2025 Hormone Research Wish List

All I want for Christmas this year is for more research on females with type 1 diabetes and hypothyroidism. Here is a list of my research ideas:

STUDY 1 How to best study the effects of the menstrual cycle on glucose control and insulin sensitivity in females with type 1 diabetes

1.   Observation/Background: There is not enough consistency in the methodology of the research on the menstrual cycle, including in females with type 1 diabetes.(1-7) Research needs to be repeated to prove and disprove findings and to reach a consensus. If the methodology keeps changing, the research is not being replicated. I would like to see a widely published, international consensus workshop with a panel of experts that have decided how best to study the effects of the menstrual cycle on glucose control and insulin sensitivity in females with type 1 diabetes. To date, and to the best of my knowledge, I have not seen this yet.  

2.  Questions: 1. What are the best ways to determine and define menstrual cycle phases? 2. What are the best hormone collection strategies? 3. What are the best glucose control/diabetes control/insulin sensitivity/insulin resistance metrics and analytic strategies?

3.   Considerations/Opinions:

Panel inclusion criteria: Experts on the panel should be knowledgeable about how women with type 1 diabetes manage their blood glucose levels. Perhaps women with decades of experience of living with type 1 diabetes should be added to the panel. 2. There should be hormone experts knowledgeable in ovarian hormones on the panel. 3. There should be endocrinologists on the panel. 4. There should be many other experts on the panel including pharmacists, mathematicians, statisticians, ethicists, and researchers knowledgeable on best practices in medical research. 

My opinions: 1. I think that the menstrual, proliferative, ovulatory, and secretory phases should be compared because of the inflection points on the menstrual cycle graphs that you see in textbooks and online. I have seen research that only compares the follicular and the luteal phases.(4) 2. As someone with type 1 diabetes, I don’t think BG or interstitial glucose levels should only be analyzed as separate measurements from insulin dosages because the two are inversely related. For example, if I take too little insulin, I will have high BG levels, but the high BG levels are not necessarily from the menstrual cycle. The opposite is true as well when taking too much insulin. When taking the correct amount of insulin, I will have in-range BG levels, but that does not mean that my BG levels are not affected by the menstrual cycle; I might have adjusted my insulin dosage perfectly in response to the menstrual cycle, and so the data are misleading in that they will not show the effect of the menstrual cycle. There has been research that accounted for this by multiplying the average daily glucose levels and the insulin dosages during a 24-h day.(6,8,9) I hope that methodology will be replicated in future research on this topic.

References:

1.  Schmalenberger KM, Tauseef HA, Barone JC, et al. How to study the menstrual cycle: practical tools and recommendations. Psychoneuroendocrinology. 2021;123:104895. doi:10.1016/j.psyneuen.2020.104895

2.    Gamarra E, Trimboli P. Menstrual cycle, glucose control and insulin sensitivity in type 1 diabetes: a systematic review. J Pers Med. 2023;13(2):374. doi:10.3390/jpm13020374

3.    Barata DS, Adan LF, Netto EM, Ramalho AC. The effect of the menstrual cycle on glucose control in women with type 1 diabetes evaluated using a continuous glucose monitoring system. Diabetes Care. 2013;36(5):e70. doi:10.2337/dc12-2248

4.   Widom B, Diamond MP, Simonson DC. Alterations in glucose metabolism during the menstrual cycle in women with IDDM. Diabetes Care. 1992;15(2):213–220. doi:10.2337/diacare.15.2.213

5.    Lundman B, Asplund K, Norberg A. Metabolic control, food intake, and mood during the menstrual cycle in patients with insulin-dependent diabetes. Int J Nurs Stud. 1994;31(4):391–401. doi:10.1016/0020–7489(94)90010–8

6.    Goldner WS, Kraus VL, Sivitz WI, Hunter SK, Dillon JS. Cyclic changes in glycemia assessed by continuous glucose monitoring system during multiple complete menstrual cycles in women with type 1 diabetes. Diabetes Technol Ther. 2004;6(4):473–480. doi:10.1089/1520915041706062

7.    Brown SA, Jiang B, McElwee-Malloy M, Wakeman C, Breton MD. Fluctuations of hyperglycemia and insulin sensitivity are linked to menstrual cycle phases in women with type 1 diabetes. J Diabetes Sci Technol. 2015;9(6):1192–1199. doi:10.1177/1932296815588226

8.    Coons A, Shubrook JH. The interaction between the female reproductive system and type 1 diabetes. Ann Infert Rep Endocrin. 2021;4(1):1026.

