Does infertility treatment cause ovarian cancer?
We are commonly asked if IVF increases the risk of ovarian cancer. Studies conducted over the past 20 years have tried to answer this question. A recent publication by van Leeuwen, et al., examined this issue carefully and produced some very interesting results.
What were the study basics?
The study published recently in Human Reproduction involved a very large retrospective analysis (data collected from the past) in the Netherlands of 25,152 infertile women (19,146 IVF and 6,006 non-IVF infertility patients) who received their infertility treatment between 1983 through 1995. The extensive follow-up period, which averaged about 15 years, made this study unique amongst others.
Why might infertility treatment result in ovarian cancer?
It has been theorized that the risk for ovarian cancer, which is estimated to be a 1/72-lifetime risk in the US, would increase because of ovarian stimulation and/or multiple ovulation sites forming across the surface of the ovary. Partially dispelling these concerns, this study did not show any increased risks for ovarian cancer for non-IVF infertile patients treated with either oral or injectable fertility medications. Also, further debunking the theory was the fact that the risk for ovarian cancer did not increase as the number of IVF cycles increased.
Is there something special about the IVF patient that increases her risk for ovarian cancer?
We also have wondered if the IVF patient simply has something wrong with her ovaries that predispose her to infertility, IVF treatments as well as ovarian/borderline ovarian cancer. The fact that there was a much larger percentage of “unexplained infertility” patients in the IVF-treated group suggests the IVF and non-IVF patient groups were indeed very different from each other.
Also understanding that borderline ovarian cancers normally make up only 20% of all ovarian cancers and are not anywhere as lethal as the more common ovarian cancers, it was somewhat unexpected to find that 46% of all ovarian cancers identified in the infertility patients in this study were borderline cancers. This high percentage of borderline lesions also suggests that something was unusual about the IVF-treated patient population.
What were some of the important findings in the study?
In reading this paper carefully, I was able to identify the following important points, some of which were not emphasized in the study:
- Tubal infertility IVF patients (i.e., past and/or chronic pelvic infections) were twice as likely to have invasive or borderline ovarian cancers.
- Those IVF patients who never conceived were twice as likely to have any ovarian cancers and three times more likely to have borderline ovarian cancers.
- In the study, the actual risk for any ovarian cancer by age 55 was estimated 1/141 (0.71%) in the IVF group compared to 1/222 (0.45%) for the normal population, an overall increased risk of 1/3rd but still a very rare event.
- Also in the study, the actual risk for borderline ovarian cancer by age 55 was approximately 1/600 for the IVF patients compared to 1/1,200 for the general population, essentially doubling the risk. Still the actual incidence was still very, very rare.
What did we really learn from the study?
While I feel the authors did an amazing job collecting and analyzing the data, I felt the discussion section missed a few very important points:
- Those that underwent IVF, especially unexplained infertility patients, may still differ in some way which may increase their risk for both prolonged infertility and ovarian/borderline ovarian cancers.
- In other words, it may not be the IVF procedure itself as much as the underlying characteristics of the IVF patients, which predispose them to ovarian cancer risks.
- Acute or chronic pelvic infections may very well increase the risk of borderline ovarian cancer.
- The fact that IVF-treated patients were far more likely to have past pelvic infections may have been responsible for many of the findings described in this study. To the best of my knowledge, this has not been described before. Interestingly, chronic inflammation in other areas of the body also predisposes to some forms of cancer. Perhaps the pelvis is the same.
- If one conceives through IVF, the risks for ovarian and borderline ovarian cancers drop to normal levels.
- Either the pregnancy helps reduce the ovarian cancer risks or those who conceive are inherently at a reduced risk for ovarian cancer compared to those who never conceive.
- This point has been found to be true with past studies that showed an increased risk of borderline ovarian cancers with the use of oral clomiphene citrate when used for more than 12 cycles without an eventual pregnancy. Once pregnancy occurred, even resulting in a miscarriage, the borderline ovarian cancer risks normalized (Rossing MA, et al. 1994).
- Current regimens used to stimulate the ovaries are very different from those used prior to 1995.
