Fertility treatments: Can they increase the risk of cancer?
Do fertility treatments like IVF treatments increase a women’s risk of cancer? This is a question that has preoccupied gynecologists in recent decades. For every study that found such a link, there is a contradictory study that proves that this is not necessarily the case. So what is the answer and what price are women willing to pay for fertility?
Fertility treatments have been accompanied for more than two decades with concerns that these treatments may cause several types of cancer, including ovarian cancer, uterus, and breast cancer.
These concerns increased in the early 1990s when several studies reported a link between fertility drugs (which cause ovaries to produce several eggs at one time) and the development of ovarian cancer.
Finding the link between link between fertility drugs and cancer
Among other things, a systematic studies review published in 1992 and 12 case studies in the United States revealed that women who received ovulation induction drugs were three times more likely to develop invasive ovarian cancer. Although the media attention has faded over the years, it turns out that the debate itself has not disappeared at all, and despite countless studies on this subject conducted in recent years, it is still in the midst and has not yet been decided.
One of the largest studies in the field, published in January 2016 in the Journal of Cancer Research and Clinical Oncology, was conducted at Soroka Hospital, Israel. From 1988 to 2013, the researchers tracked 106,031 women with and without a history of fertility problems.
They found that fertility treatment drugs such as Gonadotropin does not increase the risk of ovarian and uterine cancer, but the risk of women who underwent IVF treatments with a higher load of hormonal drugs was 3.9 times higher, and the risk of uterine cancer was 4.6 higher, compared with women who did not undergo fertility treatments at all. The risk found was statistically significant.
“IVF treatments pose a significant long-term risk for ovarian and uterine cancer,” the study authors conclude.
“In order to put things in perspective, the absolute risk of women going through IVF to suffer from ovarian and uterine cancer is still very low,” said one of the study’s researchers, Prof. Eyal Shiner, director of the Department of Obstetrics and Gynecology at Soroka Hospital.
“The risk of ovarian cancer in the IVF group is less than 0.3%, but it is higher than for women who did not go through IVF, which is less than 0.1%.”
Israel is a global leader in the field of fertilization. With a 42% increase in vitro fertilization treatments occurred within the last two years and a new record of 37,270 treatment cycles in 2016. Or as Prof. Motti Pensky, director of the gynecological endoscopy unit at Assaf Harofeh Hospital, put it: “Israel is the world champion and second or third places are far behind”
Another Israeli study was published in 2012 in the journal Gynecological Endocrinology. It covered 2,431 women who began receiving fertility boosters in 1964-1974 and concluded that these drugs might increase the risk of uterine cancer.
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As for ovarian cancer, a study presented at the 2015 meeting of the American Society for Fertility in Baltimore found that the risk of women undergoing IVF to develop ovarian cancer was about 30 percent higher than those who did not.
Over the course of nine years, the study followed 255,786 women undergoing IVF therapy in England, Wales and Scotland between 1991 and 2010. However, most of the studies from recent years that focused on ovarian cancer and found a link between fertility and ovarian therapy indicated a higher risk of Borderal ovaries cancer – tumors whose malignant potential is relatively low, develop slowly and have fewer expansion chances than invasive cancer.
For example, an Australian study published in a Gynecological Oncology Journal tracked women aged 22-40 who underwent fertility treatments for 20 years and found that these women had a 2.46-fold increased risk of developing borderline ovarian cancer.
With regard to breast cancer, a study published in 2016 in Breast Cancer Research indicated that for women with fertility problems, fertility treatments may affect the density of breast tissue that can be a risk factor for breast cancer.
In a study conducted by the Karolinska Institute in Sweden among 43,313 women, it was found that women with a history of infertility had more dense breast tissue than women without fertility problems. However, this association was more pronounced in women receiving hormonal fertility drugs.
But it turns out that any study that found a link between fertility treatments and breast, ovarian or uterine malignancy, there is another study that found no connection. For example, a review of studies that included eight studies with 746,455 participants and published in the International Journal of Gynecological Cancer found no association between fertility treatments and the risk of malignancies.
