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Menstrual cycle disorders after therapy with iodine-131

      Objective

      To investigate any abnormalities of the menstrual cycle and/or pregnancy in women <40 years old who had received radioiodine (I-131) therapy for thyroid cancer.

      Design

      Case-control study.

      Setting

      General military hospital in Athens, Greece.

      Patient(s)

      Forty-five women of childbearing age with thyroid cancer that were treated with I-131 from December 1996 to May 2003 were compared to 83 age-matched control females.

      Intervention(s)

      The patients’ charts were reviewed, and in addition patients were contacted by telephone and asked detailed questions about their previous gynecologic history and any problems after treatment (menstrual cycle and pregnancy).

      Main Outcome Measure(s)

      Abnormalities of menstrual cycle and/or pregnancy.

      Result(s)

      Overall, 14 of 45 women (31.1%) had menstrual cycle irregularities after treatment. Eight patients (17.8%) had normal menstrual cycles before therapy and six (13.3%) had pretreatment menstrual cycle irregularities that persisted or were exaggerated after therapy. In the control group, 12 of 83 women (14.5%) reported menstrual cycle irregularities. The patients’ menstrual cycle and menses irregularities were significantly increased after I-131 therapy (P=.02) compared with the control group and seemed to increase with age. After therapy a total of seven children were borne by 6 of the 45 patients (13.3%). No premature births or miscarriages were noted.

      Conclusion(s)

      The study found a significant increase of patients with menstrual cycle and/or menses irregularities after treatment with I-131. However, therapy with I-131 did not result in any subsequent pregnancy abnormalities such as premature births or miscarriages.

      Key Words

      The treatment of primary thyroid cancer includes total thyroidectomy and radioactive iodine (I-131) therapy if there are clinical nodes, nonencapsulated tumor, or multifocal tumor and simple lobectomy in encapsulated solitary tumors (
      • Bonnin C.
      • Trojani M.
      • Corcuff J.B.
      • Bonichon F.
      Outcome of 111 thyroid papillary carcinomas. Retrospective study from 1953 to 1994. Experience of Bergonie Institute.
      ). For recurrent thyroid cancer, I-131 treatment without surgery appears to be enough for small scintigraphically detected tumors, but it offers no advantage to surgery alone in clinically detected recurrent disease (
      • Coburn M.
      • Teates D.
      • Wanebo H.J.
      Recurrent thyroid cancer Role of surgery versus radioactive iodine (I131).
      ).
      Treatment with I-131 may result in menstrual cycle irregularities or abnormalities in concurrent or subsequent pregnancies. A previous study in women treated with I-131 for differentiated thyroid cancer has shown menstrual cycle alterations in 27% of patients, accompanied by increased serum gonadotropin concentrations. In those patients, there was no correlation between the I-131 doses absorbed, use of oral contraceptive, or thyroid autoimmunity (
      • Raymond J.P.
      • Izembart M.
      • Marliac V.
      • Dagousset F.
      • Merceron R.E.
      • Vulpillat M.
      • et al.
      Temporary ovarian failure in thyroid cancer patients after thyroid remnant ablation with radioactive iodine.
      ). A large study compared 627 females with differentiated thyroid carcinoma who received I-131 therapy with 187 untreated females and found no significant differences in the fertility rate, birth weight, or prematurity between the two groups (
      • Dottorini M.E.
      • Lomuscio G.
      • Mazzucchelli L.
      • Vignati A.
      • Colombo L.
      Assessment of female fertility and carcinogenesis after iodine-131 therapy for differentiated thyroid carcinoma.
      ).
      In the present study, we investigated the menstrual cycle irregularities and pregnancy abnormalities in childbearing-age women after treatment with I-131. The results were evaluated in association with the age and the histologic type of thyroid cancer.

