Here at the Network, we often receive emails or calls from women seeking health care information about specific procedures or tests. Something different’s been happening recently, however: we’ve received several messages from women asking the Network to explore the safety of a drug commonly used in fertility treatments: Lupron® (leuprolide acetate). This drug was originally developed for advanced prostate cancer patients, but is now commonly used to treat women with endometriosis and fibroids, and to aid assisted reproduction procedures. Lupron® is a Gonadotropin-Releasing Hormone Analog/Agonist (GnRH); these drugs shut down the pituitary gland, thereby reducing the amount of testosterone produced by men, and estrogen produced by women. For women, this causes the rapid and artificial onset of menopause – potentially with incapacitating and long-lasting effects.
“My own story is that after taking Lupron [for endometriosis] I now have bone loss, severe bone and joint pain requiring heavy painkillers to get out of bed, chest pain, tachycardia, fibromyalgia and horrible memory loss, hair loss and weight gain. Prior to Lupron I ran and boxed everyday. I was healthy even though endometriosis caused significant pain. It has now been a year since my Lupron treatments and my life is in medical shambles.”
The women contacting the Network relate very similar experiences: they were healthy but — after using Lupron® – they report having lost their health, their jobs, and more. While only a small percentage of women seem to have such a severe reaction, there is no way to predict who will experience these frightening and debilitating side-effects. Nor does there seem to be any interest on the part of either the Food and Drug Administration (FDA) or Lupron®’s manufacturer to further investigate the drug’s safety or adverse events. One woman who wrote to the Network about her experiences asked, “Who is watching out for us?”
The FDA reports that, as long ago as 1999, it had received adverse drug reports about Lupron® from 4,228 women and 2,943 men.1 These side effects included: tingling, itching, headache and migraine, dizziness, severe joint pain, difficulty breathing, chest pain, nausea, depression, emotional instability, dimness of vision, fainting, weakness, amnesia, hypertension, muscular pain, bone pain, nausea/vomiting, asthma, abdominal pain, insomnia, chronic enlargement of the thyroid, liver function abnormality, vision abnormality, and anxiety, and others.2 In 325 of these cases, the women required hospitalization; 25 women died.3 At the time, the FDA said that it did not have enough staff capacity to assess any causal effect in these cases.
Lupron®’s original manufacturer, Takeda-Abbott Pharmaceuticals (TAP) Pharmaceuticals, has stated that the drug’s side effects are temporary and should last no longer than six months after stopping the medication.4 But, surveys conducted by the Endometriosis Research Center (a patient advocacy group) with women who took Lupron® has indicated that over half of the respondents (51.67%) experienced side effects lasting for longer than six months; for almost one-quarter (23%) of the women, side effects lasted longer than five years.5 Other clinical studies have found that almost three-quarters (72%) of women taking Lupron® experience memory difficulties, and that these memory problems can last as long as six months after the study was conducted.6
The company seems to know that something’s not right. 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.’” 7 But the company never invested in that follow-up research, and the FDA hasn’t yet required it to.
Lupron® for Endometriosis and Fibroids
The FDA approved Lupron® to treat both endometriosis and anemia associated with uterine fibroids. Endometriosis is a painful, chronic disease that affects over five million women and girls in the U.S.8 It occurs when tissue lining the uterus is found outside the uterus, usually in the abdominal-pelvic cavity. This misplaced tissue develops into growths or lesions that respond to the menstrual cycle like the uterine lining: each month the tissue builds up, breaks down, and sheds. Unlike menstrual blood, however, the blood and tissue shed from endometrial growths have no way to leave the body. The result is internal bleeding and inflammation that can cause pain, infertility, scar tissue formation, adhesions, and bowel problems.
