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Perimenstrual anaphylaxis

Question:

Reviewed: February 24, 2020
12/12/2014
We recently met a 16 year-old female who has had 6 menstrual related episodes of anaphylaxis for her past 6 cycles always occurring 2-4 hours after the onset of menstruation; clearly not prior to menstruation. The episodes generally resolve within 2-3 hours of epinephrine and antihistamines. She continues to take Benadryl regularly for 24 hours.

Interestingly, at the very onset of menstruation the patient takes 600 mg of ibuprofen and takes once or twice daily for the first 3 days of menstruation. She had been using ibuprofen regularly for 3 months prior to these episodes for a stress fracture of her foot and had no problems. Since these episodes have started she has not used ibuprofen outside the first 3 days of menstruation.

Are we likely dealing with catamenial anaphylaxis vs autoimmune progesterone dermatitis syndrome vs mast cell disorder vs idiopathic vs nsaid allergy?

It seems unlikely that this is due to ibuprofen since she continues to take ibuprofen for up to 3 days.

It seems unlikely due to progesterone allergy because the anaphylaxis should occur premenstraully when the progesterone levels are peaking.

My plan is as follows:
1. Skin test for progesterone. (I will try to get several different preparations and do prick test with undiluted and then make dilutions for intradermals, but I'm not sure how far to dilute and maximum dose to use without getting an irritant reaction?)

Assuming the test is negative, then would have patient start progesterone base BCP to suppress menses, but would likely give first dose in ICU?

Should aspirin, ibuprofen or cox 2 inhibitor, celecoxib also be used?

If the progesterone skin test is positive, then alternatives must be sought. In addition to using other modalities for menstrual suppression, would treatment with nsaids still be beneficial in this case?

I probably would also challenge with ibuprofen first just to verify that she is not allergic.

We did send a serum tryptase, but family was not keen on sending 24 urine for histamine and prostaglandins.

Finally, what's the long term prognosis for this young patient?

Answer:

I do not think there are answers to many of your questions as many of the issues related to catamenial anaphylaxis are not resolved and the phenomenon may have variable pathogenetic mechanisms.

Progesterone skin testing is a reasonable first step but many women with catamenial anaphylaxis are negative (see Bauer et al (25% positive) and Ask The Expert question from archives). Also, please note the comments from Dr.Winnograd in the Ask The Expert question related to peanut contamination of some progesterone products giving a positive skin test due to the peanut content. The bottom line is the progesterone test is may have false positive and false negative results. The progesterone concentrations generally used are 0.1 and 1.5 mg/ml for prick and intradermal testing (Bauer et al; Park et al; Stranahan et al; Magen et al). There are a number of other suggested progesterone testing protocols. Please do a search on here for progesterone.

I would advise against a progesterone challenge if the skin test is negative due to the limited information from the skin testing and the concerns expressed by Dr. Winnograd (see below). Suppression of progesterone with gonadotropin releasing hormone therapy is most often mentioned, although Dr. Winnograd refers to using estrogen suppressive therapy.

Prostaglandin inhibitor therapy has been reported by Bernstein et al to be beneficial but the response is inconsistent (see Bauer et al). There are theoretical arguments for using prostaglandin inhibitors due to suppression of PgF2a (affects mast cell mediator release) and PgI2 (vasodilator). The statement in Bauer et al is that “The role of COX inhibitors in catamenial anaphylaxis remains unclear at this time.” I think that is the best we can say currently.

The timing of symptoms in catamenial anaphylaxis is variable, with many having onset after menstruation (see Bauer et al with 4 of 8 having onset after menses). I do not know if we can conclude that progesterone is not playing a role with onset after onset of menstruation as the symptoms may be modified by changes in progesterone concentrations rather than absolute levels.

The prognosis is also unclear with most women continuing to experience symptoms unless placed on gonadotropin releasing hormone therapy or undergoing oophorectomy. Pregnancy effects are also variable.