      Methods

      From December 1996 to May 2003, 45 women <40 years of age with thyroid carcinoma had total thyroidectomy followed by I-131 treatment. The therapeutic dose was 3.7 MBq for all patients. After therapeutic I-131 administration, all patients were given thyroid hormone replacement therapy and remained in euthyroid status. The medical charts of the patients were reviewed in detail, and in addition the patients were contacted by telephone to assess their current status. The age of the patients, histologic type of cancer, I-131 dose, pretreatment and posttreatment menstrual history, and pregnancy history were recorded.
      Menstrual cycle irregularities were defined as follows: increased or decreased length of menstrual cycle for a period of 28 ± 4 days; increased or decreased menses for subjective increase or decrease of menstrual blood according to patients and control individuals. The patients who were treated with I-131 were given instructions to avoid pregnancy for at least 8 months after the last iodine dose. The control group consisted of 83 females without thyroid abnormalities carefully matched for age with the patient group. These women were randomly selected among relatives or friends of other patients admitted to the surgical service for a variety of surgical procedures.
      Because this was a retrospective study and no medical intervention was performed related to the study, no institutional review board approval was required by our hospital. However, all patients were informed that the information they provided would be included in a study, and they gave a verbal consent.
      For statistical evaluation the paired χ2 test with one degree of freedom and Yates correction was applied to all patient and control group values. Patients that were treated with I-131 and had menstrual cycle abnormalities after therapy were compared with the control group. Values of P<.05 were considered significant.

      Results

      Forty-five women <40 years of age with differentiated thyroid carcinoma treated with total thyroidectomy and I-131 were analyzed. The mean interval time from the I-131 treatment to assessment was 64.6 months (range 27–107 months). Before therapy, 39 patients had normal menstrual cycles, but 6 patients had either irregular menstrual cycles or menses (Fig. 1). After therapy, 14 patients (31.1%) showed menstrual cycle or menses irregularities (Fig. 1). This group of patients included eight patients with stable periods before I-131 therapy who developed menstrual cycle abnormalities after therapy and the six patients who already exhibited menstrual cycle irregularities before therapy. The abnormalities in the eight post-treatment patients were lengthening or shortening of menstrual cycle in two, menses irregularities in two, and both menstrual cycle and menses irregularities in four patients. The remaining six patients, who already had irregular menstrual cycles before I-131 treatment, continued demonstrating irregular periods after treatment or had exacerbation of their irregularities.
      Figure thumbnail gr1
      FIGURE 1The effect of iodine-131 therapy on menstrual cycle and/or menses in premenopausal women. There were significantly more abnormalities of the menstrual cycle after therapy (P=.02). No statistical difference was noted between the pretherapy patients’ values compared to the control group (P=.83). MC = menstrual cycle, length of menstrual period; Menses = amount of menstrual blood.
      Sioka. I-131 therapy and menstrual cycle. Fertil Steril 2006.
