Speaker 1: Welcome to AACE Podcasts. Thanks for tuning in as we elevate clinical endocrinology by taking deep dives into trends and topics that can help us improve our patient care and global health. Find the latest episodes on aace.com/podcasts. And now let's meet the endocrine experts who will be talking with us today.

Dr. Tangpricha: Hi, my name is Vin Tangpricha and I'm the host of today's AACE Podcast, also serve as the editor in chief of Endocrine Practice. Today we have a special guest, Dr. Ty Carroll, who has just published a paper at Endocrine Practice in the January issue entitled Hormonal Contraceptive Use is Associated With a Decreased Incidence of Hypothyroidism. Hi, Dr. Carroll. Thanks for joining.

Dr. Carroll: Thanks for having me.

Dr. Tangpricha: Could you introduce yourself to the audience, what you do and your clinical and research interests are?

Dr. Carroll: Sure. As was stated, my name is Ty Carroll. I'm an endocrinologist at the Medical College of Wisconsin in Milwaukee. I'm a clinical endocrinologist, a fellowship program director, and have several different hats. My normal research interest is in cortisol and pituitary adrenal disease, but this was an interesting topic that actually was brought to me by a very eager medical student who was the first author, Shawna Gloe. So, really, she gets a lot of credit for this idea and the execution.

Dr. Tangpricha: Great, thanks. This paper generated a lot of social media attention when it first got published. I think it was retweeted or re-Xed many times and shared among many groups and caught a lot of people's attention. So I guess my first question, how did you and your medical student even come up with this idea?

Dr. Carroll: Well, there was a fairly recent publication that looked at hormonal contraception and the risk of hypothyroidism. They concluded that hormonal contraception increased the risk of hypothyroidism over, and I guess I don't quite recall what the duration of their study was. And it was really interesting because obviously there are so many women on hormonal contraception. Hypothyroidism is probably the most common or one of the most common endocrine disorders, and to really wonder what that association was. And so that was the genesis of this project.

Dr. Tangpricha: Right. This was a very large study, over 18,000 patients. Can you explain the database and the study set up?

Dr. Carroll: Sure. We're fortunate to have the TriNetX database from our healthcare system that, I believe, covers somewhere around, I want to say a 5 to 8 million lives, and so we can query the database through anonymized results and pull out all kinds of different, whether it's diagnoses, lab values, et cetera. And so we were able query the database to find individuals who had a diagnosis of hypothyroidism.

We select this 10 year time period, largely because when we started to go back too much farther than that, the data's a little bit scant, and that also gave us a little bit of time between the end of when we searched and the possible development of hypothyroidism. So we were able to identify the different groups, whether it was estrogen-containing hormone therapy, progesterone, and we broke that off into all forms of progesterone other than IUDs and then our control groups. So we were able to sort for those and then determine which of the patients had a diagnosis of hypothyroidism or were prescribed levothyroxine.

Dr. Tangpricha: Going to the title of your paper, you concluded that women on hormonal contraceptive had less risk of hypothyroidism. Is that correct?

Dr. Carroll: Yeah. A little bit to our surprise, it was contrary to the previously reported study, but the data showed it, certainly when we didn't have any adjustments, that it looked like the group in the estrogen-containing group was neutral, but progesterone group did have a benefit. And then when we adjusted for race and ethnicity, which was pretty important, and also obesity or BMI, it looks like that any previous hormonal contraception use decreased the risk of developing hypothyroidism.

Dr. Tangpricha: So any oral contraceptive use, including estrogen or progesterone. Any of them.

Dr. Carroll: Any of the formats. The one thing that I think sticks out to me that I'm still scratching my head about as to why is even the IUD, the progestin IUD, group had a lower risk. It's a little hard in my mind to fathom why that is. We really went back over the data, especially in the IUD group, to see, "Okay, "Well, did we have a problem with our data that somehow would've skewed it that way?" And at least the data, as it is, showed that even that form of hormonal contraception decreased the eventuality of developing hypothyroidism.

