IVF, , and Women’s Health July 14, 2006

Ovarian stimulation and IVF are outweighed by the woman’s follicular oocyte retrieval are used most benefit of being able to give development cycle with often for couples attempting to birth to a biologically related hormones to induce the ovary use in vitro fertilization to have child or children. to produce more than one a biologically related child. In follicle simultaneously and IVF, oocytes (eggs) are IVF techniques have been therefore produce more eggs. removed from a woman’s body used not only to help couples Women react differently to the after she has taken drugs to have their own children, but many different drug protocols stimulate egg production. Eggs also to provide oocytes that can that are used, and for some, the are fertilized in a laboratory be donated to an infertile drugs cause OHSS, which dish, and one or more resulting couple seeking to have a baby brings severe and sudden health embryos are transferred to the using a donor egg. More risks to the patient, ranging woman’s uterus to initiate a recently, ovarian stimulation from mild symptoms of . and oocyte retrieval have been abdominal discomfort to renal used to collect oocytes for use failure and death. To date, more than one in embryonic stem cell million babies have been born research. All women who undergo worldwide as a result of IVF ovarian stimulation are at risk and in 2003 U.S fertility clinics Each of these procedures for this condition. However, reported 112,872 IVF cycles. raises issues about the impact some data demonstrate that Although there has been and risk of ovarian stimulation OHSS may occur less considerable medical literature and oocyte retrieval for frequently among women who exploring the possible health women. This paper explores undergo COH for oocyte effects of in vitro fertilization what is and what is not known donation, as compared to those to babies born from this about the risks of ovarian who continue on with IVF for technology, the potential health stimulation and oocyte the purpose of having children. risks to the women who retrieval, for both a prospective Sauer et al (1996) found that undergo this process have been and a prospective egg fewer than 2 percent of oocyte less extensively studied. donor. However, as this white donors developed severe OHSS paper describes, more following a standard No medical procedure is conclusive data about the risks stimulation cycle, less than the without risks, and ovarian of ovarian stimulation and rate of OHSS among IVF stimulation and oocyte retrieval oocyte retrieval to women are patients, which ranges from 2 is no exception. Possible short- needed. percent to 50 percent. Other term risks include excessive research has supported this hyperstimulation resulting from Short-Term Risks finding. (Morris et al., 1995). the drugs used to stimulate It has been suggested that the ovulation. Possible longer- The primary known short- subsequent development of term risks include reproductive term risk of ovarian stimulation OHSS is directly related to the or gynecological cancers. It is is ovarian hyperstimulation presence of a hormone called clear from the rapid growth of syndrome (OHSS). Controlled human chorionic IVF that, for many women and ovarian hyperstimulation (also (HCG) and that the production couples, the potential risks of know as COH) modulates the of endogenous HCG by a