In summary, I would favor catamenial anaphylaxis and not autoimmune progesterone dermatitis, idiopathic anaphylaxis, mast cell disorder or NSAID induced anaphylaxis. The value of progesterone IgE testing is questionable but is a consideration. There is no uniform treatment plan but most would try to suppress progesterone with either estrogen therapy or gonadotropin releasing hormone therapy. I would be very cautious in the use of progesterone treatment, although this has been reported to be beneficial. NSAID therapy is controversial but has been helpful (Bernstein). Antihistamine therapy may be preventative and is worth a try. Epinephrine autoinjectors should be provided. The effects of pregnancy are difficult to predict.

Bauer, Cindy S., et al. "Heterogeneity in presentation and treatment of catamenial anaphylaxis." Annals of Allergy, Asthma & Immunology 111.2 (2013): 107-111.
Abstract
Background: Few reports have documented the uncommon association of the female menstrual cycle with anaphylaxis, an entity known as cyclic or catamenial anaphylaxis.
Objective: To examine cases of perimenstrual anaphylaxis, focusing on differences in presentation and response to treatment, in the hopes of enriching the description of this rare entity.
Methods: A cohort of 8 women with catamenial anaphylaxis were identified and retrospectively compared with regard to age at onset, organ involvement, diagnostic studies, and response to therapy.
Results: The median age at onset was 34 years (range, 14-40 years), and the median number of perimenstrual anaphylactic episodes at presentation was 10 per patient (range, 4-24 per patient). Most had cutaneous and gastrointestinal symptoms. The results of extensive investigations for anaphylactic triggers were negative, and masquerading conditions, such as carcinoid syndrome, pheochromocytoma, and systemic mastocytosis, were ruled out in all patients. Skin test results for progesterone were negative in all but 1 of 4 patients tested. None had elevated total serum IgE levels. Response to suppressive treatments regimens varied considerably, but none treated with high-dose systemic steroids had improvement. Similarly, ketotifen, celecoxib, rofecoxib, and oral contraceptives failed to control the anaphylactic reactions. Although antihistamines failed in 7 patients, 1 had improvement. Others responded to leuprolide, medroxyprogesterone, or salpingo-oophorectomy.
Conclusion: Whether the mechanism causing cyclical anaphylaxis may involve hypersensitivity to progesterone or prostaglandins, the variable response to suppressive medications in these cases suggests that catamenial anaphylaxis is a heterogeneous disorder in which a number of mechanisms and mediators may play a role. It is an emergent and probably underrecognized entity in the medical literature.

Possible progesterone-related anaphylaxis
Q: I have been following a 12 year-old female patient with recurrent episodes of facial angioedema, pruritus, urticaria and respiratory distress over the past 6-7 months. She has been treated with IM epinephrine on 2 occasions. The symptoms seem to occur 1-2 days prior to the onset of menstruation. One consideration was autoimmune progesterone urticaria and angioedema. As I understand it, symptoms related to this "progesterone sensitivity" occur during the luteal phase of the menstrual cycle as progesterone levels peak. This patients symptoms occur 1-2 days prior to menstruation, a time in which progesterone levels should be dropping significantly leading up to menstruation. Intradermal testing to progesterone (0.1mg/mL and 1 mg/mL) was negative. She has never been treated with exogenous progesterone. She denies the use of NSAIDs or other medications for menstrual cramping. A CBC and differential, ESR (7mm/hr), complete metabolic panel, tryptase level (3 ng/mL) and total IgE level (46 kU/L) were all well within normal limits.

The timing of her symptoms as they relate to menses suggests catamenial anaphylaxis. Interestingly, most of her episodes have occurred during meals. An exhaustive evaluation of possible food triggers, including multiple challenges, was unrevealing. I suspect the temporal relationship to meals is coincidental, but I also wonder if there is a connection.

I currently have her on 10 mg of cetirizine starting 1 week prior to estimated menses and continuing through her period. Her last episode was milder with the cetirizine, but she was symptomatic nonetheless.

