Original Article
Elena M. Morariu, MD1; Magdalene Szuszkiewicz-Garcia, MD2; Esther I. Krug, MD3; Bianca Durando Lemos, MD4; Louise DeRiso, RN, MSN5; Mary Beth Tedesco, RN, MSN1; Glory L. Koerbel, RN, MSN5; Stephen J. Winters, MD6; Mary T. Korytkowski, MD1 ABSTRACT Objective: Menstrual irregularities, reproductive abnormalities, and androgen excess are reported to be more prevalent in women with type 1 diabetes (T1D). The objective of this study was to investigate the prevalence of menstrual irregularities, reproductive abnormalities, and androgen excess among women with T1D and their agematched controls. Methods: A survey requesting information regarding menstrual and reproductive histories was administered to all participants. Results were stratified according to age (18 to 40, 40 to 50, and >50 years). Results: There were no significant differences between women with and without diabetes in age at menarche, cycle length, or androgen excess in any group. Women who selfreported difficulty with glycemic control were more likely to report irregular menses than controls (P = .04). Among women who reported ever being pregnant, there were fewer pregnancies (P = .02) and live births (P = .002) in women with T1D. Women with T1D reported a lower frequency of
Submitted for publication November 21, 2014 Accepted for publication January 27, 2015 From the 1University of Pittsburgh, Division of Endocrinology and Metabolism, Department of Medicine, 2University of Texas Southwestern Medical Center, Division of Endocrinology and Metabolism, 3Sinai Hospital of Baltimore, Division of Endocrinology, Johns Hopkins University School of Medicine, 4University of Florida College of Medicine, Department of Dermatology, 5University of Pittsburgh, Clinical and Translational Science Institute, and 6Division of Endocrinology and Metabolism, University of Louisville. Address correspondence to Dr. Mary T. Korytkowski, University of Pittsburgh, Division of Endocrinology and Metabolism, Department of Medicine, Falk, Suite 560; 3601 Fifth Avenue, Pittsburgh, PA 15213. E-mail: [email protected]. Published as a Rapid Electronic Article in Press at http://www.endocrine practice.org on March 18, 2015. DOI: 10.4158/EP14560.OR Copyright © 2015 AACE.
750
oral contraceptive use (P = .003), despite being less likely to smoke (P = .016). Conclusion: Menstrual and reproductive abnormalities were not observed more frequently in women with T1D in this study. Subtle but measurable differences in menstrual and reproductive function were confined to the subgroup of women who perceived poor control of their diabetes. Additional prospective studies of T1D and menstrual and reproductive function would be useful. (Endocr Pract. 2015;21:750-760) Abbreviations: BMI = body mass index; CVD = cardiovascular disease; DCCT = Diabetes Control and Complications Trial; FAD = Familial Autoimmune and Diabetes; HbA1c = glycated hemoglobin; HC = hormonal contraception; T1D = type 1 diabetes INTRODUCTION The menstrual and reproductive history is an important but frequently overlooked aspect of the medical history (1). This is particularly important for women with T1D, who are reported to have more menstrual dysfunction and reproductive abnormalities when compared to women without diabetes (1-4). These abnormalities have been observed to extend across the reproductive lifespan (2-3). Delayed menarche, menstrual irregularities (2,3,5-11), and symptoms of androgen excess (acne, hirsutism) are all reported with a higher frequency in adolescent and young adult women with T1D than their age-matched counterparts. Women with T1D have fewer pregnancies and live births (3,12) and experience earlier menopause compared with women without diabetes (13). Such reproductive abnormalities have been identified as potential markers of enhanced risk for cardiovascular disease (CVD) (14-16). The Familial Autoimmune and Diabetes (FAD) (3) study is one of the few previous epidemiologic studies that evaluated menstrual irregularities and other reproductive
751
abnormalities in women with T1D across the reproductive lifespan (2,8,9,17). The subjects included in FAD were women diagnosed between 1950 and 1965 who participated in the Pittsburgh T1D registry (3). This time period represents the era preceding publication of the Diabetes Control and Complications Trial (DCCT), which prompted the initiation of strategies for achieving and maintaining glycated hemoglobin (HbA1c) levels of 50 All ages Control 18-40 41-50 >50 All ages
WHR
Age at diagnosis (years)
Age at menarche (years)
OC use (%)
24.4 ± 4.8 27.8 ± 4.9 28.9 ± 4.8 25.9 ± 5.1
0.78 ± 0.06 0.82 ± 0.06 0.86 ± 0.09 0.80 ± 0.07
12.6 ± 8.0 15.3 ± 9.7 22.1 ± 10.9 14.4 ± 9.2
12.8 ± 1.7 12.6 ± 1.2 11.8 ± 1.6 12.6 ± 1.6
72.5a 40.7 55.6 60.9b
25.2 ± 5.1 27.8 ± 6.8 26.9 ± 4.1 26.2 ± 5.7
0.79 ± 0.06 0.80 ± 0.07 0.81 ± 0.04 0.80 ± 0.06
-----
12.7 ± 1.4 12.1 ± 1.4 12.4 ± 1.8 12.5 ± 1.4
86.0a 85.2 50.0 81.6b
Number
Age (years)
BMI (kg/m2)
51 27 9 87
29.8 ± 6.0 45.9 ± 2.9 54.3 ± 4.4 37.3 ± 10.6
50 27 10 87
29.7 ± 6.0 45.7 ± 2.5 54.4 ± 4.0 37.5 ± 10.7
Abbreviations: BMI = body mass index; OC = oral contraceptive; WHR = waist to hip ratio. a P60 days Pregnancies Number of live births Cycle length >45 days >60 days Pregnancies Number of live births Cycle length >45 days >60 days Pregnancies Number of live births Cycle length >45 days >60 days Pregnancies Number of live births
Type 1 diabetes 31.1 ± 12.5 37.3% 32.0% 0.7 ± 1.1 0.5 ± 0.8 35.4 ± 18.8 38.5% 30.8% 2.1 ± 1.7 1.3 ± 1.1 37.8 ± 27.2 50.0% 37.5% 1.3 ± 0.5 0.9 ± 0.8 33.2 ± 16.5 38.8% 32.1% 1.2 ± 1.4 0.8 ± 1.0
Control 30.5 ± 10.5 33.3% 24.5% 0.8 ± 1.4 0.6 ± 1.0 30.1 ± 8.5 30.8% 23.1% 2.4 ± 2.2 1.5 ± 1.2 28.4 ± 2.1 40.0% 30.0% 2.5 ± 1.5 2.1 ± 1.3 30.2 ± 9.2 33.3% 24.7% 1.5 ± 1.8 1.0 ± 1.2
P value .8 .7 .4 .8 .7 .2 .6 .5 .6 .5 .3 .5 .6 .04a .03a .2 .5 .3 .8 .1
type 1 diabetes versus control.