Uterine fibroids are benign growths on the uterus’ muscular wall that can cause pelvic pain, heavy bleeding, clotting, and pain during sex. Around three-quarters (77%) of all women of reproductive age in the U.S. will develop fibroids, and 25 percent will experience negative symptoms as a result.9 African-American women are about three times more likely to develop fibroids than women of other racial groups.10
The exact cause of these conditions is not yet known (although there may be a link with estrogen production or exposure to the environmental toxin dioxin) and no non-invasive tests exist to provide a definitive diagnosis. Treatment for fibroids has traditionally involved a complete hysterectomy, which is not an option for women who want to get pregnant later. For endometriosis, laparoscopic or abdominal surgery to remove endometrial lesions can produce relief, but may fail if the surgeon is unskilled or the disease is particularly severe. For these reasons, many doctors encourage women with these conditions to use drug therapy to adjust estrogen levels in an effort to shrink fibroids or lesions. Despite the fact thatno drug has been proven to provide lasting relief for either condition, Lupron® has emerged as the most-frequently prescribed medication for women with fibroids and endometriosis.
Lupron® for Infertility Treatment
Lupron® is also widely used as part of Assisted Reproductive Technology (ART) — fertility treatments such as in vitro fertilization (IVF) in which both eggs and sperm are handled. The Centers for Disease Control and Prevention (CDC) notes that more than one percent of all U.S. births result from assisted reproductive technologies.11 (ART does not include treatments in which only sperm is handled, like artificial insemination, or when the woman takes drugs only to stimulate eggs but they are not retrieved.)
Assisted reproductive technology efforts use GnRHs as part of the process of harvesting donor and non-donor eggs. The hormones are injected into the woman’s body to shut down the ovaries; then other drugs are used to stimulate egg production and facilitate multiple egg extraction. (The eggs are fertilized in a lab and then implanted into the woman.) Lupron® is among the most common GnRH analogs used as part of this process. IVF patients report that they are told that the use of GnRHs is an essential step; some have been required to take Lupron® to continue their IVF treatment, despite any objections they may have had.
There have been no prospective or clinical studies on Lupron®’s safety for ART patients and the FDA has not approved Lupron® for use in infertility treatment or assisted reproduction procedures such as IVF. Its use occurs “off label”, an option that allows an FDA-approved drug to be used for medical purposes neither originally specified in the drug’s approval nor described on the drug’s labeling.
I have been to a total of 17 doctors since taking Lupron with many different diagnoses and there doesn’t seem to be an end in sight. I don’t know why we can’t seem to get someone in the medical field to look into the on-going side effects of this drug. There is something definitely wrong with a drug when you go from being perfectly healthy to having all kinds of medical problems and you know that in your heart it started while on Lupron. I do know that I am not alone. I used to think I was but I have personally spoken to people that have taking Lupron and they are experiencing the same problems.
Significant Safety Concerns
Lupron® is an “antineoplastic agent”, meaning that it is a cancer chemotherapy drug. Like all antineoplastics, Lupron® is harmful to both cancerous and non-cancerous cells — particularly to pregnant women and developing fetuses. In addition to the harmful side-effects reported by women using Lupron® for its approved uses, there are concerns about its effects when used as part of assisted reproductive technologies, such as IVF.
The National Institutes of Health (NIH) and the Occupational Safety and Health Administration (OSHA) categorize Lupron® as a “hazardous drug” that health care workers should only handle when wearing protective gowns and gloves.12 They also recommend that health care professionals who intend to conceive or father a child avoid handling Lupron® or other such hazardous drug for three months before conception.13
Abbott’s patient education materials note that the FDA advises women who are, or may become, pregnant not to take Lupron® because of the risks to the developing fetus.14 The drug information describes “major fetal abnormalities” seen in pregnant rabbits after Lupron® was injected at doses 1/1200–1/12 the human pediatric dose.15 The company states that women who are pregnant should not use Lupron®, recommends the use non-hormonal contraception to prevent pregnancy while on Lupron®, and encourages those who think they might be pregnant to contact their health care providers immediately.16 The popular website, Drugs.com, states flatly: “Lupron causes birth defects.”17
Yet, despite these risks, and the fact that women may experience side effects months after discontinuing the drug, Lupron® is prescribed not only for approved uses to treat endometriosis and fibroid, but also for off-label use in assisted reproductive technologies.
