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April 17, 2003

Citizen Petition
The undersigned submit this petition under 21 CFR 10.30 of the Federal Food, Drug, and Cosmetic Act to request Dr. Mark McClellan, the Commissioner of Food and Drugs, revoke the approval for the marketing of the devices categorized as menstrual cups (21CFR 884.5400) because there is a high likelihood that the use of these devices as directed will endanger a woman’s reproductive health by inducing endometriosis.

Action Requested
The FDA administrative record for the two menstrual cups currently marketed shows that neither was required to submit clinical data regarding their safety (see FDA Freedom of Information (FOI) Files: The Keeper: Record K870803, 1987; Instead, softcup: Record K971303, 1997 (abridged versions attached(Addendum A)). Until the manufacturers of the menstrual cups can submit suitable animal and clinical data to support that these devices can be safely used as directed without increasing the risk or severity of endometriosis, we hereby request the approval for the sale of menstrual cups be revoked.


Statement of Grounds

Summary
Menstrual cups, when used as currently recommended, can be worn for 12 hour periods during menstruation. They are designed to fit either over the cervix or within the vagina tightly enough so no menstrual debris is released from the body while a cup is in place.
Obstructions of the cervix and vagina are commonly recognized as important factors in inducing endometriosis. The cervical outlet obstruction inherent in the use of menstrual cups is likely to increase the incidence and severity of endometriosis among women who use these products.

Detailed Statement of Grounds

Menstrual Cups and Endometriosis
A. Menstrual Cups: Approval History and Current Use
Currently there are two menstrual cups approved for sale by the FDA: 1. The Keeper (www.keeper.com), a flexible rubber cone, that sits intravaginally to occlude menstrual discharge, and 2. Instead (www.Softcup.com), a plastic diaphragm-shaped disc that covers the mouth of the cervix with an impermeable barrier. The Keeper is a reusable product. Instead is intended for one time use and disposal. The package inserts for both products recommend they be used for periods of time not to exceed 12 hours. The possible effect of these products on the risk of endometriosis is not mentioned in the package inserts.
The approval records for both products show that neither manufacturer was required to submit any clinical data to demonstrate their safety when used as directed (FOI Files(attached)). Thus the possible effects of these products on reproductive health have not been reviewed by the Food & Drug Administration.
Among the possible reproductive effects of the menstrual cups, there is a physiologically credible mechanism whereby their use would increase the incidence or severity of endometriosis.

