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Obesity and assisted conceptionion
9.1
Introduction
The World Health Organization defines obesity as abnormal or excessive fat accumulation that impairs health. Obesity is most commonly defined using body mass index (BMI). The percentage of obese women (BMI ≥30) in the United Kingdom has increased from 16.4% in 1993 to 23.8% in 2004. In the reproductive age group, a third of the women are overweight (BMI 25–30) and one in five are obese.
Overweight women are known to be at a higher risk of menstrual dysfunction and ovulatory problems. This is due to altered secretion of pulsatile GnRH, resulting in altered SHBG, ovarian/adrenal androgens, and luteinising hormone (LH). Obese women are more likely to experience reproductive problems and therefore seek assisted conception treatment.
In women undergoing assisted reproduction techniques (ART), obesity has been associated with the need for higher doses of gonadotrophins, increased cycle cancellation rates, and fewer oocytes retrieved. Lower rates of embryo transfer (ET), pregnancy and live birth have also been reported, as have higher miscarriage rates. However, other studies have been unable to find any negative impact of obesity on ART outcome. A recent survey of assisted reproduction clinics in the United Kingdom demonstrates a wide variation in their approach towards obese infertile women. Obstetrics data suggest that maternal and foetal risks increase in the obese individuals.
The main cause of infertility in the obese relates to disturbances in ovulation. These, for the most part, can be resolved with a combined approach involving weight reduction strategies together with pharmacologically induced ovulation induction. Refractory dysovulation occurs with greater frequency in the obese, and for them, the use of ART has to be considered. ART, specifically IVF, will address the issues of egg and sperm availability, as well as tubal infertility for the obese, just as it does for the general infertile population. There is no definitive evidence that unexplained infertility occurs with greater frequency in the obese; though given the abovementioned remarks with respect to oocyte, embryo, and endometrial factors, one might have expected this to be the case. The practical issues that arise through the use of these techniques in overweight women need to be considered carefully.
9.1.1
Cycle effects
The impact of obesity on reproductive function is complex. The association between obesity and anovulation is well established. Obesity induces a series of hormonal changes of insulin resistance, hyperinsulinemia, low sex hormone- binding globulin, elevated androgens, increased peripheral conversion of androgens to oestrogens, increased free insulin- like growth factor 1, and high leptin. The combined effect of these changes causes hypothalamic dysfunction, aberrant gonadotropin secretion, reduced folliculogenesis, and lower luteal progesterone levels resulting in anovulation.
Increased levels of serum and follicular fluid leptin are described with increasing BMI. High levels of leptin impair follicular development and reduce ovarian steroidogenesis through direct effects on theca and granulose cells. There is also an inverse relationship of increasing BMI with reduced serum adiponectin levels. The low adiponectin levels are associated with elevated serum insulin levels, which increase circulating androgen levels in part linked to a reduction in the production of sex hormone binding globulin by the liver.
The trend to hyperandrogenism in the obese is also contributed by IGF-1-mediated effects on LH-induced steroidogenesis by theca cells. Enhanced androgen production causes granulosa cell apoptosis with direct consequences for follicle function. The increased availability of androgens for peripheral conversion to oestrogens in adipose tissue has pituitary effects with impaired FSH production affecting the ovarian follicular development. The clinical manifestations of the biochemical disturbances described include anovulatory cycles and subfertility. Ovarian dysregulation associated with hyperandrogenism, insulin resistance, menstrual irregularity, and infertility is commonly found in women with polycystic ovarian syndrome, many of whom are obese.
However, even in ovulatory women, obesity appears to inhibit natural fecundity and prolong the time to conception. A Dutch study showed women with a BMI of 35 had a 26% lower likelihood of spontaneous pregnancy, and women with a BMI of 40 had a 43% lower likelihood of spontaneous pregnancy than women with a BMI between 21 and 29.
9.1.2
Effects on the oocyte
A number of studies have suggested that oocyte yield after stimulation for IVF may be affected in the obese. Quantitative effects have been described where increased doses of gonadotrophins are required to elicit an ovarian response, and the ultimate yield of cumulus–oocyte complexes may be less than in normal weight controls. This may be linked to disturbances in leptin production or sensitivity as described earlier. Some studies have suggested that fertilisation rates of oocytes retrieved may be impaired in the obese, but this observation has not been consistent. Prospective studies are needed to clarify this issue. The observation of increased risks of miscarriage in the obese after IVF has been attributed by some to qualitative effects on oocytes leading to aberrant embryo development.
9.1.2.1
Effects on embryos
As with oocytes, the literature is not consistent with respect to the effects of obesity on embryonic development. Some studies have suggested that markers of embryo quality differ in the obese. Furthermore, there may be less available surplus embryos for cryostorage potentially having an impact on cumulative pregnancy rates per episode of ovarian stimulation. Some have suggested that these observed effects are unreliable since studies may not have taken into account potential confounders such as age, parity, and duration of infertility. Further work is required to inform this controversial debate.
9.1.2.2
Effects on the endometrium
Obesity may also alter the endometrium. There is evidence of altered endometrial gene expression during the implantation window of natural cycles in obese women. Similarly, there is evidence of lower implantation and clinical pregnancy rates in obese donor egg recipients.
There is an increase in miscarriage rate in the obese both in natural conception and that associated with infertility treatment. Specific to IVF, a 50% increased risk of miscarriage in women with a BMI of 30 kg/m 2 has been described. While embryo quality will be an important determinant of implantation potential, studies using an egg donation model suggest that endometrial factors are likely to be involved in this phenomenon as well. The precise mechanism is not understood but ovarian steroid regulation of endometrial development, perturbations in inflammatory and coagulation pathways, perhaps linked to insulin resistance, have been suggested to be involved.
9.1.3
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