Genetics & Public Policy Center • 1717 Massachusetts Ave. NW • Suite 530 •Washington, DC 20036 •202.663.5971 • www.DNApolicy.org 1 woman following embryo further escalation of clinical and help reduce occurrence of transfer may increase the risk signs and symptoms, and OHSS. of OHSS (Sauer et al., 1996; additional care measures Morris et al., 1995). offered by an intensive care There are also short-term unit are often required for the health risks associated with the OHSS is generally management of OHSS. OHSS oocyte retrieval process, classified into three categories management includes including those from bleeding, based on severity, from mild to supportive therapy for infection, and anesthesia. severe (Navot et al, 2001). decreased blood volume and (Sauer, 2001). Pain and anxiety Mild OHSS is associated with organ dysfunction until these are other issues that have been only minimal pain and other systems return to normal less well studied (Jordan et al., mild symptoms and is often function (Gardner et al., 2001). 2004). regarded as an acceptable endpoint of the controlled New drug protocols are Long-Term Risks ovarian hyperstimulation. being developed to decrease the “Mild OHSS is routinely risk of OHSS. One example is Some studies have inflicted on a large proportion the use of drugs such as followed women who have of women undergoing so called gonadotropin releasing undergone ovarian stimulation COH, thus mild OHSS is hormone (GnRH) antagonists. and oocyte retrieval for long nothing more than an This class of drugs directly periods of time to assess the acknowledgement that COH blocks cellular receptors and long-term increased health has indeed been achieved” prevents an initial hormonal risks of these procedures. (Navot et al, 2001). Moderate surge thought to induce the These studies have focused on OHSS involves abdominal pain OHSS cascade of events. whether there is an increased and bloating, nausea, and Another technique that may risk for gynecological diarrhea. Clinically, any reduce the risk of OHSS is malignancies such as ovarian, indications of fluid shifts are withholding the administration breast, or endometrial cancer. detectable only with an of HCG to trigger final oocyte Though some studies have ultrasound. This stands in maturation before retrieval focused on egg donors, most of contrast to severe OHSS in (Orvieto et al 2005; Navot et al, these data have been collected which fluid shifts are apparent 2001). In addition, recent from infertile women in the abdomen and throughout research has resulted in the undergoing these procedures as the body tissues and organs. discovery of a gene that codes a part of IVF in order to have a Symptoms include severe for the Follicle Stimulating child. Although the procedures abdominal bloating, distention Hormone (FSH) receptor. involved in ovarian stimulation and pain, shortness of breath, Identification of this gene may and oocyte retrieval are the abnormally low blood pressure provide important predictive same regardless of the purpose, and high pulse rate. This information about an individual women undergoing these massive shift in volume out of patient’s response to ovarian procedures as a part of IVF the blood vessels and into the stimulating drugs and allow for may have underlying surrounding tissue results in better dosing to prevent OHSS physiological differences from impaired organ function, most (Greb et al., 2005; Daelmans et fertile women who undergo the notably in the liver and kidney. al., 2004). In the future, procedures to donate eggs Hospital management is knowing more about this gene either to an infertile couple or indicated for moderate OHSS, may help identify women who to embryonic stem cell with the strategy of preventing are at increased risk for OHSS research. For example, as a

Genetics & Public Policy Center • 1717 Massachusetts Ave. NW • Suite 530 •Washington, DC 20036 •202.663.5971 • www.DNApolicy.org 2 result of the underlying Table 1: IVF Drugs , infertile women may Drugs that may be used before oocyte retrieval be at greater risk for long-term Kind of Drug: Purpose of Drug: health issues, such as GnRH (gonadotropin releasing Preparatory gynecological cancers. Thus, it hormone) agonist and GnRH - Prevent early ovulation is unclear whether the risks antagonist - Improve follicular response identified in women Combined hormone oral Preparatory undergoing IVF may be contraceptives - Prevent functional cyst translatable to fertile women development that have been going through ovarian associated with decreased stimulation and oocyte pregnancy rates donation for other reasons. - Used as contraceptive to prevent pregnancy before Studies on the risk of GnRH agonist/antagonist gynecological cancers—such as administration breast, ovarian, and uterine hMG (Human Menopausal Superovulation malignancies—dominate the gonadotropin) - Induce multiple follicular literature about the potential development long-term risk of COH. FSH (Follicle Stimulating Superovulation However, the association with Hormone) - Enhance early follicle cell non-gynecological development malignancies also has become LH (Luteinizing Hormone) Superovulation an area of growing interest. -Assist in follicular There has been very limited development discussion of the other long- HCG (human chorionic Preovulation term medical risks (e.g. the gonadotropin) - Used to trigger final follicular development of hypertension or maturation and ovulation diabetes). Drugs that may be used before Kind of Drug: Purpose of Drug: Gynecologic Cancer Progesterone - Used to prepare the uterine lining for embryo transfer, Much of the discussion to implantation, and early date about pregnancy drugs and cancer addresses the - Supplement endogenous risks associated with the use of hormones one drug in particular, Estrogen - Required to induce receptors clomiphene citrate. for progesterone Clomiphene is used for Drugs that may be used after embryo transfer ovulation induction among Kind of Drug: Purpose of Drug: women who have stopped Progesterone - Maintain optimal levels to ovulating or those undergoing permit pregnancy but which is not commonly used Estrogen - Maintain optimal levels to for oocyte donation or IVF. permit pregnancy Some, but not all studies have identified a positive association

