Menstrual Disturbances in Various Thyroid Diseases
Endocrine Journal 2010, 57 (12), 1017-1022
Or i g i n a l Menstrual disturbances in various thyroid diseases
Yoko Kakuno, Nobuyuki Amino, Maki Kanoh, Miho Kawai, Miyuki Fujiwara, Misao Kimura, Ayako Kamitani, Kaori Saya, Reiko Shakuta, Sanae Nitta, Yasuko Hayashida, Takumi Kudo, Sumihisa Kubota and Akira Miyauchi
Kuma Hospital, Center for Excellence in Thyroid Care, Kobe 650-0011, Japan
Abstract. The prevalence of menstrual disturbances, including secondary amenorrhea, hypomenorrhea, oligomenorrhea, hypermenorrhea, polymenorrhea and irregular menstrual cycle were prospectively examined in 586 patients with hyperthyroidism due to Graves’ disease, 111 with hypothyroidism, 558 with euthyroid chronic thyroiditis, 202 with painless thyroiditis and 595 with thyroid tumor. In the overall patient group, the prevalence did not different from that in 105 healthy controls. However, patients with severe hyperthyroidism showed a higher prevalence of secondary amenorrhea (2.5%) and hypomenorrhea (3.7%) than those (0.2% and 0.9%, respectively) with mild or moderate hyperthyroidism. Moreover, patients with severe hypothyroidism had a higher prevalence (34.8%) of menstrual disturbances than mild- moderate cases (10.2%). Menstrual disturbances in thyroid dysfunction were less frequent than previously thought.
Key words: Hyperthyroidism, Hypothyroidism, Menstrual disturbance, Amenorrhea
IT has been reported that thyroid dysfunction is fre- tively, and found that thyroid dysfunction was less fre- quently associated with menstrual disturbances. quently associated with menstrual irregularities than Amenorrhea was one of the earlier known clinical previously considered [7, 8]. changes associated with hyperthyroidism, as reported In this study, we prospectively studied 2052 patients by von Basedow in 1840 [1]. Since then, amenorrhea with various thyroid diseases and examined menstrual has frequently been reported, along with a number of disturbances, including secondary amenorrhea, hypom- other changes in the menstrual cycle, including oli- enorrhea, oligomenorrhea, hypermenorrhea, polymen- gomenorrhea, hypomenorrhea and anovulation. These orrhea and irregular menstrual cycle, and compared disturbances have been reported in more than half the with those in healthy controls. patients with hyperthyroidism [2, 3]. On the other hands, hypermenorrhea and polymen- Patients and Methods orrhea have also been reported in about 50~80 % of patients with hypothyroidism [2-4]. These changes are Patients sometimes related to ovulatory disturbance and subse- We prospectively investigated untreated female quent infertility [5, 6] and thus clinicians have focused patients who attended the out patient clinic in Kuma on these problems for long time. Hospital and were in the reproductive age between 20 However, these previous studies were performed in and 45 years old. Thyroid diseases were diagnosed the 1950s and 1960s in a small number of patients with according to the Diagnostic Guidelines of the Japan thyroid dysfunction. Krassas et al. reevaluated the Thyroid Association (http://thyroid.umin.ac.jp/en/frame. prevalence of menstrual disturbances both in hyperthy- html). As for thyroid dysfunction, 586 patients with roidism and hypothyroidism in 1994 and 1999, respec- hyperthyroidism due to Graves’ disease and 111 patients with hypothyroidism were examined. For Received Jul. 15, 2010; Accepted Sep. 7, 2010 as K10E-216 Released online in J-STAGE as advance publication Oct. 2, 2010 comparison to control patients, we further examined Correspondence to: Nobuyuki Amino, M.D., Kuma hospital, 8-2- 558 euthyroid patients with chronic thyroiditis, 202 35 Shimoyamate-dori, Chuo-ku, Kobe 650-0011, Japan. patients with painless thyroiditis and 595 patients with E-mail: [email protected] thyroid tumor (489 benign and 106 malignant tumors). ©The Japan Endocrine Society 1018 Kakuno et al.
