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Variations in Morning Serum Cortisol Levels Based on Sex and Pubertal Status
Dr. Sarah Tsai discusses his recent findings from his study surround serum morning cortisol levels.
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Learn more about Sarah Tsai, MD
Sarah Tsai, MD
Sarah Tsai, MD is a Pediatric Endocrinologist; Assistant Professor of Pediatrics, University of Missouri-Kansas City School of Medicine.Learn more about Sarah Tsai, MD
Transcription:
Variations in Morning Serum Cortisol Levels Based on Sex and Pubertal Status
Melanie Cole, MS (Host): Welcome to Transformational Pediatrics. I'm Melanie Cole, and today we’re discussing variations on morning serum cortisol levels based on sex and pubertal status. Joining me is Dr. Sarah Tsai. She’s a pediatric endocrinologist with Children’s Mercy Kansas City. Dr. Tsai, it’s such a pleasure to have you join us today. It’s such an interesting topic that we’re examining today. Since the signs and symptoms of adrenal insufficiency are often non-specific, can the diagnosis be challenging? Why is correctly identifying it so important?
Sarah Tsai, MD (Guest): Sure. Adrenal insufficiency often has very non-specific symptoms. It’s something that is important not to miss because it can be fatal if undiagnosed. So people with adrenal insufficiency will often feel very tired, they will feel week, they may feel nauseated, they may have vomiting, they may not recover well from illness, and they may sometimes feel depressed. You may have loss of your armpit hair or hair in your pubic area. In children, you may not grow well. That is where we will often pick it up as pediatric endocrinologists. Your adrenal glands are responsible for secreting cortisol as well as some androgens, which are male type hormones. When you are ill or undergoing a major stress—for example, a broken bone or something like that—your adrenal glands will pump out lots of cortisol to help you get through those periods of stress. If your adrenal glands do not make enough cortisol then you may not be able to recover properly from stress and can go into something called adrenal crisis where you get a lot of decompensation in your body. You can significantly drop your heart rate, blood pressure, and become hypoglycemic. You can sometimes have electrolyte abnormalities depending on the type of adrenal insufficiency that you have. That can extremely dangerous. So that’s why it’s really important to be able to diagnose it accurately and quickly.
Host: So as we set the stage to discuss your studies, what should cortisol levels be in the morning? How do they vary throughout the day? What's different about the pediatric population in regards to cortisol levels from adults?
Dr. Tsai: So your cortisol level peaks in the morning at around 8:00 a.m. Then it gradually falls throughout the day to its lowest point at midnight. Children who are less than two years old have not yet established a diurnal rhythm with their cortisol. So their peak does not occur in the same fashion and could happen at any type. Anyone over age two pretty much has an established cortisol peak at around 8:00 a.m. Even by 9:00 a.m. the level starts to fall. Now what a normal morning cortisol level is in the morning is something that’s not totally clear when you review the medical literature. That was one of the main inspirations for doing this study. When you look at morning cortisol levels and the averages that you see, I think it would be reasonable to say that if you have a morning cortisol at about 8:00 a.m. or greater than nine or ten, you're probably adrenally sufficient. Less than five certainly would be of concern for potential adrenal insufficiency. Just to be clear, there are different units of measurement. So with the cortisol levels that are measured in other countries like in Europe or Canada, that would be nanomoles per liter. In the United States we are talking in micrograms per decaliter. So about 10 micrograms per decaliter is a pretty reasonable morning cortisol level looking at males or females of any age or pubertal stage.
Host: So doctor, what are the known concerns regarding screening and data collection? You just mentioned in other countries it’s measured a little differently. As it relates to adrenal insufficiency and serum morning cortisol levels, what are some concerns that you have?
Dr. Tsai: Well the biggest concern is if you get a morning cortisol on a patient and it falls sort of in a gray area like maybe in the five to ten range, what do you do with that and how do you interpret that as a provider? Does that vary with the patients’ age or pubertal stage or whether they're male or female? I think that it does. That’s something that was not really described before. Males appear to have a slightly lower morning cortisol levels than females, in particular when they are pre-pubertal. Why? I don’t know. Definitely that’s something we noticed at a different study and at a larger scale than this one. So it is important to take those factors into consideration when you're trying to identify somebody with adrenal insufficiency. It’s great to have a good screen. So a morning cortisol is a pretty easy screen to do. You can just ask someone to come to the lab at 8:00 a.m. and you can do one blood test and it’s over. Then hopefully you'll get a clear answer. It’s a lot easier than having them come in for a stimulation test, which is a more involved and more costly method of diagnosing adrenal insufficiency. It’s certainly less convenient for the patient. So if this is a really good screen, we just need to be able to interpret it correctly.
