Tracing the Origins of Female Infertility

Women are not well researched. The female sex is underrepresented in many large studies where they test things like new therapies to prevent and treat the more common medical problems such as heart attacks and strokes. It is very difficult to disabuse people of the conviction that these are typical male afflictions. Yet women are affected by such cardiovascular maladies in the exact same frequency as men albeit at a more advanced age. On average they fall prey to these ailments ten to fifteen years later then the male sex. Before menopause, which on average occurs at fifty years of age, women are more or less solidly protected against vascular disease and its consequences.

But how exactly does this protection from disease originate and why is it much less pronounced in some women than in others? It is astonishing that these questions have still today not been answered. The only thing which seems assured is that certain factors which impact fertility play an important role in safeguarding their overall health. But the processes involved are much more complex than at first presumed. Moreover there is very little heed given to the observation that the so-called diminished ovarian reserve, which is one major cause for infertility in women, might mean much more than just that. Ovarian reserve, the number of viable ova (oocytes) to be found at a given time in the ovaries, is a gauge of female fertility. “It is physiologically normal,” says Lynae Brayboy, “that the ovaries age earlier than other female organs. However, if women suffer from diminished ovarian reserve, there is an increased risk of heart attack, stroke, osteoporosis, and presumably also dementia.”

Brayboy has spent five months as a Fellow of the College for Life Sciences at the Wissenschaftskolleg zu Berlin studying in vivo methods to test mitochondria and apply these techniques to study female infertility: “It has become clear that women whose ovaries have been removed have a shorter life expectancy than their female peers who have not undergone such a procedure. So there would seem to be a close connection between a woman’s fertility and the state of her health. We should therefore keep a very watchful eye on patients with limited fertility because according to all that we know today the condition of reduced fertility is symptomatic of a much more deep-seated health problem.” She wants to know the precise nature of this health problem and how to tackle it.

Lynae Brayboy grew up in St. Petersburg, Florida, as an undergraduate attended Florida A&M University, then went on to study at Temple University School of Medicine and completed a residency in Obstetrics and Gynecology at Abington Memorial Hospital. Her main interest is reproductive medicine. She says that from the very beginning of her medical training she realized that the health of women was much less well researched than that of men, and it is particularly in the sphere of reproductive medicine that there are still great gaps in our knowledge. Her special focus is on women with a diminished ovarian reserve – when the ovaries contain fewer oocytes and/or are of inferior quality. Brayboy estimates that “about one-third of all women at our clinic who undergo in vitro fertilization have a diminished ovarian reserve. In the general populace the proportion of effected women is some 11 percent, at least in America. Sometimes the response to ovarian stimulation is so reduced that the most aggressive treatment of in vitro fertilization fails. Some of these patients will then opt for an egg donation, a procedure which is prohibited in Germany.” She emphasizes that pregnancies with donated ova will remarkably often issue in complications, for example preeclampsia. Formerly known as toxemia of pregnancy, this medical condition is extremely dangerous for both mother and child and is accompanied by a series of disorders – e.g. high blood pressure, kidney damage and the accumulation of water in the tissue. The physician summarizes her own hypothesis, which however still must be tested, in the following way: “Many scientists go by the assumption that such pregnancy complications spring from the donor egg, that is they are constituting a kind of allergic reaction. In my opinion the gestational hypertension is there because the diminished ovarian reserve is a symptom of pre-pregnancy cardiovascular disease which increases the risk for hypertension in pregnancy and heralds also future cardiovascular diseases.

According to Brayboy there are a number of reasons why the causes of diminished ovary reserves have been subject to so little scrutiny: “In the 1970s and 1980s the premature aging of ovaries was less conspicuous than today, for back then the women giving birth to their first child were generally younger than is the case presently.” In the meantime, many women are over thirty or even forty years of age when they first become mothers. But at this stage in their life the ovary reserves are clearly more reduced than between the ages of twenty and thirty, and if you add to that an accelerated aging process of the ovaries, then a woman can have problems getting pregnant at a relatively early age – i.e. in her late 20s or early 30s. A girl is born with one to two million ova and by the time she reaches puberty there are only some 50,000 to 300,000 left. This decline continues until menopause. So the number and quality of ova are substantially determined by a woman’s age, but not only, since her genetic background and external factors are also important. Brayboy says that “smoking, certain environmental toxicants, and also chemotherapy can all accelerate the natural aging process of ovaries.” But many of her patients, who cannot become pregnant in the natural way because of diminished ovarian reserves, were never exposed to toxic substances. In such cases the fertility problem must then have other causes. Brayboy is bothered by how women so affected have hitherto all been treated in the same way: “Women who come to our clinic for in vitro fertilization all receive the same medication. I’m very frustrated by this. Poor fertility can have a variety of causes. We have work to do until we understand the origins of each individual’s disease.”