Genetics & Public Policy Center • 1717 Massachusetts Ave. NW • Suite 530 •Washington, DC 20036 •202.663.5971 • www.DNApolicy.org 3 between clomiphene and issue. (Salahab et al., 2005; health issues, are more likely to malignancies, both gynecologic Mohdavi et al., 2006) be diagnosed at an earlier stage. and non-gynecologic. (Rossing et al., 1994; Whittemore et al., Ovarian Cancer Breast Cancer 1994). Concerns about clomiphene often have carried The data concerning the Studies addressing the risk over to a similar concern about link between infertility of breast cancer from infertility gonadoptropins, a separate set treatment and ovarian cancer treatment are somewhat of drugs used to induce are limited by several factors. conflicting. Some studies controlled ovarian First, sample groups in the suggest an increased breast hyperstimulation. studies have been small. cancer risk while others do not. Second, there has not been For instance, a study by In 2005, a systematic long-term follow-up with Burkman noted that, in general, review of nearly 100 studies patients. Third, many of these infertility drug use is not examined the incidence of investigations have been associated with an increased breast, ovarian, endometrial, conducted as cohort studies, risk of breast cancer. However, melanoma, and other which are not considered as those women who used a malignancies. (Brinton et al., reliable as randomized specific hormone, Human 2005). In general, that review controlled trials. (Gordis, Menopausal gonadotropin concluded that while some 2004). (hMG), for at least six studies had shown a link treatment cycles or months had between ovarian stimulation Brinton et al. (2005) a two to three-fold increased drugs (both those used to concluded from a systematic risk of breast cancer (Burkman induce ovulation and those review of multiple studies that et al, 2003). However, the used to stimulate the ovaries there “is no conclusive link investigators make note that for IVF purposes) and cancer between fertility drug use and these data should be risk, many of these studies had ovarian cancer.” A few trends approached with caution, given significant shortcomings. Two did exist among the studies. the number of limiting and later studies similarly First, ovarian cancer occurred confounding elements to the concluded that there is no clear predominantly among study. In another investigation, evidence that infertility nulliparous women (women Brinton and collegues treatment causes cancer but that who have borne no children). concluded that the data about additional data are needed to However, this group already is the risk of breast cancer thoroughly investigate this at an increased baseline risk of following infertility treatment malignancies because of their are inconsistent. It is reproductive histories. Second, particularly difficult to tease some studies found an increase out the effects of in borderline ovarian tumors on breast cancer risk. Breast among women who underwent cancer is a malignancy often IVF. However, it has been directly related to the hormonal proposed that the environment of the women, an gonadotropins used might have environment that can be induced the growth of already temporarily increased by existing borderline tumors and gonadotropin administration. In that these women, because of addition, many of the studies their increased awareness of on this topic relied on the