      Comparison of the confidence limits of the menstrual cycle alterations between the group of patients that developed irregular menstrual cycles after I-131 therapy and the control group showed significantly more alterations after therapy (P=.02), whereas comparison between the group of patients who had irregular menstrual cycle before I-131 therapy and the control group did not reveal any significant statistical differences in menstrual cycles or menses (P=.83).
      The effect of age on the menstrual cycle abnormalities after I-131 treatment is depicted in Table 1. Among the 45 patients, 7 (15.6%) were in the 20–25 years age group, 10 (22.2%) in the 26–30 years age group, 16 (35.6%) in the 31–35 years age group, and 12 (26.6%) in the 36–40 years age group. Comparison of the confidence limits of the various patient groups and control values before and after therapy with I-131 showed a trend toward a positive correlation of menstrual cycle or menses irregularities with increasing age, although the results did not reach statistical significance (Table 1).
      TABLE 1Effect of I-131 treatment on the menstrual cycle according to age.
      Age (y)Abnormal menstrual cycle/menses
      Control groupBefore therapyAfter therapy
      20–254/11 (36.4%)2/7 (28.6%), P=1.003/7 (42.8%), P=.79
      26–302/16 (12.5%)1/10 (10%), P=.732/20 (20%), P=.61
      31–353/33 (9.1%)2/16 (12.5%), P=.194/16 (25%), P=.14
      36–403/21 (14.3%)1/12 (8.3%), P=.455/12 (41.7%), P=.09
      20–40 (all)12/83 (14.5%)6/45 (13.3%), P=.8314/45 (31.1%), P=.02
      Statistically significant, P<.05.
      Note: Menstrual cycle = length of menstrual period; menses = amount of menstrual blood. The abnormalities of menstrual cycle increased with the patient’s age in the I-131–treated patient group but not before therapy, compared with the control group. For the whole I-131–treated patient group, the menstrual cycle/menses abnormalities were statistically significant.
      Sioka. I-131 therapy and menstrual cycle. Fertil Steril 2006.
      a Statistically significant, P<.05.
      The association between the histologic type of thyroid cancer and the menstrual cycle or menses irregularities is shown in Table 2. Overall, there were 38 patients with papillary carcinoma, 3 with follicular carcinoma, 1 with Hurhtle carcinoma, and 3 with mixed carcinoma. The menstrual cycle and menses abnormalities among the different histologic subgroups are depicted in Table 2.
      TABLE 2Type of thyroid cancer and effect of I-131 on the menstrual cycle.
      Cancer histologyNo. (%)Normal MC/menses after I-131Abnormal MC/menses after I-131
      Papillary38 (84.4%)2612
      Follicular3 (6.7%)21
      Hurhtle cell1 (2.2%)01
      Mixed cell3 (6.7%)30
      Total4531 (68.9%)14 (31.1%)
      Note: MC = menstrual cycle, length of menstrual period; menses = amount of menstrual blood.
      Sioka. I-131 therapy and menstrual cycle. Fertil Steril 2006.
      Among all patients in our study, 24 women had children before therapy with I-131 and avoided further pregnancy. In the remaining 21 patients, 9 single and 3 married women did not wish to become pregnant. In addition, one woman had problems conceiving before I-131 and continued having problems after treatment, one woman conceived before the period of 8 months after treatment and elected to have an abortion, and one woman who tried to conceive failed owing to her husband’s infertility. A total of seven children were born from the remaining six (13.3%) women who conceived after I-131 treatment. These children had normal birth weight and were without congenital abnormalities. No premature births or miscarriages were noted.

