these results are inconsistent with what is generally believed and written in the classic thyroid textbooks concerning

the frequency and partem of menstrual disturbances in thyrotoxicosis (23,24) and indicate that such opinions should be revised. We also found smoking aggravates the development of menstrual disturbances in thyrotoxicosis. Fifty percent of the patients with abnormal menstruation were smokers, compared with 19% of the patients with normal periods. We also found that patients with menstrual disturbances had higher total T4 levels and that the levels were higher in smokers with abnormal periods. Thus, total T4 levels appear to be an important factor related to the development of menstrual abnormalities in thyrotoxicosis, in contrast with total triiodothyronine levels for wich no such correlation was found. Hyperthyroidism in women has been linked to reduced fertility, although most thyrotoxic women remain ovulatory according to the results of endometrial biopsies(20). Joshi etal. (21) found that 3 (5.8%) out of 52 thyrotoxic females had primary or secundary infertility. We measured progesterone levels, a fertility parameter, in the middle of the luteal phase of the cycle in 74 women of reproductive age, 37 of whom had Graves disease and 37 of whom were euthyroid controls matched for age and weight. All patients and controls had normal menstruation. We remeasured progesterone levels at the same phase of the cycle, 4 months after the initiation of therapy with antithyroid drugs when the thyrotoxic patients were euthyroid. We found that progesterone levels were decreased before treatment in comparison with controls and were unrestored 4 months after carbimazole therapy (25). However, because endometrial biopsies were not performed in this study, we could not reach any final conclusion. The use of radioiodine in the Management of Hyperthyroidism and Thyroid Cancer in Patients of Reproductive Age. Iodine 131 is used widely in the diagnosis and treatment of thyroid diseases (26,27). The notion that radiation is mutagenic and may affect gonads (thereby resulting in genetic damage to offspring) has raised concern regarding the use of radioiodine in the management of thyroid disorders in patients during their reproductive years. In the following, we examine the use of radioiodine before conception and appraise what is known about consequences of 131 I therapy on subsequent pregnancies and on fertility. For convenience, common conversion equivalents for traditional and SI notation are presented in table 2 (3,28). In general, the radiation dose delivered to the ovary is approximately 0.14 cGy after administration of I mCi 131 I in normal subjects (29). Robertson and Gorman (30) reported that in Graves patients, the mean radiation dose to the uterus was 0.17 rad and to the ovary was 0.14 rad/mCI of 131 I administered, as determined by a simplified schema (30). Briere and Philippon

(31) used an intrauterine dosimeter to measure directly the absorbed dose to the same organs and found the dose of radiation administered to be 0.18 rad/mCi. Among 10 patients tested, the correlation coefficient for the dose as measured and the calculated dose was r=0.88 (31). A dose of 0.14 rad/mCi of radioiodine administered is a resonable approximation of the true gonadal dose. As the thyroid uptake of 131 I increases, the dose to the gonad diminishes because more of the iodine is held up in the thyroid and decays before reaching the bladder (30). Impaired renal function increases gonadal dose (30,32). To put the typical gonad dose for treatment of Graves disease in perspective, the doses to the ovary from a variety of common radiological diagnostic procedures are illustrated in table 3 (28). It as been estimated, using worst case assumptions, that if the rate of spontaneus birth anomalies is 800 per 100000 pregnancies and if all 100000 women had received 10 mCi of radioiodine before they became pregnant, then the rate of congenital anomalies would increase to 803 (33). One may reasonably conclude that the genetic hazard incident to radioiodine therapy in Graves disease is very small, and exposure to 131 I is not contraindicated in those patients because of risk of compromised fertility. For the thyroid cancer patients with sacral metastases treated with radioiodine, a uterine dose of 160 rad was recorder (31). However, the administered dose was not specified. In a recent study, Schlumberger et al. (34), using mathematical models that take into account the individual morphology of the patient, estimated the ovary dosage to be roughly threefold higher than the MURD estimation of 0.14 cGy/37 MBq (1 mCi) (29,35). There are only a few reports in the literature concerning the fertility of female patients with thyroid cancer treated with 131 I (36,37), although this is not an uncommon problem. Raymond et at. (38) reported temporary ovarian failure in 18 out of 66 females with thyroid cancer treated with 131 I, the average dose of which was 10.0= 2.2 (range, 4-12.1) GBq. Specifically, all had temporary amenorrhea associated with hot flashes. Fifteen of these 18 women developed amenorrhea before the sixth month after 131 I administration. Amenorrhea never occured immediatly after 131 I therapy. The period of amenorrhea was brief, lasting less than 6 months in 14 of the 18 women. Patients with temporary amenorrhea had high serum FSH-LH values, wich clearly indicate the presence of ovarian failure. In one study, Dottorini et at. (39) investigated 814 women of childbearing age with thyroid cancer. The fertility of 627 women who received 131 I therapy was compared to 187 untreated women. Also, the carcinogenic affect was evaluated by comparing the incidence of second rumors in 730 patients treated with 131 I to an internal control group, as well as with the local population incidence. They found that among the children born to treated women, only one case of ventricular septal defect and patent ductus arterious was registered. All other children, from both groups, were in good health and grew normally.

