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Menstrual Disturbances in Various Thyroid Diseases Endocrine Journal 2010, 57 (12), 1017-1022 ORIGINAL 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.
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