- The current risk factors could be better, worse or the same as those described in the study because IVF protocols have significantly changed since 1995.
The risks for ovarian and borderline ovarian cancer for infertility patients undergoing IVF may be incrementally increased compared to the non-IVF population. Interestingly, far less lethal borderline ovarian cancers are found in a greater percentage in this very special patient population. Confounding factors, such as tubal factor infertility with acute/chronic infections, may increase the risk for ovarian malignancy in this patient population.
No matter how statistically significant the findings are, one still must note that the actual risks described in this study for women age 55 are still extraordinarily rare: 1/141 for any ovarian cancer and 1/600 for borderline ovarian cancers. These risks also are unlikely to deter a highly motivated infertility patient. Keep in mind that the average risk for a genetically abnormal child in IVF-treated patients is probably closer to 1/100, which is far higher than any of the risks for cancer listed in the current study. Let us all keep our perspective.
Still, we need to collect further data as many of the women in the study were only in their middle 50’s and the risks for ovarian cancer generally increase with age.
Above all, an IVF conception may very well reduce the ovarian cancer risks significantly. If conception never occurs, this may signal physicians to monitor the unsuccessful patients more carefully for future potential ovarian malignancies, although the actual incidence of the disease may still be quite rare.
Congratulations to the researchers who put an amazing amount of work into this study and we thank them for their dedication to infertile patients and to those of us who care so much for them.
Craig R. Sweet, M.D.
Specialists in Reproductive Medicine & Surgery, P.A.
van Leeuwen FE, Klip H, Mooij TM, van de Swaluw AM, Lambalk CB, Kortman M, Laven JS, Jansen CA, Helmerhorst FM, Cohlen BJ, Willemsen WN, Smeenk JM, Simons AH, van der Veen F, Evers JL, van Dop PA, Macklon NS, Burger CW. Risk of borderline and invasive ovarian tumours after ovarian stimulation for in vitro fertilization in a large Dutch cohort. Hum Reprod. 2011 Dec;26(12):3456-65.
Rossing MA, Daling JR,Weiss NS, Moore DE, Self SG. Ovarian tumors in a cohort of infertile women. N Engl J Med 1994;331:771–776.
How common is polycystic ovarian syndrome?
Polycystic ovarian syndrome (PCOS) is one of the most common endocrine diseases affecting about six percent of reproductive age women. PCOS is one of the main reasons women have difficulty conceiving. About half of all women who do not ovulate on a regular basis will be diagnosed with PCOS.
In recognition of PCOS Awareness Month, I've developed this review for patients dealing with this disease.
How is PCOS diagnosed?
As a syndrome, PCOS is a constellation of findings. Alone, it really is not a disease but simply a label. But physicians use these labels to our patients’ advantage. If we suspect PCOS, we will search for the problems that commonly accompany PCOS, minimizing their effect while possibly changing the course of the illness.
PCOS requires at least two of these three problems for a diagnosis:
- Ovulatory dysfunction: irregular cycles or blood progesterone levels that indicate failed ovulation.
- Ovarian hyperandroginism: excess male hormones including an unusual amount of facial/body hair or elevated male hormones, such as testosterone, in blood tests.
- Polycystic ovaries on transvaginal ultrasound: more than 12 small 3-9mm follicles within each ovary as seen on an ultrasound. At times, we will see the signs of a classic “necklace,” with small cystic follicles located on the periphery of the ovary and which look like a pearl necklace.
Clinically, there seem to be two main types of PCOS: 1) Patients who were essentially born with the problem and have never really had normal cycles, and 2) Patients who have had normal cycles but demonstrate symptoms as they gain weight. Upwards of 80% of all PCOS women are heavy, but 20% can be quite slender.
Other issues include thyroid problems, elevations of the pituitary hormone prolactin and a handful of rare inheritable enzyme deficiencies. These problems need to be screened for and ruled out before settling on the diagnosis of PCOS.
PCOS is probably the single most common diagnosis we see in our patients. Its incidence has been increasing over the last 20 years as the US population has shifted from normal weight to the overweight, obese and morbidly obese categories.