9.    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412–9.

STUDY 2: The menstrual cycle and insulin requirements in people with type 1 diabetes

1.    Observation: As a woman with type 1 diabetes (T1D), I notice menstrual cycle fluctuations in my insulin requirements, especially my actual carb/insulin ratios.

2.    Questions: 1. Do actual carb/insulin ratios change throughout the menstrual cycle phases (menstrual, proliferative, ovulatory, secretory phases) for women of reproductive age with type 1 diabetes? 2. Do basal insulin requirements change throughout the menstrual cycle phases for women of reproductive age with type 1 diabetes? 3. Does insulin sensitivity change throughout the menstrual cycle phases for women of reproductive age with type 1 diabetes?

3.    Background: In some women with insulin dependent diabetes mellitus, the menstrual cycle and ovulatory hormone fluctuations have been shown to have an impact on blood glucose management which is not well-understood.(1–5) A subset of women experience increased hyperglycemia during the luteal phase. However, even when tracking their menstrual cycles, many females report being reactive rather than preventative when managing their BG levels due to the danger of potentially triggering hypoglycemia.(6) More research is needed so that females can feel more comfortable adjusting their insulin dosages throughout their menstrual cycles.

4.    Hypotheses: 1. Actual carb/insulin ratios change throughout the menstrual cycle (menstrual, proliferative, ovulatory, secretory phases) for women of reproductive age with type 1 diabetes. 2. Basal insulin requirements change throughout the menstrual cycle phases for women of reproductive age with type 1 diabetes. 3. Insulin sensitivity changes throughout the menstrual cycle phases for women of reproductive age with type 1 diabetes.

5.    Tests: In females of reproductive age, not in perimenopause, with type 1 diabetes (T1D), and using hybrid closed loop systems, measure estrogen and progesterone levels and insulin sensitivity throughout 3 separate menstrual cycles during the menstrual, proliferative, ovulatory, and secretory phases. Participants will eat predetermined meals but must take the necessary actions to correct high and low blood glucose levels and record these events and actions taken. Insulin sensitivity will be measured in 3 ways: 1. Take the product of the total daily insulin and the average daily blood glucose (TDI x ADBG) to account for the inverse relationship of insulin dosages and blood glucose levels.(3,7) 2. Retrospectively add the pre-meal insulin dosage and any potential post-meal correction insulin dosages; add the carbs per meal and the post-meal carbs eaten for any potential low blood glucose levels; and divide the total carbs per meal by the total insulin taken around mealtime. The result will be the estimate of the actual carb/insulin ratio. 3. Perform hyperinsulinemic clamp studies on the participants during the 4 different menstrual cycle phases. Within-subject and between-subject comparisons will be made to account for the variations within subjects and between subjects.

References:

1.    Widom B, Diamond MP, Simonson DC. Alterations in glucose metabolism during the menstrual cycle in women with IDDM. Diabetes Care. 1992;15(2):213–220. doi:10.2337/diacare.15.2.213

2.    Lundman B, Asplund K, Norberg A. Metabolic control, food intake, and mood during the menstrual cycle in patients with insulin-dependent diabetes. Int J Nurs Stud. 1994;31(4):391–401. doi:10.1016/0020–7489(94)90010–8

3.    Goldner WS, Kraus VL, Sivitz WI, Hunter SK, Dillon JS. Cyclic changes in glycemia assessed by continuous glucose monitoring system during multiple complete menstrual cycles in women with type 1 diabetes. Diabetes Technol Ther. 2004;6(4):473–480. doi:10.1089/1520915041706062

4.    Brown SA, Jiang B, McElwee-Malloy M, Wakeman C, Breton MD. Fluctuations of hyperglycemia and insulin sensitivity are linked to menstrual cycle phases in women with type 1 diabetes. J Diabetes Sci Technol. 2015;9(6):1192–1199. doi:10.1177/1932296815588226

5.    Coons A, Shubrook JH. The interaction between the female reproductive system and type 1 diabetes. Ann Infert Rep Endocrin. 2021;4(1):1026.

