Australasian Science: Australia's authority on science since 1938

The Biggest Fertility Issue

Credit: Olivier Le Moal/Adobe

Credit: Olivier Le Moal/Adobe

By Tod Fullston, Jemma Evans & Macarena Gonzalez

Emerging evidence indicates that an obese mother or father predisposes their child to obesity via nutritional signals conveyed before birth.

Australia is currently ranked as one of the fattest nations in the world. The Australian Bureau of Statistics reports that a staggering 15 million (63%) Australians are overweight (BMI>25, 8.5 million) or obese (BMI>30, 6.5 million), and that the biggest increases are being seen in the morbidly obese class (BMI>40). Obesity is a known risk factor for debilitating diseases including type 2 diabetes, heart disease and cancer.

More recently the impact on younger people of reproductive age has become evident, with an increased prevalence of obesity coinciding with a decrease in fertility and increased reliance on assisted reproductive technologies (Fig. 1).

It is well-accepted that a woman’s lifestyle affects her fertility, with obesity just as detrimental as smoking and alcohol consumption. It is also becoming clear that obesity impairs a man’s fertility. Couples who have at least one overweight or obese partner take longer to become pregnant, and are much more likely to be infertile or to require assisted reproduction. There are many reasons why this occurs.

High blood sugar levels and insulin resistance, which are associated with obesity, have widespread effects on female reproductive organs, including altered hormonal signals from the brain that lead to abnormal menstrual cycles and anovulation.

Polycystic ovary syndrome (PCOS) is an endocrine disorder that is tightly linked to obesity; depending on ethnicity, 30–50% of women with PCOS are overweight or obese. These women are not only predisposed to metabolic disruptions such as

dyslipidaemia and insulin resistance, they also present with impaired ovarian function and anovulation in many cases. Clinical evidence suggests that the severity of PCOS symptoms correlates with increased adipose tissue. Evidence from animal studies suggests that the continuous production of pro-inflammatory factors, primarily from adipose tissue, disrupts ovarian follicular dynamics.

The negative effects of obesity on ovarian function also decrease the quality of a woman’s eggs. The oocytes from obese women often show delayed maturation and meiotic defects, malfunction of cellular structures, and altered epigenetic profiles. This leads to poor embryo development, with many of the embryos derived from “obese eggs” failing to develop to the stage at which they can implant into the uterus.

There is also an inverse correlation between body mass index and levels of anti-Mullerian hormone, which can be used as a surrogate measure of oocyte number. Thus obesity may also cause premature ovarian ageing, with a reduction of the ovarian reserve effectively shortening the reproductive lifespan for obese women.

In men, obesity can be associated with lower testosterone, which leads to impaired semen parameters. Although it’s contentious whether obesity consistently affects sperm count, motility and morphology, it’s becoming evident that sperm quality is poorer in obese men.

Following fertilisation, the newly formed embryo attaches to the inner lining of the womb, the endometrium, and the outer cells of the embryo (which go on to form the placenta) must invade the tissues to gain access to the mother’s blood supply so that it can access oxygen and essential nutrients. This attachment and implantation phase of early pregnancy is governed by a complex dialogue of signals between the embryo and the mother’s endometrium, and depends on the endometrium becoming “receptive” to the embryo. Indeed, two-thirds of pregnancy failures are attributed to the failure of this intricate process.

Compelling evidence from assisted reproduction and miscarriage databases shows that obese women are more likely to experience recurrent miscarriages. As miscarriage often results from impaired or altered implantation of the embryo into the mother’s endometrium, it’s possible that obesity affects maternal–foetal communication during this process. Indeed, some of the signals between the embryo and the endometrium are not effectively functioning in obese women.

The impact of obesity on the endometrium has been examined in studies where oocytes donated by lean women and fertilised by lean fathers were implanted into obese recipients to remove the effect of obesity on both the egg and sperm. When the embryos from lean donors were transplanted into obese recipients there was a reduced chance of implantation into the endometrium, fewer live births and an increased risk of miscarriage, suggesting that obesity also has negative impacts on the womb.