improvements in glycemic management have attenuated the previously observed menstrual abnormalities reported in women with T1D (1-3,8). More menstrual irregularities were observed in women with T1D who reported difficulty maintaining glycemic control. These women also reported more diabetes-related complications compared to women who did not perceive difficulty in controlling their diabetes. It is unclear if poor glycemic control or overall poorer health accounts for these findings. However, these findings are consistent with earlier reports showing increased menstrual irregularities in women with poorly controlled diabetes (2,5,6,23). In one study of 245 women age 18 to 49 years, higher HbA1c concentrations (10.5% versus 9.2%) were observed among women reporting oligo- and amenorrhea (2). Other studies in adolescents have shown menstrual irregularities and cycle length variability to correlate with HbA1c (6,23). Menstrual irregularity was also reported with greater frequency in the subgroup of women over 50 years of age. Though the number of women in this group was small, the finding supports that women who lived with diabetes in the pre-DCCT era are more likely to have irregular menses. The prevalence of self-reported menstrual irregularity was higher in our population of women with T1D and
controls (44 and 30%, respectively) compared to previous reports (3). In a Danish study of women with T1D diagnosed before age 30, there was a 21.6% prevalence of any menstrual disorder, defined as oligomenorrhea, polymenorrhea, and amenorrhea in women with T1D compared to 10.8% of controls (2). In the Coronary Artery Calcification in T1D study, self-reported menstrual irregularity and amenorrhea reached 30% in women with T1D, compared to 19% in controls (14). Although some differences may be due to BMI and environmental differences such as diet, these described differences in prevalence rates may be more attributable to variability in the definition of menstrual irregularities and how questions were asked. In the FAD study, which examined American women with T1D age-grouped by decade, the prevalence of any menstrual problem (long cycles, long menstruation, and heavy menstruation) exceeded 50% in all groups and was reported twice as frequently in T1D aged less than 30 years compared to controls (3). One important finding was the lower percentage of women with T1D who reported using HC when compared to controls. Despite the need for family planning in regards to glycemic management in women with diabetes during their reproductive years, these women were less likely to
755
use HC. This finding is consistent with previously reported lower rates of HC use among women with T1D (2,3,14). It is not clear if the low use of HC among women in this study was due to personal choice or a reluctance of physicians to prescribe these agents to women with diabetes, particularly in light of perceived adverse cardiovascular effects of using HC and the already increased risk of CVD in women with T1D (24,25). Marriage or relationship status, not known for the subjects in this study, may also affect women’s choices regarding contraception. Among women who reported a pregnancy, there were fewer pregnancies and live births reported in those with T1D. There were no differences in the percentage of women reporting infertility or having undergone fertility treatment in any subgroup. These findings are consistent with a previous study reporting that the ability of women with T1D to conceive is normal, but that they have fewer pregnancies and fewer live births (2,3,26). This may reflect the personal choice of many women with T1D given the recommendations for strict glycemic control before and during pregnancy (27) and their concerns with maternal and fetal morbidities. In addition, pregnancy presents additional burdens to the lives of women with diabetes, with the need for more frequent blood glucose monitoring, more attention to dietary intake, and more frequent office visits. In this study, no correlation was observed between perception of ease of diabetes control and number of pregnancies. The lower number of pregnancies among women with T1D in the over age 50 years group is difficult to interpret given the small sample size but may reflect a time when many women with T1D were counseled against pursuing a pregnancy (28). In addition to menstrual abnormalities, a higher prevalence of androgen excess and hirsutism has been variably reported in young women with T1D when compared with young women without diabetes (10,17,29-34). Androgen levels were not measured in the current study, which makes the presence of hirsutism and acne the only surrogate variables that were used to define androgen excess. However, the prevalence and severity of hirsutism in this study differs from what has been described in some earlier reports (11,17,32). One major reason for this difference may be that the current study used only self-reports of excess or abnormal hair growth and acne, whereas prior studies were based on physical examination performed by an investigator (11,17). Self-report may vary with subjects’ perception of whether some body hair is normal or abnormal, but it is unlikely to differ between women with diabetes and controls. The importance of investigating menstrual and reproductive abnormalities in women with T1D lies partly in the risk of CVD, which may be associated with these abnormalities (14-16,35). There are several reports linking menstrual disorders with risk for CVD in nondiabetic women, particularly in women with polycystic ovary syndrome,
where risk may be mediated through factors related to the metabolic syndrome (35,36). In one review of studies investigating links between reproductive abnormalities and CVD in postmenopausal women, only menstrual irregularity, pregnancy loss, and age at menopause were observed as important historical findings (37). In this prior report, menstrual irregularity was reported with a greater frequency in women with T1D, a group already at increased risk for CVD (14,38,39). Menstrual and reproductive abnormalities may serve as markers for, or as aggravating factors, for this risk. One interesting finding in this study was that women with T1D were less likely to smoke. It is possible that women with T1D, being aware of cardiovascular risk of having diabetes, chose to avoid additional risk conferred by smoking. There are several limitations to the current study. First, this was a survey of self-reported data. The validity of survey findings depends exclusively on the accuracy of recall and reporting by participants. Subjects were reassured that investigators were blinded to their names once the questionnaire was completed as a way of increasing reliable reporting. In addition, not all women provided specific information regarding the length of their menstrual cycles, as some had very irregular menses. In an attempt to address this, menstrual length was reported as the average of the range of dates which may have either over- or underestimated true cycle length. No measures of sex hormones were obtained as part of this study, which could have provided more information regarding more subtle menstrual abnormalities that could be masked in women reporting regular menstrual cycles (40). Also, we do not have HbA1c values to correlate abnormalities to any objective measure of glycemic control. Another limitation is that the subjects were predominantly Caucasian, limiting generalizability to other racial groups. Yet another limitation is that the number of women reporting menopause was too low to make any comparison between women with and without diabetes. Data on age of menopause in women with T1D are limited, with one study showing that both T1D and menstrual irregularities are each independent risk factors for early menopause (13) and another showing that women with T1D and microvascular complications experience menopause at an earlier age than the general population (41). CONCLUSION In summary, the major findings in this study were a lower likelihood of HC use among all women with T1D and more frequently reported irregular menses in women who reported difficulty with glycemic management. The observation of fewer pregnancies and live births among women with T1D is likely due to factors unrelated to reproductive dysfunction. Future studies that prospectively investigate menstrual disorders according to current glycemic status are planned.
