What is Progesterone Intolerance and Sensitivity?

If your body seems to “flip a switch” after ovulation, you’re not imagining it and you’re not alone. Speaking of Women's Health Podcast host Dr. Holly Thacker talks through a lesser-known but very real problem: progesterone allergy and progesterone intolerance, often grouped under progestogen hypersensitivity. The most important clue is timing, with symptoms that reliably worsen in the luteal phase when progesterone rises and then ease when your period starts and hormones fall.

Dr. Thacker walks through what progesterone is supposed to do in women’s health and why it can still trigger trouble for some people, whether it’s your own endogenous progesterone or synthetic progestins in hormonal birth control, fertility treatment, IUDs, or menopausal hormone therapy. She covers the full range of symptoms, from cyclical hives, rashes, itching, swelling, and asthma-like breathing issues to mood changes, anxiety, migraines, breast tenderness, bloating and heartburn. We also explain the difference between a true allergy that can be dangerous and an intolerance that can feel awful but may respond to smarter dosing, timing and formulation choices.

Transcript

Real-Life Allergy Stories And Safety

Holly L. Thacker, MD 0:10

Welcome to the Speaking of Women's Health Podcast. I'm your host, Dr. Holly Thacker, and I am back in the Sunflower House for a new edition of our Speaking of Women's Health podcast. And on today's podcast, we're gonna go into an interesting, um, somewhat rare problem, but one that I have seen uh a number of times over my career. And it's progesterone allergy or progesterone intolerance. And there is a variety of different reactions to natural progesterone that some women can experience, but few have heard about. So if you've ever felt significantly worse in the second half of your menstrual cycle, the so-called luteal phase, it occurs after ovulation, after uh the egg is released, and then the corpus luteum makes progesterone. Progesterone is the hormone that protects the lining of the uterus, prepares it to accept a fertilized egg if pregnant, and if not pregnant, to shed orderly. Some women certainly have felt worse in the second half of their cycle just through PMS. Um many women, um probably 10% to maybe 30% have reported feeling uh not as good on synthetic hormonal birth control. Um some women have reported having unusual skin reactions or even changes in respiration around ovulation. So if you've had any of these symptoms, um you might be dealing with more than just, quote, the normal hormonal fluctuation.

