Diagnosis and management of progesterone hypersensitivity
Question:
12/6/2022
A 27-year-old female was referred for reaction to her oral contraceptive pills. After the birth of her first child in 2020, she started Norethindrone and within a week of being on this medication developed pruritic urticaria that would appear on either her torso or extremities. She cannot recall the correlation of the episodes and dose time of the pill. Hives would not last more than 15 minutes and resolved without any need for medications. No other associated symptoms reported.
Norethindrone was stopped 2 months later and the episodes resolved. She got pregnant while being off her OCP. Her pregnancy course was uncomplicated without any episodes of urticaria or pruritus. After the birth of her second child, she started on ethinyl estradiol and norgestimate (Tri-sprintec) pill, which she had previously tolerated prior to her first pregnancy. Again, within week of being on this medication she started to develop episodes of urticaria on her extremities and/or torso with pruritus. No other symptoms. This medication was stopped and she was started on Sprintec-28 (ethinyl estradiol and norgestimate) with reproducible hives and pruritus. 5 months ago, this was stopped and she was switched to drospirenone pill. She initially was tolerating it but again a week later was developing hives and itching on most days she was taking the pill and on the days she took the placebo did not have episodes of hives or pruritus. She is still taking the pill at this time and does not treat the hives when they do occur as they do not last more than 15 minutes.
Based on history, there is suspicion that patient likely has an exogenous progesterone hypersensitivity. I was considering skin testing to progesterone and excipients in all the above OCPs to evaluate for progesterone hypersensitivity even though the sensitivity and specificity of this testing are unknown and false positive reactions can frequently occur. However, since patient continues to take the medication and is reluctant to stop taking it as she does not want to get pregnant, I am not sure if skin testing is appropriate and if management should include symptom management with oral anti histamines at this time.
Answer:
This definitely sounds like a case of exogenous progesterone hypersensitivity. Progestogen hypersensitivity, (a.k.a. autoimmune progesterone dermatitis or APD) was first described in 1964 [1]. Symptoms were noted as a pruritic, clustered, vesicular skin rash but rashes have been reported to vary from plaques, urticaria with or without angioedema, eczema, fixed drug eruptions, and erythema multiforme.[2] Now, it is commonly accepted that this is an IgE mediated disease.
There is now a helpful progesterone specific IgE immunoassay to assist in diagnosis and well-defined treatment algorithms that can be used to manage PH successfully.[2,3] The management of these cases can be guided by the presence of specific IgE to progesterone. Skin testing can induce irritant reactions at high progesterone concentrations in oil because it is not water-soluble. Skin testing has limited use as a diagnostic test.
A suggested algorithm for management is in Bernstein et al. 2020.
Since the endpoint of the current diagnostic algorithm is to take an exogenous progestogen (progesterone), it is appropriate to continue your patient on the OCP medication without skin prick testing. Standard medical management includes using H1/H2 antagonists, leukotriene antagonists, or omalizumab to control symptoms similarly as you would chronic urticaria. Your initial treatment can start with a second-generation H1-antagoinist and if not effective at the regular dosing, it should be increased to up to four times the FDA-recommended dose. I recommend your patient continue the OCP with symptomatic treatment of hives.
1. Shelley WB, Preucel RW, Spoont SS. Autoimmune progesterone dermatitis. Cure by Oophorectomy JAMA. 1964;190:35–8.
2. Bernstein JA. Progestogen Sensitization: a Unique Female Presentation of Anaphylaxis. Curr Allergy Asthma Rep. 2020 Jan 28;20(1):4.
3. Ghosh D, Bernstein JA. Development of a progesterone-specific IgE assay for diagnosing patients with suspected progestogen hypersensitivity. Ann Allergy Asthma Immunol. 2019;122(6):616–22.
Sincerely,
Carla M. Davis, MD, FAAAAI