In searching for the pathological processes which accelerate the demise of ova and thereby prematurely exhaust the ovarian reserve, the scientist has already been able to obtain valuable insights. Her patients have also given her fresh impulses and she cites an example: “Some time ago a woman with cancer wanted to know whether ova are capable of protecting themselves from chemotherapeutic medication. I was very preoccupied with this question, for it is extremely relevant. Many of my patients suffer from cancer and must therefore submit to chemotherapy. Only a small number of them can afford to have their own oocytes frozen before undergoing cancer treatment. That’s why I thought it important to search for possible protection measures of the ova so that I would be able to give these women an answer to their questions.”

Brayboy studied a transport protein by the name of MDR-1 (Multi-Drug Resistance) which rids the body of toxic substances and waste products. This cleansing action is undertaken in such places as the gastro-intestinal tract, the kidneys and liver, and in the vessel cells of the blood-brain barrier. As her investigations showed, the detoxification protein also plays an important role in the oocyte. Among other things it rids the female gamete of chemotherapeutics. Brayboy concedes that “MDR-1 has gotten a bad press for a long time because cancer cells as well as bacteria have the ability to produce large amounts of this transport protein and thus defend against chemotherapy and antibiotics respectively. That’s why these drugs frequently lose their effect.” But conversely it is also inauspicious when transport proteins are lacking or don’t function because of a defect. She goes on to explain: “Mice with genetically conditioned deficiencies of MDR-1 cannot sufficiently dispose of toxins and metabolic waste. These compounds can then wreak havoc in the body. The gastro-intestinal tract is among those organs that they especially afflict. The affected mice develop intestinal inflammations which resemble those of Crohn’s disease in humans.”

It was only recently that Brayboy made another important discovery. She and her colleagues were able to demonstrate in mice that ova have a considerable supply of MDR-1 at multiple sites. Hence the transport protein is to be found not only in the outer casings but in the membranes of the mitochondria – the cellular power plants – of the oocytes. But if the detoxification protein cannot perform its duties or is entirely missing, then large amounts of oxygen radicals accumulate in the oocyte or egg. Yet an overload of these chemically highly aggressive substances is a considerable burden for the cellular energy suppliers; at the same time, it damages the ova where the overworked mitochondria are located. This is what emerges from the animal-experiment studies of the scientist. So Brayboy regards it as conceivable that the diminished ovarian reserve of her patients has similar origins; that is to say, also in conjunction with a genetically conditioned malfunction of MDR-1 or one that might have been later acquired. She says: “I want to address this question in detail. But I would like to first understand how the mitochondria’s dysfunctions impact the maturation of ova and embryos.” Brayboy thinks it very probable that such defects compromise early embryonic development. In those first days the newly emergent life is completely dependent on the mitochondria’s energy drip. She explains: “After fertilization by the sperm it is some five days before the fertilized ovum and ensuing embryo has traveled through the fallopian tube and implanted itself in the womb. During this period the ovum has no access to a blood supply, instead it draws its energy exclusively from the mitochondria. If the cellular power plants are unable to cover the energy needs of the growing embryo then this early developmental process presumably comes to a standstill. At least we assume this to be the case.” Brayboy’s team wanted to find out whether a premature depletion of the ovarian reserve goes back to genetically conditioned defects of the transport protein MDR-1.

Mutations in the gene that contains the construction manual for the transport protein MDR-1 are extremely frequent. But according to current findings, the overwhelming majority of these have no health consequences – at least no overt ones. One of the innumerable genetic variants, however, is under suspicion for slightly lessening the function of MDR-1 and thus fostering breast cancer. Brayboy wants to undertake a detailed investigation of the degree to which such disorders impair female fertility, and she would like nothing better than to devote herself exclusively to answering just such scientific questions.