Do menstrual cups cause endometriosis?
In 2003, Armand Lione, Ph.D., president of Associated Pharmacologists
and Toxicologists, petitioned the American Food and Drug Administration
to revoke the approval for the marketing of menstrual cups because he thought
there was a high likelihood that they caused endometriosis. The FDA disagreed,
writing that there was insufficient evidence. Read the petition, below;
the FDA's response is here.
Also, read FDA's classification of menstrual cups
in the Federal Register, 3 April 1979 & 26 Feb. 1980.
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.
533 Fourth St., SE Washington, DC 20003-4222 202.544.0711
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)
*Reference enclosed
Addendum B:
CEDER Adverse Event Report:
Menstrual Cups,
APT Citizen Petition
CEDER/MAUDE Database Adverse Report
BRAND NAME KEEPER CUP TYPE OF DEVICE MENSTRUAL CUP MANUFACTURER
(Section D) THE KEEPER CO.
3243 GLENDORA AVE.
CINCINNATI OH 45220
DEVICE EVENT KEY 254005 MDR REPORT KEY 262262 EVENT
KEY 245881 REPORT NUMBER 262262 DEVICE SEQUENCE NUMBER
1 PRODUCT CODE HHE REPORT SOURCE VOLUNTARY REPORT DATE
02/10/2000 1 DEVICE WAS INVOLVED IN THE EVENT 1
PATIENT WAS INVOLVED IN THE EVENT DATE FDA RECEIVED 02/11/2000
IS THIS AN ADVERSE EVENT REPORT? YES IS THIS A PRODUCT PROBLEM
REPORT? NO DEVICE OPERATOR HEALTH PROFESSIONAL WAS DEVICE
AVAILABLE FOR EVALUATION? NO PATIENT OUTCOME HOSPITALIZATION
OTHER REQUIRED INTERVENTION ADVERSE EVENT OR PRODUCT PROBLEM
DESCRIPTION REPORT DATE: 02/10/2000 MDR TEXT KEY: 892088 Patient
Sequence Number: 1 PT HAD A RECENT SURGERY. PT HAS BEEN USING THE
KEEPER CUP FOR ABOUT SIX YEARS. ACCORDING TO PT IT'S A MENSTRUAL CUP THAT'S
WORN INTERNALLY; IT'S SOLD THROUGH MAGAZINE CLASSIFIEDS ESPECIALLY THE HERB
COMPANION AND NOW AT THEIR WEBSITE WWW.KEEPER.COM. CLICK TO USAGE TO SEE
A PICTURE OF THE DEVICE. PT HAS INCREASING MONTHLY PAIN FOR THE LAST 3 YEARS.
THE PAIN IS MUCH DIFFERENT FROM CRAMPS. SOMETIMES ULTRAM AND FLEXERIL DON'T
EVEN "DENT" THE PAIN. LAST MONTH PT HAD ENDOMETRIOSIS SURGERY
AS PART OF AN ENDOMETRIOSIS STUDY. PT'S DR FOUND VERY LITTLE ENDOMETRIOSIS;
JUST WHAT HAD SLIPPED OUT AROUND THE TUBAL LIGATION PT HAD NINE YEARS AGO.
WHAT PT DID FIND WAS THAT UTERUS HAS BECOME COMPLETELY ENDOMETRIAL, AS CONFIRMED
BY LAB RESULTS. DR DESCRIBED UTERUS AS BLANCHING WHEN TOUCHED, LIKE YOU
COULD WRITE ON IT AND SEE THE WORDS. THE DIAGNOSIS IS "ADNOMYOSIS"
AND PT WAS ASKED TO START CONSIDERING A HYSTERECTOMY TO RELIEVE THE PAIN.
PT WROTE THE KEEPER CUP CO. THEY SAY THIS PRODUCT HAS NEVER BEEN EVALUATED
FOR ENDOMETRIOSIS. SINCE PT SEES THEM ADVERTISING A LITTLE MORE EACH YEAR,
PT HOPES NO ONE ELSE HAS THE SAME OUTCOME. PT ASKS FDA TO PLEASE CONSIDER
LOOKING INTO THIS. PT IS ALL FOR ALTERNATIVE HEALTHCARE WHEN IT DOES GOOD
AND NO HARM.
April 2003
Addendum A: Citizen Petition, Menstrual Cups
FDA Records for the Approval of
The Menstrual Cups:
(abridged)
The Keeper, K870803/A
and
Instead, K971303
Acquired through the FDA Freedom Of Information Office,
11/13/02 and 01/30/03
For additional information, contact:
Armand Lione, Ph.D.
202.544.0711
ArmandLione@hotmail.com
(Note: If you are receiving this document by email, the remainder of
this 7 page addendum will be found in a separate PDF document.)
533 Fourth St., SE Washington, DC 20003-4222 202.544.0711 | 