756
ACKNOWLEDGMENT
DISCLOSURE
There has been no duplicate publication or submission elsewhere (excluding abstracts). No external funding was obtained for this study.
Dr. Mary Korytkowski has received grant support from Sanofi Aventis and has served as an ad hoc consultant for this company. The other authors have no multiplicity of interest to disclose.
APPENDIX QUESTIONNAIRE ON MENSTRUAL ABNORMALITIES Date ___________
ID# ________ (to be filled out by investigator)
1. How old are you now? ________ 2. What is your ethnic background?
A. B. C. D. E.
Black Hispanic White American Indian Other (specify) _____________
3. How tall are you? _______ (inches) 4. What is your present weight? _______ (pounds) 5. What is your measured smallest waist circumference? ________ (inches) 6. What is your measured biggest hip circumference? _______ (inches) 7. Do you have diabetes mellitus?
Yes
No (Skip to question 9)
8. If you answered Yes to question 7, please answer questions “a” through “h” a. At what age did you find out that you have diabetes? _______ b. Do you take insulin injects? c. Have you ever used pills for treatment of your diabetes? If yes, please list names of pills
Yes No Yes No
____________________________________________ d. e. f. g. h.
Do you check your blood sugars daily? Do you know your recent hemoglobin A1c reading? Do you find your diabetes is difficult to control? Have you ever been told that you have a diabetic eye problem? Have you ever been told that you have a diabetic kidney problem?
Yes Yes Yes Yes Yes
No No No No No
9. Do you have any first-degree relatives (mother, father, sister, brother, son, daughter) with diabetes mellitus? Yes No If you do, indicate relationship____________________________________________ __________________________________________________________________
757
10. Do you have any other medical problems besides diabetes mellitus? Yes No If you do, please list: _________________________________________________ ___________________________________________________________________ ___________________________________________________________________ 11. Do you take any medications? Yes No If you do, please list the medications and specify the reason for taking each medication: Medication 1 2 3 4 5 6
Reason 1 2 3 4 5 6
Medication 7 8 9 10 11 12
Reason 7 8 9 10 11 12
12. How old were you when you had your first menstrual period? _______ 13. Are you still having menstrual periods? Yes No If no, how old were you when you had your last spontaneous menstrual period? _______ 14. Have you had a hysterectomy? If yes, were your ovaries left in?
Yes No Yes No
15. If you are postmenopausal or had a hysterectomy, do you take estrogen replacement therapy? Yes No If no, please list reasons you are not using replacement therapy: ____________________________________________________________________ ____________________________________________________________________ 16. Are/Were your menstrual cycles regular? Yes No 17. On average, what are/were the lengths of your cycles? (starting from the first day of one menstrual bleeding to the first day of the next menstrual bleeding) ___________ 18. On average, what is the length of your menstrual bleeding? _______ days 19. Have you ever had intervals between your menstrual periods a. longer than 45 days? Yes No b. longer than 60 days? Yes No If you answered yes to any of the above, at what age? _______________________
758
20. Have you ever used birth control pills? Yes No If yes, list the names of pills and for how long you were taking them ____________________________________________________________________ ____________________________________________________________________ 21. How many pregnancies have you had? Live births Miscarriages Abortions 22. Did you have diabetes mellitus during any of your pregnancies? Yes No 23. Have you ever had any infection of your reproductive organs (uterus, fallopian tubes, ovaries)? Yes No If you answered yes, please specify _______________________________________ ____________________________________________________________________ 24. Have you ever had problems becoming pregnant?
Yes No
25. Have you ever undergone any infertility treatment? Yes No If you answered yes, please specify ____________________________________________________________________ ____________________________________________________________________ 26. Have you ever had hair growth on parts of your body other than your scalp, armpits, or pubic hair? Yes No If you answered yes, please specify: a. upper lip Yes No b. chin Yes No c. facial Yes No d. chest Yes No e. thighs Yes No At what age did you first notice hair growth on these parts of your body? ________ 27. Have you ever had acne problems after your teenage years? Yes No 28. If you have ever suffered from severe acne, please indicate your age at that time. ______ to _______ years Not applicable 29. Do you presently or have you ever smoked? Yes No If you answered yes, please specify: a. How many packs per day? ________________________ b. For how many years? ________________________ c. When did you quit? ________________________
759
REFERENCES 1. Codner E, Merino PM, Tena-Sempere M. Female repro-
duction and type 1 diabetes: from mechanisms to clinical findings. Hum Reprod Update. 2012;18:568-585. 2. Kjaer K, Hagen C, Sandø SH, Eshøj O. Epidemiology of menarche and menstrual disturbances in an unselected group of women with insulin-dependent diabetes mellitus compared to controls. J Clin Endocrinol Metab. 1992;75: 524-529. 3. Strotmeyer ES, Steenkiste AR, Foley TP, Berga SL, Dorman JS. Menstrual cycle differences between women with type 1 diabetes and women without diabetes. Diabetes Care. 2003;26:1016-1021. 4. Codner E, Soto N, Merino PM. Contraception, and pregnancy in adolescents with type 1 diabetes: a review. Pediatr Diabetes. 2012;13:108-123. 5. Deltsidou A. Age at menarche and menstrual irregularities of adolescents with type 1 diabetes. J Pediatr Adolesc Gynecol. 2010;23:162-167. 6. Gaete X, Vivanco M, Eyzaguirre FC, et al. Menstrual cycle irregularities and their relationship with HbA1c and insulin dose in adolescents with type 1 diabetes mellitus. Fertil Steril. 2010;94:1822-1826. 7. Picardi A, Cipponeri E, Bizzarri C, Fallucca S, Guglielmi C, Pozzilli P. Menarche in type 1 diabetes is still delayed despite good metabolic control. Fertil Steril. 2008; 90:1875-1877. 8. Yeshaya A, Orvieto R, Dicker D, Karp M, Ben-Rafael Z. Menstrual characteristics of women suffering from insulindependent diabetes mellitus. Int J Fertil Menopausal Stud. 1995;40:269-273. 9. Adcock CJ, Perry LA, Lindsell DR, et al. Menstrual irregularities are more common in adolescents with type 1 diabetes: association with poor glycaemic control and weight gain. Diabet Med. 1994;11:465-470. 10. Zachurzok A, Deja G, Gawlik A, Drosdzol-Cop A, Malecka-Tendera E. Hyperandrogenism in adolescent girls with type 1 diabetes mellitus treated with intensive and continuous subcutaneous insulin therapy. Endokrynol Pol. 2012;64:121-128. 11. Samara-Boustani D, Colmenares A, Elie C, et al. High prevalence of hirsutism and menstrual disorders in obese adolescent girls and adolescent girls with type 1 diabetes mellitus despite different hormonal profiles. Eur J Endocrinol. 2012;166:307-316. 12. Whitworth KW, Baird DD, Stene LC, Skjaerven R, Longnecker MP. Fecundability among women with type 1 and type 2 diabetes in the Norwegian Mother and Child Cohort Study. Diabetologia. 2011;54:516-522. 13. Dorman JS, Steenkiste AR, Foley TP, et al. Menopause in type 1 diabetic women: is it premature? Diabetes. 2001;50: 1857-1862. 14. Snell-Bergeon JK, Dabelea D, Ogden LG, et al. Reproductive history and hormonal birth control use are associated with coronary calcium progression in women with type 1 diabetes mellitus. J Clin Endocrinol Metab. 2008;93:2142-2148. 15. Taponen S, Martikainen H, Järvelin MR, et al. Metabolic cardiovascular disease risk factors in women with self-reported symptoms of oligomenorrhea and/or hirsutism: Northern Finland Birth Cohort 1966 Study. J Clin Endocrinol Metab. 2004;89:2114-2118. 16. Wang ET, Cirillo PM, Vittinghoff E, Bibbins-Domingo K, Cohn BA, Cedars MI. Menstrual irregularity and
17.