Genetics & Public Policy Center • 1717 Massachusetts Ave. NW • Suite 530 •Washington, DC 20036 •202.663.5971 • www.DNApolicy.org 4 patient to report her fertility cancer, than the use of fertility There are numerous drug dosage and duration many drugs alone. At the same time, examples of the underlying years after the initial treatment the investigators comment that causes of infertility being for infertility, raising questions more definitive evidence is linked to gynecological about accuracy and utility of required before dismissing this malignancies. Breast, the data. Finally, as is the case potential association (Modan et endometrial, and ovarian with ovarian cancer, any al., 1998). malignancies all can be caused increased incidence of breast by chronic exposure to cancer may be linked with the Could the Underlying Cause reproductive hormones arising effects of fertility agents on an of Infertility Raise the Risk of from within the woman’s body, existing tumor that may be Malignancies? which can happen as part of detected earlier because of the infertility. The absence of patient’s increased awareness An analysis of the risk of ovulation (anovulation) and of and attention to her health. gynecological cancers resulting polycystic ovarian syndrome from infertility treatment must (PCOS), two medical Endometrial Cancer take into account whether the conditions implicated in underlying medical conditions infertility, also have been The data regarding that contribute to infertility associated with an increased endometrial cancer is not as may independently place risk of breast and endometrial robust as that for breast and women at higher risk for cancer (Brinton et al., 2005; ovarian cancer. In addition, the gynecological malignancies. Baron et al., 2001; Pierpoint et majority of research in this area Many studies have al., 1998; Dahlgren et al., 1991; pertains to the use of demonstrated that women with Escobedo et al., 1991). clomiphene and the risk of primary (never able to Endometriosis, another factor cancer. Though there is conceive) and secondary in infertility, also has been evidence that there is a two- (previously able to conceive linked with an increased risk of fold increase in relative risk of before experiencing infertility) ovarian cancer and malignant endometrial cancer among infertility have a higher risk of melanoma (Brinton et al., 2004; clomiphene users, this same gynecologic malignancies than Stern et al., 2001; Modesitt et trend was not noted among IVF the average population (Brinton al., 2002; Ness 2003). patients (Althuis et al., 2005a). et al., 2004; Modan et al., 1998; Hydrosalpinx, a collection of There have been very few Rossing et al., 1994; Althuis et fluid in the fallopian tubes, has studies that have looked al., 2005a). Notably, the been linked with infertility directly at the effect of IVF- increased risk has been found resulting from implantation specific agents. Most cohort among women with infertility failure and ovarian cancer studies have not identified an who have undergone infertility (Brinton et al., 2005). increase risk of endometrial treatment and those who have cancer specifically with IVF not (Brinton et al, 2004). One Non-Gynecologic Cancer agents. However, some of the study documented this as a 23 studies that have identified an percent increased risk of cancer There has been limited increased risk of endometrial among women with infertility, research into any link between cancer interpret this more as a providing consistent findings infertility treatment and the risk function of long-term with other authors (Brinton et of non-gynecologic cancers. A unopposed estrogen exposure, a al., 2005). 20-year retrospective study of hormonal state associated with the risk of classically hormone- infertility and endometrial sensitive, non-gynecologic

Genetics & Public Policy Center • 1717 Massachusetts Ave. NW • Suite 530 •Washington, DC 20036 •202.663.5971 • www.DNApolicy.org 5 malignancies—including other psychological conditions Future Research thyroid cancer, colon cancer, (Norsigian, 2005; Lazar, 1999.) and malignant melanoma— Most of these cases have not More research in the areas found that there was little to no been reported or evaluated with of ovarian stimulation and association of these specific formal research protocols. health outcomes must be cancers and common ovulation Many of the circulated case completed before definitive stimulating drugs: reports lack specific and conclusions can be drawn about gonadotropins, Pergonal, essential information about the the risks for women. Existing Humegon, and Metrodin. cause of the initial studies have been limited in a (Althuis et al., 2005b). gynecological condition variety of ways, yet there has warranting treatment with been some evidence that the Other Medical Lupron, medication dosage and drugs used in ovarian Considerations duration of treatment (Lazar, stimulation and oocyte retrieval 1999, entries from the may be associated with Little research to date has Infertility Network). From a increased risk of cancer. focused on the risk of non- review of the available reports Priorities for future research malignant medical conditions of these women, it appears as if ought to include: following ovarian stimulation many were treated with Lupron • Reducing the risk of OHSS and oocyte retrieval. Medical for endometriosis or uterine without impaired pregnancy conditions, such hypertension fibroids, conditions that require rates and developing the means or diabetes, or gynecologic higher doses of GnRH agonist to identify women who are at a conditions, such as uterine for treatment than used for increased risk of OHSS before fibroids or pelvic pain, have not ovarian stimulation and oocyte initiating treatment. been robustly examined. One retrieval (Lazar, 1999). Similar • Long-term evaluation of study that looked specifically at findings have not been larger populations of women the risk of gynecologic diseases observed among patients who who have undergone infertility following IVF did not identify undergo GnRH agonist treatment, with more accurate a positive association (Klip, treatment for other conditions. information about the patients’ 2003). Another study that For instance, the specific infertility treatments examined the theoretic musculoskeletal symptoms (e.g., dosages, durations, drug possibility of accelerated reported among these women name). following IVF also who have been treated with • Studies examining the long- did not identify a negative large doses of a GnRH agonist term health outcomes of outcome among these women have not been observed among women undergoing ovarian (de Boer, 2005). Additional men with prostate cancer or stimulation and oocyte retrieval research is indicated in this children with precocious for oocyte donation as area. puberty who undergo therapy compared to the outcomes of with the same medication women undergoing stimulation Several case reports have (Tanaka, 2005; Almeida, and retrieval for IVF, to better described women who have 2004). There have not been understand whether other been treated with the GnRH rigorous studies on these factors, such as a woman’s agonist Lupron who have outcomes in large enough study underlying infertility, play a reported symptoms including populations to be able to role in the long-term risks of musculoskeletal weakness and quantify any possible risk. cancer or other diseases. pain, depression, memory impairment, loss of libido and