Dr. Tangpricha: I'm surprised that the estrogen group didn't pan out when you looked at subgroups. I could see how estrogen could be anti-inflammatory, maybe. Most of these women had autoimmune thyroid disease, I'm assuming, and I would've thought that estrogen would've been beneficial.

Dr. Carroll: I think in the initial analysis, it didn't reach statistical significance. And I think one of those reasons was that the estrogen group, it certainly was a large portion of the white population, and one thing I think that's interesting is what groups got what form of contraception. I think that speaks a little bit to the socioeconomics of the area and hormonal contraception. That's probably a much larger discussion for a different podcast. But I think that that, the large Caucasian in the estrogen group, probably skewed that. And then once we did the analysis and looked at the different subgroups, even the oral estrogen group did have a lower risk than the controls.

Dr. Tangpricha: Oh, okay. That's good. I think you touched upon it in your paper, the potential mechanism is through dampening autoimmunity or what do you think potential mechanism is?

Dr. Carroll: I think that that's the easiest explanation, whether that's the truth. Often the easiest explanation isn't the truth, but certainly, like you mentioned, whether estrogen has an anti-inflammatory component to it, that certainly would make sense to me. But then why the progesterone group? Why the IUD group that had a strong decrease in the risk? Why that panned out isn't quite clear to me, and I think that's an area where we need more research in this topic, either prospectively or with other databases to confirm these results, will be important.

Dr. Tangpricha: It's interesting that the IUD group had potential benefit. Are there other unmeasured variables like iodine intake or better diet something that could be associated with decrease in hypothyroidism?

Dr. Carroll: I certainly think that there are. One thing that we saw is that the IUD group was really strongly swayed toward the white population. Again, there's probably social determinants of health in here that may play a role. One thing we weren't able to account for in our database was markers of autoimmunity. So we did not look at thyroid antibodies. My guess is that a lot of patients that were diagnosed with hypothyroidism didn't have those measured. So I think it would have skewed the groups a bit about who had antibodies measured and who didn't. But we did not look at that, and I think that's certainly one criticism of this study, is that we weren't able to look at any of those markers of autoimmunity.

Dr. Tangpricha: My other question was how did you define hypothyroidism? Was it an ICD code diagnosis or was it based on TSH?

Dr. Carroll: Yeah, so we looked at ICD-9 and 10 codes. Obviously we went back to 2010, so we had to use ICD nine. We used all the hypothyroidism codes and people who are women who were prescribed levothyroxine. We did not use TSH. Again, one could argue that that might have been a good way to look at it. The data just looked a little bit more reliable and clean when we looked at the ICD codes as opposed to lab values.

Part of the problem, as I'm sure you well know, anytime you're using a large database, is to get all the data that you want. I would've loved to have looked over all 18,000 charts, but that wasn't going to be a feasible study. I'm sure that many of these patients were probably only seen a few times in our healthcare system, and that's why a lot of these patients were excluded, just from lack of insufficient data.

Dr. Tangpricha: The reason I was asking that was maybe there'd be a larger population of subclinical hypothyroidism and maybe there'd be some sort of signal there. I don't know if you have any comments about that?

Dr. Carroll: I think that these are all excellent points and we thought about, if we want to confirm this going forward, how would we do this on probably a smaller but more detailed scale? I think that that's certainly an area where we would look at TSH, we'd look at T4, we'd look at thyroid antibodies and try to follow some of these patients prospectively, or at least go back in a smaller group and really look at some of the more detailed data.

Dr. Tangpricha: Are you aware of any data in trials where women were given estrogen, maybe in the Women's Health Initiative trial or something else where they looked at thyroid function status?

Dr. Carroll: I'm not aware of any specific trials where this has been tested, if you will.

Dr. Tangpricha: I wonder if there would be some blood or cohort data you can look at from these trials that might be easy to measure some TSHs and antibodies.

Dr. Carroll: Yeah, that's certainly these large databases that are very well documented and have health outcomes, have a lot of blood work. That's fantastic idea is to have access to those and be able to look at it in a more detailed fashion.