The fertility rate (the ratio of live births per 1000 fertile females per year) was 23 for the women in the first group and 19 for the those in the untreated group. A 95% confidence interval for the difference in fertility rates between the two groups ranged from 13.97 to -5017: the P value for chisquare distribution was 0.39, N.S. which suggests that the use of 131 I for therapeutic purposes does not reduce fertility in women. This group also found that the risk of a second tumor is low and lacks clinical impact. Studies on pregnancy outcomes and offspring among patients treated with 131 I for thyroid carcinoma failed to reveal any significant 131 I-related effects (36,37, 39-41). The value of this information is limited, however , given the small number of patients studied and the lack of internal controls. In one recent study, Schlumberger et al. (34) presented data on 2.113 pregnancies conceived after exposure to 30-100 mCi of 131 I given for thyroid cancer or thyroid remnant ablation. The incidenses of stillbirth, preterm birth, low birth weight congenital malformation, and death during the first year of life were not significantly different between pregnancies conceived before and after radioiodine therapy. The incidence of thyroid disease and malignancy was not significantly different between the children born before and those born after the maternal radioiodine exposure. Miscarriages were more frequent (40%) among the 10 women treated with 131 I (mean dose 109 mCi) in the year immediately preceding conception. These data do not establish that no risk exists, but they indicate that the risk is less than other more common hazards of pregnancy. Also, they indicate that the risk of a second tumor or of damage to the gonads of women treated with 131 I is low and has no clinical significance. Fertility in the long term is not disturbed, and 131 I treatment is not contraindicated for this reason. Nevertheless, it should be avoided for at least I year after the radioiodine exposure because of the increased risk of miscarriages and also to ensure complete elimination of the radionuclide and permit confirmation of complete disease remission (37). Another interesting problem is the use of radioiodine in lactating women. Although there are different opinions regarding the exact amount of labeled iodine excreted in breast milk, all authors agree that therapeutic administration of 131 I to the mother should be accompanied by immediate cessation of breastfeeding for the infant (42-45). Hypothyroidism. The reproductive tract appears to develop normally in cretins; thus, hypothyroidism during fetal life does not appear to affect the normal development of the reproductive tract (46). Hypothyroidism from infancy, if untreated , leads to sexual immaturity; hypothyroidism beginning before puberty causes a delay in onset of puberty followed by anovulatory cycles (47). Paradoxically, in some cases of juvenile hypothyroidism , precocious puberty and galactorrhea have been reported (48). This is probably due to a spillover effect: TSH, PRL, FSH, and LH are all glycoproteins and may have interlapping actions (49).

Women with hypothyroidism have decreased rates of metobolic clearance of androstenedione and estrone and an increase in peripheral aromatization (50). The 5a/5b ratio of the metabolites of androgens is decreased in hypothyroid women, and there is an increase in the excretion of 2oxigenated estrogens (51). The binding activity of sex hormone-binding globulin in plasma is decreased, with the result that the plasma concentrations of both testosterone and estradiol are decreased , but their unbound fractions are increased. The alterations in steroid metabolism disappear when the euthyroid state is restored (52).