How do you diagnose pre-diabetes in the PCOS patient?
To diagnose insulin and glucose problems, commonly called pre-diabetes, we prefer a 10-12 hour fast with baseline glucose and insulin levels rather than fasting glucose levels alone. The endocrine system is then challenged by having the patient drink 75 grams of glucose (Glucola®), which is called a Glucose Tolerance Test (GTT). Two hours later, insulin and glucose levels are repeated to complete the study. We do not require blood tests every 30 minutes as some protocols suggest, since the fasting and two-hour results are sufficient.
Insulin resistance or actual diabetes is present in nearly half of all PCOS patients. The more the patient weighs, the more likely the diagnosis.
What really causes PCOS?
While many women believe their hormone imbalance is mainly caused by testosterone, insulin seems to be the key hormonal culprit. Excess insulin stimulates the ovaries to produce excess male hormones. Also, excess insulin predisposes the PCOS patient to numerous medial problems, including cholesterol elevation, hypertension and possibly heart disease. Insulin is the key.
How is PCOS best treated?
Treatment in the overweight PCOS patient includes diet, exercise, weight loss and aggressive prevention and treatment of pre-diabetes (insulin resistance and/or glucose intolerance).
Beyond this basic treatment, there are generally two treatment pathways: the “quality of life path” and the “pregnancy path”.
Quality of Life Path
PCOS patients who are not trying to get pregnant should follow the quality of life path and focus on treating the signs and symptoms. Because they don’t shed the inner endometrial lining on a regular basis, PCOS patients are at greater risk for abnormal uterine bleeding, anemia, endometrial polyps, pre-cancer and eventually, even cancer of the lining of the uterus. Hormonal control is used in this pathway. We also suggest aggressive treatment for hair growth, including the use of hormones, electrolysis or laser hair removal. The psychological affects of excess facial and body hair on women should not be minimized and may be the primary concern for PCOS patients.
We recommend that PCOS patients who want to get pregnant use a winning combination of diet, exercise, weight loss and anti-diabetic medications such as metformin (Glucophage®) that are combined with ovulatory medications. Metformin helps in a number of ways including dropping male hormone levels in half and assisting in weight loss. Gas and diarrhea results when too many carbohydrates are consumed while taking metformin, so patients must learn to eat better to avoid the symptoms.
Our practice commonly uses letrazole (Femara®) to stimulate ovulation but sometimes we need to prescribe the old tried and true clomiphene citrate (Clomid®). We occasionally have to suppress the adrenal male hormones through the addition of dexamethasone. We need to be very careful about prescribing injectable follicle stimulating hormone (FSH) medications for PCOS patients since they tend to open the floodgates, resulting in a release of multiple eggs and the potential for a multiple pregnancy. Overstimulation of the ovaries can also lead to significant illness.
Miscarriages seem to occur more often in the PCOS patient. It may have to do with their weight and abnormal insulin levels. While somewhat controversial, even PCOS patients without obvious glucose/insulin problems may benefit from metformin treatment. It must be understood that while these drugs have been extensively studied in the treatment of diabetes, insulin resistance, glucose intolerance and PCOS, the FDA has not granted official approval for the use of these drugs for PCOS.
PCOS patients also more commonly experience gestational diabetes during pregnancy. Weight gain during pregnancy should be held in check as excessive amounts of weight gained can result in insulin dependent diabetes during pregnancy and even afterwards. Pregnancy complications are more common in patients with gestational and insulin dependent diabetes, so an obstetrician will need to carefully monitor a PCOS patient during her pregnancy.
What are long-term concerns for the PCOS patient?
Women with PCOS are at significant risk of developing insulin and non-insulin dependent diabetes mellitus, uterine cancer, elevated lipids, hypertension and cardiovascular disease.
Will a PCOS diagnosis and treatment be covered by insurance?
