THE NATIONAL LUPRON VICTIMS NETWORK
Return to: THE NATIONAL LUPRON VICTIMS NETWORK Homepage LUPRON: NEVER APPROVED FOR INFERTILITY
DAILY Lupron Injections are NOT approved for infertility treatment DAILY Lupron Injections are only approved for men with advanced prostate cancer
FETAL RISK:
According to the package insert, DAILY Lupron injections and MONTHLY Lupron Depot are both rated Pregnancy Category X Drugs by the FDA.
"The PDA's Pregnancy Categories are based on the degree to which available information has ruled out risk to the fetus, balanced against the drug's potential benefits to the patient. Ratings range from "A," for drugs that have been tested for teratogenicity under controlled conditions without showing evidence of damage to the fetus, to "D" and "X" for drugs that are definitively teratogenic. The "D" rating is generally reserved for drugs with no safer alternatives. The "X" rating means that there is absolutely no reason to risk using the drug in pregnancy." (1)
A = CONTROLLED STUDIES SHOW NO RISK. Adequate, well controlled studies in pregnant women have failed to demonstrate risk to the
fetus.
B = NO EVIDENCE OF RISK IN HUMANS. Either animal findings show risk, but human findings do not; or, if no adequate human studies
have been done, animal findings are negative
C = RISK CANNOT BE RULED OUT. Human studies are lacking, and animal studies are either positive for fetal risk, or lacking as well.
However, potential benefits may justify the potential risk.
D = POSTITIVE EVIDENCE OF RISK. Investigational or post-marketing data show risk to the fetus. Never-the-less, potential benefits may
outweigh the potential risk.
X = LUPRON = CONTRAINDICATED IN PREGNANCY. Studies in animals or human, or investigational or post-marketing reports have
shown fetal risk which clearly outweighs any possible benefit to the patient. (1)
A teratogen is a drug or other agent that causes abnormal development. (2)
According to the package insert:
•      "Lupron is contraindicated (against medical advice) in women who are or may become pregnant while receiving the drug." (3) This statement appears in the package insert for both DAILY Lupron injections and MONTHLY Lupron Depot. (3)
•      "1/600th the human dose causes major fetal abnormalities in rabbits when administered on day 6 of pregnancy." (3)
"The most frequently observed malformations in rabbits were vertebral anomalies and hydrocephalus (J.D.Miller, personal communication, Tap Pharmaceuticals, Inc., 1992)" (4)
The following congenial anomalies have been reported to the US Food and Drug Administration as part of the Spontaneous Reporting System/Division of Epidemiology and Surveillance:
Congenital Anomaly:
ASD
Cardiac Problems [Unspecified]
Coarction of the Aorta
Enlarged Liver
Enlarged Spleen
Growth Retardation
Hyperplastic Aortic
Imperforate Anus
Rectovaginal Fistula
Spinal Fusion
Spinal Muscular Atrophy
Thirteen Ribs
Underdeveloped Brain (5)
I. QUOTES FROM THE LITERATURE
1.     In 1988, the following appeared in the medical literature: "Physicians using Leuprolide Acetate as an adjuvant for ovulation induction should consider obtaining detailed, written informed consent from the patient prior to instituting therapy." (6) It should be noted that informed consent from a patient is generally not required by a doctor when prescribing drugs.
2.     According to information that THE NATIONAL LUPRON VICTIMS NETWORK has received "clinical studies for Lupron's use in treating   infertility have been discontinued."