Progesterone’s Role Across The Cycle

Allergy Versus Intolerance And Testing Pitfalls

Symptoms In Skin Mood Gut And Breathing

Why It Happens And How To Diagnose

Treatment Options Beyond Just Stopping

When To Seek Care And Next Steps

Dr. \ 2:09

Now, this podcast, of course, is just for education and empowerment. It's not medical advice. So if you think you have any type of allergy to anything, I mean, allergies can even turn into anaphylaxis and cause swelling, angioedema of the mouth, the tongue, and throat, and it can actually cause death. Food allergies, nuts, medication, antibiotic. Um it's it's very frightening. In fact, I decided to become a physician when I watched my own father, a physician, treat an anaphylactic bee sting reaction to my brother with an injection of epinephrine that he had in his black medical bag. He had an a medical office and then he also had another office uh in our home. And so uh we were outside and my brother got stung. He later had desensitization, but he always carries an epi pen with him. Although the last time he had to use it, he didn't have his reading glasses with him. He's kind of vain, and your arm only goes so long, and he was trying to to uh recall how to use the epinephrine pen. Um, my oldest son, who's been on the podcast, Stetson, he uh called me very visibly upset when his daughter Artemis, my first granddaughter, and I just found out I'm having a fourth granddaughter. Um I'm so excited. When she had an allergic reaction after he fed her a whole container of uh cashews, and instead of driving to the hospital that he lived across the street from where she was born, where they have a pediatric emergency room, he put her in the car to drive her to my house. And I was on the golf course with his uh younger brother at the time, and I'm trying to do the conversion, call my local um EMS to find out if they had a pediatric dose of EpiPen, which they didn't. So I am trying to figure out what the conversion is. But luckily I had purchased uh an antihistamine, you know, Zyrtech, and I think that it's good to have a medical kit at home of antihistamines, of aspirin, in case someone's having chest pain and you're instructed to put one under the tongue, um, basic first aid supplies, and to know what your emergency resources are. And certainly, if anyone in your family has had nut allergy or anaphylactic allergy, you have to understand and know how to administer epinephrine. And uh many locations are now carrying it, schools, um, because you can really save someone's life. Um so anyway, Artemis did get testing, she did have a significant cashew allergy and a little cross-reactivity with pistachios, and she underwent desensitization, which is uh generally more successful the younger you are, and now she can eat cashews, thank goodness. Uh, but I still always make sure I have that EpiPen around because witnessing it in patients and also in family members, and just remembering how quick my brother got swollen and had trouble breathing was very, very dramatic. So, talking about progesterone allergy, um, it's it's probably better understood not necessarily as a classical anaphylactoid allergy, but more as a progestogen, progesterone hypersensitivity or intolerance. And these conditions can affect women during the reproductive years, during pregnancy when progesterone levels are very high in perimenopause. Generally the progesterone levels tend to fall. That's one reason why periods can come closer together, why there can be more blood clots. But sometimes this situation can be misunderstood, misdiagnosed, or even dismissed entirely. Um, what's the role of progesterone in women's health? It's produced after ovulation and it plays a central role in regulating your menstrual cycle, very important role in supporting early pregnancy. In fact, some women are given progesterone suppositories in early pregnancy to help sustain the pregnancy if it's thought that there's any progesterone insufficiency. Progesterone provides a balance to estrogen in women that have an endymetrium, and it can influence mood and sleep. Natural progesterone is converted in the brain to allopnenolone, which is a natural sedative hypnotic. But for some women, whether progesterone, whether it's quote, natural or bioidentical or whether it's synthetic, it can trigger reactions that can interfere with daily life. So, what is a progesterone allergy? Well, progestogen hypersensitivity, pH, is a condition wherein the body has a reaction to progesterone. And also this can happen with synthetic forms of progestins, which are often used for fertility treatments, in hormonal contraceptives, and also in menopausal regimens. The presentation of pH is varied. It can start as early as the first time of the first period, which is termed menarchy. Although, generally speaking, the first period or bleeding that a girl or teenager experiences is generally an estrogen withdrawal because it takes a while to ovulate and to make the progesterone. And these reactions can occur in into the point of menopause in a reproductive aged woman. And just the diagnosis of menopause, it's a retrospective diagnosis, looking back saying, oh, that was the last ovulation, the last period. And of course, women who don't have a uterus but still have ovaries, or women who've had an endometrial ablation with scarring of the uterus, or women that might have a progestin intrauterine system like a morena or lileta or chylina, IUD for contraception or for bleeding control, because morena can be used to treat dysfunctional uterine bleeding, may not even have a period, but still possibly being cycling or being exposed to progesterone. So these reactions can occur with the person's own bodily progesterone or to oral or vaginal bioidentical progesterone. The oral form, there's only one formulation on the market called prometrium, which is natural progesterone in a gelatin capsule mixed and microdized with peanut oil. And of course, peanuts are a whole other