Host: Well then how does that help us better understand the influences on laboratory evaluation when you're looking for adrenal insufficiency?
Dr. Tsai: So a lot of things influence morning cortisol levels. Certainly the most important thing is the time at which they were drawn. So 8:00 a.m. really is the best time to draw it. Once you get beyond that first hour of the day—even beyond the first half hour—the levels do drop significantly. Doing a random cortisol level in the afternoon or even late morning is not helpful at all. They're very difficult to interpret. If they're less than five, it might be suggestive that something is wrong and needs further explanation. Probably the next step after that would be to do a morning cortisol at 8:00 a.m. That’s just your body’s physiologic kind of response and how it releases the cortisol. When we’re interpreting those morning cortisol levels, it’s important also to take into consideration is this patient male or female? Have they gone through puberty yet? Those appear to be important factors when looking at this. So males appear to have a slightly lower morning cortisol levels, especially if they're Tanner ones. So if I got a cortisol level of nine back in a Tanner one male, I would be okay with that even though previous studies have shown that you may only want to consider something above 10 or even something above 13 or 14 a normal value. That study really helped me clinically in terms interpreting these levels because in pre-pubertal kids, maybe about a nine for a male maybe about a 10/11 for a female is completely fine.
Host: So then tell us about your study. What did it examine? What was the design? Tell us about some of the results that you can across.
Dr. Tsai: It was a retrospective study. We looked back over 10 years. The range for the dates was 2007 to 2017. What we did is we did retrospective taper review. So every single patient in this study had confirmed adrenal sufficiency with an ACTH stim. Then what we did was we looked at the morning cortisol levels in patients who were known to be adrenally sufficient. Then we stratified then based on their age, their Tanner staging, and whether they were male or female. All of the Tanner staging was done by a pediatric endocrinologist who was familiar with how to do that. That is what we did. We did find that among pre-pubertal children, there was a statistically significant difference between males and females and what their morning cortisol levels was. Interestingly when we looked at individuals who were Tanner stage two to five, there was not a significant difference between males and females in terms of their morning cortisol level. However, sex was predictive of the serum morning cortisol levels over all. That was significant as well with females overall having higher morning cortisol levels.
Host: So interesting. Dr. Tsai since much of the data collected to determine appropriate values for morning cortisol levels are derived from the adult population in the past and may not accurately represent the pediatric physiology, what are some of the strengths of your study? How is it different from other studies?
Dr. Tsai: Well our study was the kind to find look at it this way. To look at only those who had been proven to be adrenally sufficient. So we didn’t just look at average morning cortisol in the population. We looked at average morning cortisol in patients where we knew they had normal adrenal function. So I think that was a definite strength of this paper. If someone had a low morning cortisol level, for example, we knew that it was not because their adrenals weren’t working. We knew that they were because they had had a stim test. Also we had a pretty good number of patients for a retrospective review in something that is actually a relatively rare condition. So that was a strength of this paper as well.
Host: So tell us about some of the challenges or limitations of your study. As you're doing that, what do you want other endocrinologists to know about this data and what the take home message in this very interesting topic is.
Dr. Tsai: The limitations of this study were that it was retrospective. We did not have a huge variation in patients in terms of their Tanner stage when we got from Tanner stages two to five. So about half of them were Tanner one and the other half was Tanner stages two to five put together. Ideally I was hoping for a good number of patients at Tanner stage two, three, four, and five. So if we had had more numbers then I think that that would have been nice to stratify everything specifically by Tanner stage. In terms of take home messages, what I would say is it would be great to have a prospective study looking at this in a larger population to really well establish what normal morning cortisol values are. It would be great to look at it with large numbers of males and females. Also ideally to have a variety of Tanner stages represented as well. I think that that is something that really needs to be done. That was a take home message for me at the conclusion of this retrospective study that we really need larger scale prospective studies. However, I do think that from the information we have so far, we do have really good evidence that sex and Tanner stage need to be taken into consideration when looking at your morning cortisol. It is a good screen. How we interpret that screening test will depend on the individual patient.
