by Judy Norsigian
In the February 2004 issue of O Magazine, Barbara Seaman's article, “Is This Any Way to Have a Baby?” caused quite a stir among infertility experts and women dealing with infertility. The article explored women's experiences with fertility drugs and underscored the paucity of long term safety data as well as the serious, occasionally irreversible problems experienced by some women using these drugs. In response, members of the American Society for Reproductive Medicine (ASRM) and the Society for Assisted Reproductive Technology (SART) posted an unusual rebuttal at the ASRM website (www.asrm.org). In the months following this confrontation, debate over fertility drugs and their health consequences has been steadily increasing.
Because embryonic stem cell research is poised to expand greatly, and somatic cell nuclear transfer (SCNT*), a cloning technique in which the nucleus of an unfertilized egg is replaced with the nucleus from a body cell, requires large numbers of women to donate eggs for research purposes, there is renewed attention to the larger question of risks to women's health from egg extraction procedures. Whether eggs are extracted for reproductive purposes — as is the case in an infertility clinic where women undergo in vitro fertilization (IVF) — or for research purpose like SCNT, the risks involved in the procedure are the same.
Because SCNT is such a rapidly growing field of research, the demand for eggs is growing as well. Since women normally produce a single egg in her monthly menstrual cycle, and the number of donors is relatively low, embryo researchers attempt to stimulate donors' ovaries to produce a larger number of eggs. Gonadotropin hormone regimens are administered, and although fertility doctors try not to over-stimulate their patients' ovaries, complications can and do occur.
The risks of multiple egg extraction do not only come in this stage of the process, however. Lupron, or leuprolide acetate, is a drug that is commonly used to shut down a woman's ovaries before stimulating them to produce multiple follicles. This drug has caused a range of problems, according to the Food and Drug Administration (FDA). Theses include rashes, vasodilation (dilation of blood vessels causing a “hot flash”), burning sensations, tingling, itching, headaches and migraines, dizziness, hives, hair loss, severe non-inflammatory joint pain, difficulty breathing, chest pain, nausea, depression, emotional instability, loss of libido, dimness of vision, fainting, weakness, asthenia gravis hypophyseogenea (severe weakness due to loss of pituitary function), amnesia, hypertension, rapid heart rate, muscular pain, bone pain, abdominal pain, insomnia, swelling of hands, general edema, chronic enlargement of the thyroid, liver function abnormality, anxiety, and vertigo. Although the FDA approved the drug for several specific uses, such as the treatment of endometriosis and fibroid-associated anemia, it has not approved Lupron for use in multiple egg extraction procedures — something that is not well understood by many women who undergo these procedures. It is legal to use a drug for a non-approved use such as this, as long as it is marketed legally for at least one approved use. Lupron is just one of many drugs used “off-label” in this fashion. However, proper studies justifying its use for egg extraction have never been formally submitted to the FDA.
The drugs used to hyperstimulate the ovaries also have negative effects, most notably a condition called Ovarian Hyperstimulation Syndrome (OHSS). Serious cases of this syndrome involve the development of cysts and enlargement of the ovaries, along with massive fluid build-up in the body. As noted in an article in Human Reproduction Update, “the reported prevalence of the severe form of OHSS is small, ranging from .05 to 5% [of women undergoing gonadotropin regimens]. Nevertheless, as this is an iatrogenic [medically induced] complication of a non-vital treatment with a potentially fatal outcome, the syndrome remains a serious problem for specialists dealing with infertility.”
Also, as noted by Dr. Suzanne Parisian, a former Chief Medical Officer at the FDA, “OHSS carries an increased risk of clotting disorders, kidney damage, and ovarian twisting. Ovarian stimulation in general has been associated with serious life threatening pulmonary conditions in FDA trials including thromboembolic events, pulmonary embolism, pulmonary infarction, cerebral vascular accident (stroke) and arterial occlusion with loss of a limb and death.” One Institutional Review Board (IRB) for Advanced Cell Technology in Massachusetts cited the risks as including “high blood pressure; fluid accumulation in the limbs; formation of blood clots which potentially could be dislodged from the involved vein or artery causing damage to vital organs such as lungs, heart or brain; intestinal problems such as decreased appetite, constipation; nausea and vomiting, diarrhea, difficulty in swallowing; intestinal bleeding, intestinal ulcers and polyps; thyroid enlargement; breast tenderness; hot flashes; bone, muscle and joint pain; anxiety; depression; blurred vision; mood swings; nervousness; numbness; taste changes; memory problems; lightheadedness; blackouts; and headaches.” 
So why is multiple egg extraction the norm in IVF clinics? With such risks involved, why don't specialists just extract the single egg that women normally release each month? The obvious reason is that if only one egg is harvested using the natural cycling that occurs each month in most women, there is a good possibility that it will not be successfully fertilized. If fertilized, it may not develop into an embryo that could be successfully implanted into a woman's uterus, thus requiring repeated surgical procedures to extract more eggs. With each IVF procedure, extracting multiple eggs obviously increases the likelihood of success.
The same reasoning can be applied to the research context, as it is important to have a larger number of eggs with which to conduct research. But, given the early stages of embryo stem cell research, with only hypothetical benefits at hand, it may be far wiser to protect women from the risks of multiple egg extraction solely for SCNT research purposes and to permit only surgical extraction of the usually single egg produced each month. Others argue that whatever the risks are — known and unknown — a woman should nevertheless have the choice to take these risks, especially if she has a strong personal investment in seeing certain therapies developed, even if they are only a distant promise.