Genetics & Public Policy Center • 1717 Massachusetts Ave. NW • Suite 530 •Washington, DC 20036 •202.663.5971 • www.DNApolicy.org 6 References

Almeida O, Waterreus A, Spry N, et al. One year follow-up study of the association between chemical castration, sex hormones, beta-amyloid, memory and depression in men. Psychoneuroendocrinology. 2004;29:1071-81.

Althuis M, Moghissi K, Westhoff C, et al. Uterine cancer after the use of clomiphene citrate to induce ovulation. American Journal of Epidemiology. 2005;161:607-15.(a)

Althuis M, Scoccia B, Lamb E et al. Melanoma, thyroid, cervical and colon cancer risk after use of fertility drugs. American Journal of Obstetrics and Gynecology. 2005;193:668-74.(b)

Ayhan A, Salman M, elik H, et al. Association between fertility drugs and gynecologic cancers, breast cancer, and childhood cancer. Acta obstetricia et gynecologica Scandinavica. 2004;83:1104-11.

Baron J, Weiderpass E, Newcomb P, et al. Metabolic disorders and breast cancer risk. Cancer Causes Contol. 2001;12:875-80.

Brinton L, Moghissi K, Scoccia B, Westhoff C, Lamb E. Ovulation induction and cancer risk. Fertility and Sterility. 2005;83:261-74.

Brinton L, Lamb E, Moghissi K et al. Ovarian cancer risk associated with varying causes of infertility. Fertility and Sterility. 2004;82:405-14.

Burkman RT, Tang MC, Malone KE, et al. Infertilty drugs and the risk of breast cancer: findings from the National Institute of Child Health and Human Development Women’s Contraceptive and Reproductive Experiences Study. Fertility and Sterility. 2003;79:844-51.

Daelmans C, Smits G, de Maertelaer V et al. Prediction of severity of symptoms in iatrogenic ovarian hyperstimulation syndrome by follicle-stimulating hormone receptor Ser680Asn polymorphism. Journal of Clinical Metabolism. 2004;90:6310-5.

Dahlgren E, Friberg L, Johanson S, et al. Endometrial carcinoma; ovarian dysfunction-a risk factor in young women. European Journal of Obstetrics and Gynecology, and Reproductive Biology 1991;41:143-50. deBoer E, Tonkwlaar I, Burger C, et al. Are cause of subfertility and in vitro fertilization treatment risk factors for an earlier start of menopause? Menopause: The Journal of the North American Menopause Society. 2005;12:578-88.

Escobedo L, Lee N, Peterson H, et al. Infertility associated endometrial cancer risk may be limited to specific subgroups of infertile women. Obstetrics and Gynecology. 1991;77:124-8.

Greb R, Behre H, Simoni M. Pharmacogenetics in ovarian stimulation. Reproductive Biomedicine Online. 2005;11:589-600.

Genetics & Public Policy Center • 1717 Massachusetts Ave. NW • Suite 530 •Washington, DC 20036 •202.663.5971 • www.DNApolicy.org 7 Gordis L. Epidemiology5th edition. Philadephia: Saunders, 2004.

Jordan C, Belar C, Williams R. Anonymous oocyte donation: a follow-up analysis of donors’ experiences. Journal of Psychomotor Obstetrics and Gynecology. 2004;25:145-151.