Regarding breast cancer, a long-term study published in JAMA 2016 found no link between IVF treatment and increased risk of developing breast cancer. The researchers relied on a database in the Netherlands and analyzed breast cancer rates among 25,108 women, of whom 19,158 began IVF and 5,950 who began other fertility treatments between 1980 and 1995. ”
After a median follow-up of 21 years, the risk of breast cancer in the IVF group was approximately 3% similar to that recorded in the general population and in the group of women who did not receive IVF treatment.
A large review study published in 2014 in the Human Reproduction journal also came to the same conclusion. Among 1,554,332 participants they did not find a link between fertility treatments and an increased risk of breast cancer. In this state of uncertainty and conflicting research, it is no wonder that opinions in the medical community are divided.
“To date, according to existing studies, I do not think fertility treatments can cause cancer,” says Dr. Tal Shavit, a senior physician in the IVF unit at Hillel Yaffe Hospital. “The only exception is perhaps borderline ovarian cancer where there is an increase, but it is a much rarer and less dangerous type of cancer than invasive cancer. ” He says the real cause of cancer is not the treatments, but the problems that caused infertility in the first place.
“Fertility patients are a group that, regardless of treatment, has an increased risk of cancer,” he says. “If we consider, for example, the risk factors for ovarian cancer, one of them is more frequent ovulation cycles throughout life. The ovaries cause DNA damage to the ovary cells, which at some point can lead to cancer.
“Women who have never had children or have had multiple ovulation cycles, which increases the risk of DNA damage and the development of ovarian malignancy, and women with infertility use fewer pills, and it is now known that the use of the pill reduces the risk of ovarian cancer ”
The connection found in quite a few of the studies stems from his methodological problems. “Previous studies have compared women who received fertility treatments to untreated women, thus not taking into account the increased risk of women who did not have children to develop cancer.” The newer studies have already compared groups of women with fertility disorders treated with fertility drugs and women with untreated fertility disorders, and this is a more logical comparison that will allow us to understand whether the treatments themselves also increase the risk of cancer. ”
Dr. Shavit’s claims are consistent with the theories that attempt to explain the mechanisms by which ovarian cancer develops.
One theory described in the research literature is called the “incessant ovulation theory.” According to this theory, the increased risk factor is the damage and repair processes that occur in each ovulation cycle in the epithelial ovary cells. When ovulation cycles are frequent and occur without pregnancy and breastfeeding timeouts, continuous damage and repair processes increase the risk of DNA damage to these cells, increasing the risk of ovarian cancer.
Another theory is the theory of “high levels of gonadotropin.” This theory holds that increased risk of ovarian cancer is an outcome of the constant exposure to gonadotropins from the pituitary gland. These hormones irritate the ovaries to produce sex hormones and eggs. In this process they stimulate the epithelium over the ovaries, thereby increasing the risk of malignant changes.
Which fertility drugs may lead to malignancy?
Because of the greater number of ovulation cycles, unmarried women are exposed to higher levels of gonadotropins for longer periods of time, thus increasing the risk of ovarian malignant changes. However, unlike Dr. Shavit’s position, these two theories also offer an alternative explanation according to which fertility drugs are the ones that stimulate the processes that lead to malignancy.
“It is important to note that the two theories also suggest that the use of fertility drugs, which promote ovulation and create conditions for high levels of gonadotropin, can also increase the risk of ovarian cancer,” said an article published in the journal Current Opinion in Obstetrics and Gynecology. “Moreover, based on this, the use of fertility drugs is particularly worrisome, especially in women with infertility who do not become pregnant despite the use of ovulation induction drugs.”
So what is really the cause of the increased risk of cancer – the fact that women did not have children and the problems that led to infertility or fertility drugs? Or perhaps a combination of all these factors together? “This riddle is very difficult to solve, and it is doubtful whether we will have an unequivocal answer in ten years,” says Prof. Pensky. “The reason for the tremendous difficulty stems from the fact that there are a lot of confounders (confusing variables) that can affect the outcome, such as age.
