Substantially increased body weight can have a significant negative impact on female fertility.

But how exactly can excess body weight affect reproductive function in women?

A possible explanation comes from a study by Natalia Igosheva and colleagues from King’s College London, London, UK, just published in PLoS.

Using an established mouse model of maternal diet-induced obesity and live cell dynamic fluorescence imaging techniques, the researchers demonstrated that maternal obesity prior to conception is associated with altered mitochondria in mouse oocytes (eggs) and zygotes.

Specifically, maternal diet-induced obesity in mice led to an increase in mitochondrial potential, mitochondrial DNA content and biogenesis. Generation of reactive oxygen species (ROS) was raised while glutathione was depleted and the redox state became more oxidised, suggestive of oxidative stress. (for my non-technical readers, it suffices to say that none of this is good for the egg or the zygote).

These altered mitochondrial properties were associated with significant developmental impairment as shown by the increased number of obese mothers who failed to support blastocyst formation compared to lean dams.

These studies show that compromised oocyte and early embryo mitochondrial metabolism, resulting from excessive nutrient exposure prior to and during conception, may underlie poor reproductive outcomes frequently reported in obese women.

While the leap from mice to women may seem a bit of a stretch, there is no doubt that in many overweight and obese women trying to become pregnant, weight loss is clearly one of the most effective strategies.

Now all we need are more effective strategies to help manage excess weight.

AMS
Edmonton, Alberta

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Igosheva N, Abramov AY, Poston L, Eckert JJ, Fleming TP, Duchen MR, & McConnell J (2010). Maternal diet-induced obesity alters mitochondrial activity and redox status in mouse oocytes and zygotes. PloS one, 5 (4) PMID: 20404917

Yesterday, on my way to the American Heart Association Meeting in Orlando, I read Malcolm Gladwell’s recently published anthology of articles he wrote for The New Yorker magazine, now published under the name, “What the Dog Saw”.

Of all the fascinating essays, the one that I found most interesting in terms of its implications for women’s health, was the story of the discovery of the birth-control pill and how it has led to a complete transformation of women’s societal role and health.

The essay starts with the story of John Rock, a devout Catholic and one of the inventors of the pill. For most of his life Rock tried (unsuccessfully) to harness acceptance for his invention by his Church as a “natural” method of birth control. The Church, however, failed to follow his argument that the pill should be considered a “natural” method, because it essentially uses a “natural” hormone (progesterone) to simply mimic a “natural” state of pregnancy and thereby prevent ovulation.

Apparently, it was also to further support his argument of “normalcy”, that Rock and his collaborator Gregory Pincus devised the idea of introducing a monthly interruption in hormone delivery to trigger monthly menstrual periods. The underlying assumption for the latter was that monthly periods were indeed “normal” for women of reproductive age.

The interesting twist in Gladwell’s essay, however, comes when he goes on to describe how throughout most of human history, women did not actually have monthly periods through most of their reproductive years.

As an example for this Gladwell cites the work by Beverly Strassmann, who studied menstrual periods amongst women in the Dogon tribe of Mali. Not only did the Dogon women on average experience their first periods at age 16, but in addition they spent so much time either pregnant or breast feeding that they generally experienced only around a 100 periods over their lifespan.

This situation is of course fundamentally different from women in Western societies today, who not only have their first periods at age 12 (in part due to increasing adiposity?), but as a result of delayed and fewer pregnancies as well as markedly shorter breast feeding, experience almost 400 periods over their lifetime.

Each menses not only involves ovulation, growth and sloughing of the endometrium, but also increased cellular division of the breast. Gladwell cites work by Malcolm Pike and others, who argue that this remarkable increase in the number of menstrual cycles explains virtually all of the excess risk for ovarian, endometrial and breast cancer seen in “Western” women.

Thus, avoiding menstrual cycles (or rather pushing these back to around 100 over a lifetime) may be a major strategy to reduce the incidence of these cancers. While giving the birth-control pill over longer time intervals (rather than just for 3 weeks at a time) may work to reduce the frequency of menses to say 4-times a year and thereby reduce the risk of ovarian and endometrial cancer, the fact that the pill still contains some estrogen may actually not do much for breast cancer. Pike and colleagues therefore apparently suggest using GnRH (gonadotropin-releasing hormone) antagonists, thereby mimicking menopause rather than pregnancy.

While, I can only assume that this concept still remains fairly controversial, if true, it certainly bears some significance for young girls, especially those with excess weight.

Readers of these pages are probably well aware that overweight girls often get their first periods significantly earlier than normal-weight girls. In addition, overweight girls may also be more reluctant to take the pill due to fear of adverse effects (hypertension, thombosis, etc.).

What if, as discussed by Gladwell, early menarche and late (as well as fewer) pregnancies truly is a major risk factor for female reproductive cancers?

What if much of this is further exacerbated by excess weight (earlier menarche, fewer pregnancies and higher estrogen levels)?

While most readers will perhaps think oral contraception acceptable for a 16 year-old, most of us would probably find any suggestion of starting a 10-year old on pills to suppress menstrual cycles rather disturbing.

I am certainly not a reproductive endocrinologist or oncologist, nor do I pretend to know much of the literature on this, but the Gladwell essay certainly got me thinking.

As always, all comments are very much appreciated.

AMS
Orlando, Florida

Does it seem like daughters are growing into women (at least physically) faster than in previous generations?

This may be an interesting consequence of the obesity epidemic, based on new research by Sarah Keim and colleagues from the National Institute of Child Health and Human Development, Bethesda, MD, USA, just published in EPIDEMIOLOGY.

In a follow-up study of the prospective Collaborative Perinatal Project, about 600 grown daughters were asked in 1987-1991 for their age at menarche and compared to data from the original Collaborative Perinatal Project (1959-1966), which included their mothers’ height and prepregnancy weight.

Compared with mothers with a BMI less than 25, the daughters of mothers with a BMI of 30 or greater were three times more likely to experience their first period at ages 12 or younger. This association remained after adjusting for maternal age at menarche, maternal parity, socioeconomic status, and other factors.

While the data clearly show an association between maternal obesity and younger menarcheal age among daughters in this study, the study of course does not prove causality nor does it provide any insight into the biological mechanisms underlying this association.

Nevertheless, I do wonder about the consequences of early menarche on the psyche and physical development of young girls born to obese mothers and its impact on future generations.

AMS
Berlin, Germany