18. 19.
20. 21. 22.
23.
24. 25.
26. 27. 28. 29.
30.
31.
32.
33.
cardiovascular mortality. J Clin Endocrinol Metab. 2011; 96: E114-E118. Escobar-Morreale HF, Roldán B, Barrio R, et al. High prevalence of the polycystic ovary syndrome and hirsutism in women with type 1 diabetes mellitus. J Clin Endocrinol Metab. 2000;85:4182-4187. McCulloch DK, Glasgow RE, Hampson SE, Wagner E. A systematic approach to diabetes management in the postDCCT era. Diabetes Care. 1994;17:765-769. The Diabetes Control and Complications Trial (DCCT) Research Group. The effect of intensive treatment of diabetes on the development and progression of long term complications in insulin dependent diabetes mellitus. N Engl J Med. 1993;329:977-986. Schroeder B, Hertweck SP, Sanfilippo JS, Foster MB. Correlation between glycemic control and menstruation in diabetic adolescents. J Reprod Med. 2000;45:1-5. Schweiger B, Klingensmith GJ, Snell-Bergeon JK. Menarchal timing in type 1 diabetes through the last 4 decades. Diabetes Care. 2010;33:2521-2523. Gaete X, Vivanco M, Eyzaguirre FC, et al. Menstrual cycle irregularities and their relationship with HbA1c and insulin dose in adolescents with type 1 diabetes mellitus. Fertil Steril. 2010;94:1822-1826. Deltsidou A, Lemonidou C, Zarikas V, Matziou V, Bartsocas CS. Oligomenorrhoea in adolescents with type 1 diabetes mellitus: relationship to glycaemic control. Eur J Obstet Gynecol Reprod Biol. 2010;153:62-66. Laing SP, Swerdlow AJ, Slater SD, et al. Mortality from heart disease in a cohort of 23,000 patients with insulintreated diabetes. Diabetologia. 2003;46:760-765. Serfaty D, Wildemeersch D, Verougstraete A, Creatsas G. European Society of Contraception oral contraceptives survey update: birth control methods in “Europe of the 12”. Int J Fertil Menopausal Stud. 1995;40(suppl 2):73-79. Codner E, Eyzaguirre FC, Iñiguez G, et al. Ovulation rate in adolescents with type 1 diabetes mellitus. Fertil Steril. 2011;95:197-202. Blumer I, Hadar E, Hadden DR, et al. Diabetes and pregnancy: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013;98:4227-4249. Steel JM. Prepregnancy counseling and contraception in the insulin-dependent diabetic patient. Clin Obstet Gynecol. 1985;28:553-566. Bizzarri C, Benevento D, Ravà L, et al. Ovarian hyperandrogenism in adolescents and young women with type I diabetes is primarily related to birth weight and body mass index. Fertil Steril. 2011;96:1497-1502. Codner E, Iñiguez G, Villarroel C, et al. Hormonal profile in women with polycystic ovarian syndrome with or without type 1 diabetes mellitus. J Clin Endocrinol Metab. 2007;92:4742-4746. Codner E, Soto N, Lopez P, et al. Diagnostic criteria for polycystic ovary syndrome and ovarian morphology in women with type 1 diabetes mellitus. J Clin Endocrinol Metab. 2006;91:2250-2256. Codner E, Escobar-Morreale HF. Clinical review: hyperandrogenism and polycystic ovary syndrome in women with type 1 diabetes mellitus. J Clinical Endocrinol Metab. 2007;92:1209-1216. Nyholm H, Djursing H, Hagen C, Agner T, Bennett P, Svenstrup B. Androgens and estrogens in postmenopausal insulin-treated diabetic women. J Clin Endocrinol Metab. 1989;69:946-949.
760 34. Amato MC, Guarnotta V, Ciresi A, Modica R, Panto F, Giordano C. No phenotypic differences for polycystic ovary syndrome (PCOS) between women with and without type 1 diabetes mellitus. J Clin Endocrinol Metab. 2014; 99:203-211. 35. Korytkowski MT, Krug EI, Daly MA, Deriso L, Wilson JW, Winters SJ. Does androgen excess contribute to the cardiovascular risk profile in postmenopausal women with type 2 diabetes? Metabolism. 2005;54:1626-1631. 36. Ehrmann DA, Kasza K, Azziz R, Legro RS, Ghazzi MN. Effects of race and family history of type 2 diabetes on metabolic status of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90:66-71. 37. de Kleijn MJ, van der Schouw YT, van der Graaf Y. Reproductive history and cardiovascular disease risk
38.
39. 40. 41.
in postmenopausal women: a review of the literature. Maturitas. 1999;33:7-36. Colhoun HM, Rubens MB, Underwood SR, Fuller JH. The effect of type 1 diabetes mellitus on the gender difference in coronary artery calcification. J Am Coll Cardiol. 2000;36:2160-2167. Costacou T, Edmundowicz D, Prince C, Conway B, Orchard TJ. Progression of coronary artery calcium in type 1 diabetes mellitus. Am J Cardiol. 2007;100:1543-1547. Sherman BM, Korenman SG. Hormonal characteristics of the human menstrual cycle throughout reproductive life. J Clin Invest. 1975;55:699-706. Sjöberg L, Pitkäniemi J, Harjutsalo V, et al. Menopause in women with type 1 diabetes. Menopause. 2011;18:158-163.