6.    Mewes D, Wäldchen M, Knoll C, et al. Variability of glycemic outcomes and insulin requirements throughout the menstrual cycle: a qualitative study on women with type 1 diabetes using an open-source automated insulin delivery system.” J Diabetes Sci Technol. 2023;17(5):1304–1316.

7. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412–9.

STUDY 3: The menstrual cycle and insulin requirements in people with type 1 diabetes and hypothyroidism

1.    Observation: As a woman with T1D and hypothyroidism, I notice menstrual cycle fluctuations in my insulin sensitivity.

2.    Question: Do estrogen fluctuations throughout the menstrual cycle affect thyroid hormone levels and insulin sensitivity throughout the menstrual cycle?

3.    Background: Hypothyroidism increases insulin sensitivity.(1) Hyperthyroidism, conversely, increases insulin requirements.(2,3) Increased estrogen levels lead to increased thyroxine dosage requirements in women with hypothyroidism.(4,5)

4.    Hypotheses: In females of reproductive age, not in perimenopause, and with type 1 diabetes (T1D) and hypothyroidism: 1. There will be a negative correlation between estrogen levels and T3/T4 levels and a positive correlation between estrogen levels and TSH levels. 2. There will be a positive correlation between estrogen levels and insulin sensitivity. 3. There will be a positive correlation between TSH levels and insulin sensitivity and a negative correlation between T3/T4 levels and insulin sensitivity.

5.    Tests: In females of reproductive age, not in perimenopause, with type 1 diabetes (T1D), using hybrid closed loop systems, and with hypothyroidism, measure estrogen levels, thyroid levels (TSH, T3, and T4), and insulin sensitivity throughout 3 separate menstrual cycles during the menstrual, proliferative, ovulatory, and secretory phases. Participants will eat predetermined meals but must take the necessary actions to correct high and low blood glucose levels and record these events and actions taken. Insulin sensitivity will be measured in 3 ways: 1. Take the product of the total daily insulin and the average daily blood glucose (TDI x ADBG) to account for the inverse relationship of insulin dosages and blood glucose levels.(6,7) 2. Retrospectively add the pre-meal insulin dosage and any potential post-meal correction insulin dosages; add the carbs per meal and the post-meal carbs eaten for any potential low blood glucose levels; and divide the total carbs per meal by the total insulin taken around mealtime. The result will be the estimate of the actual carb/insulin ratio. 3. Perform hyperinsulinemic clamp studies on the participants on days with elevated estrogen levels. Within-subject and between-subject comparisons will be made to account for the variations within subjects and between subjects.

References:

1. Shah JH, Motto GS, Papagiannes E, Williams GA. Insulin metabolism in hypothyroidism. Diabetes. 1975;24(10):922–925.

2. Barzilai N, Cohen P, Barzilai D, Karnieli E. Increased insulin responsiveness and insulin clearance in thyrotoxicosis. Isr J Med Sci. 1985;21(9):722–726.

3. Nijs HG, Radder JK, Frölich M, Krans HM. Increased insulin action and clearance in hyperthyroid newly diagnosed IDDM patient. Restoration to normal with antithyroid treatment. Diabetes Care. 1989;12(5):319–324.

4.  Arafah BM. Increased need for thyroxine in women with hypothyroidism during estrogen therapy. N Engl J Med. 2001;344(23):1743-1749. 

5. Alexander EK, Marqusee E, Lawrence J, Jarolim P, Fischer GA, Larsen PR.

   Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med. 2004;351(3):241-249. 

6. Goldner WS, Kraus VL, Sivitz WI, Hunter SK, Dillon JS. Cyclic changes in glycemia assessed by continuous glucose monitoring system during multiple complete menstrual cycles in women with type 1 diabetes. Diabetes Technol Ther. 2004;6(4):473–480. doi:10.1089/1520915041706062

7. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412–9.

STUDY 4: The menstrual cycle, glucagon response, and insulin requirements in people with type 1 diabetes

1.    Observation: As a woman with type 1 diabetes (T1D), I notice menstrual cycle fluctuations in my insulin requirements, especially my actual carb/insulin ratios.