3.     "One cannot exclude the possibility that GnRH-a in pharmacological dosages may be cytotoxic against oocytes..." (7)
4.     "Conclusion: If no selection against chromosomally abnormal oocytes takes place at the time of fertilization, more abnormal oocytes are harvested with GnRHa/hMG protocols than with CC/hMG." (Please note that this study did not employ Lupron, but did employ two other GnRH analogues.) (8)
5.     "They were ... playing with their embryos, as well. Scientists like Cohen noticed that Lupron embryos were different. They grew faster, developed more rapidly. They were more fragile when frozen and less likely to survive thawing. Nobody knew why or what it meant for the long term health of the woman or any resulting child." (9)
6.    "The rate of development of embryos obtained during down-regulated cycles [with Lupron] was significantly higher than that of embryos developing in conventional stimulation cycles." (10)
7.     "...there was a decreased incidence of implantation of embryos from patients who were exposed to analogs. It is suggested that embryos from down-regulated cycles should be cryopreserved earlier to correct for their accelerated development." (10)
8.     "The proportion of thawed embryos leading to normal birth appeared higher in the control group than in the LA-treated [Lupron] group (7 of 55; 13% versus 1 of 49; 2%, respectively)." (10)
9.     "GnRH-a[nalogue] acts directly in the mature rabbit follicle to trigger meiotic maturation of oocytes while concomitantly increasing the rate of oocyte degeneration. However, oocytes matured in vitro by GnRH-a, unlike hCG-treated oocytes, are not necessarily cytoplasmically mature." (7)
10.   "...the adjunctive use of leuprolide for controlled ovarian hyperstimulation and intrauterine insemination does not improve cycle fecundity compared with treatment cycles that do not include adjunctive leuprolide [Lupron] therapy." (11)
11.   "Leuprolide Acetate [Lupron] (10-4 to 10-5 M) had a stimulatory effect on spontaneous contractions of human myometrium and fallopian tube in vitro. "(12)
12.   "There is also evidence that cycles using GnRH analogs and hMG are associated with higher E2 levels and higher doses of hMG but that these oocytes are of lower quality than those retrieved from cycles using hMG alone. "(13)
13.  Twenty-three patients that conceived with Lupron (duration of exposure to Lupron ranged from 11-28 days; 1 -2 mg/day) yielded the following pregnancy outcomes: 2 tubal pregnancies, 2 chemical pregnancies, 6 miscarriages, 9 term deliveries, and 4 ongoing pregnancies. "The incidence of adverse pregnancy outcome [10/19 = 52.6%] is higher than previously reported in the literature. These data therefore suggest that inadvertant administration of Lupron during early pregnancy may not be as safe as has been assumed." (14)
14.   "While some studies demonstrate an improvement in intermediate end-points such as an increased number of mature oocytes retrieved and embryos available for transfer, a significant effect has not been demonstrated on the rate of live births per stimulated cycle." (15)
15.   "Lupron Depot has no effect on pregnancy rates and should not be used as a fertility promoting drug. "(16)
IT. Neurological Symptoms Reported With IVF
As of 1994, paresthesia was the 3rd most common side effect reported to the FDA for women.(5) Paresthesia is an abnormal spontaneous sensation, such as of burning, pricking, tickling, or tingling. (2)
In 1990 Dr. Ashkenazi and colleagues reported the following neurological symptoms after exposure to a GnRH analog for IVF-ET.(17)
Patient 1;
8 days after only 1 monthly injection of a GnRH analog "the patient started to complain of various neurological symptoms, such as severe headaches of the migraine cephalic type, numbness and tingling of the face, paresthesia and weakness of hands, arms, and legs, and sensory ataxia. These signs were first felt along one side of the body, and several days later on the other side. "(17) In the next IVF cycle, she was treated with a different GnRH-analog, this time in the form of a nasal spray. "Ten [10] days later, identical neurological signs appeared, severe headaches, numbness of the face, and paresthesias of the right hand and leg. "(17)
Patient 2:
Twelve (12) days after only 1 monthly injection "the patient started to complain of severe unilateral (left) migraine headaches, as well as of paresthesias, weakness, and numbness of the left arm and hand."(17) "During the next IVF cycle 3 months later, she was again" given the same GnRH-analog and "10 days later her symptoms, mainly unilateral headaches, and left arm/hand numbness and paresthesia, recurred. "(17)
Patient 3:
Ten (10) days after only 1 monthly injection for an IVF cycle, "the woman started to complain of paresthesia and numbness of her left hand. "(17) In the following IVF cycle, she was treated with the same GnRH-analog and "10 days later the patient complained of severe migraine, numbness of the left side of the face, as well as paresthesia and numbness of her left hand."(17)
Dr. Ashkenazi et al stated that "the mechanisms of action responsible for this complication is not clear. "(17) However, "a direct effect of potent GnRH-analog on the central nervous system resulting in neurological effects independent of the hypothalamus-pituitary-gonadal axis is
posssible."(17)
Dr. Ashkenazi points out that "it is quite possible that mild cases with minor symptoms have escaped notice; thus, the occurence of this type of complication may be far more common than we realize. "(17)
In 1991, Dr Penzias and colleagues reported a case of "transient facial and neck paresthesia" with a GnRH-analog in a 26-year-old woman being treated for endometriosis.(18) On the 23rd day of the medication the patient noted left breast pain, and the "onset of lower facial and neck tingling and numbness on the side contralateral [opposite] to drug administration. "(18)
It should be noted that these four cases were the only cases reported in the medical literature that discuss paresthesia. In addition, the following statistics have been reported:
• 14 % developed paresthesia of the hand when given Lupron Depot (3.75 mg) for fibroids. (19)
• 7 % developed paresthesia when given Lupron Depot (3.75 mg) for endometriosis. (20)
•5% developed paresthesia of the hand when given Lupron Depot (1.88 mg) for fibroids.(19)

REFERENCES:
(1) Physician's Desk Reference, 1994; p. 2687.