B. Endometriosis
Endometriosis is a chronic condition that is typically diagnosed clinically because of severe dysmenorrhea. Asymptomatic cases of endometriosis are often diagnosed during peritoneal surgery. In rare cases, endometriotic growths are found outside the peritoneum and the reproductive tract. Since endometriosis develops over an extended time period, the origins of this condition are subject to hypothetical explanations, and no one hypothesis appears to explain all manifestations of the disease (Guarnaccia et al, 2000; Evers, 1996; Cramer & Missmer, 2002). However, a diverse assortment of clinical and animal data are consistent with the Sampson (menstrual reflux) hypothesis for explaining the origins of peritoneal endometriosis (Sampson, 1927; Guarnaccia et al, 2000; Evers, 1996; Cramer & Missmer, 2002; D’Hooghe & Debrock, 2002). Sampson suggested that peritoneal endometriosis develops when fragments of functional endometrium are released from the surface of the uterus during menstruation and refluxed back through the Fallopian tubes to reach the peritoneal cavity. Some endometrial fragments attach to peritoneal surfaces, growing and degenerating, cyclically, in conjunction with the menstrual cycle. These ectopic endometrial growths sometimes cause inappropriate adhesions between peritoneal tissues and organs, producing debilitating pain. When endometrial tissues occlude the fimbriated ends of the fallopian tubes, endometriosis can cause infertility.
There are several sources of clinical and experimental data that support the Sampson hypothesis and the role that “out flow obstruction” can play in the induction of endometriosis.(figure 1)
First, the collected anatomical analyses of the distribution of endometriotic growths in the peritoneum are consistent with the fallopian tubes as a source for the seeding tissue (Guarnaccia et al, 2000).
Second, women born with congenital defects of their reproductive tract which prevent menstrual debris from being discharged through the cervix or vagina typically develop severe forms of endometriosis (Pinsonneault O, Goldstein DP, 1985; Hanton et al, 1966; Olive & Henderson, 1987; Geary & Weed, 1973; Farber M, Marchant, 1975; Maciulla et al, 1978; Niver et al, 1980; Nunley & Kitchin, 1980; SanFilippo et al, 1986). Some clinicians have also analyzed this population sufficiently to report that women without functional endometrial tissues (another aspect of their developmental abnormalities) do not develop endometriosis (Olive & Henderson, 1987).
Third, several observations in the baboon model for endometriosis (D'Hooghe et al, 1994; D'Hooghe et al, 1995; D’Hooghe et al., 1996) appear to support the Sampson hypothesis, and the role of out flow obstruction in the induction of endometriosis. These observations include a demonstration of the increased incidence of retrograde menstruation in baboons with spontaneous endometriosis (D’Hooghe et al., 1996); intrapelvic injection of menstrual endometrium causing experimental endometriosis similar to that observed in spontaneous disease (D'Hooghe et al, 1995); and surgically induced cervical occlusion leading to retrograde menstruation and endometriosis (D'Hooghe et al, 1994).
Retrograde menstruation appears to occur in most women (Halme & Hall, 1984). This has been demonstrated in a variety of ways, including the detection of endometrial cells in the dialysate of peritoneal dialysis patients (Blumenkrantz et al., 1981). Since retrograde menstruation is relatively common, but endometriosis appears to occur in a fraction of menstruating women, multiple factors apparently interact to produce symptomatic endometriosis. In an animal model of endometriosis, one group of researchers has demonstrated that the successful survival and growth of endometrial cells correlated directly with the amount of tissue (represented by its weight) injected into the peritoneum (D'Hooghe et al, 1995). Additional research is being focused on the possible role that immune factors may play on the elimination of menstrual debris. In some women a defect in immunosurveillance may play a role in the clearing of menstrual debris, suggesting that women unable to clear menstrual debris go on to develop disease (Cramer & Missmer, 2002)

Epidemiological data has shown that women with early menarche, short menstrual cycles or longer periods of menstruation are more likely to suffer from endometriosis (7,8,20,22-24). These findings are consistent with the Sampson reflux hypothesis for the origin of peritoneal endometriosis. On one hand, the more frequent the challenge (i.e. in women with early onset of menstruation and those with shorter cycles) or the larger the challenge (i.e. in women with longer periods of menstruation), the more likely it is that a woman will develop endometriosis. Some clinicians also have drawn attention to epidemiological data showing a lower incidence of endometriosis among women who have given birth and suggested that the enlargement of the cervical opening (and corresponding reduction in resistance to menstrual outflow) to explain this finding (Cramer & Missmer, 2002). Dysmenorrhea is a strong risk factor for endometriosis, but it has generally been considered to represent a symptom of existing disease, since it is easy to imagine that monthly bleeding from pelvic lesions is painful. However, some data suggest that dysmenorrhea may correlate with stronger uterine contractility (Schulman et al., 1983), and one reviewer has suggested an alternate interpretation: dysmenorrhea may be associated with some degree of outflow obstruction, caused by stronger uterine cramping, and an increased propensity to retrograde menstruation (Cramer & Missmer, 2002).
Consistent with these observations, the mechanical occlusion of the cervix or vagina during menstruation would be expected to substantially increase the retrograde flow of menstrual discharge. This mechanical occlusion would thereby increase the seeding of the peritoneal cavity with endometrial cells. Menstrual cups are, in essence, removable cervical and vaginal occlusion devices. Thus, the increased menstrual retention produced by the use of the menstrual cups is likely to have endometriosis-promoting effects.