Klip H, van Leeuwen F, Schats R, et al. Risk of benign gynaecological diseases and hormonal disorders according to responsiveness to ovarian stimulation in IVF: a follow-up study of 8714 women. Human Reproduction. 2003;18:1951-58.

Lazar K. Wonder drug for men alleged to cause harm in women. Boston Herald. Part 1. August 22, 1999, Part 2 August 23, 1999, and Part 3 August 24, 1999.

Mahdavi A, Pejovic T, and Nezhat F. Induction of ovulation and ovarian cancer: a critical review of the literature. Fertility and Sterility. 2006;85:819-26.

Modan B, Ron E, Lerner-Geva, et al. Cancer incidence in a cohort of infertile women. American Journal of Epidemiology. 1998;361:1810-12.

Modesitt S, Tortolero-Luna G, Robinson J, et al. Ovarian and extraovarian enometriosis-related cancer. Obstetrics and Gynecology. 2002;100:788-95.

Morris, RS, Paulson RJ, Sauer MV, Lobo RA. Predictive value of serum oestradiol concentrations and oocyte number in severe ovarian hyperstimulation syndrome. Human Reproduction. 1995. 10:811-14.

Navot D, “Severe Ovarian Hyperstimulation Syndrome”, in Textbook of Assisted Reproductive Techniques: Laboratory and Clinical Perspectives eds. Gardner D, Weissman A, Howles C, Shoham Z. Martin Dunitz, Ltd.: London, 2001.

Ness R. Endometriosis and ovarian cancer: Thoughts on shared pathophysiology. American J. of Obstetrics and Gynecology. 2003;189:280-94.

Norsigian J. Hearing on human cloning and embryonic stem cell research after Seoul: Examining exploitation, fraud, and ethical problems in the research. Presented to the Subcommittee on Criminal Justice, Drug Policy, and Human Resources, March 7, 2006.

Orvieto R. Can we eliminate severe ovarian hyperstimulation syndrome? Human Reproduction. 2004;20:320-22.

Pierpoint T, McKeigue P, Issacs A, et al. Mortality of women with polycycstic ovary syndrome at long- term follow-up. Journal of Clinical Epidemiology. 1998;51:581-6.

Rossing M, Daling J, Weiss N et al. Ovarian tumors in a cohort of infertile women. New England Journal of Medicine. 1994;331:771-6.

Salhab M, Sarakbi A, Mokbel K. In vitro fertilization and breast cancer risk: a review. International Journal of Women’s Medicine. 2005;50:259-66.

Genetics & Public Policy Center • 1717 Massachusetts Ave. NW • Suite 530 •Washington, DC 20036 •202.663.5971 • www.DNApolicy.org 8 Sauer M, Paulson R, Lobo R. Rare occurrence of ovarian hyperstimulation syndrome in oocyte donors. International Journal of Obstetrics and Gynecology. 1996;52:259-62.

Sauer M. Egg donor solicitation: Problems exist, but do abuses? American Journal of Obstetrics and Gynecology. 2001;1:1-2. Stern R, Dash R, Bentley R. Malignancy in endometriosis: frequency and comparison of ovarian and extraovarian types. International Journal of Gynecologic Pathology. 1997;176:572-79.

Tanka T, Niimi H, Matsou N, et al. Results of long-term follow-up after treatment of central precocious puberty with leuprorelin acetate: Evaluation of effectiveness of treatment and recovery of gonadal function. The TAP-144-SR Japanese study group on central precocious puberty. Journal of Clinical Endocrinology and Metabolism. 2005;90:1371-76.

Venn A, Watson L, Bruinsma F, et al. Risk of cancer after the use of fertility drugs with in-vitro fertilization. The Lancet. 1999;354:1586-90.

Whittemore AS. The risk of ovarian cancer after treatment for infertility. New England Journal of Medicine. 1994;331:805-06.

Prepared by Ruth Farrell, Susannah Baruch and Kathy Hudson with graphics by Sheryl Wood

Genetics & Public Policy Center • 1717 Massachusetts Ave. NW • Suite 530 •Washington, DC 20036 •202.663.5971 • www.DNApolicy.org 9