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Influence of excess
thyroid hormone on the female reproductive tract and ovarian function
Children born with neonatal Graves' disease have no defects in the reproductive system that can be related to this disease. Hyperthyroidism occurring prior to puberty has been reported to delay the onset of menses3; however, others have reported no significant effect of hyperthyroidism on the age of menarche4. Saxena et al5 found that in hyperthyroid girls, the mean age of menarche was slightly advanced over that of their control population without thyroid disease. Plasma estrogen levels may be two- or three fold higher in hyperthyroid than in normal women during all phases of the menstrual cycle6. However, hyperthyroidism results in increased levels of sex hormone - binding globulin (SHBG)7,8. Whether the increase in plasma estrogens is entirely attributable to the elevated SHBG or whether there is an actual increase in unbound estrogen, as in the case of hyperthyroid men, remains to be determined. The metabolic clearance rate of 17-β-estradiol is decreased in hyperthyroidism and thought to be largely due to increased binding of 17-β-estradiol to SHBG9. Changes also occur, in circulating androgen metabolism in hyperthyroid women. Mean plasma levels of testosterone and androstenedione increase10. The production rates of testosterone as well as that of androstenedione are significantly elevated in hyperthyroid women in comparison with normal females. The conversion ratio of androstenedione to estrone, as well as testosterone to estradiol is increased in hyperthyroid women2. Akande and Hockaday11 found that the mean LH levels in both the follicular phase and the luteal phase of menstrual cycle are significantly higher in hyperthyroid women than in euthyroid females. We found the same when we investigated female patients in the middle of the luteal phase of the cycle12. However , LH peaks may be absent in cases who have amenorrhea. Serum LH levels decrease to normal after a few weeks of treatment with antithyroid drugs13. Baseline FSH levels may be increased although data are limited12,14. However, there are some reports which claim that FSH levels are normal15,16. The mechanism of increase in serum LH and FSH in hyperthyroid women is unclear. Tanaka et al14 reported that hyperthyroxinemia results in an augmented gonadotropin response to gonadotropin-releasing hormone. Others, however, have been unable to confirm such an abnormality15. We investigated 37 female thyrotoxic patients, all in reproductive age, with normal periods and the same number of age-weight-matched euthyroid controls. In all patients and controls LH, FSH, and PRL levels were measured before and 30 and 60 min after a combined administration of hypothalamic hormones TRH and LHRH. In all the patients, the same procedure was repeated 4 months after the initiation of antithyroid drugs, while euthyroid. We found that gonadotropin response was increased before treatment and remained slightly increased 4 months after treatment in comparison with controls12. Usually, all these biochemical abnormalities are corrected, after treatment. Hyperthyroidism, menstrual function and fertility Biochemical and hormonal abnormalities, nutritional disturbances and emotional upheavals associated with hyperthyroidism may all or in part influence menstrual function. One of the earliest reports of clinical changes in hyperthyroidism was the occurrence of amenorrhoea which was reported by von Basedow in 184017. Amenorrhoea has since been frequently reported, as well as a number of other changes in the menstrual cycle, including oligomenorhoea, hypomenorrhoea and anovulation. The frequency of menstrual abnormalities in the contemporary studies are not the same as in the earlier series. This is because now both hyper- and hypothyroidism are diagnosed at an earlier stage than before, thanks not only to the better diagnostic tests available, but also to greater awareness in the public and easier access to medical care. In particular, Benson & Dailey18, found that out of 221 hyperthyroid patients 58% had oligomenorrhoea or amenorrhoea and 5% polymenorrhoea. This is in general agreement with other older studies as those of Goldsmith et al19. Tanaka et al14 found that 8 out of 41 thyrotoxic patients had amenorrhoea and 15 hypomenorhoea. More recently in India, Joshi et al20 found menstrual irregularities in 64.7% of hyperthyroid women, compared to 17.2% of healthy controls. These irregularities sometimes preceded thyroid dysfunction. However, in one recent study, we found irregular cycles in only 46 (21.5%) out of 214 thyrotoxic patients. Twenty-four of them had hypo-, 15 poly-, 5 oligo- and 2 hypermenorrhoea. None had amenorrhoea. From a similar number of normal controls, 18 (8.4%) had irregular periods, 12 of whom had oligomenorrhoea (Table 1)21. By definition, oligo-, poly- and amenorrhoea concern the duration of menstrual cycle, while hypo- hypermenorrhoea and menorrhagia the amount of the menstrual flow. Thus, oligomenorrhoea was identified when the interval between 2 periods was more than 35 days, polymenorrhoea less than 21 days and amenorrhoea, in women with previous normal periods, when there was no menstruation for more than 3 months22,23. Hypomenorrhoea was arbitrarily defined when there was more than 20% decrease in menstrual flow, hypermenorrhoea when there was more than 20% increase in menstrual flow in comparison with the previous periods, while menorrhagia was defined as heavy menstrual bleeding.
Although this finding indicates that menstrual disturbances in thyrotoxicosis is 2 times more frequent than in the normal population, it is still lower than what has been described. These results are inconsistent with what is generally believed or written in the classic thyroid textbooks concerning the frequency and pattern of menstrual disturbances in thyrotoxicosis24,25 and indicate that such opinions should be revised. We also found that smoking aggravates the development of menstrual disturbances in thyrotoxicosis. Fifty per cent 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 TT4 levels, and that the levels were higher in smokers with abnormal periods. (Fig. 1, 2). Thus TT4 levels appear to be an important factor related to the development of menstrual abnormalities in thyrotoxicosis, in contrast with TT3 for which no such correlation was found.
Hyperthyroidism in women has been linked to reduced fertility, although most thyrotoxic women remain ovulatory according to results of endometrial biopsies19. Joshi et al20 found that 3 (5.8%) out of 52 thyrotoxic females had primary or secondary infertility. We measured progesterone levels, a fertility parameter, in the middle of the luteal phase of the cycle in 74 women all in reproductive age, 37 of whom had Graves' disease and 37 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 in the thyrotoxic patients, when they were euthyroid. We found that progesterone levels were decreased before treatment in comparison with controls and were unable to be restored 4 months after carbimazole therapy26. However, as endometrial biopsies have not been done in this study we are unable to reach final conclusions. |
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with normal periods. Bars indicate mean + SD.