Table 1 Definition of menstrual disturbances
Secondary amenorrhea: No menstruation for more than 3 months in women with previous normal periods Hypomenorrhea: More than 20 % decrease in menstrual flow compared with previous periods or those of normal women Oligomenorrhea: Interval between 2 periods is more than 39 days but less than 3 months Hypermenorrhea: More than 20 % increase in menstrual flow in comparison with previous periods or those of normal women Polymenorrhea: Interval between 2 periods is less than 24 days Irregular menstrual cycle: Irregular menstrual cycle although the interval between 2 periods is within 25~38 days
The patients with chronic thyroiditis, who were asso- Statistical analysis ciated with hypothyroidism, were included into the Comparison of frequencies between patient groups group of hypothyroidism. Destructive thyrotoxicosis and healthy controls was analyzed using Fisher’s exact in patients with painless thyroiditis was carefully dis- probability test or chi-square test. Differences were tinguished from Graves’ hyperthyroidism [9]. Patients considered significant atp <0.05. who were pregnant, within one year after delivery or lactating baby were excluded from this study. One Results hundred and five healthy female staff subjects in Kuma Hospital, ranging from 20 to 45 years old, were also Prevalence of secondary amenorrhea, hypomenor- examined for menstrual disturbances for comparison to rhea, oligomenorrhea, hypermenorrhea, polymenorrhea thyroid patients. and irregular menstrual cycle in patients with hyperthy- To examine the relation between the severity of dis- roidism, hypothyroidism, chronic thyroiditis, painless ease and menstrual disturbances, patients with hyper- thyroiditis and thyroid tumor are summarized in Table thyroidism were subdivided into four groups based on 2, and these data are compared with those of healthy serum levels of free T4: less than 4 and 4 and more controls. The prevalence of any of these disturbances (normal range 0.7~1.6 ng/dL), or free T3: less than was never significantly higher than that of healthy con- 30 and 30 and more (normal range 1.7~3.7 pg/mL). trols. When the groups of euthyroid chronic thyroidi- Moreover, the relation between estimated duration of tis, thyroid tumor and healthy controls are combined to disease and menstrual disturbances was also analyzed one group of euthyroid controls (n=1258), menstrual in patients with hypothyroidism. Severity of disease disturbances were found in 197 subjects (15.7%). This was evaluated by serum levels of TSH and divided into frequency was not different from that in hyperthyroid- two groups: serum TSH less than 100 and 100 and more ism and hypothyroidism. (normal range 0.3~5.0 μIU/mL). Then, the prevalence Menstrual disturbances were analyzed in relation to of menstrual disturbances was compared between the the severity of hyperthyroidism. There were no dif- two groups. ferences in these disturbances between the groups of mildly or moderately elevated T4 and severely ele- Definition of menstrual disturbances vated T4 (Table 3). Similarly, hyperthyroid patients The menstrual history for 6 months before dis- were divided into two groups based on serum FT3 ease diagnosis was first examined by medical -inter levels. Severe group (FT3 30 pg/mL and more) had view sheet and the reported data were confirmed by a significantly higher prevalence of secondary amen- the preliminary examination. When menstrual infor- orrhea (2.5%) than that (0.2%) among those with mild mation was not sufficiently clear even after prelimi- or moderate hyperthyroidism (FT3 less than 30). Total nary examination, patients were excluded from this frequency of menstrual disturbances was found in study. As for menstrual disturbances, secondary amen- 23.5% of severe hyperthyroidism and this was signifi- orrhea, hypomenorrhea, oligomenorrhea, hypermenor- cantly higher than that (16.3%) of mild or moderate rhea, polymenorrhea and irregular menstrual cycle were hyperthyroidism (Table 3). Moreover, prevalence of examined. Definitions of these disturbances were based hypomenorrhea (3.7%) in the severe group was signif- on the Terminology Guidelines of Japan Society of the icantly higher than that among healthy controls (0%). Obstetrics and Gynecology, as shown in Table 1. Influence of estimated disease duration was analyzed, but there were no differences between groups divided Menstrual disturbance in thyroid disease 1019
Table 2 Frequency of menstrual disturbances in various thyroid diseases and healthy controls Hyper- Hypo- Chronic Painless Thyroid Healthy thyroidism thyroidism thyroidids thyroidids tumor controls 586 (%) 111 (%) 558 (%) 202 (%) 595 (%) 105 (%) Age (mean±SD) 33.3±6.8* 34.9±5.8** 33.3±6.9* 32.4±6.3 36.0±6.6** 31.6±6.0 Secondary amenorrhea 5 (0.9) 2 (1.8) 8 (1.4) 6 (2.9) 2 (0.3) 0 (0) Hypomenorrhea 10 (1.7) 0 (0) 4 (0.7) 3 (1.5) 3 (0.5) 0 (0) Oligomenorrhea 25 (4.3) 6 (5.4) 34 (6.1) 15 (7.4) 24 (4.0) 14 (13.3) Hypermenorrhea 2 (0.3) 0 (0) 2 (0.4) 0 (0) 2 (0.3) 2 (1.9) Polymenorrhea 21 (3.6) 2 (1.8) 14 (2.5) 2 (1.0) 5 (0.8) 2 (1.9) Irregular menstrual cycle 44 (7.5) 7 (6.3) 44 (7.9) 9 (4.5) 30 (5.0) 7 (6.7) Total 107 (18.3) 17 (15.3) 106 (19.0) 35 (17.3) 66 (11.0) 25 (23.8) Data indicate the numbers of patients and numbers in parentheses indicate percentages. Significantly different from controls at p < 0.05(*) and p < 0.01(**).