Elena M. Morariu, MD1; Magdalene Szuszkiewicz-Garcia, MD2; Esther I. Krug, MD3; Bianca Durando Lemos, MD4; Louise DeRiso, RN, MSN5; Mary Beth Tedesco, RN, MSN1; Glory L. Koerbel, RN, MSN5; Stephen J. Winters, MD6; Mary T. Korytkowski, MD1 ABSTRACT Objective: Menstrual irregularities, reproductive abnormalities, and androgen excess are reported to be more prevalent in women with type 1 diabetes (T1D). The objective of this study was to investigate the prevalence of menstrual irregularities, reproductive abnormalities, and androgen excess among women with T1D and their agematched controls. Methods: A survey requesting information regarding menstrual and reproductive histories was administered to all participants. Results were stratified according to age (18 to 40, 40 to 50, and >50 years). Results: There were no significant differences between women with and without diabetes in age at menarche, cycle length, or androgen excess in any group. Women who selfreported difficulty with glycemic control were more likely to report irregular menses than controls (P = .04). Among women who reported ever being pregnant, there were fewer pregnancies (P = .02) and live births (P = .002) in women with T1D. Women with T1D reported a lower frequency of
Submitted for publication November 21, 2014 Accepted for publication January 27, 2015 From the 1University of Pittsburgh, Division of Endocrinology and Metabolism, Department of Medicine, 2University of Texas Southwestern Medical Center, Division of Endocrinology and Metabolism, 3Sinai Hospital of Baltimore, Division of Endocrinology, Johns Hopkins University School of Medicine, 4University of Florida College of Medicine, Department of Dermatology, 5University of Pittsburgh, Clinical and Translational Science Institute, and 6Division of Endocrinology and Metabolism, University of Louisville. Address correspondence to Dr. Mary T. Korytkowski, University of Pittsburgh, Division of Endocrinology and Metabolism, Department of Medicine, Falk, Suite 560; 3601 Fifth Avenue, Pittsburgh, PA 15213. E-mail: [email protected]. Published as a Rapid Electronic Article in Press at http://www.endocrine practice.org on March 18, 2015. DOI: 10.4158/EP14560.OR Copyright © 2015 AACE.
750
oral contraceptive use (P = .003), despite being less likely to smoke (P = .016). Conclusion: Menstrual and reproductive abnormalities were not observed more frequently in women with T1D in this study. Subtle but measurable differences in menstrual and reproductive function were confined to the subgroup of women who perceived poor control of their diabetes. Additional prospective studies of T1D and menstrual and reproductive function would be useful. (Endocr Pract. 2015;21:750-760) Abbreviations: BMI = body mass index; CVD = cardiovascular disease; DCCT = Diabetes Control and Complications Trial; FAD = Familial Autoimmune and Diabetes; HbA1c = glycated hemoglobin; HC = hormonal contraception; T1D = type 1 diabetes INTRODUCTION The menstrual and reproductive history is an important but frequently overlooked aspect of the medical history (1). This is particularly important for women with T1D, who are reported to have more menstrual dysfunction and reproductive abnormalities when compared to women without diabetes (1-4). These abnormalities have been observed to extend across the reproductive lifespan (2-3). Delayed menarche, menstrual irregularities (2,3,5-11), and symptoms of androgen excess (acne, hirsutism) are all reported with a higher frequency in adolescent and young adult women with T1D than their age-matched counterparts. Women with T1D have fewer pregnancies and live births (3,12) and experience earlier menopause compared with women without diabetes (13). Such reproductive abnormalities have been identified as potential markers of enhanced risk for cardiovascular disease (CVD) (14-16). The Familial Autoimmune and Diabetes (FAD) (3) study is one of the few previous epidemiologic studies that evaluated menstrual irregularities and other reproductive
751
abnormalities in women with T1D across the reproductive lifespan (2,8,9,17). The subjects included in FAD were women diagnosed between 1950 and 1965 who participated in the Pittsburgh T1D registry (3). This time period represents the era preceding publication of the Diabetes Control and Complications Trial (DCCT), which prompted the initiation of strategies for achieving and maintaining glycated hemoglobin (HbA1c) levels of 50 All ages Control 18-40 41-50 >50 All ages
WHR
Age at diagnosis (years)
Age at menarche (years)
OC use (%)
24.4 ± 4.8 27.8 ± 4.9 28.9 ± 4.8 25.9 ± 5.1
0.78 ± 0.06 0.82 ± 0.06 0.86 ± 0.09 0.80 ± 0.07
12.6 ± 8.0 15.3 ± 9.7 22.1 ± 10.9 14.4 ± 9.2
12.8 ± 1.7 12.6 ± 1.2 11.8 ± 1.6 12.6 ± 1.6
72.5a 40.7 55.6 60.9b
25.2 ± 5.1 27.8 ± 6.8 26.9 ± 4.1 26.2 ± 5.7
0.79 ± 0.06 0.80 ± 0.07 0.81 ± 0.04 0.80 ± 0.06
-----
12.7 ± 1.4 12.1 ± 1.4 12.4 ± 1.8 12.5 ± 1.4
86.0a 85.2 50.0 81.6b
Number
Age (years)
BMI (kg/m2)
51 27 9 87
29.8 ± 6.0 45.9 ± 2.9 54.3 ± 4.4 37.3 ± 10.6
50 27 10 87
29.7 ± 6.0 45.7 ± 2.5 54.4 ± 4.0 37.5 ± 10.7
Abbreviations: BMI = body mass index; OC = oral contraceptive; WHR = waist to hip ratio. a P60 days Pregnancies Number of live births Cycle length >45 days >60 days Pregnancies Number of live births Cycle length >45 days >60 days Pregnancies Number of live births Cycle length >45 days >60 days Pregnancies Number of live births
Type 1 diabetes 31.1 ± 12.5 37.3% 32.0% 0.7 ± 1.1 0.5 ± 0.8 35.4 ± 18.8 38.5% 30.8% 2.1 ± 1.7 1.3 ± 1.1 37.8 ± 27.2 50.0% 37.5% 1.3 ± 0.5 0.9 ± 0.8 33.2 ± 16.5 38.8% 32.1% 1.2 ± 1.4 0.8 ± 1.0
Control 30.5 ± 10.5 33.3% 24.5% 0.8 ± 1.4 0.6 ± 1.0 30.1 ± 8.5 30.8% 23.1% 2.4 ± 2.2 1.5 ± 1.2 28.4 ± 2.1 40.0% 30.0% 2.5 ± 1.5 2.1 ± 1.3 30.2 ± 9.2 33.3% 24.7% 1.5 ± 1.8 1.0 ± 1.2
P value .8 .7 .4 .8 .7 .2 .6 .5 .6 .5 .3 .5 .6 .04a .03a .2 .5 .3 .8 .1
type 1 diabetes versus control.