I have seen reports using various regimens of antihistamines and anti-inflammatory meds. Lupron has also been used. All have had mixed results. Any suggestions for confirming a diagnosis and treating, keeping in mind that she is only 12 years old, would be greatly appreciated.

A: I have copied two abstracts and a reference for you below which are germane to your inquiry. As you can see, there are two salient points that can be obtained from these references:

1. The Meggs reference was one of the first well-studied cases of progesterone-related anaphylaxis. In this case, IgE anti-progesterone was not demonstrated and therefore the demonstration of a positive skin test is not a sine qua non for the diagnosis. There are probably alternative mechanisms involved other than IgE-mediated histamine release.

2. Catamenial anaphylaxis related to progesterone sensitivity can occur a day or so before the menses. Progesterone levels are usually still reasonably high at that time.

Having said that, of course, we are still not certain that your patient has progesterone-related anaphylaxis. Clearly, if she were older, I would give a trial of menses suppression with Lupron. In our experience this has been quite useful in the few cases we have seen. At her age, however, one would approach this with more caution. Alternatively, you could try birth control pills. I would suggest calling in an OBGYN specialist, particularly if you have one that specializes in pediatric OBGYN, to advise you on the risks of suppressing menses. If you did prevent these episodes with menstrual suppression, then it would be a reasonably good proof of concept that you were dealing with anaphylaxis related to progesterone secretion or other hormonal influences. If she did not respond, it would, on the other hand, suggest to you that she has idiopathic anaphylaxis which by coincidence has occurred timed with the menstrual cycle. My guess, however, is that she will respond to suppression and that she does have progesterone-related anaphylaxis.

While doing this, of course, I would continue her antihistamine therapy and also consider adding an H2 antagonist.

Finally, if you will note, one of the references copied below was coauthored by Dr. I. L. Bernstein (first author). I therefore feel certain that he has recently reviewed the literature regarding "catamenial anaphylaxis" and thus I am also sending your question to him to get his perspective, which may be more up-to-date than mine in this regard. As soon as I hear from Dr. Bernstein, I will forward his comments to you.

In the meantime, you could consider initiating the suggestions noted above.

Iran J Allergy Asthma Immunol. 2007 Jun;6(2):97-9.
Autoimmune progesterone anaphylaxis.
Bemanian MH, Gharagozlou M, Farashahi MH, Nabavi M, Shirkhoda Z.
Source
Department of Pediatrics, Shahid Sadoughi Hospital, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. mhbemanian@razi.tums.ac.ir
Abstract
Progesterone induced dermatitis is a rare disorder. It typically occurs in females due to an autoimmune phenomenon to endogenous progesterone production, but can also be caused by exogenous intake of a synthetic progestin. Here in, we present a case of autoimmune progesterone anaphylaxis (AIPA) observed in an adolescent female. The patient is an 18-year-old Caucasian female with no significant past medical history and no prior exogenous hormone use, who presented to her primary care physician complaining of cyclic skin eruptions with dyspnea, cough and respiratory distress. She noted that her symptoms occurred monthly, just prior to her menses. An intradermal skin test using 0.1 cml of progesterone was performed. The patient developed a 15 mm wheal after 15 minutes, confirming the diagnosis of AIPA. The patient was started on a continuous regimen of an oral conjugated estrogen (0.625 mg). The skin eruptions and respiratory symptoms have not returned since the initiation of this therapy. Autoimmune progesterone dermatitis manifests via the occurrence of cyclic skin eruptions. Women with the disorder commonly present with dermatologic lesions in the luteal phase of the menstrual cycle, if there are any other organ involvement in addition to skin (e.g. lung, GI) the reaction should be called as autoimmune progesterone anaphylaxis. Diagnosis of AIPA is confirmed by performing a skin allergen test using progesterone.