      Discussion

      In the present study we investigated whether treatment of thyroid cancer with surgery followed by I-131 irradiation and thyroid hormone replacement affects menstrual cycle or causes abnormalities in subsequent pregnancies in women of reproductive age. We found 14 women (31.1%) with menstrual cycle irregularities independently of whether they had stable or unstable menstrual cycles before therapy with I-131. Our results are in accordance with another study in 66 women after I-131 therapy that found 18 patients with menstrual cycle abnormalities during the first year after therapy (
      • Raymond J.P.
      • Izembart M.
      • Marliac V.
      • Dagousset F.
      • Merceron R.E.
      • Vulpillat M.
      • et al.
      Temporary ovarian failure in thyroid cancer patients after thyroid remnant ablation with radioactive iodine.
      ).
      It is improbable that the menstrual cycle abnormalities were due to thyroid gland dysfunction, because all our patients were receiving thyroid hormone replacement and were in euthyroid status. It is possible that the menstrual cycle abnormalities after I-131 therapy were due to a direct effect of the radiation to the ovaries. It has been estimated that after I-131 administration the ovary could receive a significant radiation dose, rendering the patient prone to developing menstrual cycle disturbances and ovarian insufficiency (
      • Izembart M.
      • Chavaudra J.
      • Aubert B.
      • Vallee G.
      Retrospective evaluation of the dose received by the ovary after radioactive iodine therapy for thyroid cancer.
      ). In the present study it appeared to be a trend toward more menstrual cycle abnormalities with increasing age, which did not, however, reach statistical significance, probably owing to relatively small number of cases. Previous studies have also suggested that ovarian sensitivity to radiation may be greater with increasing age (
      • Vini L.
      • Hyer S.
      • Al-Saadi A.
      • Pratt B.
      • Harmer C.
      Prognosis for fertility and ovarian function after treatment with radioiodine for thyroid cancer.
      ).
      No definite correlation could be determined between histologic cancer type and menstrual cycle and menses irregularities, because the vast majority of patients had papillary carcinoma and only a few other subtypes. However, our results indicated that in patients with papillary thyroid carcinoma treated with I-131, the incidence of menstrual cycle and menses abnormalities approached 32% (12/38).
      Our study did not show any abnormalities of subsequent pregnancies after treatment with I-131, such as premature births or miscarriages. Previous studies have investigated the effect of I-131 treatment on subsequent pregnancies. One study reported similar incidences of stillbirth, preterm birth, low birth weight, congenital malformation, and death during the first year of life before or after I-131 therapy. However, that study found an increased incidence of miscarriage after surgery for thyroid cancer (20%), both before and after I-131, compared with the incidence before surgery (11%) (
      • Schlumberger M.
      • De Vathaire F.
      • Ceccarelli C.
      • Delisle M.J.
      • Francese C.
      • Couette J.E.
      • et al.
      Exposure to radioactive iodine-131 for scintigraphy or therapy does not preclude pregnancy in thyroid cancer patients.
      ). In another study, one woman was unable to conceive after I-131 therapy, and four premature births and 14 miscarriages occurred, but no congenital abnormalities were reported in the offspring (
      • Vini L.
      • Hyer S.
      • Al-Saadi A.
      • Pratt B.
      • Harmer C.
      Prognosis for fertility and ovarian function after treatment with radioiodine for thyroid cancer.
      ).
      It is known that thyroid dysfunction may cause menstrual disturbances and reduced fertility in hypothyroidism and there may be an association between the presence of thyroid antibodies and fetal loss (
      • Lazarus J.H.
      Thyroid dysfunction: reproduction and postpartum thyroiditis.
      ). However, all our patients were euthyroid, because they were receiving thyroid hormone replacement therapy after I-131 treatment. A previous study found no increase of genetic defects or congenital malformations in the offspring of 41 young women (aged between 19 and 39 years) treated with high doses of I-131 for thyroid carcinoma (
      • Ehrenheim C.
      • Hauswirth C.
      • Fitschen J.
      • Martin E.
      • Oetting G.
      • Hundeshagen H.
      Genetic risk after high dose radioiodine therapy with regard to gonadal dose.
      ). In a case report, a woman with a papillary thyroid cancer and unsuspected pregnancy was treated with I-131. Subsequently, the pregnancy was terminated, and examination of the fetus showed atrophy, sclerosis, and subcapsular interstitial fibrosis of the thyroid gland, but karyotype analysis demonstrated no radiation-induced chromosomal aberrations (
      • Arndt D.
      • Mehnert W.H.
      • Franke W.G.
      • Woller P.
      • Laude G.
      • Rockel A.
      • et al.
      Radioiodine therapy during an unknown remained pregnancy and radiation exposure of the fetus A case report.
      ).
      In summary, the present study demonstrated that I-131 therapy for thyroid cancer was associated with menstrual cycle abnormalities in 31.1% of women <40 years of age. In several of these patients (6 of 14) the menstrual cycle abnormalities existed before I-131 therapy and persisted after treatment, but in the majority (8 of 14) the abnormalities were new. However, there were no abnormalities of subsequent pregnancies after treatment with I-131. With the possible exception of miscarriages, as noted in other studies (
      • Schlumberger M.
      • De Vathaire F.
      • Ceccarelli C.
      • Delisle M.J.
      • Francese C.
      • Couette J.E.
      • et al.
      Exposure to radioactive iodine-131 for scintigraphy or therapy does not preclude pregnancy in thyroid cancer patients.
      ), there is no evidence that exposure to radioactive iodine affects the outcome of subsequent pregnancies and offspring.

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