(WOMENSENEWS)— Dr. David Keefe is the Stanley H. Kaplan professor and chair of obstetrics and gynecology at New York University’s School of Medicine and specializes in reproductive endocrinology and infertility. He recently spoke by phone about what is known and what remains mysterious about infertility.
At this year’s Women’s Health Congress you gave an update on infertility. What updates are there?
So much of infertility is unexplained. So I focused the update on the frontiers of infertility research; what are we learning, where are things headed in understanding unexplained infertility.
It turns out that a large percentage of unexplained infertility is actually related to chromosome problems that emerge in the embryo itself rather than being transmitted through the egg or through the sperm.
They arise as the egg matures or during or after fertilization and there’s a new technology that’s being widely used with this today. It would typically be used after a couple tries the initial low-tech approaches. If that fails and they go to IVF, [in vitro fertilization], about 70-to-80 percent of those women going through IVF, before the embryos are put back in, will have the embryos tested for chromosome problems using next-generation sequencing, which is this genome technology that’s revolutionizing medicine.
Before transferring the eggs, we make a little scratch in the shell around the embryo, and we let the part of the embryo destined to become the soma sort of buckle out, and then we take some of those cells and check all of the chromosomes and make sure there are two copies of each of the 23 pairs of chromosomes. [And if a chromosome is missing that egg won’t be implanted.]. In doing that, the success rate, even if a woman has just one normal embryo, the success rate is about 65 percent. And it’s not affected by her age.
So it appears that much of the effect of aging is mediated through the presence or absence of chromosome abnormalities in each embryo. Now the probability of having a chromosomally normal embryo does go down with age. But it allows women to, in many cases, avoid miscarriages because the miscarriages that increase with advancing age result from chromosome abnormalities. So by only transferring chromosomally normal embryos, we’re able to significantly reduce the risk of miscarriage.
The other thing that we’re doing is elective egg freezing. By removing the eggs while a woman is still in a fertile phase of her life and then freezing them, we’re able to lock in the fertility rate of that age.
What are you researching?
In my research we’re looking at why are there so many chromosome abnormalities in the embryos from women who are older. Nobody knows why. But we’ve been working for some time on a theory that it has to do with a very specific part of the chromosome, the telomeres.
It turns out that telomeres are very important in regulating the aging in many cells, from plants to humans. They are involved with the alignment of chromosomes very early in development. Using animal models, we were able to show that the disruption of telomeres, genetically or pharmacologically in mice, can cause mice to end up looking indistinguishable from older women in that they have fewer eggs and they don’t readily implant.
We’ve also found a number of women that have a genetic condition that disrupts their telomeres and they also have accelerated aging of their reproductive system. We have ongoing research in which we’re studying the ability of telomere length measurement in eggs to predict the presence or absence of these chromosome abnormalities in embryos. The direct application of this research would help women when deciding to freeze their eggs. Do they need to? Or are they one of the chosen who doesn’t have to worry about this due to higher chances of fertility later in life? We hope to be able to help women make more personalized decisions.
To back up a bit, what do we mean when we say infertility?
It has a specific definition. If a woman is 35 or older it means that she has tried to get pregnant unsuccessfully for at least six months. Under 35, she’s tried unsuccessfully for one year. The reason there’s a different criteria depending on age is that after 35 the fertility rate declines with age. So it’s kind of a moving target and we don’t want to have to wait too long and force a woman to meet more stringent criteria. And behind those numbers is the reality that the chances of getting pregnant in a couple that are essentially normal are only 20-25 percent. I think many people are shocked by the relative inefficiency of fertility in humans. So the definition then depends on the age of the woman largely because we don’t want to wait too long in a woman who’s past age 35.
What are some of the causes of infertility?
Fertility can be divided broadly into factors that are exclusive to the woman, factors that are exclusive to the man, and a combination of factors. So in a woman, there can be irregular cycle, like for example if a woman does not ovulate every month because of polycystic ovaries or because she does extensive exercising or dieting or has a hormone imbalance – any of those can keep her from ovulating. There can be a blockage of the fallopian tubes due to endometriosis or prior infections. There are uterine factors like fibroids. Many women have them, but the presence of the fibroids themselves doesn’t lower fertility. However, if fibroids arise in the inner part of the uterus where the embryo needs to stick, that can have a disruptive effect on implantation or cause a miscarriage. Scar tissue can be a problem if she had prior procedures that disrupted the normal and the protective layer of the uterus.
From the male side, it basically boils down to sperm problems; low count, low motility or both. Ejaculatory problems, some men cannot ejaculate or they ejaculate back into their bladder. Some men have a problem having an erection and some men have very low sperm production because of nervous problems or because they have testicular failure from prior trauma or some genetic condition. And then very much so with infertility, probably more than any disease, you can have a little of this a little that. It’s not common to have a single problem.
And behind all of these causes of infertility there’s a recurrent theme that whatever the problem is, at the end of the day, the woman’s age is the single biggest predictor of whether the treatment will work. So even if the couple walks in and the man has no sperm on his semen analysis, the best predictor of whether they will conceive is how old she is.
Because frequently, even in that seemingly dire situation, we can get a few sperm from the testicle with a biopsy and then it would depend on the viability of the woman’s eggs. And that drops initially slowly after 35 but accelerates after 38 and is mainly unsuccessful after 43.
How many women are affected by infertility?
It’s generally thought that about 12 percent of couples are affected by infertility. It’s pretty substantial and it goes up with age. So in younger women that number is lower and in older women, particularly in their late 30s to early 40s, that number can be much higher.
What are some of the current treatments?
Typically, we do a limited number of validated tests to identify that all of the ingredients are present. We want to make sure the woman is ovulating. The presence of regular menstrual cycles between 25-34 days generally is indicative of ovulatory cycle. We want to be sure that there are no hormonal imbalances; that there’s no low thyroid or high prolactin and no excess of male androgen. We want to make sure her fallopian tubes are open and make sure the uterus is normal. And then we check the sperm in the man; look at motility, the concentration, and the shapes, because there are some that are abnormal. And then having done that, the initial treatment is targeted to the specific condition.
If her fallopian tubes are blocked, we would proceed directly to in vitro fertilization.
Much more commonly we might see an irregular cycle in which case we would regulate ovulation. If it’s low thyroid, we would treat the low thyroid. If it’s high prolactin [a hormone produced by the pituitary gland], we would treat the high prolactin. If there’s an imbalance of hormones leading to what we call polycystic ovaries, we would induce ovulation with a very gentle stimulant, a pill that the woman would take for five days.
And then many times, particularly in the practices of specialists, very frequently you see women in which all of the testing is normal. We call that unexplained infertility and it’s very common. In my practice, probably 60 percent of the women have it. In that setting we can still help them.
There are very effective treatments for unexplained infertility. Generally, we optimize the timing of the ovulation and we use a very low-tech procedure where we concentrate the sperm onto a small drop and then place the drop of sperm at the top of the uterus where the egg will drop. And doing that we can overcome some of the relative inefficiency of human reproduction. We do that for a limited number of times and if that doesn’t work, we go to IVF.