My exposure to Lupron began in 1989, and shortly thereafter I began having multiple health problems, and have subsequently amassed a room full of documents, correspondences and medical literature devoted to the risks of Lupron. Since testifying in March 2003 on these risks in Congress (where I nearly puked on the Senate floor), I’ve been hospitalized 33 times, and am now disabled and had to retire from my career as a psychiatric RN. It’s been very difficult, especially these last five years, but at least I’ve finally been able to start my website: www.LupronVictimsHub.com.
If the drug is doing what it should and helping women suffering from fibroids, endometriosis, or infertility, that’s one thing. But what if the drug doesn’t work or was approved based on faulty data? According to at least one activist, the clinical studies filed with the FDA on Lupron®’s effectiveness at reducing endometriosis-related pain were based on small numbers of women who were also allowed to take other pain-killers (including narcotics) at the same time.18 The Endometriosis Research Center’s survey found that almost half of the responding women (48.19%) reported Lupron® to be “intolerable” and “not helpful” for relief of their endometriosis symptoms.19
Even more startling, the Federal Dept. of Health and Human Services’ Office of Research Integrity determined that the lead investigator involved with studies on Lupron®’s use in treating fibroids and endometriosis committed scientific misconduct, and admitted to falsifying or fabricating 80 percen of the data in two published studies on Lupron®.20 The Federal Register noted that the investigator “altered and fabricated information in permanent patient medical records and notes by changing dates, changing and adding text, and fabricating notes for clinic visits that did not occur.” 21 Those studies were retracted.
It is devastating to agree to an FDA-approved drug, under the care of a physician you trust, only to find yourself sicker than you could possibly imagine, in pain, and unable to get treatment or even be believed.
Avoiding Long-Term Harm: The Informed Rx Decision-Making Consortium
Lupron® is a hazardous drug with side-effects that can last for weeks or months after the drug is discontinued, but do the women taking it know that? It’s not clear how much patients are being informed about Lupron®’s risks – certainly some people might decide that the drug’s harmful effects outweigh the potential benefits. In addition, the fact that the drug has not been approved or assessed for use in ART procedures such as IVF may be of particular concern to both patients and egg donors.
One researcher has commented: “GnRH analogs [like Lupron] are not like any other medication currently available for treatment of disease. As we continue to learn more about these analogs’ mechanisms of action, it is increasingly apparent that they do not just affect the gonadal [sex] hormones, but are powerful modulators of autonomic neural function.”22 Shouldn’t we know more about these drugs — and Lupron® in particular?
It is an enormous problem that no data are being gathered on Lupron®’s long-term effects on women using the drug for endometriosis, fibroids, or ART. We believe that women must receive complete information about Lupron®’s efficacy and effects in order to make a truly informed decision about whether or not to take the drug. To determine Lupron®’s short- and long-term effects, and create conditions under which patients can provide true informed consent, the NWHN believes that several measures are needed.
The FDA has recently received funding for additional oversight activities and NWHN believes that the agency should review the safety and efficacy of Lupron® for both its approved and off-label uses. As part of this process, the FDA must require Abbott Pharmaceuticals to conduct the assessment of Lupron®’s long-term effects on bone density that the company itself has said were needed. To gather up-to-date information on adverse events, a registry should be established to monitor the drug’s effect on women, as well as on any children exposed to Lupron® either before conception or as part of their mother’s IVF. Women who have experienced adverse events are encouraged to report them to the FDA by contacting MedWatch at http://www.fda.gov/medwatch/report/consumer/consumer.htm.
In order to halt this drug from causing damage to even one more woman’s health, a concerted effort of women, physicians, health officials, researchers and media is needed. The decision to raise public awareness so that other women could be spared the physical, emotional and financial burdens Lupron causes would truly be in the interest of women’s health around the country. The people who are considering taking Lupron are the ones who have the right to know that they are risking a lifetime of symptoms that may cost them their jobs, spouses, savings and quality of life.