Host: Thank you so much doctor for joining us today and telling us about the results of your study. That was really an interesting segment and so informative. Thank you again. This has been transformational pediatrics with Children’s Mercy Kansas City. To refer your patient or for more information, please visit childrensmercy.org. Please also remember to subscribe, rate, and review this podcast and all the other Children’s Mercy podcasts. I'm Melanie Cole.
Variations in Morning Serum Cortisol Levels Based on Sex and Pubertal Status
Melanie Cole, MS (Host): Welcome to Transformational Pediatrics. I'm Melanie Cole, and today we’re discussing variations on morning serum cortisol levels based on sex and pubertal status. Joining me is Dr. Sarah Tsai. She’s a pediatric endocrinologist with Children’s Mercy Kansas City. Dr. Tsai, it’s such a pleasure to have you join us today. It’s such an interesting topic that we’re examining today. Since the signs and symptoms of adrenal insufficiency are often non-specific, can the diagnosis be challenging? Why is correctly identifying it so important?
Sarah Tsai, MD (Guest): Sure. Adrenal insufficiency often has very non-specific symptoms. It’s something that is important not to miss because it can be fatal if undiagnosed. So people with adrenal insufficiency will often feel very tired, they will feel week, they may feel nauseated, they may have vomiting, they may not recover well from illness, and they may sometimes feel depressed. You may have loss of your armpit hair or hair in your pubic area. In children, you may not grow well. That is where we will often pick it up as pediatric endocrinologists. Your adrenal glands are responsible for secreting cortisol as well as some androgens, which are male type hormones. When you are ill or undergoing a major stress—for example, a broken bone or something like that—your adrenal glands will pump out lots of cortisol to help you get through those periods of stress. If your adrenal glands do not make enough cortisol then you may not be able to recover properly from stress and can go into something called adrenal crisis where you get a lot of decompensation in your body. You can significantly drop your heart rate, blood pressure, and become hypoglycemic. You can sometimes have electrolyte abnormalities depending on the type of adrenal insufficiency that you have. That can extremely dangerous. So that’s why it’s really important to be able to diagnose it accurately and quickly.
Host: So as we set the stage to discuss your studies, what should cortisol levels be in the morning? How do they vary throughout the day? What's different about the pediatric population in regards to cortisol levels from adults?
Dr. Tsai: So your cortisol level peaks in the morning at around 8:00 a.m. Then it gradually falls throughout the day to its lowest point at midnight. Children who are less than two years old have not yet established a diurnal rhythm with their cortisol. So their peak does not occur in the same fashion and could happen at any type. Anyone over age two pretty much has an established cortisol peak at around 8:00 a.m. Even by 9:00 a.m. the level starts to fall. Now what a normal morning cortisol level is in the morning is something that’s not totally clear when you review the medical literature. That was one of the main inspirations for doing this study. When you look at morning cortisol levels and the averages that you see, I think it would be reasonable to say that if you have a morning cortisol at about 8:00 a.m. or greater than nine or ten, you're probably adrenally sufficient. Less than five certainly would be of concern for potential adrenal insufficiency. Just to be clear, there are different units of measurement. So with the cortisol levels that are measured in other countries like in Europe or Canada, that would be nanomoles per liter. In the United States we are talking in micrograms per decaliter. So about 10 micrograms per decaliter is a pretty reasonable morning cortisol level looking at males or females of any age or pubertal stage.
Host: So doctor, what are the known concerns regarding screening and data collection? You just mentioned in other countries it’s measured a little differently. As it relates to adrenal insufficiency and serum morning cortisol levels, what are some concerns that you have?
Dr. Tsai: Well the biggest concern is if you get a morning cortisol on a patient and it falls sort of in a gray area like maybe in the five to ten range, what do you do with that and how do you interpret that as a provider? Does that vary with the patients’ age or pubertal stage or whether they're male or female? I think that it does. That’s something that was not really described before. Males appear to have a slightly lower morning cortisol levels than females, in particular when they are pre-pubertal. Why? I don’t know. Definitely that’s something we noticed at a different study and at a larger scale than this one. So it is important to take those factors into consideration when you're trying to identify somebody with adrenal insufficiency. It’s great to have a good screen. So a morning cortisol is a pretty easy screen to do. You can just ask someone to come to the lab at 8:00 a.m. and you can do one blood test and it’s over. Then hopefully you'll get a clear answer. It’s a lot easier than having them come in for a stimulation test, which is a more involved and more costly method of diagnosing adrenal insufficiency. It’s certainly less convenient for the patient. So if this is a really good screen, we just need to be able to interpret it correctly.