allergy issue. But also the synthetic progestins that are found in hormonal contraceptives or fertility treatments. And so when someone has an allergy, it can be just the immune system hyperreacting or misidentifying a certain substance or protein as a threat. So the symptoms typically worsen after ovulation because that's when the progesterone levels rise. Some women can have hives or rashes or eczema, swelling of the lips, the eyes, the face, itching from release of histamine, could even involve wheezing or asthma-like symptoms, and in severe cases, anaphylaxis, which is definitely life-threatening. Now, usually the symptoms improve once the hormone levels fall and menstruation begins, because that's when the estrogen and progesterone levels fall. And you have been listening to the Speaking of Women's Health podcast. I'm your host, Dr. Holly Thacker in the Sunflower House. We're in season four, and we're talking all things uh progesterone, intolerance, allergy, imbalance. Um at the beginning of season one, I podcasted an updated version of my book, The Cleveland Clinic Guide to Menopause, and I have a whole chapter about the symphony of the different female sex hormones and how they interact, and what a delicate balance it is, and how various hormones affect other hormones, and how different stages in life, other medical problems, medications, metabolism can affect levels of hormones. And certainly measurements of hormones can be very dicey because they're picograms, very tiny, tiny, tiny amounts. And there's substances that can interfere with checking hormones, and a notorious one is biotin, B7. And a lot of women take high doses of biotin in hair vitamins like neutrofol, although there's one brand or formulation of neutrofol that does not have um biotin in it. And biotin really helps the nails more than the hair. I did a whole podcast on biotin if you want to know more about that. But what you should know is if you have your blood drawn for hormones, thyroid, cardiac functioning, you have to be off high-dose biotin for three days or 72 hours, and that's really important. So most of the time a person just has an intolerance to progesterone, more so than a true, true allergy. But this progesterone intolerance refers to kind of a collection of adverse symptoms that can be triggered by either natural endogenous or exogenous, meaning the person takes it into their system, or synthetic progestins. And this can involve the brain, the mood symptoms, the nervous system, rather than the immune reaction per se. Or it can affect the immune system and the skin and potentially the respiratory system. So some of these symptoms of what we call progesterone intolerance as opposed to true allergy or anaphylaxis. Some women feel more anxious or irritable or no mood swings, depression, emotional blunting, fatigue, uh, progesterone, and progestins do stimulate mitoses in the breast. So the luteal phase or after ovulation is generally the worst time to get a mammogram or a breast exam. Progesterone can kind of slow down the GI system, so some women notice more bloating. Natural progesterone relaxes the lower esophageal sphincter, and so heartburn issues can occur. And if you didn't hear the podcast we did on gastroesophageal reflux, that's a good one to go back to. Any hormonal fluctuations can trigger headaches or migraines. And we did a great podcast on migraines, and half the population has migraines. Also, uh, there can just simply be worsening premenstrual symptoms, and severe PMS is termed premenstrual dysphoric disorder, PMDD, which can be treated with lifestyle changes, nutrition, calcium, the complex, and we have a few FDA-approved drugs. The first class was SSRI selective serotonin reuptake inhibitors, including low-dose fluoxetine, uh brand name Prozac, but came onto the market specifically for PMDD is seraphem. And uh that was a that was a big improvement probably a decade and a half ago. Um and the the first hormonal contraceptive agent that was FDA approved was Yas, uh, which is synthetic ethenyl estradiol with drosperinone. And drosperinone is a very interesting progestogen. It's it's really an analog of spiranolectone, a diuretic, but it does protect the uterus. And it's a mild diuretic and it's favorable on mood and doesn't negatively affect uh sexual function. The dermatologists like it for skin and hair, and um, any women who've had mood issues, we tend to like it. Um there's a newer form of hormonal contraceptives with the same three milligrams of drosperinone, but instead of synthetic ethenyl estradiol, it's a natural E4 estetrol, which is the estrogen that's made in the placenta. So it's a natural estrogen. And so I've had a lot of good luck uh with using that agent in perimenopausal women, and it doesn't seem to stimulate the breast as much or coagulation or blood pressure factors. But in general, if you're over 35 and use any type of tobacco, even once a week or once a month, then you're pretty much eliminated from a lot of hormonal contraceptive agents. So these progesterone intolerance symptoms, um, which can be in the mood realm, the breast realm, the gut realm, generally appear in the luteal phase, or when starting either hormonal contraceptive therapy, which is much stronger, even low-dose hormonal contraceptive, is like four times the amount of, say, menopausal hormone therapy. Um, why do these conditions occur? Well, there can be several factors. Certainly, immune system dysregulation, uh, a sensitivity to a synthetic progestin, uh, underlying autoimmune tendencies or allergies. And I did a podcast with a rheumatologist about well, why are women so much more predisposed to autoimmune problems, which they are lupus, rheumatoid arthritis, scleroderma, crest syndrome. Um women are several fold more likely to have autoimmune conditions, whereas males who have 10 times the testosterone that we females have, that tends to suppress or lower autoimmune reactions. And it's really important to try to