improvements in glycemic management have attenuated the previously observed menstrual abnormalities reported in women with T1D (1-3,8). More menstrual irregularities were observed in women with T1D who reported difficulty maintaining glycemic control. These women also reported more diabetes-related complications compared to women who did not perceive difficulty in controlling their diabetes. It is unclear if poor glycemic control or overall poorer health accounts for these findings. However, these findings are consistent with earlier reports showing increased menstrual irregularities in women with poorly controlled diabetes (2,5,6,23). In one study of 245 women age 18 to 49 years, higher HbA1c concentrations (10.5% versus 9.2%) were observed among women reporting oligo- and amenorrhea (2). Other studies in adolescents have shown menstrual irregularities and cycle length variability to correlate with HbA1c (6,23). Menstrual irregularity was also reported with greater frequency in the subgroup of women over 50 years of age. Though the number of women in this group was small, the finding supports that women who lived with diabetes in the pre-DCCT era are more likely to have irregular menses. The prevalence of self-reported menstrual irregularity was higher in our population of women with T1D and
controls (44 and 30%, respectively) compared to previous reports (3). In a Danish study of women with T1D diagnosed before age 30, there was a 21.6% prevalence of any menstrual disorder, defined as oligomenorrhea, polymenorrhea, and amenorrhea in women with T1D compared to 10.8% of controls (2). In the Coronary Artery Calcification in T1D study, self-reported menstrual irregularity and amenorrhea reached 30% in women with T1D, compared to 19% in controls (14). Although some differences may be due to BMI and environmental differences such as diet, these described differences in prevalence rates may be more attributable to variability in the definition of menstrual irregularities and how questions were asked. In the FAD study, which examined American women with T1D age-grouped by decade, the prevalence of any menstrual problem (long cycles, long menstruation, and heavy menstruation) exceeded 50% in all groups and was reported twice as frequently in T1D aged less than 30 years compared to controls (3). One important finding was the lower percentage of women with T1D who reported using HC when compared to controls. Despite the need for family planning in regards to glycemic management in women with diabetes during their reproductive years, these women were less likely to
755
use HC. This finding is consistent with previously reported lower rates of HC use among women with T1D (2,3,14). It is not clear if the low use of HC among women in this study was due to personal choice or a reluctance of physicians to prescribe these agents to women with diabetes, particularly in light of perceived adverse cardiovascular effects of using HC and the already increased risk of CVD in women with T1D (24,25). Marriage or relationship status, not known for the subjects in this study, may also affect women’s choices regarding contraception. Among women who reported a pregnancy, there were fewer pregnancies and live births reported in those with T1D. There were no differences in the percentage of women reporting infertility or having undergone fertility treatment in any subgroup. These findings are consistent with a previous study reporting that the ability of women with T1D to conceive is normal, but that they have fewer pregnancies and fewer live births (2,3,26). This may reflect the personal choice of many women with T1D given the recommendations for strict glycemic control before and during pregnancy (27) and their concerns with maternal and fetal morbidities. In addition, pregnancy presents additional burdens to the lives of women with diabetes, with the need for more frequent blood glucose monitoring, more attention to dietary intake, and more frequent office visits. In this study, no correlation was observed between perception of ease of diabetes control and number of pregnancies. The lower number of pregnancies among women with T1D in the over age 50 years group is difficult to interpret given the small sample size but may reflect a time when many women with T1D were counseled against pursuing a pregnancy (28). In addition to menstrual abnormalities, a higher prevalence of androgen excess and hirsutism has been variably reported in young women with T1D when compared with young women without diabetes (10,17,29-34). Androgen levels were not measured in the current study, which makes the presence of hirsutism and acne the only surrogate variables that were used to define androgen excess. However, the prevalence and severity of hirsutism in this study differs from what has been described in some earlier reports (11,17,32). One major reason for this difference may be that the current study used only self-reports of excess or abnormal hair growth and acne, whereas prior studies were based on physical examination performed by an investigator (11,17). Self-report may vary with subjects’ perception of whether some body hair is normal or abnormal, but it is unlikely to differ between women with diabetes and controls. The importance of investigating menstrual and reproductive abnormalities in women with T1D lies partly in the risk of CVD, which may be associated with these abnormalities (14-16,35). There are several reports linking menstrual disorders with risk for CVD in nondiabetic women, particularly in women with polycystic ovary syndrome,
where risk may be mediated through factors related to the metabolic syndrome (35,36). In one review of studies investigating links between reproductive abnormalities and CVD in postmenopausal women, only menstrual irregularity, pregnancy loss, and age at menopause were observed as important historical findings (37). In this prior report, menstrual irregularity was reported with a greater frequency in women with T1D, a group already at increased risk for CVD (14,38,39). Menstrual and reproductive abnormalities may serve as markers for, or as aggravating factors, for this risk. One interesting finding in this study was that women with T1D were less likely to smoke. It is possible that women with T1D, being aware of cardiovascular risk of having diabetes, chose to avoid additional risk conferred by smoking. There are several limitations to the current study. First, this was a survey of self-reported data. The validity of survey findings depends exclusively on the accuracy of recall and reporting by participants. Subjects were reassured that investigators were blinded to their names once the questionnaire was completed as a way of increasing reliable reporting. In addition, not all women provided specific information regarding the length of their menstrual cycles, as some had very irregular menses. In an attempt to address this, menstrual length was reported as the average of the range of dates which may have either over- or underestimated true cycle length. No measures of sex hormones were obtained as part of this study, which could have provided more information regarding more subtle menstrual abnormalities that could be masked in women reporting regular menstrual cycles (40). Also, we do not have HbA1c values to correlate abnormalities to any objective measure of glycemic control. Another limitation is that the subjects were predominantly Caucasian, limiting generalizability to other racial groups. Yet another limitation is that the number of women reporting menopause was too low to make any comparison between women with and without diabetes. Data on age of menopause in women with T1D are limited, with one study showing that both T1D and menstrual irregularities are each independent risk factors for early menopause (13) and another showing that women with T1D and microvascular complications experience menopause at an earlier age than the general population (41). CONCLUSION In summary, the major findings in this study were a lower likelihood of HC use among all women with T1D and more frequently reported irregular menses in women who reported difficulty with glycemic management. The observation of fewer pregnancies and live births among women with T1D is likely due to factors unrelated to reproductive dysfunction. Future studies that prospectively investigate menstrual disorders according to current glycemic status are planned.