When implantation of the embryo does occur in an obese mother there are further adverse consequences, such as inadequate placental development that can result in serious complications. For instance, obesity is currently the leading risk factor for pre-eclampsia in the developed world.

Thus the intra-uterine environment is vitally important for pregnancy success, and evidence clearly shows that maternal obesity disrupts this environment at multiple levels.

More alarmingly, clinical and animal studies demonstrate that the current obesity epidemic affects not only parents but also the health of their future generations.

Recent attention given to “three-parent reproduction” has highlighted the importance of mitochondria in the oocyte. Mitochondria are the powerhouse of cells, and those in the egg are transferred to all of the offspring’s tissues. The oocytes and embryos from obese mothers are often metabolically abnormal, displaying suboptimal mitochondrial activity that could be inherited by the offspring and thus placing them at greater risk of metabolic diseases, including obesity during their life.

Obesity throughout pregnancy or during breastfeeding also increases the chance of the child becoming obese. This likely occurs through the supply of excess calories to the child from the mother, and again demonstrates that obesity and diet can have negative impacts throughout the entirety of pregnancy and beyond.

These problems are magnified for obese couples because obesity-induced changes in sperm also compromise the health of offspring. Obese men are more likely to father obese children, and even their grandchildren have an increased risk of developing diseases such as diabetes.

Of course, these human studies are heavily confounded by common genetic predispositions to obesity and cultural factors involving poor dietary habits, both of which can be passed from parent to child. However, experiments in which animals are fed a high-fat diet to mimic obesity are able to better pinpoint how changes to sperm can lead to obesity in offspring.

These animal studies have clearly demonstrated that male obesity leads to the transmission of obesity to their offspring for up to two generations. It might be difficult to imagine how paternal nutritional signals are transmitted to offspring, but exciting new research is revealing previously unknown molecular components, including epigenetic modifications to the DNA and microRNA carried by the sperm into the egg. These molecular components of sperm are modified by obesity, and likely form part of the mechanism by which the metabolic characteristics of fathers are inherited by their progeny. It is these changes to sperm that are believed to transmit the signal from the father to the embryo at fertilisation and program the embryo on a growth trajectory that results in poor offspring health.

While obesity is clearly detrimental to both male and female fertility, as well as offspring health, these effects appear to be reversible. Recent studies of weight management programs for obese patients undergoing assisted reproductions have shown promising effects on their fertility.

Clinical and animal studies have shown that a change in lifestyle, such as exercise and modest weight loss, can improve the fertility outcomes of overweight and obese women. Interestingly, a mild exercise regimen during pregnancy improve pregnancy and birth outcomes in overweight and obese women despite not causing an effect on their body weight. If weight loss can be achieved, even a 5–10% reduction in the body weight of obese women improves metabolic and reproductive parameters such as circulating insulin, hormone levels, menstrual cycle regularity and ovulation.

Lifestyle changes regarding diet not only influence weight loss but can increase conception and live birth rates. Dietary interventions, such as reduced calorie intake, have a positive effect on the severity of the metabolic symptoms of PCOS, most likely due to improved insulin sensitivity and a dampening of chronic inflammation.

The study of the relationship between dietary habits and fertility outcomes in different communities, and their impact on disorders like PCOS, open a window for understanding the importance of a healthy diet on the reproductive health of women.

Similarly, the discovery of effective interventions that overcome the detrimental effects of male obesity on fertility and offspring health are providing promising results. For example, in an animal model of male obesity, diet or exercise restored not only fertility but also the molecular make-up of sperm and the health of offspring. This research is yet to be translated into the human setting.

There is mounting evidence that either a mother’s or a father’s obesity can not only impair their own fertility and chances of conceiving, but also impact on the future health outcomes of their children. Emerging evidence also suggests that when both parents are obese that these effects are compounded. The discovery of effective obesity interventions that translate into human use will provide both short-term benefits to the fertility of the individuals undergoing them and long-term health benefits for future generations.

Tod Fullston is NHMRC Peter Doherty Fellow at The University of Adelaide’s Robinson Research Institute, where Macarena Gonzalez is a PhD student. Jemma Evans is a Senior Research Officer at The Hudson Institute of Medical Research.