The coverage of PCOS will depend upon the insurance company. Your physician will try to emphasize the medical diagnoses that are seen with PCOS, such as an ovulatory dysfunction, hirsutism, glucose intolerance or insulin resistance, but coverage cannot be guaranteed. The diagnosis of infertility for the PCOS patient is less often covered but it entirely depends on the particular insurance plan. Medications such as metformin are commonly available free at some pharmacies and supermarkets, so co-pays aren’t even necessary to obtain the medication.
Can PCOS be cured?
In patients that have always had menstrual issues, even when young and slender, an actual cure has not yet been found. However, in the population who became symptomatic after weight gain, diet, exercise, weight loss and medications may actually result in a cure. This “cure” continues as long as the patient’s weight remains close to the level when ovulation and regular cycles returned.
PCOS is a metabolic disease and will require careful control for most patients throughout their lives. That doesn’t mean that the PCOS patient can’t have a family or will always have to suffer the symptoms. Through dedication by the PCOS patient with the assistance of your obstetrician/gynecologist or your friendly neighborhood reproductive endocrinologist, the signs and symptoms of PCOS can certainly be controlled and minimized.
Craig R. Sweet, M.D.
Medical & Practice Director
Specialists In Reproductive Medicine & Surgery, P.A.
Documents of Interest to the PCOS Patient:
ASRM PATIENT FACT SHEET, Ovarian Drilling for Infertility
ASRM, Hirsutism and Polycystic Ovarian Syndrome, Patient Information Series
ASRM, Patient Fact Sheets, Polycystic Ovarian Syndrome
ASRM, Patient Fact Sheet. Ovarian Drilling for Infertility
PCOS Links of Interest:
The PCOS Challenge:
Today, the good people of Mississippi will go to the polls to exercise their constitutional right to vote. One of the items they will cast their ballot on is Mississippi Ballot Initiative #26, which would give “personhood” to a fertilized egg. If enacted, this law will cause a chilling effect that will be felt throughout the infertility field as other states like Florida and Ohio, to name just two, gear up for similar referenda in 2012. The passage of Mississippi Initiative 26 will signal the start of a dangerous precedent, that if it gains momentum, will cause dire consequences for many of my patients.
This isn’t just about abortion, although this is what the proponents would like you to believe. Let me be clear, I don’t think the intention of the well-meaning individuals who may vote for this Initiative want to do harm. In fact, I am certain, people voting for the initiative probably feel they are saving lives. The problem is that Initiative 26’s proponents have not given the voters the right facts about the law’s devastating consequences in the state of Mississippi. The list of unintended consequences extends far and wide and involves women’s healthcare, the legal world and the infertile patient as well as the providers of their medical care.
Consequences to Women’s Healthcare
The following are very likely consequences of the passage of the amendment:
- - The total outlawing of abortion, even in the cases of incest and rape.
- - Outlawing of the vast majority of contraceptives including the IUD, the “morning-after pill” and Depo-Provera. Even hormonal contraceptives including oral contraceptives, patches and rings will thin the uterine lining preventing implantation. If interpreted as such, they will be outlawed. The only contraception that will probably remain will be condoms and we know how much men like to take a shower with a raincoat on….
- - How can a physician surgically remove a tubal ectopic pregnancy thus terminating the life of an “embryo-person”? No, really, could someone tell me how a physician will be able to care for a patient with a life-threatening ectopic pregnancy?
- - Are we really going back to the “good old days” when women were dying on a regular basis from botched backstreet abortions? Who will take care of the orphans?
Consequences to the Legal World
There are literally thousands of instances where the word “person” is written in the Mississippi statutes, each of which will have to be carefully reviewed to see how three-day old eight-cell stage embryos fit in. Think of the possible consequences:
- - How will cryopreserved embryos inherit? Exactly what rights will they have?
- - If embryos are created in Mississippi by a couple visiting from another state or another country, are they instantly going to be US citizens or citizens of the state of Mississippi?
- - Will all embryos that do not survive have to undergo a burial? If they die unexpectedly, are they to undergo an autopsy?
- - Women who smoke, drink in excess or use recreational drugs are at an increased risk for miscarriages. Are they to be charged with manslaughter or perhaps even murder if they are aware that their behavior could end the life of an “embryo-person”?