Host: Well then how does that help us better understand the influences on laboratory evaluation when you're looking for adrenal insufficiency?
Dr. Tsai: So a lot of things influence morning cortisol levels. Certainly the most important thing is the time at which they were drawn. So 8:00 a.m. really is the best time to draw it. Once you get beyond that first hour of the day—even beyond the first half hour—the levels do drop significantly. Doing a random cortisol level in the afternoon or even late morning is not helpful at all. They're very difficult to interpret. If they're less than five, it might be suggestive that something is wrong and needs further explanation. Probably the next step after that would be to do a morning cortisol at 8:00 a.m. That’s just your body’s physiologic kind of response and how it releases the cortisol. When we’re interpreting those morning cortisol levels, it’s important also to take into consideration is this patient male or female? Have they gone through puberty yet? Those appear to be important factors when looking at this. So males appear to have a slightly lower morning cortisol levels, especially if they're Tanner ones. So if I got a cortisol level of nine back in a Tanner one male, I would be okay with that even though previous studies have shown that you may only want to consider something above 10 or even something above 13 or 14 a normal value. That study really helped me clinically in terms interpreting these levels because in pre-pubertal kids, maybe about a nine for a male maybe about a 10/11 for a female is completely fine.
Host: So then tell us about your study. What did it examine? What was the design? Tell us about some of the results that you can across.
Dr. Tsai: It was a retrospective study. We looked back over 10 years. The range for the dates was 2007 to 2017. What we did is we did retrospective taper review. So every single patient in this study had confirmed adrenal sufficiency with an ACTH stim. Then what we did was we looked at the morning cortisol levels in patients who were known to be adrenally sufficient. Then we stratified then based on their age, their Tanner staging, and whether they were male or female. All of the Tanner staging was done by a pediatric endocrinologist who was familiar with how to do that. That is what we did. We did find that among pre-pubertal children, there was a statistically significant difference between males and females and what their morning cortisol levels was. Interestingly when we looked at individuals who were Tanner stage two to five, there was not a significant difference between males and females in terms of their morning cortisol level. However, sex was predictive of the serum morning cortisol levels over all. That was significant as well with females overall having higher morning cortisol levels.
Host: So interesting. Dr. Tsai since much of the data collected to determine appropriate values for morning cortisol levels are derived from the adult population in the past and may not accurately represent the pediatric physiology, what are some of the strengths of your study? How is it different from other studies?
Dr. Tsai: Well our study was the kind to find look at it this way. To look at only those who had been proven to be adrenally sufficient. So we didn’t just look at average morning cortisol in the population. We looked at average morning cortisol in patients where we knew they had normal adrenal function. So I think that was a definite strength of this paper. If someone had a low morning cortisol level, for example, we knew that it was not because their adrenals weren’t working. We knew that they were because they had had a stim test. Also we had a pretty good number of patients for a retrospective review in something that is actually a relatively rare condition. So that was a strength of this paper as well.
Host: So tell us about some of the challenges or limitations of your study. As you're doing that, what do you want other endocrinologists to know about this data and what the take home message in this very interesting topic is.
Dr. Tsai: The limitations of this study were that it was retrospective. We did not have a huge variation in patients in terms of their Tanner stage when we got from Tanner stages two to five. So about half of them were Tanner one and the other half was Tanner stages two to five put together. Ideally I was hoping for a good number of patients at Tanner stage two, three, four, and five. So if we had had more numbers then I think that that would have been nice to stratify everything specifically by Tanner stage. In terms of take home messages, what I would say is it would be great to have a prospective study looking at this in a larger population to really well establish what normal morning cortisol values are. It would be great to look at it with large numbers of males and females. Also ideally to have a variety of Tanner stages represented as well. I think that that is something that really needs to be done. That was a take home message for me at the conclusion of this retrospective study that we really need larger scale prospective studies. However, I do think that from the information we have so far, we do have really good evidence that sex and Tanner stage need to be taken into consideration when looking at your morning cortisol. It is a good screen. How we interpret that screening test will depend on the individual patient.
Host: Thank you so much doctor for joining us today and telling us about the results of your study. That was really an interesting segment and so informative. Thank you again. This has been transformational pediatrics with Children’s Mercy Kansas City. To refer your patient or for more information, please visit childrensmercy.org. Please also remember to subscribe, rate, and review this podcast and all the other Children’s Mercy podcasts. I'm Melanie Cole.