My son is starting his second year residency in obstetrics and gynecology. He, like I was 30 years ago, is turned on by reproductive medicine and enjoys performing gynecologic surgery. When I decided then to specialize in reproductive endocrinology and infertility (REI) I was looking forward to being on the frontier of fertility medicine. The details of Reproductive physiology were being unraveled in real time and IVF had just reported its first successful pregnancies. In those days, microsurgery of the fallopian tubes was commonly performed by REIs as well as endometriosis and fibroid surgery.

During my fellowship, surgery was a huge part of my training. I travelled to Nashville to train with one of the world’s experts in laser laparoscopy. I practiced my tubal microsurgery skills weekly on anesthetized rats in a plastic surgical lab. I assisted on reproductive surgery several cases every week throughout my fellowship.

Myself and other fellows performed research on basic reproductive physiology questions that had yet to be worked out. Personally, my interest was polycystic ovarian disease and its relationship to weight gain. I studied male hormone production in the ovary and the adrenal gland before and after significant weight loss. I discovered that there was an inverse relationship between weight loss and male hormone production and that this was mediated through insulin. These were exciting times. If only we had metformin back then, I would have proven that in addition to weight loss, we could decrease insulin levels and therefore male hormone levels with metformin.

Today, discoveries in reproductive physiology are much more esoteric than it was when I was a fellow. Reproductive surgery, in particular tubal microsurgery and laser laparoscopy for endometriosis and adhesions is usually replaced with in vitro fertilization (IVF) which has become so much more successful, less invasive and therefore a preferable option. Most causes of infertility, if they are not successfully treated with ovulation induction and intrauterine insemination (IUI) can be overcome with IVF.

In the 1980’s when I was a fellow, IVF was grossly inefficient and we had to transfer multiple embryos to achieve a pregnancy. Consequently, triplets and quadruplets were not rare occurrences. In many programs, they constituted over 10% of all pregnancies. Today, we can often transfer one embryo at a time minimizing the risk of multiple pregnancies. We can freeze excess embryos so many patients need go through only one stimulation and retrieval and still have multiple transfers providing them with an excellent chance of conceiving a baby from their efforts.

Today, we get excited about advances in preembryo genetic screening and diagnosis and contemplate the current and future potential of eliminating hereditary medical disorders. This involves highly trained laboratory personnel who perform the latest technologic advances. In 2010, the REI, in general is removed from a hands on involvement with the frontiers of Reproductive Medicine and instead works like a film producer gathering his team including these lab personnel, nurses, etc and directing them as to how to approach his patients’ fertility problems. It used to be that he used the microscope and laser laparoscope to perform the tubal and endometriosis surgery. The IVF retrieval and transfer were new procedures that were still being perfected.

Today, they are the routine cases performed daily by the REI.

My son looks at the REI of today as a doctor who starts his day with 1-2 hours of ultrasound that is part of the daily ovulation monitoring for IUI and IVF. Many REIs no longer perform more surgery than hysteroscopy and occasional laparoscopy or myomectomy in addition to their retrievals. These are all considered routine procedures now. The current frontier in infertility is limited pretty much to the laboratory. Though many of us consider ourselves expert in stimulations, retrievals and transfers and while we know we make a significant difference in our patients’ outcomes our work does not appear or feel as glamorous as it once did. Perhaps, he will decide, as I did, that the pleasure in helping women build their families is sufficient reward. Or perhaps, this Nintendo generation, will seek a more apparently exciting lifestyle. How about that Robotic surgery?

There is no convincing association with ovarian cancer for any of the 4 different types of drugs used to treat infertile women.

I am often asked whether the medications we use in our fertility treatments can cause ovarian cancer. In the past, conflicting stories have been published mainly in the newspapers and non medical magazines. Recently, a scientific forum, Medscape Medical News, reviewed research on this topic and the good news is summarized below.

On February 10, 2009 — It was concluded in the largest study of the subject to date that Fertility drugs do not increase the risk for ovarian cancer. There was no convincing association with ovarian cancer for any of the 4 different types of drugs used to treat infertile women — gonadotrophins (Bravelle, Menopur, Gonal F, Follistim), clomiphene citrate (Clomid, Serophene), human chorionic gonadotrophin (HCG,Novadrel, Ovidrel) and gonadotropin releasing hormone agonist/antagonist (Lupron, Ganirelix, Cetrotide).

Instead, the data suggest that factors related to the diagnosis of infertility (for example, genetic or biological factors) — and not the use of fertility drugs — increase the overall risk for ovarian cancer.

However, they also point out that there is a major limitation to this study — many of the participants have not yet reached the age at which the incidence of ovarian cancer peaks (early 60s).