Dr. Tangpricha: You mentioned it was another study that was different from your study. It showed the opposite finding. Why do you think the studies were so different?

Dr. Carroll: They were performed in a little different manner. Their study, and I'm trying to recall the specifics of, I believe it was Key et al. that they looked at patients over, I believe, a shorter duration, but they also took into account the exposure of the estrogen. And that's one thing we weren't able to do with our database is to look at the overall exposure of these medications. So if a woman was prescribed or received estrogen at any time during our study period, they fell into the estrogen group or progesterone, et cetera. Whereas the other study, they had the ability to see how long the exposure was and were able to say, "Well, with longer exposure of estrogens in particular," They didn't look at progestins, but they just looked at estrogen. And the longer the estrogen exposure, it actually increased risk in their study with hypothyroidism.

Dr. Tangpricha: Now, some people might read this paper and say, "Oh, well, aunt Betty has thyroid disease. Maybe she should go on estrogen." Is that something we're ready to say yet?

Dr. Carroll: I would not use this data to make that treatment decision. I certainly think that this is food for thought about how do we design a trial looking at women who are receiving hormonal contraception, and does it decrease the risk of hypothyroidism, especially in, perhaps, women who have autoimmunity who have a high risk of developing hypothyroidism, strong family history, and look to see if there's another indication to use hormonal contraception. Does that decrease their risk in the long run? And that's where, I think, I would use this data.

I think this data, to me, is a prompt as to, "Okay, what do we study now? How can we look at this in a real, more detailed treatment-driven fashion?" But I certainly wouldn't use this to say, "Well, somebody's already got hypothyroidism and we should give them some form of hormonal contraception," And I think we need to prove this going forward, that it really does decrease the risk. But I think this is the first step of a couple that may lead to some difference in treatment decisions.

Dr. Tangpricha: Someone who already has hypothyroidism and goes on hormone contraceptive, is there any money pitfalls? Anything we need to worry about?

Dr. Carroll: Well, certainly oral estrogen, many women need to have their dose of thyroid hormone adjusted, obviously, because of binding globulins, et cetera. But I think that's really the main caveat here, is oral estrogens and need for adjustment of thyroid hormone. The other forms, progestins and non-oral forms of hormonal contraception, probably don't play much role.

Dr. Tangpricha: Okay. So that's probably a very important thing to remember. Someone who's on L-thyroxine, 100 micrograms going to start an estrogen, you may have to bump up the dose, right?

Dr. Carroll: Absolutely.

Dr. Tangpricha: How much would you bump up the dose if they're on 100?

Dr. Carroll: I think there's several different ways to approach it. My general take is it's pretty easy for most of our patients to get another TSH, and so I just recommend they get another TSH in a month or two after they've started their hormonal contraception. Some would just increase the dose right away. A little bit akin to a woman in pregnancy, though. I think we've got a little bit more leeway if we're just starting an oral contraceptive as opposed to a woman who is pregnant and has hypothyroidism on therapy, where many people would just increase their dose by two tablets a week.

Dr. Tangpricha: Okay. That's a good approach. How about the other way around? Someone on oral contraceptives and starts on hormone therapy, that's not going to be less effective oral contraceptive, is it?

Dr. Carroll: No, we don't think so.

Dr. Tangpricha: Just want to make sure. Yeah, this has been a great conversation. Do you have a few take-home messages for our audience listening today?

Dr. Carroll: I really think that this is an interesting finding that should be a light bulb to some other investigators that might be interested in this topic, and to think about how can we design additional studies to confirm these results. I think any time when you have studies that have differing results, we need to figure out which direction the truth lies. I'm sure there are nuances that, as in every situation, are the case, but to help us know how to use this data later on.

Dr. Tangpricha: Thank you so much, Dr. Carroll, for joining us. This has been a very enlightening talk, and for people who want to read his article by him and his medical student, you can read it at Endocrine Practice in the January issue. Thanks so much, Ty, again, for joining us and hope you continue forward with this research.

Dr. Carroll: Vin, it's been my pleasure. Thanks for having me.

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