Table 3 Severity of hyperthyroidism and menstrual disturbances FT4 (ng/dL) FT3 (pg/mL) Less than 4 4 and more Less than 30 30 and more Healthy controls 456 (%) 130 (%) 424 (%) 162 (%) 105 (%) Secondary amenorrhea 3 (0.7) 2 (1.5) 1 (0.2) 4 (2.5)* 0 (0) Hypomenorrhea 6 (1.3) 4 (3.1) 4 (0.9) 6 (3.7)a 0 (0) Oligomenorrhea 20 (4.4) 5 (3.8) 16 (3.8) 9 (5.6) 14 (13.3) Hypermenorrhea 1 (0.2) 1 (0.8) 1 (0.2) 1 (0.6) 2 (1.9) Polymenorrhea 17 (3.7) 4 (3.1) 17 (3.8) 4 (2.5) 2 (1.9) Irregular menstrual cycle 34 (7.5) 10 (7.7) 30 (7.1) 14 (8.6) 7 (6.7) Total 81 (17.8) 26 (20.0) 69 (16.3) 38 (23.5)* 25 (23.8) Data indicate numbers of patients and numbers in parentheses indicate percentages. * Significantly high at p<0.05 compared to the group with a FT3 less than 30 pg/mL. a Significantly high at p<0.05 compared to healthy controls.
Table 4 Estimated duration of hyperthyroidism and menstrual disturbances Estimated duration Estimated duration Less than 6 months 6 months and more Less than 1 year 1 year and more Healthy controls 427 (%) 159 (%) 489 (%) 97 (%) 105 (%) Secondary amenorrhea 3 (0.7) 2 (1.3) 5 (1.0) 0 (0) 0 (0) Hypomenorrhea 5 (1.2) 5 (3.1) 7 (1.4) 3 (3.1) 0 (0) Oligomenorrhea 18 (4.2) 7 (4.4) 20 (4.1) 5 (5.2) 14 (13.3) Hypermenorrhea 0 (0) 2 (1.3) 1 (0.2) 1 (1.1) 2 (1.9) Polymenorrhea 15 (3.5) 6 (3.8) 19 (3.9) 2 (2.1) 2 (1.9) Irregular menstrual cycle 31 (7.3) 13 (8.2) 35 (7.2) 9 (9.3) 7 (6.7) Total 72 (16.9) 35 (22.0) 87 (17.8) 20 (20.6) 25 (23.8) Data indicate numbers of patients and numbers in parentheses indicate percentages. by short and long disease durations (Table 4). was significantly higher than that in the mild or moder- In hypothyroidism, patients were also divided into ate group (10.2%) (Table 5). the mild or moderate group (TSH less than 100 μIU/ mL) and severe group (TSH 100 μIU/mL or more). Discussion Prevalence of individual menstrual disturbance was not significantly different between the two groups but It has long been thought that thyroid dysfunc- total frequency of menstrual disturbances was found in tion was frequently associated with menstrual distur- 34.8% of patients with severe hypothyroidism and this bances. However, in this study, the prevalence of men- 1020 Kakuno et al.
Table 5 Severity of hypothyroidism and menstrual disturbances TSH (μIU/mL) Less than 100 100 and more Healthy controls 88 (%) 23 (%) 105 (%) Secondary amenorrhea 0 (0) 2 (8.7) 0 (0) Hypomenorrhea 0 (0) 0 (0) 0 (0) Oligomenorrhea 4 (4.5) 2 (8.7) 14 (13.3) Hypermenorrhea 0 (0) 0 (0) 2 (1.9) Polymenorrhea 0 (0) 2 (8.7) 2 (1.9) Irregular menstrual cycle 5 (5.7) 2 (8.7) 7 (6.7) Total 9 (10.2) 8 (34.8)* 25 (23.8) Data indicate numbers of patients and numbers in parentheses indicate percentages. * Significantly high at p<0.01 compared to the group showing a TSH level less than 100.