756
ACKNOWLEDGMENT
DISCLOSURE
There has been no duplicate publication or submission elsewhere (excluding abstracts). No external funding was obtained for this study.
Dr. Mary Korytkowski has received grant support from Sanofi Aventis and has served as an ad hoc consultant for this company. The other authors have no multiplicity of interest to disclose.
APPENDIX QUESTIONNAIRE ON MENSTRUAL ABNORMALITIES Date ___________
ID# ________ (to be filled out by investigator)
1. How old are you now? ________ 2. What is your ethnic background?
A. B. C. D. E.
Black Hispanic White American Indian Other (specify) _____________
3. How tall are you? _______ (inches) 4. What is your present weight? _______ (pounds) 5. What is your measured smallest waist circumference? ________ (inches) 6. What is your measured biggest hip circumference? _______ (inches) 7. Do you have diabetes mellitus?
Yes
No (Skip to question 9)
8. If you answered Yes to question 7, please answer questions “a” through “h” a. At what age did you find out that you have diabetes? _______ b. Do you take insulin injects? c. Have you ever used pills for treatment of your diabetes? If yes, please list names of pills
Yes No Yes No
____________________________________________ d. e. f. g. h.
Do you check your blood sugars daily? Do you know your recent hemoglobin A1c reading? Do you find your diabetes is difficult to control? Have you ever been told that you have a diabetic eye problem? Have you ever been told that you have a diabetic kidney problem?
Yes Yes Yes Yes Yes
No No No No No
9. Do you have any first-degree relatives (mother, father, sister, brother, son, daughter) with diabetes mellitus? Yes No If you do, indicate relationship____________________________________________ __________________________________________________________________
757
10. Do you have any other medical problems besides diabetes mellitus? Yes No If you do, please list: _________________________________________________ ___________________________________________________________________ ___________________________________________________________________ 11. Do you take any medications? Yes No If you do, please list the medications and specify the reason for taking each medication: Medication 1 2 3 4 5 6
Reason 1 2 3 4 5 6
Medication 7 8 9 10 11 12
Reason 7 8 9 10 11 12
12. How old were you when you had your first menstrual period? _______ 13. Are you still having menstrual periods? Yes No If no, how old were you when you had your last spontaneous menstrual period? _______ 14. Have you had a hysterectomy? If yes, were your ovaries left in?
Yes No Yes No
15. If you are postmenopausal or had a hysterectomy, do you take estrogen replacement therapy? Yes No If no, please list reasons you are not using replacement therapy: ____________________________________________________________________ ____________________________________________________________________ 16. Are/Were your menstrual cycles regular? Yes No 17. On average, what are/were the lengths of your cycles? (starting from the first day of one menstrual bleeding to the first day of the next menstrual bleeding) ___________ 18. On average, what is the length of your menstrual bleeding? _______ days 19. Have you ever had intervals between your menstrual periods a. longer than 45 days? Yes No b. longer than 60 days? Yes No If you answered yes to any of the above, at what age? _______________________
758
20. Have you ever used birth control pills? Yes No If yes, list the names of pills and for how long you were taking them ____________________________________________________________________ ____________________________________________________________________ 21. How many pregnancies have you had? Live births Miscarriages Abortions 22. Did you have diabetes mellitus during any of your pregnancies? Yes No 23. Have you ever had any infection of your reproductive organs (uterus, fallopian tubes, ovaries)? Yes No If you answered yes, please specify _______________________________________ ____________________________________________________________________ 24. Have you ever had problems becoming pregnant?
Yes No
25. Have you ever undergone any infertility treatment? Yes No If you answered yes, please specify ____________________________________________________________________ ____________________________________________________________________ 26. Have you ever had hair growth on parts of your body other than your scalp, armpits, or pubic hair? Yes No If you answered yes, please specify: a. upper lip Yes No b. chin Yes No c. facial Yes No d. chest Yes No e. thighs Yes No At what age did you first notice hair growth on these parts of your body? ________ 27. Have you ever had acne problems after your teenage years? Yes No 28. If you have ever suffered from severe acne, please indicate your age at that time. ______ to _______ years Not applicable 29. Do you presently or have you ever smoked? Yes No If you answered yes, please specify: a. How many packs per day? ________________________ b. For how many years? ________________________ c. When did you quit? ________________________
759
REFERENCES 1. Codner E, Merino PM, Tena-Sempere M. Female repro-
duction and type 1 diabetes: from mechanisms to clinical findings. Hum Reprod Update. 2012;18:568-585. 2. Kjaer K, Hagen C, Sandø SH, Eshøj O. Epidemiology of menarche and menstrual disturbances in an unselected group of women with insulin-dependent diabetes mellitus compared to controls. J Clin Endocrinol Metab. 1992;75: 524-529. 3. Strotmeyer ES, Steenkiste AR, Foley TP, Berga SL, Dorman JS. Menstrual cycle differences between women with type 1 diabetes and women without diabetes. Diabetes Care. 2003;26:1016-1021. 4. Codner E, Soto N, Merino PM. Contraception, and pregnancy in adolescents with type 1 diabetes: a review. Pediatr Diabetes. 2012;13:108-123. 5. Deltsidou A. Age at menarche and menstrual irregularities of adolescents with type 1 diabetes. J Pediatr Adolesc Gynecol. 2010;23:162-167. 6. Gaete X, Vivanco M, Eyzaguirre FC, et al. Menstrual cycle irregularities and their relationship with HbA1c and insulin dose in adolescents with type 1 diabetes mellitus. Fertil Steril. 2010;94:1822-1826. 7. Picardi A, Cipponeri E, Bizzarri C, Fallucca S, Guglielmi C, Pozzilli P. Menarche in type 1 diabetes is still delayed despite good metabolic control. Fertil Steril. 2008; 90:1875-1877. 8. Yeshaya A, Orvieto R, Dicker D, Karp M, Ben-Rafael Z. Menstrual characteristics of women suffering from insulindependent diabetes mellitus. Int J Fertil Menopausal Stud. 1995;40:269-273. 9. Adcock CJ, Perry LA, Lindsell DR, et al. Menstrual irregularities are more common in adolescents with type 1 diabetes: association with poor glycaemic control and weight gain. Diabet Med. 1994;11:465-470. 10. Zachurzok A, Deja G, Gawlik A, Drosdzol-Cop A, Malecka-Tendera E. Hyperandrogenism in adolescent girls with type 1 diabetes mellitus treated with intensive and continuous subcutaneous insulin therapy. Endokrynol Pol. 2012;64:121-128. 11. Samara-Boustani D, Colmenares A, Elie C, et al. High prevalence of hirsutism and menstrual disorders in obese adolescent girls and adolescent girls with type 1 diabetes mellitus despite different hormonal profiles. Eur J Endocrinol. 2012;166:307-316. 12. Whitworth KW, Baird DD, Stene LC, Skjaerven R, Longnecker MP. Fecundability among women with type 1 and type 2 diabetes in the Norwegian Mother and Child Cohort Study. Diabetologia. 2011;54:516-522. 13. Dorman JS, Steenkiste AR, Foley TP, et al. Menopause in type 1 diabetic women: is it premature? Diabetes. 2001;50: 1857-1862. 14. Snell-Bergeon JK, Dabelea D, Ogden LG, et al. Reproductive history and hormonal birth control use are associated with coronary calcium progression in women with type 1 diabetes mellitus. J Clin Endocrinol Metab. 2008;93:2142-2148. 15. Taponen S, Martikainen H, Järvelin MR, et al. Metabolic cardiovascular disease risk factors in women with self-reported symptoms of oligomenorrhea and/or hirsutism: Northern Finland Birth Cohort 1966 Study. J Clin Endocrinol Metab. 2004;89:2114-2118. 16. Wang ET, Cirillo PM, Vittinghoff E, Bibbins-Domingo K, Cohn BA, Cedars MI. Menstrual irregularity and
17.