understand the root cause if possible, because obviously treatment may differ depending on whether the issue is immune-based or just simply sensitivity-based. So, in terms of diagnosing a true progesterone allergy, the diagnosis may include a detailed symptom history, which you know that's usually always where we start with a history in physical. The woman may be asked to track her symptoms across the menstrual cycle. There's a lot of good menstrual tracking apps. And when you go in to see your uh physician or a women's health nurse practitioner, it's kind of good if you can bring in information and kind of be organized with what your symptoms are and when they occur. Allergy testing may occur with progesterone, but it has to be under an allergist or a specialist supervision. And then, of course, other dermatologic skin and hormonal conditions have to be ruled out. But because this progesterone allergy is really rare, the women that have made it to my office, uh, some of them have gone a long time being undiagnosed. Now, diagnosing the progesterone intolerance, it's typically diagnosed based on what the symptoms pattern is, timing in relation to progesterone exposure, improvement when progesterone or progestins are stopped. And this is really a clinical diagnosis because there's no simple specific lab test. So, what are the treatment options for progesterone allergy? Well, it depends on the severity. It may include avoiding a synthetic progesteron, switching to a non-hormone contraceptive, using antihistamines or corticosteroids for allergic symptoms, potentially working in conjunction with an allergist for a desensitization protocol. Like I mentioned, my granddaughter Artemis, we had to start with a fraction of a fraction of uh organic um cashew ingested on just a tiny bit of food. And the first time it was done, she had an allergic reaction and she had to get an epinephrine shot. And um we had to slowly work up a little tiny bit more each week. And if we kind of overdid it just by a tiny bit, we had it by these special measuring, um very tiny micro measurements, then her mouth would be itchy and swollen. But thankfully, it worked. She was desensitized. So for any kind of desensitization or allergy testing, it really has to be done by an allergist and immunologist. So treatment approaches might be switching from a synthetic progesterone, if it's just an intolerance, to a natural progesterone, sometimes using lower doses or a different delivery method, adjusting the timing of therapy. If the woman is reproductive aged, uh, you know, there are many non-hormonal birth control options. And then, of course, the supportive aspects of helping any central nervous system issue or mood issue through lifestyle and holistic medical strategies. Many women tolerate progesterone better if it's transdermal through the skin or vaginal rather than orally. But transdermal progesterone cream is not well absorbed. You'd have to swim in it, and that still might not be enough to protect the endometrium. So the patches, we have two patches that have natural estrogen with a progestin. One is the COMBI patch, also available as Evoral Conte, that has natural estradiol and norethydrone acetate in a twice a week patch, which is every 84 hours, 3.5 days, not every four days or two days out of the week that I remember. No, that's not accurate. You always want to keep hormone levels constant. And then there's a one weekly patch that has bioidentical estradiol in a slightly lower than average dose. And with a different progesterone, levournergesterol, which is the same progestin in a birth control pill like low oval. It's the same progestin in a morena or lilette or uh or chylina intrauterine device. Now there is progesterone gel crinone, but it's off-label at protecting the endometrium. Now, thankfully, we have some other options. And one of the options I go to when women can't tolerate even natural progesterone, particularly if they have a lot of breast sensitivity, is using a designer hormone duave, which is conjugated estrogens in a 0.45 milligram dose, so a little less than the average standard menopausal 0.625 premerin dose. And it has 20 milligrams of basadoxifene, which is a sister medicine to tamoxifen. And tamoxifen is used to treat and prevent breast cancer and has some estrogen effects. And this basadoxifine downregulates estrogen stimulation at the endometrium. And so for women that need their uterus protected, now if you don't have a uterus and you don't have endometriosis, well then you don't need any progesterone at all, and you can just use estrogen. And I have, in fact, sent some women for elective benign hysterectomy simply to remove the uterus and endometrium so that they could avoid taking progesterone or progestin. That's kind of like one of you know your last options. But if I can use duavet, and in women who are breast cancer survivors or women who've had DCIS, sometimes we favor it because estrogen is favorable on the breast but stimulates the uterus. Progesterone protects the uterus but stimulates the breast and sometimes irritates the brain. Conversely, natural progesterone raises the seizure threshold by kind of dampening down the central nervous system so that in someone with seizures, just giving estrogen can sometimes irritate the brain, even though it might be a mood elevator. I don't really like to separate the estrogen from the progesterone in most women who have a uterus because since 30% of women have some intolerance to progesterone or it kind of downregulates the good kind of MAO inhibitor mood elevation that estrogen can give, that they don't take the progesterone and it's to protect their uterus. So I'd rather know about it. And technically the only FDA-approved way of giving oral prometrium natural progesterone is cycle days one through twelve with continuous estrogen. And some of these Instagram influencers, people who write books and are selling their products, uh, and we're a nonprofit, whatever you