Those who oversee the ethical conduct of research, especially members of IRBs, are supposed to think carefully about risk/benefit ratios when deciding whether to approve a research protocol. Embryo cloning research poses significant challenges in this regard. The aforementioned IRB approved a protocol for SCNT several years ago and included in the informed consent document the following language: “Severe lung and blood clot events have resulted in death.” They clearly decided that it was ethical to ask women to take such risks as long as they informed them about them. Others might argue just the opposite.
Reading the stories of young women who agreed to be multiple egg donors for IVF clinics and ended up with tragic consequences give reason to think carefully about whether these risks are justifiable in the research context. Many advocates believe that such risk-taking would not be ethical, partly because true informed consent is not possible in the absence of better data, particularly regarding Lupron.
One of the more serious issues needing far greater attention is the absence of quality long-term safety data on the infertility drugs commonly used. There are hundreds, if not thousands, of anecdotal reports, however, showing that complications are not short-lived. As noted in a three-part series in the Boston Herald:
“Seven of the women interviewed for this story say they suffered memory loss and bone aches while on Lupron, and that the problems continue years after stopping the drug. Some say seizures and serious vision problems that started while on Lupron also haven't gone away.
One woman, Linda Abend in southern New Jersey, started a National Lupron Victims Network after her 34-year-old sister was hospitalized with seizures while taking Lupron in 1991 for a benign fibroid. Abend says her sister continues to suffer daily seizures, plus debilitating bone and muscle pain eight years later. And Abend said she has heard from more than 1,000 people nationwide - mostly women - who also report serious side effects that continue after stopping Lupron.
The FDA says it has not tracked claims of such long-term effects.…”
In a report submitted by TAP Pharmaceuticals to the FDA in April 1998, researchers wrote that they were “concerned'' because more than one-third of the women they studied who took Lupron did not “demonstrate either partial reversibility'' or “a trend toward return”' of bone mass in the six months after they stopped taking the drug. Further, the researchers noted some women lost as much as 7.3 percent of their bone density during treatment — more than twice the amount the drug's packaging lists in its warnings. The researchers concluded, “A more complete assessment of the effects of Lupron on [bone density] can only be made with longer term follow-up of these patients.''
Some women's health advocates argue that it is premature to collect eggs for SCNT, especially when it involves multiple egg extraction, because the substantial risks to egg donors are not offset by any clear benefit. In the case of IVF, the best infertility clinics can now offer 30-40% success rates, so that women undergoing multiple egg extraction — whether to achieve a pregnancy themselves, or to be an egg donor for another woman — know that there is a clear potential benefit, and one that is of inestimable value: a baby.
The risk/benefit ratio is vastly different in the case of SCNT, where the possible benefits of such research at this stage are entirely hypothetical. It is far from clear that SCNT will lead to any viable therapies, and much of what we need to know can be learned from studying embryo stem cells derived from embryos that would otherwise be discarded by couples who are no longer pursuing IVF. Thousands of such embryos are now available at infertility clinics and could be used for embryo stem cell research. When embryo stem cell research begins to offer possible therapies, perhaps a stronger case can then be made for pursuing SCNT.
Although SCNT is likely to provide an opportunity to study the progression of certain rare diseases, some of this research can be pursued with embryos, rejected during the increasing prevalent process of preimplantation genetic diagnosis (PGD). These, too, are embryos that would not be used for reproduction, and thus would be discarded unless they were used for research.
Given that, even with new, more efficient techniques, researchers in South Korea needed to extract 185 eggs before they were able to produce a single cloned embryo, from which they could develop a line of embryonic stem cells to study further, pressure will increase to accelerate the collection of eggs through more widespread use of multiple egg extraction. Already, advertisements for egg donors are commonplace on many college campuses, where young women are motivated to undergo egg extractions for much-needed income, $4,000-7,000 per extraction in most cases, as well as for altruistic reasons. Both of these motivations could influence thousands more young and/or economically disadvantaged women to undergo risky egg extraction procedures solely for research, under circumstances where the risk/benefit ratio is far less clear. Once again, this will be an arena where we will see the mantra of “reproductive choice” co-opted and falsely applied.
In addition, new techniques may be developed that would obviate the need to use hormones for multiple egg extraction, providing even more justification for a cautious approach. A technique called “in vitro maturation,” or IVM, may make it possible to obtain multiple eggs without hormone injections. An article in the July 15, 2003 New York Times claims, “Doctors have found that a few days before ovulation, as many as 30 to 50 egg follicles have begun to mature. Normally, only one will fully ripen for ovulation, and the rest are lost. But if the eggs are removed before ovulation, many of them can be matured in the laboratory.” 
The push for SCNT will be strong in the coming years. Because the most vocal critics of this research are from the anti-abortion community, many pro-choice advocates are reluctant to get involved with this debate for fear of lending support to the wide anti-choice agenda. Although there are those who have deliberately confused this issue, whatever the practical purpose of egg collection may be, it is important to insist that health concerns for women not take a back seat.
Judy Norsigian is a co-author of Our Bodies, Ourselves and co-founder of the Boston Women's Health Book Collective, now called Our Bodies Ourselves. She serves as the organization's Executive Director and is involved with numerous women's health initiatives nationally and internationally.
1. Delvigne, Annick and Rozenberg, Serge. “Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review” Human Reproduction Update, vol. 8, no. 6, 2002, pp 559-577.
2. From Dr. Parisian's February 2005 memo now posted at www.ourbodiesourselves.org
3 .Consent to Participate in a Study Involving Egg Donation for Stem Cell Research
5. Norsigian, Judy, “Risks to women in embryo cloning,” Boston Globe, February 25, 2005,
6. Lazar, Kay “Wonder drug for men alleged to cause harm in women” Boston Herald, August 22, 23, 24, 1999.
8. Duenwald, Mary “After 25 Years, New Ideas in the Prenatal Test Tube,” New York Times, July 15, 2003.