18. 19.
20. 21. 22.
23.
24. 25.
26. 27. 28. 29.
30.
31.
32.
33.
cardiovascular mortality. J Clin Endocrinol Metab. 2011; 96: E114-E118. Escobar-Morreale HF, Roldán B, Barrio R, et al. High prevalence of the polycystic ovary syndrome and hirsutism in women with type 1 diabetes mellitus. J Clin Endocrinol Metab. 2000;85:4182-4187. McCulloch DK, Glasgow RE, Hampson SE, Wagner E. A systematic approach to diabetes management in the postDCCT era. Diabetes Care. 1994;17:765-769. The Diabetes Control and Complications Trial (DCCT) Research Group. The effect of intensive treatment of diabetes on the development and progression of long term complications in insulin dependent diabetes mellitus. N Engl J Med. 1993;329:977-986. Schroeder B, Hertweck SP, Sanfilippo JS, Foster MB. Correlation between glycemic control and menstruation in diabetic adolescents. J Reprod Med. 2000;45:1-5. Schweiger B, Klingensmith GJ, Snell-Bergeon JK. Menarchal timing in type 1 diabetes through the last 4 decades. Diabetes Care. 2010;33:2521-2523. Gaete X, Vivanco M, Eyzaguirre FC, et al. Menstrual cycle irregularities and their relationship with HbA1c and insulin dose in adolescents with type 1 diabetes mellitus. Fertil Steril. 2010;94:1822-1826. Deltsidou A, Lemonidou C, Zarikas V, Matziou V, Bartsocas CS. Oligomenorrhoea in adolescents with type 1 diabetes mellitus: relationship to glycaemic control. Eur J Obstet Gynecol Reprod Biol. 2010;153:62-66. Laing SP, Swerdlow AJ, Slater SD, et al. Mortality from heart disease in a cohort of 23,000 patients with insulintreated diabetes. Diabetologia. 2003;46:760-765. Serfaty D, Wildemeersch D, Verougstraete A, Creatsas G. European Society of Contraception oral contraceptives survey update: birth control methods in “Europe of the 12”. Int J Fertil Menopausal Stud. 1995;40(suppl 2):73-79. Codner E, Eyzaguirre FC, Iñiguez G, et al. Ovulation rate in adolescents with type 1 diabetes mellitus. Fertil Steril. 2011;95:197-202. Blumer I, Hadar E, Hadden DR, et al. Diabetes and pregnancy: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013;98:4227-4249. Steel JM. Prepregnancy counseling and contraception in the insulin-dependent diabetic patient. Clin Obstet Gynecol. 1985;28:553-566. Bizzarri C, Benevento D, Ravà L, et al. Ovarian hyperandrogenism in adolescents and young women with type I diabetes is primarily related to birth weight and body mass index. Fertil Steril. 2011;96:1497-1502. Codner E, Iñiguez G, Villarroel C, et al. Hormonal profile in women with polycystic ovarian syndrome with or without type 1 diabetes mellitus. J Clin Endocrinol Metab. 2007;92:4742-4746. Codner E, Soto N, Lopez P, et al. Diagnostic criteria for polycystic ovary syndrome and ovarian morphology in women with type 1 diabetes mellitus. J Clin Endocrinol Metab. 2006;91:2250-2256. Codner E, Escobar-Morreale HF. Clinical review: hyperandrogenism and polycystic ovary syndrome in women with type 1 diabetes mellitus. J Clinical Endocrinol Metab. 2007;92:1209-1216. Nyholm H, Djursing H, Hagen C, Agner T, Bennett P, Svenstrup B. Androgens and estrogens in postmenopausal insulin-treated diabetic women. J Clin Endocrinol Metab. 1989;69:946-949.
760 34. Amato MC, Guarnotta V, Ciresi A, Modica R, Panto F, Giordano C. No phenotypic differences for polycystic ovary syndrome (PCOS) between women with and without type 1 diabetes mellitus. J Clin Endocrinol Metab. 2014; 99:203-211. 35. Korytkowski MT, Krug EI, Daly MA, Deriso L, Wilson JW, Winters SJ. Does androgen excess contribute to the cardiovascular risk profile in postmenopausal women with type 2 diabetes? Metabolism. 2005;54:1626-1631. 36. Ehrmann DA, Kasza K, Azziz R, Legro RS, Ghazzi MN. Effects of race and family history of type 2 diabetes on metabolic status of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90:66-71. 37. de Kleijn MJ, van der Schouw YT, van der Graaf Y. Reproductive history and cardiovascular disease risk
38.
39. 40. 41.
in postmenopausal women: a review of the literature. Maturitas. 1999;33:7-36. Colhoun HM, Rubens MB, Underwood SR, Fuller JH. The effect of type 1 diabetes mellitus on the gender difference in coronary artery calcification. J Am Coll Cardiol. 2000;36:2160-2167. Costacou T, Edmundowicz D, Prince C, Conway B, Orchard TJ. Progression of coronary artery calcium in type 1 diabetes mellitus. Am J Cardiol. 2007;100:1543-1547. Sherman BM, Korenman SG. Hormonal characteristics of the human menstrual cycle throughout reproductive life. J Clin Invest. 1975;55:699-706. Sjöberg L, Pitkäniemi J, Harjutsalo V, et al. Menopause in women with type 1 diabetes. Menopause. 2011;18:158-163.