do or don't do doesn't affect our nonprofit or our salaried physicians at the Cleveland Clinic are selling things and kind of appealing to the marketing type terms. And since the one cancer that hormone therapy can increase is uterine cancer if there's an imbalance in the hormones. That's why it's very important to protect the uterus. So it's been a really nice advance to have basadoxifene, which is combined with estrogen in the form of duave. One pill, one dose is all. Sometimes it's not enough for women that are very young or who have had their ovaries removed or physically hormonally castrated and have really bad symptoms and might need a higher dose. Some insurances don't cover it. It was off the market during COVID and it came back on the market a few years ago. So cost has been an issue, but in the podcast that I did an update on how to lower the cost of medications, I was happy that the first hormone formulation that I saw on the government's Trumprx.gov site, which links to either coupons or directly to the manufacturer to reduce drug prices, which is always a great thing, duave was listed. So I was very happy about that because in patients that I have that are cancer survivors or very sensitive to progesterone or have increased risk for breast cancer or cannot tolerate progesterone or progestins, that's a certain niche for that medication. Another option has been using non-progestins that protect the uterus, like that drosperinone, which is in Yaz and Biaz and Nextellus. It's also an angelique, which is natural estrogen with drosperinone, and the European dose of two milligrams of drosperinone with one milligram of estradiol in Europe is also approved to treat hypertension because of the mild diuretic aspects. But you can get plain drosperinone in the form of slind, which is a progestin-only hormonal contraceptive. So I've had some women with progestin intolerance or even allergy be able to tolerate SLINT and allow them not to have to go onto hysterectomy. So if you think you might have progestin intolerance or issues, you know, who should you seek out? Well, you should definitely seek out healthcare professional advice. If you notice defined cyclical symptoms, especially cyclical rashes or hives. Um if you have severe PMS or PMDD symptoms that are completely resolved once you get your period. Now, there are women who have depression or mood disorders that get worse premenstrually, and so it still has maybe needs to be treated, and therapy may need to be upped, particularly for those two weeks, or maybe ovulation needs to be stopped. Women that have hormonal changes linked to hormonal medications. I always like to evaluate them for other things as well, like do they have untreated sleep apnea? Do they have vitamin deficiencies? Low levels of vitamin D affect mood and energy, low levels of zinc do, imbalances in the omega-3 ratios to omega-6. We have a couple podcasts on omegas, uh sleep disorders, untreated other medical problems, lifestyle issues, a lot of that can be significantly improved. So it's not just the hormones. If you have any kind of breathing issues or asthma or allergic type reactions, particularly when you're on progesterone or having higher levels of endogenous progesterone, symptoms that clearly get worse right after you ovulate or when starting on progesterone. So coming in with your symptoms, seeing an experienced women's health clinician can help determine whether your symptoms are allergy, intolerance, hormonal imbalance, or something else. Because you really deserve to feel good and uh to be empowered and not be bogged down or be um a prisoner in your hormonal fluctuations. So, in closing, uh progesterone allergy and progestin intolerance can be misunderstood because they're not very common and they can significantly impact a woman's quality of life. Uh recognizing the symptoms and understanding the differences is certainly the first step in getting the right care. So if you notice patterns in your cycle or reactions to hormonal medications, please don't ignore them because your symptoms are real and you do deserve answers. Bring in all your supplements, bring in your medications, bring in that menstrual tracker. Make sure you have a list of things that you've tried that have helped or that have not helped. That will help get to the bottom of things. And certainly if you are diagnosed with this condition, particularly if you have something else wrong, like abnormal PAPS or abnormal bleeding, maybe you've had an endometrial ablation, you might have symptomatic fibroids, maybe you have adenomiosis where the lining of the uterus grows into the muscle, and really the effective treatment for that is hysterectomy. Maybe you've got some early prolapse, the organs coming down, it's affecting bowel and bladder. So if you're done with childbearing and you have a gynecologic problem and you have an intolerance or allergy to progesterone, then trying to do backflips to save the uterus is really probably not the right thing. Not that we want to gratuitously do hysterectomies, we've certainly done far too many hysterectomies in the past, but it's uh a great option for well-selected women and our minimally invasive gynecologist, and we've had some discussions about MIGs physicians, there's get extra training, uh, they do minimally invasive surgery. A lot of my patients go home the same day. It's definitely not your mother or grandmother's hysterectomy. It still is major surgery, though. Um, but for some women it really does provide quite a lot of relief. So this has been the Speaking of Women's Health podcast, and we like to share uh information, expert guidance, and resources. Don't forget to uh check out our website, speakingofwomenshealth.com. Follow us on Instagram, Facebook, at LinkedIn, or on YouTube, Rumble. Uh, and be sure to subscribe wherever you listen to podcasts and never miss an episode. I'm Dr. Thacker. Thanks for listening. Remember, be strong, be healthy, and be in charge.