In addition, the NWHN has initiated a public education and policy campaign to get the word out about the misuse and dangers of Lupron® and other drugs. Along with the Center for Medical Consumers, the Endometriosis Association, and Our Bodies Ourselves, we have formed The Informed Rx Decision-Making Consortium. The Consortium will work to educate women about inappropriate drug use and provide tools to help them make better-informed decisions about prescription drugs — including how to determine what works, what doesn’t, and what cost-effective alternatives exist. For more information about the Consortium and the campaign, visit the NWHN’s website in the coming months (www.nwhn.org).
This article was written by: Susan K. Flinn, MA
Susan K. Flinn is the Editor of the WHA. Lynne Millican, RN, BSN, provided support and significant assistance with this article; the majority of the research cited comes from her work. For more information about Lupron and this issue, or to read many of the articles cited, see Ms. Millican’s excellent website: www.LupronVictimsHub.com
1 Norsigian J, “Concerns about Lupron™ (leuprolide acetate), used in the process of extracting eggs from women (for IVF, research cloning, and potentially for inheritable human modifications), OBOS Health Resource Center, October 2002, accessed 9/5/08 fromhttp://www.ourbodiesourselves.org/book/companion.asp?id=25&compID=67&page=5
2 Norsigian J, “Egg Donation for IVF and Stem Cell Research: Time to Weigh the Risks to Women’s Health,” OBOS Health Resource Center, 2005, accessed 9/5/08 fromhttp://www.ourbodiesourselves.org/book/companion.asp?id=31&compID=97&page=3
3 Norsigian J, “Concerns about Lupron™ (leuprolide acetate), used in the process of extracting eggs from women (for IVF, research cloning, and potentially for inheritable human modifications)”, OBOS Health Resource Center, October 2002. Accessed 9/5/08 fromhttp://www.ourbodiesourselves.org/book/companion.asp?id=25&compID=67&page=5
4 In 2008, Abbott Pharmaceuticals and Takeda Pharmaceutical Company concluded this joint venture; Abbott Pharmaceuticals now manufacturers Lupron (other pharmaceutical companies also manufacture GnRHa drugs).
5 Endometriosis Research Center (ERC), “Use of GnRH Agonists Prior to an Endometriosis Diagnosis,” Delray, FL: ERC, 2003, p. 2.
6 Varney NR, Syrop C, Kobe CS et al, “Neuropsychologic Dysfunction in Women Following Leuprolide Acetate Induction of Hypoestrogenism”, Journal of Assisted Reproduction and Genetics 1993; 10(1):53; and Newton C, Slota D, Yuzpe AA et al, “Memory complaints associated with the use of gonadotropin-releasing hormone agonists: a preliminary study”, Fertility and Sterility 1996; 65(6):1253, cited in Millican L, “Cloning: A Risk to Women,” Testimony Before the U.S. Senate, Subcommittee on Science, Technology and Space, March 27, 2003. Available online at: insert www.LupronVictimsHub.com.
7 Norsigian J, “Egg Donation for IF and Stem Cell Research: Time to Weigh the Risks to Women’s Health,” OBOS Health Resource Center, 2005, accessed 9/5/08 from http://www.ourbodiesourselves.org/book/companion.asp?id=31&compID=97&page=3. Citing Lazar K, “Wonder drug for men alleged to cause harm in women,” Boston Herald, August 22, 23, 24, 1999.
8 US. Dept of Health and Human Services (HHS), “Women’s Healthcare Forum — Endometriosis,” Rockville, MD: HHS, August 2008. Accessed 9/8/08 fromhttp://www.womenshealthcareforum.com/endometriosis.cfm.
9 National Institute of Child Health and Human Development (NICHD), “Fact Sheet — Uterine Fibroids”, Rockville, MD: NICHD, December 22, 2005. Accessed 9/8/08 fromwww.nichd.nih.gov/publications/pubs/upload/uterine_fibroids_2005.pdf.
10 National Institute of Child Health and Human Development (NICHD), “Fact Sheet — Uterine Fibroids”, Rockville, MD: NICHD, December 22, 2005. Accessed 9/8/08 fromwww.nichd.nih.gov/publications/pubs/upload/uterine_fibroids_2005.pdf.