C. Potential for Reflux With Menstrual Cups and Other Menstrual Products
A clear distinction can be made between the menstrual occlusion that results from the use of menstrual cups and the occlusive potential of absorbent menstrual products such as tampons. Simply described, a menstrual absorbent product, such as a tampon, can retain the menstrual discharge within its structure until its absorbent capacity is exceeded. When a tampon is saturated, it too can become an obstructive device that would increase the reflux of endometrial tissues. However, the saturation of a tampon would also produce vaginal leakage, prompting its removal.
In contrast, menstrual cups are composed of impervious, non-absorptive materials. Since fluids are non-compressible, any discharge being held in the cavity of a menstrual cup can be readily refluxed back into the uterine cavity, as well as the fallopian tubes and eventually into the peritoneum. It should also be noted that clinical studies using menstrual cups have shown that the debris they collect does contain viable endometrial cells (Koks et al, 1997). Although quantitative data on their effect on endometrial reflux has not yet been collected, it can be anticipated that a woman wearing a menstrual cup might inadvertently apply compressive forces and promote endometrial reflux when assuming a number of routine positions that compress the vaginal space or apply pressure to the cervical os. One of the available products (Softcup) is recommended for use during sexual intercourse. The mechanical effects on menstrual reflux in this situation also await evaluation.
In the research literature on endometriosis, one reviewer has suggested that larger fragments of endometrium may have higher invasive potential, once they enter the peritoneal cavity (Evers, 1996). Therefore, future research also needs to address whether cervical or vaginal occlusion during menstruation generates increased fluid reflux through the uterus, altering the size distribution of dislodged endometrial tissue. Available research techniques have monitored endometrial cells in peritoneal fluid during menstruation in women and in animal studies (Bartosik et al, 1986; Kruitwagen et al, 1991; D’Hooghe et al.,2001). This approach could be used to evaluate the role played by menstrual cups.

D. Endometriosis Risk in Specialized Populations
Given the concerns expressed above about how the use of menstrual cups might increase the risk of endometriosis, this adverse effect would not be expected among women who had ligated fallopian tubes. However, a review of the one adverse report involving the menstrual cups and endometriosis in the CEDER/MAUDE database (Addendum B(attached)) shows that it involved problems apparently resulting from menstrual obstruction associated with the use of the Keeper, in a women with ligated fallopian tubes. In this case the reporting physician described the patient’s uterus as “completely endometrial” and hysterectomy was recommended.
Endometriosis is a relatively common problem in teenage women. The superficial convenience of the menstrual cups for young women active in athletic competitions would make them an attractive choice for use during menstruation. However, as discussed above, until data is collected on effects of mechanical forces on the endometrial reflux associated with the use of menstrual cups, their use during strenuous activities, such as athletic competitions, is a prominent point of concern.

E. Epidemiological Monitoring
Since the onset of endometriosis is apparently influenced by a variety of factors, which include diverse elements such as individual anatomy and immune function, the epidemiology of endometriosis is not clearly defined (Cramer & Missmer, 2002). This fact suggests that the clinical demonstration of an increase in the incidence of endometriosis in association with menstrual retention devices will be a complex task, making caution even more important in this matter, while research data is being collected.



Conclusion

Based on the theoretical concerns discussed above and the limited clinical reports in the FDA databases, current users of menstrual cups should be informed of the possible risk of endometriosis associated with these products, and the sale of menstrual cups as OTC devices should be discontinued until sufficient data on their safety has been collected and analyzed.


Environmental impact
The petitioners claim a categorical exclusion from this requirement under Secs. 25.30 - 25.34 of 21(1) CFR.

Certification
The undersigned certify, that, to the best knowledge and belief of the undersigned, this petition includes all information and views on which the petition relies, and that it includes representative data and information known to the petitioners which are unfavorable to the petition.

For Associated Pharmacologists & Toxicologists*:


(Signature)______________________________________________________
Armand Lione, Ph.D., President, APT

(Name of petitioner)__Associated Pharmacologists & Toxicologists_

(Mailing address)_____533 – 4th St. SE Washington, DC 20003-4222_

(Telephone number)____(202) 544-0711___________

(email)____ArmandLione@Hotmail.com_____________


For The Endometrosis Research Center:


(Signature)_ _____________
Heather C. Guidone, Director of Operations, ERC

(Name of petitioner)___Endometriosis Research Center______________

(Mailing address)_____630 Ibis Drive, Delray Beach, FL 33444______

(Telephone number)______ (561) 274-7442__

(email)______EndoFl3@aol.com_____________




* To whom correspondence about filing this petition should be addressed.



References*

Bartosik D, Jacobs SL, Kelly LJ: Endometrial tissue in peritoneal fluid. Fertil Steril 46:796-800, 1986.

Blumenkrantz MJ, Gallagher N, Bashore RA, Tenckhoff H: Retrograde menstruation in women undergoing chronic peritoneal dialysis. Obstet Gynecol 57:667-70, 1981.