J Womens Health (Larchmt). 2011 Apr;20(4):643-8. Epub 2011 Mar 18.
A case of progesterone-induced anaphylaxis, cyclic urticaria/angioedema, and autoimmune dermatitis.
Bernstein IL, Bernstein DI, Lummus ZL, Bernstein JA.
Source
Department of Internal Medicine, Division of Immunology/Allergy Section, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0563, USA.
Abstract
Objective: Women have exhibited anaphylaxis, urticaria/angioedema, and autoimmune progesterone dermatitis (APD) coinciding with the progesterone premenstrual rise. We report a detailed immunological evaluation of such a woman responsive to a gonadotropin hormone-releasing agonist (GHRA).
Methods: Skin testing, enzyme-linked immunosorbent assays (ELISAs), leukocyte histamine release (LHR), and inhibition assays were performed to demonstrate progesterone immunoresponsiveness.
Results: Serum specific-progesterone immunoglobulin G (IgG) and IgE were detected initially and disappeared 6 months after GHRA treatment. Dose-response LHR using patient basophils was observed for different hormones but after 3 months persisted only for 5ß-pregnanediol. Preincubation with mouse antiprogesterone monoclonal antibody (PmAb) or mifepristone, a progesterone inhibitor, over a range of doses inhibited specific progesterone-induced LHR. Experiments with varying progesterone concentrations and a fixed dose of anti-IgE resulted in 100% LHR at a concentration as low as 0.016?nmol/mL, which, without anti-IgE, failed to release histamine.
Conclusions: This is the first report of combined recurrent anaphylaxis, cyclic urticaria/angioedema, and APD induced by immunoresponsiveness to progesterone.

Progesterone Sensitivity as a Cause of Recurrent Anaphylaxis
William J. Meggs, M.D., Ph.D., Ora Hirsch Pescovitz, M.D., Dean Metcalfe, M.D., D. Lynn Loriaux, M.D., Ph.D., Gordon Cutler, Jr., M.D., and Michael Kaliner, M.D.
N Engl J Med 1984; 311:1236-1238.

Sincerely,
Phil Lieberman, M.D.

Dr David Bernstein responded to your inquiry, and stated that he concurred with the original reply we sent you with no additional remarks. Thank you again for your inquiry.

Phil Lieberman

Dear Colleagues,
A few months ago I sent in an inquiry about progesterone anaphylaxis which was diagnosed in a young acquaintance.

I just read your response to an inquiry into progesterone sensitivity dated 6/22/2011. In this response, you advise to suppress ovulation in a 12 year old girl with catamenial facial angioedema and other symptoms at the end of the luteal phase.

I have to strongly advise not to do that, or if, to do it under strict medical supervision: patients who are sensitive to progesterone often have the same reaction to synthetic progesterone. The patient I wrote about was prescribed oral contraceptives and sent home. She ended up in anaphylactic shock and the intensive care shortly after taking the first pill.

I would suggest to try continuous estrogen for a while to see what effect that has. Eventually, ovulation suppression will have to be initiated anyway if the patient goes into shock every month and all else fails. It is a real conundrum in these young women.

Case reports of cross sensitivity to progesterone derivatives are found on patient blogs, like the one from this young woman:

“I am 19 years old and I have it on proven record that I am allergic to progesterone, It causes my chest to tighten and an awful cough. Been on birth control forms of progesterone 2x both ended with a trip to the ER or me hyperventailating on the softball field. I am trying to get the actual test so I can be put on medicine to stop the production of progesterone because my tight chest and cough reappear 10-15 days before a period and do not end until 2-3 days after. It is life disrupting and frankly scary. Am I on the right track?”

On another note, there are problems with skin testing for progesterone sensitivity, because of the use of peanut-oil based progesterone and the frequent peanut sensitivities patients will have, clouding the results; sensitivity testing should be done with a water (or was it alcohol?) based progesterone, which is not commercially available but can be compounded by knowledgeable pharmacists; as the mixture is not stable it needs to be compounded right before use.

Sincerely,
Corinne Winograd, M.D.
I hope this information is of help to you and your patient.

All my best.
Dennis K. Ledford, MD, FAAAA