The study, headed by Allen Jensen, PhD, assistant professor of cancer epidemiology at the Danish Cancer Society’s Institute of Cancer Epidemiology, in Copenhagen, Denmark, is reported online February 5 in BMJ(British Medical Journal).

These data are reassuring but cannot absolutely rule out a very small increase in ovarian cancer or one that occurs much later in life.

Main Limitation Is Age of Participants
A link between fertility drugs and increased risk for ovarian cancer was suggested by several studies in the early 1990s, and this has created concern for patients undergoing infertility treatment. However, many of the studies over the past 8 to 10 years have been very small and none were able to reject or confirm the hypothesis.

This study was the largest because it included 156 women with ovarian cancer, more than 3 times as many as any previous cohort.

The main limitation of the study, however, is the age of the participants. These were young women, they were first evaluated for infertility at a median age of 30 years. Despite a long follow-up, the median age of these women at the end of the follow-up period was 47 years. This is below the usual age at which women are diagnosed with ovarian cancer, which reaches a peak incidence in women in their early 60s. So there is a possibility that there could still be a spate of ovarian cancers diagnosed as these women age, which could alter the conclusions.

This is a question that nobody can answer yet, we should say that the data so far are reassuring with this observation period, and with this age of the cohort, we cannot see any association with an increase in the risk of ovarian cancer.

The researchers intend to revisit the data at regular points in the future to check on the progress of the study cohort with “passive surveillance,”. The Danish system of personal identification numbers and nationwide health and cancer registries will allow them to track any new diagnosis of ovarian cancer.

Cannot Exclude Small Possibility
The Danish study investigated the records of 54,362 women with infertility problems, and compared 156 women who developed invasive epithelial ovarian cancer with 1241 controls.
However, although this study was much larger than previous investigations, it still could not exclude the possibility of a small increase in the risk for ovarian cancer in users of fertility drugs, The rate ratio for use of any fertility drug was 1.03, but the upper bound of the 95% confidence interval was 1.47.

Larger numbers of women will need to be studied to answer this question, and these will come with further follow-up of the cohort as they enter the age range where ovarian cancer is most common. Some women who take fertility drugs will inevitably develop ovarian cancer by chance alone, but current evidence suggests that women who use these drugs do not have an increased risk.

Clinical Context
Infertility has previously been associated with an increased risk for ovarian cancer. In an epidemiologic study of 3837 women treated for infertility, Rossing and colleagues demonstrated that infertility increased the risk for malignant ovarian tumors by a factor of 2.5 vs the overall community prevalence of ovarian cancer. This study, which was published in the September 22, 1994, issue of the New England Journal of Medicine, also suggested that the use of clomiphene in particular could increase the risk for ovarian cancer, particularly in women who had used the medication for more than 1 year.

The current study uses a large cohort of women to examine the effects of different fertility medications on the risk for ovarian cancer.

Study Highlights
• The study cohort consisted of women referred to Danish hospitals or infertility clinics between 1963 and 1998. A total of 54,362 women had data available for analysis.
• Cases of ovarian cancer were documented with use of 2 national registries: 176 women were diagnosed with epithelial ovarian cancer during a median follow-up of 16 years, and 156 women had data for analysis.
• The main outcome of the study was the relationship between fertility drugs and the risk for ovarian cancer. The 156 women with ovarian cancer were compared vs 1241 women from the infertile cohort who did not have ovarian cancer.
• The median year for entry into the infertility clinics was 1989, and the median age at the first evaluation for infertility was 30 years.
• The median time from entry into the cohort until the diagnosis of ovarian cancer was 14.5 years.
• Overall, the use of fertility drugs did not significantly affect the incidence of ovarian cancer. Fertility drugs were used by 49% and 50% of women with and without ovarian cancer, respectively.
• Clomiphene was the most widely used fertility drug, followed closely by human chorionic gonadotropins. Other gonadotropins and gonadotropin-releasing hormones were used less frequently.
• Nulliparity (No births) conferred an especially high risk for ovarian cancer in these women with infertility. The risk for ovarian cancer decreased with a higher number of births.
• The use of oral contraceptives and the cause of infertility did not significantly affect the risk for ovarian cancer.
• After adjustment for parity (Births), none of the individual fertility drugs were associated with a significant effect on the risk for ovarian cancer. The number of cycles used or the number of years since first use did not affect this conclusion.
• Similarly, combination treatment with multiple fertility drugs did not appear to increase the risk for ovarian cancer.
• Serous tumors were the most common histologic type of ovarian cancer. Clomiphene use was associated with a higher risk for serous tumor vs no use of fertility drugs but only in women who used clomiphene at least 15 years before the diagnosis of ovarian cancer.
• Previous research has found that infertility is associated with an increased risk for ovarian cancer, particularly in women who used clomiphene for more than 12 months.
• The current study suggests that fertility drugs do not significantly increase the risk for ovarian cancer.