2.    Questions: Do postprandial glucagon response levels change throughout the menstrual cycle phases in females with type 1 diabetes? Is there a negative correlation between postprandial glucagon response levels and carb/insulin ratios?

3.    Background: In some women with insulin dependent diabetes mellitus, the menstrual cycle and ovulatory hormone fluctuations have been shown to have an impact on blood glucose management which is not well-understood.(1–5) A subset of women experience increased hyperglycemia during the luteal phase. However, even when tracking their menstrual cycles, many females report being reactive rather than preventative when managing their BG levels to avoid potentially triggering hypoglycemia.(6) Studies have also shown that in people with type 1 diabetes, there is an inappropriate glucagon response to glucose as well as mixed meal consumption.(7,8) More research is needed to understand the causes of these fluctuations in insulin sensitivity throughout the menstrual cycle in some females with T1D and if the glucagon response to glucose and food consumption may play a role.

4.    Hypotheses: Postprandial glucagon response levels change throughout the menstrual cycle phases in females with type 1 diabetes. There is a negative correlation between postprandial glucagon response levels and carb/insulin ratios.

5.    Tests: In females of reproductive age, not in perimenopause, with type 1 diabetes (T1D), and using hybrid closed loop systems, measure estrogen and progesterone levels, glucagon response levels, and actual carb/insulin ratios throughout 3 separate menstrual cycles during the menstrual, proliferative, ovulatory, and secretory phases. Participants will eat predetermined meals but must take the necessary actions to correct high and low blood glucose levels and record these events and actions taken. Actual carb/insulin ratios will be estimated by retrospectively adding the pre-meal insulin dosage and any potential post-meal correction insulin dosages; adding the carbs per meal and the post-meal carbs eaten for any potential low blood glucose levels; and dividing the total carbs per meal by the total insulin taken around mealtime. The result will be the estimate of the actual carb/insulin ratio. The glucagon response to meals will be measured throughout the 4 different phases of the menstrual cycle. Within-subject and between-subject comparisons will be made to account for the variations within subjects and between subjects.

References:

1.    Widom B, Diamond MP, Simonson DC. Alterations in glucose metabolism during the menstrual cycle in women with IDDM. Diabetes Care. 1992;15(2):213–220. doi:10.2337/diacare.15.2.213

2.    Lundman B, Asplund K, Norberg A. Metabolic control, food intake, and mood during the menstrual cycle in patients with insulin-dependent diabetes. Int J Nurs Stud. 1994;31(4):391–401. doi:10.1016/0020–7489(94)90010–8

3.    Goldner WS, Kraus VL, Sivitz WI, Hunter SK, Dillon JS. Cyclic changes in glycemia assessed by continuous glucose monitoring system during multiple complete menstrual cycles in women with type 1 diabetes. Diabetes Technol Ther. 2004;6(4):473–480. doi:10.1089/1520915041706062

4.    Brown SA, Jiang B, McElwee-Malloy M, Wakeman C, Breton MD. Fluctuations of hyperglycemia and insulin sensitivity are linked to menstrual cycle phases in women with type 1 diabetes. J Diabetes Sci Technol. 2015;9(6):1192–1199. doi:10.1177/1932296815588226

5.    Coons A, Shubrook JH. The interaction between the female reproductive system and type 1 diabetes. Ann Infert Rep Endocrin. 2021;4(1):1026.

6.    Mewes D, Wäldchen M, Knoll C, et al. Variability of glycemic outcomes and insulin requirements throughout the menstrual cycle: a qualitative study on women with type 1 diabetes using an open-source automated insulin delivery system.” J Diabetes Sci Technol. 2023;17(5):1304–1316.

7.    Hare KJ, Vilsbøll T, Holst JJ, Knop FK. Inappropriate glucagon response after oral compared with isoglycemic intravenous glucose administration in patients with type 1 diabetes. Am J Physiol Endocrinol Metab. 2010;298(4):E832-837. doi: 10.1152/ajpendo.00700.2009. 

8.    Sherr J, Tsalikian E, Fox L, Buckingham B, Weinzimer S, Tamborlane WV, et al; Diabetes Research in Children Network. Evolution of abnormal plasma glucagon responses to mixed-meal feedings in youth with type 1 diabetes during the first 2 years after diagnosis. Diabetes Care. 2014;37(6):1741-1744.