Disastrous Consequences to the Infertility Patient and Provider
It is clear that the proponents of initiative 26 feel the infertile patients are expendable. They don’t care that women and men’s lives and the families of Mississippi will be severely affected:
- - Embryologists might be charged with manslaughter if embryos fail to survive in the laboratory.
- - Will the laboratory even try to thaw frozen embryos understanding that at least 10-20% of them will not survive the thaw? Will the less expensive frozen embryo transfer procedures just disappear?
- - If the physician transfers the embryos but the patient doesn’t conceive, will the physician be blamed? Will the doctor be accused of manslaughter for the failed implantation?
- - Will frozen embryos be able to be moved outside of or into the state of Mississippi? Will Fedx take the chance of being accused of manslaughter should a transport tank fail in transit?
What will probably happen is that IVF will continue but physicians will only remove 2-3 eggs in a cycle. This will greatly increase the cost of the infertility treatment and result in much lower success rates. Those that can afford will go elsewhere. Who cares? For one, I do and I will bet every one of my patients will if Initiative 26 passes in Mississippi and they move on to other states, including Florida.
Well-Meaning Intentions With Unintended Consequences
This initiative is a really bad idea and has far more unintended consequences that I can even outline here in this short blog. The abortion decision is a personal decision between a woman, her partner, her conscience, her religion and her creator. We’ve been through this for years and years and the majority of Americans agree with this statement.
If Mississippians pass this law today, I know my work fighting the consequences of the Personhood Movement has just begun. Florida most likely will be one of the next states in their crosshairs. I will be forced to spend time, money and effort fighting these initiatives that I could otherwise devote to building families by encouraging the donation of unused embryos to patients in need. Instead of helping bring children into this world, I will be working diligently so I can prevent similar misguided political acts from destroying my patients’ dreams. Let’s hope the voters of Mississippi don’t find out too late that their actions have stymied the very goal they were trying to achieve – building loving families that would otherwise not exist.
Vote “No” on Initiative 26.
Craig R. Sweet, M.D.
Medical & Practice Director
Specialists In Reproductive Medicine & Surgery, P.A.
Pregnancy Loss Remembrance Day – October 15, 2012
Craig R. Sweet, M.D.
Medical and Practice Director
Specialists in Reproductive Medicine & Surgery, P.A.
Over the Past 27 Years:
Starting my OB/GYN residency in 1985 with completing my fellowship in reproductive endocrinology, infertility & genetics in 1991, I can recall hundreds of pregnancy losses over the past 26 years. There were so many tears, emergency D&Cs, and especially, so many unanswered questions in the tear-filled eyes of my patients.
Nearly all of the women seemed to blame themselves. They felt it was something they did wrong. Perhaps it was the sex they had with their partners. Did they cause the loss by not resting enough? Did they worry the pregnancy into destruction? Was it punishment for a prior pregnancy termination? Was there really a vengeful God? Whose fault was it? What did they do wrong? The questions went on and on. I wanted to find some answers.
The Beginning of my Research:
In 1988-9, the last two years of my OB/GYN residency, I began one of my first real research studies into the causes of pregnancy loss. At that time, we thought that about one-half of all pregnancy losses were genetically abnormal. The method used to provide this estimate was flawed requiring the laboratory to grow miscarriage cells. When the pregnancy didn’t grow well inside a perfect womb, the chances for growth in the laboratory were severely hampered. Not only did the cells frequently fail to grow with no answers provided, the most common reported result was 46,XX (normal female). The 46XX result was was reported twice as often as the 46,XY result (normal male). Understanding that there aren’t twice as many girls born as boys, we suspected that the healthier maternal cells, which are always mixed in with the miscarriage cells, overgrew the poorly growing baby’s cells in culture. Since the two different cell lines didn’t come “color coded,” there was no easy way for the laboratory to tell if the results reflected the mother’s cells (often) or the baby’s true chromosome makeup, termed karyotype. Overall, we found the karyotype truly reliable in only 30%+ of the spontaneous loss cases.