CEDER Adverse Event Report*: MDR Text Key: 892088; 02/11/2000.(see addendum B, below)

Cramer DW, Missmer SA: The epidemiology of endometriosis. Ann NY Acad Sci 2002; 955:11-22.

D'Hooghe TM, Bambra CS, Suleman MA, Dunselman GA, Evers HL, Koninckx,PR: Development of a model of retrograde menstruation in baboons (Papio anubis). Fertil Steril 1994;62:635-8.

D'Hooghe TM, Bambra CS, Raeymaekers BM, De Jonge I, Lauweryns JM, Koninckx PR: Intrapelvic injection of menstrual endometrium causes endometriosis in baboons (Papio cynocephalus, Papio anubis). Am J Obstet Gynecol 1995;173:125-34.

D'Hooghe TM, Bambra CS, Raeymaekers BM, Koninckx PR. Increased incidence and recurrence of retrograde menstruation in baboons with spontaneous endometriosis. Hum Reprod 1996;11:2022-5.

D'Hooghe TM, Bambra CS, Xiao L, Peixe K, Hill JA: Effect of menstruation and intrapelvic injection of endometrium on inflammatory parameters of peritoneal fluid in the baboon (Papio anubis and Papio cynocephalus). Am J Obstet Gynecol 2001;184:917-25.

D’Hooghe TM, Debrock S: Endometriosis, retrograde menstruation and peritoneal inflammation in women and baboons. Hum Reprod Update 8:84-88, 2002.

Evers JLH: The defense against endometriosis. Fert Steril 66:351-3, 1996.

Farber M, Marchant DJ: Congenital absence of the uterine cervix. Am J Obstet Gynecol 121:414, 1975.

Geary WL, Weed JC: Congenital atresia of the uterine cervix. Obstet Gynecol 42:213-7, 1973.

Guarnaccia MM, Silverberg K, Olive DL: Endometriosis and Adenomyosis. in Textbook of Gynecology, 2nd ed., Copeland LJ, ed., WB Saunders, Philadelphia. 2000, pp. 687-722.

Halme J, Hall JL: Retrograde menstruation in healthy women and in patients with endometriosis. Obstet Gynecol 1984;64:151-4.

Hanton Em, Malkasian GD Jr, Dockerty MB et al: Endometriosis associated with complete or partial obstruction of menstrual egress. Report of 7 cases. Obstet Gynecol 28:626-9, 1966.

Kruitwagen RFPM, Poels LG, Willemsen WNP, de Ronde IJY, Jap PHK, Rolland R: Endometrial epithelial cells in peritoneal fluid during the early follicular phase. Fertil Steril 55:297-303,1991.

Koks CA, Dunselman GA, de Goeij AF, Arends JW, Evers JL:
Evaluation of a menstrual cup to collect shed endometrium for in vitro studies. Fertil Steril 1997; 68:560-4

Maciulla GJ, Heine MW, Christina CD: Functional endometrial tissue with vaginal agenesis. J Reprod Med 21:373, 1978.

Niver DH, Barette G, Jewelewicz R: Congenital atresia of the uterine cervix and vagina: Three cases. Fertil Steril 33:25, 1980.

Nunley WC, Kitchin JD: Congenital atresia of the uterine cervix with pelvic endometriosis. Arch Surg 115:757, 1980.

Olive DL, Henderson DY: Endometriosis and mullerian anomalies. Obstet Gynecol 69:412-5, 1987.

Pinsonneault O, Goldstein DP: Obstructing malformations of the uterus and vagina. Fertil Steril 44:241-7, 1985.

Sampson JA. Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol 1927;24:422-69.

SanFilippo JS, Wakim NG, Schikler KN et al: Endometriosis in association with uterine anomaly. Am J Obstet Gynecol 154:39, 1986.

Schulman H, Duvivier R, Blattner P: The uterine contractility index: a research and diagnostic tool in dysmenorrhea. Am J Obstet Gynecol 1983;145:1049-58.

Schwartz B, Gaventa S, Broome CV et al: Nonmenstrual toxic shock syndrome associated with barrier contraceptive: report of a case-control study. Rev Infect Diseases II(supp 1):S43-8, 1989.

USFDA Freedom of Information (FOI) Files (abridged)*: The Keeper: Record K870803, 1987; Instead, softcup: Record K971303. (See Addendum A, below)