(2) Stedman's Medical Dictionary. Williams and Wilkins Company. Baltimore, 1979.
(3) Physicians Desk Reference, 1992, 1993, 1994, 1995.
(4) Briggs, Freeman & Yaffe. Drugs in Pregnancy and Lactation. 4th Edition.
(5) Adverse Reactions Reported to US Food and Drug Administration as Part of the Spontaneous Reporting System/Division of Epidemiology, through December, 1994.
(6) Leuprolide Acetate: Applications in Gynecology. Current Problems in Obstetrics and Gynecol Pert, November/December, 1988: p. 209-229.
(7) Yoshimura Y. Nakamura Y, Ando M, Shiokawa S, Koyama N, Nanno T. Direct effect of gonadotropin-releasing hormone agonists on the rabbit ovarian follicle. Fertility & Sterility. 57:5:1992: p. 1091-1097.
(8) DeSutter P, Dhont M, Vandekerckhove D. Hormonal Stimulation for in Vitro Fertilization^ Comparison of Fertilization Rates and Cytogenetic Findings in Unfertilized Oocytes. Journal of Assisted Reproduction and Genetics 9:3:1992:p. 254-258.
(9) Hotz RL. Designs on Life. Pocket Books, a division of Simon & Schuster Inc. New York, NY 1991.
(10) Keenan D, Cohen J. Stimulation cycles suppressed with gonadotropin-releasing hormone analog yield accelerated embryos. Fertility and Sterility. 55:4:1991:p. 792-796.
(11) Dodson WC, Walmer DK, Hughes CL, Yancy SE, Haney AF. Adjunctive Leuprolide Therapy Does Not Improve Cycle Fecundity in Controlled Ovarian Hyperstimulation and Intruterine Insemination of Subfertile Women. Obstetrics and Gynecology. 78:2: 1991:p . 187.
(12) Kendall J, Mathias J, VanHook J. Leuprolide acetate stimulates smooth muscle of the human reproductive tract. Fertility & Sterility. 56:5:1991 :p. 993-994.
(13) Stadtmauer L, Ditkoff EC, Session D, Kelly A. High dosages of gonadotropins are associated with poor pregnancy outcomes after in vitro fertilization-embryo transfer. Fertility and Sterility. 61:6: 1994: p. 1058-1064.
(14) Karande VC, Rinehart JS, Pratt DE, Gleicher N. Is the Inadvertant Administration of Leuprolide Acetate in Early Human Pregnancy Truly Associated With Normal Outcomes? Fertility and Sterility. Program Supplement. April 17-21: 1996; p. A27.
(15) Plosker GL, Brogden RN. Leuprorelin. Drugs. 48: 6: 1994; p. 930-967.
(16) US Food and Drug Administration. NDA #20-011
(17) Ashkenazi J, Goldman JA, Dicker D, Feldberg D, Goldman GA Adverse neurological symptoms after gonadotropin-releasing hormone analog therapy for in vitro fertilization cycles. Fertility & Sterility. 1990; 53: 4: p. 738-740.
(18) Penzias AS, Gutmann JN, Seifer DB, DeCherney AH. Facial and neck paresthesia associated with nafarelin administration. Fertility & Sterility. 1991; 56: 2: p. 357-358.
(19) Watanabe Y, Nakamura G, Matsuguchi H, Nozaki M, Sano M, Nakano H. Efficacy of a low-dose leuprolide acetate depot in the treatent of uterine leiomyomata in Japanese women. Fertility & Sterility. 1992; 58; 1: p.66-71.
(20) Facts and Comparisons, 1994.
This Is A Work In Progress
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