strual disturbances in patients with hyperthyroidism were reported in the 1950s and 1960s and but not suf- and hypothyroidism, including secondary amenorrhea, ficient because of the limited number of patients and hypomenorrhea, oligomenorrhea, hypermenorrhea, possible biased selection of cases who demonstrating polymenorrhea and irregular menstrual cycle, was not severe hyperthyroidism. Our data in this study are sim- different from those in healthy controls. ilar to those of Krassas et al. [7], although they could The most impressive report in hyperthyroidism due not find any cases of amenorrhea. We found amenor- to Graves’ disease was the presence of secondary amen- rhea in 0.9% of 586 patients with Graves’ hyperthy- orrhea described by Dr. von Basedow in 1840 [1]. Since roidism. Interestingly, this prevalence was increased to then, it has generally been considered that there is a 2.5% among severe cases (FT3 30 pg/mL or more) and high frequency of amenorrhea in patients with Graves’ amenorrhea is 10 times more frequent in severe cases disease. In 1952, Goldsmith et al. found amenorrhea compared to that in mild or moderate cases (0.2%). in 3 of 18 (16.7%) patients with Graves’ disease and, When the severity of disease was stratified by serum moreover, they found hypomenorrhea in 14 (77.8%) FT4 levels, we could not demonstrate a significant dif- patients [2]. They finally found menstrual disturbances ference. FT3 may be more directly related to the path- in 94.4% of patients. In 1955, Benson et al. examined ological state in Graves’ disease. 221 patients with Graves’ disease and amenorrhea was Painless or silent thyroiditis shows destructive tran- found in 10 (4.5%) patients. Hypomenorrhea and/or sient thyrotoxicosis, usually within a 3 month duration, oligomenorrhea were found in130 (58.8%) patients [3]. in the early stage of disease [11, 12]. The concept of Unfortunately these two studies did not examine the this disease was newly established around 30 years ago healthy controls and they may have examined only typ- [11], and there are no data on menstrual disturbances ically severe cases of Graves’ disease, since diagnostic in this disease. Hence, we investigated this point. As laboratory tests were not well advanced at that time. expected, there was no significant increase in frequency In 1993, Joshi et al. studied 68 patients with hyperthy- of menstrual disturbances in painless thyrpoiditis. It is roism and found 3 cases (4.4%) of amenorrhea [10]. possible that the short duration of thyrotoxicosis would They also found 30 patients (44.1%) with hypomenor- not influence the menstrual disturbances. rhea/ oligomenorrhea and this prevalence was signifi- In hypothyroidism, high frequency of menstrual dis- cantly higher than that among healthy controls (8.1%). turbances has also been emphasized for a long time. In In 1994, Krassas et al. examined 214 patients with 1952, Goldsmith et al. [2] examined 10 patients with hyperthyroidism but they could not find any patients myxedema and menstrual disturbances were found in with secondary amenorrhea [7]. Moreover, the fre- 80% of them. In 1955, Benson et al. [3] also found high quencies of hypomenorrhea, oligomenorrhea, hyper- frequency of hypermenorrhea or polymenorrhea:18 menorrhea, and polymenorrhea did not different from (58%) of 31 patients with hypothyroidism who devel- those of normal controls. oped hypothyroidism after treatment of hyperthyroid- Summarizing these data in hyperthyroidism, studies ism. In 1964, Scott et al. [4] examined 50 patients with Menstrual disturbance in thyroid disease 1021 myxedema and found 2 cases (4%) of amenorrhea, and reproductive activity. Consequently, it is necessary furthermore, 23 cases (46%) with menorrhagia, metror- to clarify the prevalence of menstrual disturbances in rhagia or monometrorrhagia. Totally 60% of them euthyroid patients with chronic thyroiditis. However, had menstrual disturbances. In 1993, Joshi et al. [10] in our review of the literature, there are no data on issue. examined 22 patients with hypothyroidism and found In this study, we examined 558 euthyroid patients with 8 cases (36.4%) of hypomenorrhea /oligomenorrhea chronic thyroidits but there was no difference in the and 5 cases (22.7%) of hypermenorrhea /polymenor- prevalence of menstrual disturbances between patients rhea. In 1999, Krassas et al. [8] examined 171 patients and normal controls. To clarify the suitability of the with hypothyroidism and found higher frequencies of protocol of this study, we further examined patients amenorrhea (5 cases, 2.9%) and hypermenorrhea (12 with thyroid tumor as patient controls and there were cases, 7.0%) than those among normal controls. In no significant abnormalities. their study, oligomenorrhea was found in 9.9% and this In conclusion, the prevalence of menstrual distur- was higher than that (5.3%) in patients with hyperthy- bances, including secondary amenorrhea, hypomen- roidism. orrhea, oligomenorrhea, hypermenorrhea, polymen- Our findings among patients with hypothyroidism orrhea and irregular menstrual cycle, in patients with are similar to those of Krassas et al. [8]. In an earlier various thyroid diseases, such as hyperthyroidism, study, they observed mainly patients with myxedema, hypothyroidism, euthyroid patients with chronic thy- which is a severe stage of hypothyroidism. Thus, the roiditis, painless thyroiditis and thyroid tumor, did not reported high frequency of menstrual disturbances may differ from that in healthy controls. However, patients not be generalized to ordinary patients with hypothy- with severe hyperthyroidism had a higher preva- roidism. Regarding this, we divided our patients into lence of secondary amenorrhea and hypomenorrhea two groups, mild/moderate and severe cases based on than those with mild or moderate disease. Moreover, the serum levels of TSH. The severe group had a higher patients with severe hypothyroidism had a higher prev- frequency of menstrual disturbances (34.8%) than the alence of menstrual disturbances than mild/moderate mild/moderate group (10.2%), suggesting that disease cases. Menstrual disturbances in thyroid dysfunction severity markedly influences menstrual disturbances. were less frequent than previously thought. It is well known that thyroid dysfunction not only influences menstrual disturbances but also affects Acknowledgments reproductive activity, fertility and pregnancy outcome [5, 13]. Even though the thyroid function is normal, We thank Ms Izumi Otsuka and Miwa Miyauchi, the presence of anti-thyroid antibodies is related to a Department of Medical Informatics, Kuma Hospital, high frequency of miscarriage [13, 14]. It is suggested for their skilful assistance. that thyroid autoimmunity itself also influences female
References
1. Von Basedow CA (1840) Exophthalmos durch 6. Lincoln SR, Ke RW, Kutteh WH. (1999) Screening for Hypertrophie des Zellgewebes in der Augenhohle. hypothyroidism in infertile women. J Reprod Med 44: Wchenscher Heilkunde 6: 197-202. 455-457. 2. Goldsmith RE, Sturgis SH, Lerman J, Stanbury JB 7. Krassas GE, Pontikides N, Kaltsas T, Papadopoulou P, (1952) The menstrual pattern in thyroid disease. J Clin Batrinos M (1994) Menstrual disturbances in thyrotoxi- Endocrinol Metab 12: 846-855. cosis. Clin Endocrinol (Oxf) 40: 641-644. 3. Benson RC, Dialy ME (1955) Menstrual pattern in 8. Krassas GE, Pontikides N, Kaltsas T, Papadopoulou hyperthyroidism and subsequent post-therapy hypothy- P, Paunkovic J, Paunkovic N, Duntas LH (1999) roidism. Surg Gynecol Obstet 100: 19-26. Disturbances of menstruation in hypothyroidism. Clin 4. Scott JC, Mussey E (1964) Menstrual patterns in Endocrinol (Oxf) 50: 655-659. myxedema. Am J Obstet Gynecol 90: 161-165. 9. Ota H, Amino N, Morita S, Kobayashi K, Kubota S, 5. Krassas GE. (2000) Thyroid disease and female repro- Fukata S, Kamiyama N, Miyauchi A (2007) Quantitative duction. Fertil Steril 74: 1063-1670. measurement of thyroid blood flow for differentia- 1022 Kakuno et al.
tion of painless thyroiditis from Graves’ disease. Clin ring painless thyroiditis: contributions of higher thy- Endocrinol 67: 41-45. roid hormone levels, younger onset, male gender, pres- 10. Joshi JV, Bhandarkar SD, Chadha M, Balaiah D, Shah ence of thyroid autoantibody and absence of goiter to R (1993) Menstrual irregularities and lactation failure repeated recurrence. Endocr J 56: 391-397. may precede thyroid dysfunction or goitre. J Postgrad 13. Abalovich M, Amino N, Barbour LA, Cobin RH, Med 39: 137-141. De Groot LJ, Glinoer D, Mandel SJ, Stagnaro- 11. Amino N (1993) Postpartum and Silent Thyroiditis. Green A (2007) Guidelines for management of thy- In: Monaco F, Satta MA, Shapiro B, Troncone L (ed) roid dysfunction during pregnancy and postpartum. Thyroid Diseases Vol. II Clinical Fundamentals and J Clin Endocrinol Metab 92: S1-S47. Therapy. CRC Press Inc., Boca Raton, FL, USA: 239- 14. Iijima T, Tada H, Hidaka H, Mitsuda N, Murata Y, 249. Amino N (1997) Effects of autoantibodies on the course 12. Nishimaki M, Isozaki O, Yoshihara A, Okubo Y, Takano of pregnancy and fetal growth. Obstet Gynecol 90: 364- K. (2009) Clinical characteristics of frequently recur- 369.