concentrations. Central obesity and body mass index (BMI) are major determinants of insulin resistance, hyperinsulinemia and hyperandrogenemia. More gonadotrophins are required to achieve ovulation in insulin resistant women. Obese women being treated with low dose therapy have inferior pregnancy and miscarriage rates. Both obese and insulin resistant women with PCOS, even on low dose FSH stimulation, have a much greater tendency to a multifollicular response and thus a relatively high cycle cancellation rate in order to avoid hyperstimulation.
The successful treatment of obesity, with or without insulin resistance, is capable of reversing its deleterious effects on fertility potential. In a study examining the effect of a change in life style programme on 67 anovulatory, obese (BMI >30) women who had failed to conceive with conventional treatment for 2 years or more, the mean weight loss was 10.2 kg after 6 months . Following the loss of weight, 60 of the 67 resumed ovulation and 52 achieved a pregnancy, 18 of them spontaneously. In addition to these impressive results, only 18 % of these pregnancies miscarried compared with a 75 % miscarriage rate in pregnancies achieved before the weight loss . This outstanding report emphasizes once again the strong connection between nutrition and fertility potential and particularly the strong association between obesity and infertility.
Obesity expresses and exaggerates the signs and symptoms of insulin resistance in women with PCOS. Loss of weight can reverse this process, improve ovarian function and the associated hormonal abnormalities. Curiously, in obese women with PCOS, a loss of just 5–10 % of body weight is enough to restore reproductive function in 55–100 % within 6 months of weight reduction .
Weight loss is thus a cheap and effective way to restore ovulation in obese, anovulatory women. If medical ovulation induction is needed, it is definitely facilitated by loss of weight and when pregnancy ensues, miscarriage rates are also greatly improved by weight loss. This should be the first line of treatment in obese women with anovulatory infertility. Metformin, an insulin sensitizing agent, is currently being widely used in infertile women with associated PCOS, particularly for those who are obese (see Chap. 10). It should not, however, be used as a first-line substitute for attempted weight loss which achieves similar, if not better results, does not involve medication or side-effects and most definitely provides long-term health benefits.
Weight loss is notoriously difficult to achieve and maintain, particularly it seems for women with PCOS. It is not enough merely to tell these patients to lose weight and come back in say 3 months time. Referral to a clinic dedicated to instruct in life style changes, diet and exercise is a necessity to achieve the goal.
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