My research goal was to examine recurrent miscarriage tissue directly without growing the cells using a device called a flow cytometer. This research took many months to complete but we learned two extraordinary things:
- Direct analysis worked well and we were able to identify pregnancies with missing or extra chromosomes using the flow cytometer.
- Many of the reported “normal” 46,XX results were actually the mother’s chromosome makeup with the pregnancies themselves found to be severely genetically abnormal.
In reality, we discovered a new method to evaluate miscarriages finding answers where few had previously existed.
Quite unexpectedly, I received an award for the research in my residency and was asked to present my data at the American Fertility Society meeting (now the American Society for Reproductive Medicine) in San Francisco, in 1989, during the first year in my sub-specialty fellowship. It was this research and work performed by many others which helped us to finally understand that 70%+ of all first trimester spontaneous losses were genetically abnormal. Later, during my fellowship, I also complemented my previous work becoming co-author on research examining autoimmune pregnancy loss wherein acquired antibodies attacked the pregnancy resulting in a miscarriage. I was still seeking answers for my patients understanding that we had a very long way to go.
My Motivation: The Parents of the Perfect Imperfect Child
No matter how imperfect the pregnancy was found to be in the laboratory, these were perfect children to the hopeful parents. These innocent and extraordinarily young lives never kept a parent up all night, vomited on their favorite dress or screamed until any sane adult would cry uncle. These pregnancies and children were flawless. They were always beautiful, always bright and always wonderful. These pregnancy losses were perfect beings in the eyes of the parents as they contained every hope and dream they held for their future children. They were potential NFL football players, fishing buddies, best friends and even future Presidents of the United States. They were everything the parents ever dreamed their children might become. It makes perfect sense that they were and, even to this day, often called angels. It was so hard form my patients to loose such a perfect being.
These pregnancy losses were perfect beings in the eyes of the parents as they contained every hope and dream they held for their future children.
In Memory of my Patients and Their Perfect Imperfect Child
We still lose about 25% of all of our pregnancies and it is heartbreaking. While we certainly try their pain, no words seem to do justice for a parent experiencing such grief. For over two decades, though, my practice has been making charitable donations in memory of their pregnancy loss. It was our little way of having something good coming out of such a sorrowful event. While I doubt it made a tremendous difference in the hearts and minds of my patients, I think it gave them some level of comfort. On this 2012 Pregnancy Loss Remembrance Day, I would like to offer a gentle challenge to all of my peers to consider paying it forward by making a similar charitable donation, or performing some other act of kindness, in memory of all of our patient’s pregnancy losses. I believe it would be appreciated by our grieving patients, good for our own souls and would serve the public in a productive and kind manner.
In the Present:
Fast-forward to last year in 2011 where I was involved in a study, now 22 years later following my first flow cytometer study, using newer technology to once again examine the pregnancy tissue directly. This newer technology was called microarray analysis. Using the microarray analysis, we now obtain reliable results 80-90% of the time again providing answers where only guesses existed in the past. I now use the less expensive, rapid and extraordinarily reliable technique on nearly all of our pregnancy losses in the practice. Showing the patients that it wasn’t the food they ate, the swim they took or the short walk they had which caused the miscarriage, but rather, a terrible but uncontrollable flaw in early development of the embryo and fetus, their perfect imperfect child is extraordinarily valuable and does provide some solace.
Sill, We have Only Just Started:
I know we have much more work to do to not only understand why pregnancies are lost but what we can do to change their destiny. Will we someday be able to treat eggs, sperm and early embryos thereby healing the genetic problems before the pregnancy advances to a point of no return? We can only hope for future intervention.
I am fully aware that answering the question of why these perfect imperfect children were lost doesn’t answer all the questions or fully diminish the self-blame that is so commonly felt, but it is a good place to start.
To the memory of all of those we lost and may they keep those of us in the field of reproductive medicine humble and motivated driving us to answer the questions our patients ask of us regarding why they lost their perfect imperfect pregnancies.
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Learn about the latest research studies from Specialists in Reproductive Medicine & Surgery, P.A. including basic laboratory studies and in-depth clinic research. For more information, visit http://www.dreamababy.com/studies-ongoing.htm.