11 CDC, “2005 Assisted Reproductive Technology Success Rates: National Summary and Fertility Clinic Report”, MMWR 2008;57(SS-5):1–23. On-line: http://www.cdc.gov/ART/ART2005 visited 9/16/08.
12 Listed as leuprolide acetate. National Institutes for Occupational Safety and Health (NIOSH), NIOSH Alert: Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in the Healthcare Setting. Cincinnati, OH: Centers for Disease Control and Prevention/NIOSH, Sept. 2004, p. 12, 37. See Millican L, “Cloning: A Risk to Women,” Testimony Before the U.S. Senate, Subcommittee on Science, Technology and Space, March 27, 2003. Available online at: insert www.LupronVictimsHub.com.
13 American Society of Health-System Pharmacists, American Hospital Formulary System Revised Guidelines 1999, Bethesda MD: ASHSP, pp. 1030-1. See Millican L, “Cloning: A Risk to Women,” Testimony Before the U.S. Senate, Subcommittee on Science, Technology and Space, March 27, 2003. Available online at: insertwww.LupronVictimsHub.com.
14 Patient Information on Treatment with Lupron Depot 3.75 mg [Endometriosis and Uterine Fibroids], and Patient Information on Treatment with Lupron Depot 11.25 mg [Endometriosis and Uterine Fibroids], Lake Forest, IL: TAP Pharmaceuticals, 2001-2004, p. 3 For more on this issue, see Millican L, “Cloning: A Risk to Women,” Testimony Before the U.S. Senate, Subcommittee on Science, Technology and Space, March 27, 2003. Available online at: insert www.LupronVictimsHub.com.
15 Lupron Depot 3.75 mg Package Insert, Lake Forest, IL: TAP Pharmaceuticals, Oct. 2005, p. 8.
16 Lupron Depot 3.75 mg Package Insert, Lake Forest, IL: TAP Pharmaceuticals, Oct. 2005, p. 6; Patient Information on Treatment with Lupron Depot 3.75 mg [Endometriosis and Uterine Fibroids]; and Patient Information on Treatment with Lupron Depot 11.25 mg [Endometriosis and Uterine Fibroids], Lake Forest, IL: TAP Pharmaceuticals, 2001-2004, p. 5.
17 http://www.drugs.com/lupron.html (visited 9/5/08)
18 FDA, New Drug Application (NDA) 20-011: Summary Basis of Approval. Lupron 3.75 mg IM for pain management in endometriosis. Approved October 1990. See Millican L, “Cloning: A Risk to Women”, Testimony Before the U.S. Senate, Subcommittee on Science, Technology and Space, March 27, 2003. Available online at: www.LupronVictimsHub.com..
19 Endometriosis Research Center, “Use of GnRH Agonists Prior to an Endometriosis Diagnosis,” Delray, FL: Endometriosis Research Center, 2003, p. 2.
20 “Findings of Scientific Misconduct”, Federal Register 1996; 61(85):19295-6. Online through:http://www.gpoaccess.gov/fr/retrieve.html. Accessed 9/17/08. cited in Millican L, “Cloning: A Risk to Women,” Testimony Before the U.S. Senate, Subcommittee on Science, Technology and Space, March 27, 2003. Available online at: insert www.LupronVictimsHub.com.
21 “Findings of Scientific Misconduct”, Federal Register 1996; 61(85):19295-6. Online through:http://www.gpoaccess.gov/fr/retrieve.html. Accessed 9/17/08. cited in Millican L, “Cloning: A Risk to Women,” Testimony Before the U.S. Senate, Subcommittee on Science, Technology and Space, March 27, 2003. Available online at: insert www.LupronVictimsHub.com.
22 Mathias JR, Clench MH, “Placebo Controlled Study Randomizing Leuprolide Acetate”, Digestive Diseases and Sciences 1995; 40(6):1405, cited in Millican L, “Cloning: A Risk to Women,” Testimony Before the U.S. Senate, Subcommittee on Science, Technology and Space, March 27, 2003. Available online at: insertwww.LupronVictimsHub.com.