“Today, more than a third of fertility patients are over 40 years old, and because the risk of cancer is higher as age increases, so it’s hard to determine if the age or IVF drugs are a leading cause”
Another important confounding factor is the type of infertility. “There are several subgroups of fertility patients, for example, in nearly 50% of the women receiving fertility treatments, the problem is with the male partner, another group is women who have ovulation problems, and another group has a mechanical problem. If infertility is due to the male factor and the woman has no fertility problems, it’s harder to claim that the original infertility problem caused cancer.
“A third confounder is the type of protocol that the woman has received, which is also very important, and the fertility drugs are constantly changing, so we should distinguish between women who were treated 20 years ago and those treated 10 years ago. A significant fourth confounding is the duration of follow-up – there are many studies that have followed women for only five years, but how can you know what will happen 15 years later? ”
Indeed, new studies are trying to take into account the various mistletoes, but the problem is that it’s not easy to do so. “The attempt to create a research system in which as many confounders can be neutralized, so that the women will be similar in age, the type of treatment they receive, the type of infertility and other variables leads to very small numbers of participants, which of course harms the validity of the study,” explains Prof. Pensky.
Whether the cause of malignancy is the treatments themselves or some factor related to infertility, one thing is certain – women undergoing fertility treatments are a risk population that needs to be monitored. Shiner says this is the most important conclusion from the studies. “As a doctor who really cares for women, I do not care what the reason is.” The bottom line is that women who have IVF are a population whose risk of long-term morbidity is high relative to the normal population and should, therefore, be monitored more closely. ”
The long-term risk of malignancy in women undergoing fertility treatments is one of the topics discussed in a recent book published by Prof. Shiner, The Long Term Effects of Medical Complications. (The long-term implications of complications in pregnancy).
“We gynecologists need to get out of the box of focusing on getting pregnant and think more about possible pregnancy complications,” he says. “Today it is clear to us that pregnancy is a window of opportunity to identify diseases and problems that may occur in the long term”.
“We now know, for example, that the risk of a woman with gestational diabetes having overt diabetes is more than 50% within five years that women with preeclampsia have increased cardiovascular risk in the long run and that complications such as a renal hernia have long-term consequences “It is quite possible that all these complications are a pregnancy problem only, but these women are still at long-term risk, as are the women in fertility treatments.”
About Fertility Treatments and breast cancer
Prof. Pensky agrees with this recommendation. “With regard to breast cancer, long-term follow-up is especially important for some groups at particular risk: one is the group of women who have been genetically proven, such as BRCA, the second group are women without genetic carriers, A third group are women who have undergone many treatments over time, as these women have had a great deal of exposure to fertility drugs.
A fourth group is the same women that unfortunately did not get pregnant despite many treatments, in light of the fact that pregnancies protect from breast and ovarian cancer to some extent due to a decreased estrogen exposure during pregnancy. Another risk group is older age – the older the woman, the greater the risk of malignancy. In these cases, it is recommended to be followed more closely – to perform periodic breast examinations more frequently and to be in contact with a breast surgeon. ”
And what about ovarian cancer?
“Unfortunately, there is very little difficulty in diagnosing ovarian cancer, and there is currently no marker or test that can detect its development at an early stage, and as proof, about 70 percent of ovarian cancer cases are diagnosed at advanced stages. In a six-month period for a gynecologist, but unfortunately one can not say in this case that closer monitoring ensures that we identify cancer early.
“However, borderline ovarian cancer, which some of the studies found fertility drugs may increase its incidence, can be diagnosed at a relatively early stage because it develops slowly and is much less aggressive than normal cancer.
“Although it is considered borderline, between malignant and benign, it is still treated as cancer, but its treatment is far less radical, and if it is caught early, a patient can live for many years after it is treated.”
Prof. Pensky recommends that women who already have children carefully consider the decision to perform fertility treatments to bring another child. Of course, couples who do not have a child will do anything to bring a child into the world, but there are quite a few couples who already have three or even four children and are willing to undergo Fertility treatments to give birth to another child, and you have to understand that there might be a price for fertility treatments. ”