Last updated:
8/8/2024
Years published: 2024
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders for assistance in the preparation of this report.
Progestogen hypersensitivity (PH) is a condition where the body has an allergic reaction to progesterone, a hormone produced by the ovaries, or to synthetic forms of progesterone called progestins, which are often used in birth control or fertility treatments.1,2 The presentation of PH is varied and can start at any time from the first period (menarche) to menopause in reproductive aged women.3
PH can cause a variety of symptoms including:1,3
PH can be classified as: 4
The timing of symptoms is important for diagnosing PH. The main diagnostic tests are progesterone skin tests and progestogen challenge if PH from synthetic progestins is suspected, which involves administering a small amount of progestin and monitoring for a reaction.4
Treatment depends on the specific symptoms each affected person has and may include medication to treat symptoms such as antihistamines for skin reactions or bronchodilators for asthma, medications to stop ovulation and reduce progesterone production and progesterone desensitization, which consist of gradually increasing exposure to progesterone under medical supervision to reduce sensitivity.1,4
Progestogen hypersensitivity (PH) symptoms can vary widely. These symptoms often occur in a cyclical pattern in women, appearing during the second half of the menstrual cycle (luteal phase) when progesterone levels are naturally higher. However, the onset of symptoms triggered by exposure to exogenous progesterone (after an assisted fertilization procedure, after the use of exogenous progestogens (contraceptives) or after using other types of steroids) is not necessarily related to the menstrual cycle.1,3
Symptoms may include:1
The exact cause of progestogen hypersensitivity is not well understood but several theories exist:1,4
For affected people with no prior exposure to synthetic progestogens, the cause of PH remains unclear.
Based on the cause, PH can be classified as:4
Progesterone levels vary throughout life, with the greatest variations during puberty and levels also change during the menstrual cycle (period) in response to the pulsatile secretion of follicle stimulating hormone (or FSH) and luteinizing hormone (or LH) by the pituitary gland, located in the brain. Progesterone levels are considerably higher in women than in men.5,6
During a period (the menstrual cycle), progesterone levels rise just before ovulation and peak during the “luteal phase” around day 21 of a 28-day menstrual cycle, generally one week prior to the start of menstruation. Progesterone is initially made by the ovarian structure known as the corpus luteum and has an important role in preparing the uterus for pregnancy. If pregnancy does not occur, the corpus luteum will regress and the progesterone levels drop. The progesterone drop will trigger menstruation.5,6 Symptoms of endogenous PH typically develop during the luteal phase.
If pregnancy does occur, progesterone levels rise throughout the pregnancy and remain high throughout pregnancy. After a baby is born, there is a rapid decrease in the progesterone levels in blood.5,6
Pregnancy can either trigger, worsen, or improve PH symptoms. When PH starts during pregnancy, the symptoms may continue or resolve after childbirth.
Symptom relief during pregnancy might be due to the gradual increase in progesterone levels or a reduction in the maternal immune response.
PH can also begin after childbirth, suggesting that high levels of progesterone during pregnancy might sensitize some women to the hormone.
Symptoms from synthetic progestogens (used in contraception or fertility treatments) as commented before, are usually related with exposure to these substances and are not tied to the luteal phase of the menstrual cycle. Various synthetic progestins can trigger PH symptoms, including:1
PH appears to be rare, with fewer than 200 reported cases, although it may be under-recognized, and there are no published estimates of incidence or prevalence.
PH predominantly affects women of reproductive age, with an average age of onset in the late 20s among patients described in the medical literature. There is a single reported case of hypersensitivity in a male patient receiving the progestin, megestrol acetate. PH was reported in very few postmenopausal women treated with progestins as part of hormone replacement therapy (HRT), as the symptoms typically disappear after menopause.3,4
Diagnosing progestogen hypersensitivity (PH) can be difficult due to the variety of symptoms and their cyclical nature.5
A detailed medical history particularly focusing on any use of synthetic progestogens, such as birth control pills, progestin injections, vaginal rings, or intrauterine devices is very important, as well as noting when symptoms occur in relation to the menstrual cycle can provide important clues for the diagnosis.5 This helps to rule out other diagnoses and shows a clear link between symptoms and exposure to progestogens.
Progesterone skin testing can be done, but it is not always reliable. An allergist may also consider a progestogen challenge, where a small amount of progestin is given under medical supervision to see if it triggers symptoms.5
As progestogen hypersensitivity is a rare condition it is often mistaken for other skin diseases. Many affected people are first treated with antihistamines and glucocorticoids, which can sometimes improve symptoms. However, the main approach to treatment involves suppressing ovulation and reducing progesterone levels, especially during the luteal phase of the menstrual cycle.
Treatment for progestogen hypersensitivity (PH) varies depending on the individual’s symptoms and their severity, and it may involve:1,2
Other treatment options that have being used with some success include: 8
Some women with PH may experience changes in their symptoms during pregnancy, with some finding relief and others experiencing worsening symptoms. Symptoms disappear in menopause.
Progestogen hypersensitivity is a condition where some people react badly to certain hormones, which can make daily life very difficult. To figure out what’s going on, it’s important for a patient to keep track of when and how symptoms appear and to share their complete medical history with their doctor. More studies are needed to learn why this happens, how to diagnose it more accurately and how to treat it better.
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For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
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For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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