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  No. 2
  G.E. Krassas
Department of Endocrinology & Metabolism "Panagia" Thessaloniki ,Greece ,

P. Perros
Endocrine Unit, Freeman Hospital ,Newcastle upon Tyne U.K.
    printed version  
The reproductive system has been regarded as relatively resistant to the effects of thyroid dysfunction. This view has been challenged by recent evidence, though most of the consequences are minor and reversible. However, the reproductive sequelae of thyroid disease are by no means trivial, particularly as the prevalence of thyroid dysfunction is high in the general population.

Sex steroid metabolism
Thyrotoxicosis increases, and hypothyroidism reduces the concentration of serum SHBG (1). Total concentration of serum testosterone may alter accordingly, although free testosterone is usually normal (2). In some men with thyrotoxicosis oestrogen production is increased (3). Basal serum gonadotrophin concentrations are usually normal in adult males with thyroid dysfunction, but increased sensitivity of gonadotrophin secretion to GnRH has been described in thyrotoxic patients (4), and the reverse in hypothyroidism (5). In rare cases of severe prolonged primary hypothyroidism, pituitary hyperplasia can cause hypopituitarism (6). Hypogonadism may also be associated with hyperprolactinaemia caused by hypothyroidism (7). These changes are reversible when euthyroidism is achieved (8).

Effects of thyroid dysfunction in early life
Maternal hypothyroidism during pregnancy, cretinism and congenital hypothyroidism are not associated with abnormal development of the male reproductive tract (9). When adequately treated, boys with congenital hypothyroidism progress through puberty normally (10). Untreated hypothyroidism in early childhood can result in delay in sexual maturation, which can be reversed by thyroid hormone therapy (11). Severe juvenile hypothyroidism may rarely be associated with precocious pseudopuberty (9).

Spermatogenesis and fertility
Defective spermatogenesis was reported anecdotally in thyrotoxic patients several decades ago (12, 13). Abalovich et al. (14) found that of 21 patients with hyperthyroidism, 43% had a low total sperm count, and the majority had sperm motility problems. In a recent detailed prospective study, 23 thyrotoxic males and 15 healthy controls were assessed (15). Semen volume of thyrotoxic patients was normal. A non-significant trend towards low sperm density, and low percentage normal sperm morphology was noted in thyrotoxic subjects. Sperm motility was significantly lower in thyrotoxic males than in controls. Following treatment of thyrotoxicosis, sperm density and motility improved but sperm morphology remained unchanged.
Hypothyroidism is associated with decreased libido or impotence (16). A small study of 5 men with primary hypothyroidism demonstrated normal sperm counts, but loss of sperm motility in some cases (17). Testicular biopsies of 6 adult males with onset of hypothyroidism in early life, revealed histological abnormalities in all patients (18). Testicular atrophy has also been reported in hypothyroid men (16). A prospective study of 10 adult patients demonstrated that short-term hypothyroidism does not cause seminal abnormalities sufficiently severe to impair male fertility (19).

The use of radioiodine in the management of hyperthyroidism and thyroid cancer in male patients of reproductive age
Reproductive function in men with thyrotoxicosis appears to be unaffected after 131| therapy (20, 21). Most studies have shown that 131| treatment for differentiated thyroid cancer may cause transient impairment of testicular function (22-24). Gonadal damage may occur in those requiring multiple treatments, particularly with cumulative doses greater than 14 GBq of 131|, and sperm banking should be considered in appropriate cases.

Sex steroid metabolism
As in men, hyperthyroidism results in increased levels of SHBG (25, 26). Plasma oestrogen levels may be twofold or threefold higher in hyperthyroid women during all phases of the menstrual cycle (27). The metabolic clearance rate of 17ß-oestradiol is decreased in hyperthyroidism due to increased binding of 17ß-oestradiol to SHBG (28). Mean plasma levels of testosterone and androstenedione are elevated (29). The production rate of testosterone and androstenedione are significantly elevated, and the conversion ratio of androstenedione to oestrone, and testosterone to oestradiol, are increased in hyperthyroid women (30). Mean LH levels in both the follicular and luteal phases are significantly higher in hyperthyroid women than in normal females (31). Serum LH levels decrease to normal after a few weeks of treatment with antithyroid drugs (32). Baseline FSH levels may be increased (33, 34), although this is refuted by some studies (35, 36). In a study by one of the authors, the gonadotropin response to GnRH was increased before treatment of hyperthyroidism and remained slightly exaggerated 4 months after treatment in comparison with controls (33).
Women with hypothyroidism have decreased metabolic clearance rates of androstenedione and oestrone and an increase in peripheral aromatization (37). The 5a/5ß ratio of the metabolites of androgens is decreased in hypothyroid women, and there is an increase in the excretion of 2-oxygenated oestrogens (38). The binding activity of SHBG in plasma is decreased, so that plasma concentrations of testosterone and oestradiol are decreased, although their unbound fractions are elevated. The alterations in steroid metabolism disappear when the euthyroid state is restored (39). Gonadotropin levels are usually normal (40). However, blunted or delayed LH response to LHRH has been reported in some hypothyroid females (35, 41).

Menstrual function and fertility
Amenorrhoea, oligomenorrhoea, hypomenorrhoea, and anovulation can occur in hyperhtyroidism. The frequency of menstrual abnormalities in recent studies differs from earlier series. In one recent study, however, we found irregular cycles in only 46 (21.5%) out of 214 thyrotoxic patients. 24 had hypomenorrhea, 15 poly-, 5 oligo-, and 2 hypermenorrhea. None had amenorrhea. From a similar number of normal controls, 18 (8.4%) had irregular periods, and of these 12 had oligomenorrhea (42). These results are inconsistent with what is generally believed and written in the classic thyroid textbooks concerning the frequency and pattern of menstrual disturbances in thyrotoxicosis (43, 44) and indicate that such opinions should be revised. Hyperthyroidism in women has been linked to reduced fertility, although most thyrotoxic women remain ovulatory according to the results of endometrial biopsies (45). 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. We found that progesterone levels were decreased before treatment in comparison with controls and were unrestored 4 months after carbimazole therapy (46).
In women of fertile age, hypothyrodism results in changes in cycle length and amount of bleeding, that is, oligo- and amenorrhea, polymenorrhea, and menorrhagia. A recent study (47), found that 40 (23.4%) out of 171 hypothyroid female patients had irregular cycles. From those, 17 had oligo-, 6 hypo-, 5 amenorrhoea, and 12 hypermenorrhoea/menorrhagia. None had poly- or hypermenorrhoea. Although this finding indicates that the frequency of menstrual disturbances in hypothyroidism is approximately three times greater than in the normal population, this is still much lower than the findings of previous similar studies. Furthermore, we found that the main menstrual irregularity was oligomenorrhoea (42.5%), which is also inconsistent with what is generally believed or written in classic thyroid texts (40, 48). Severe hypothyroidism is commonly associated with diminished libido and failure of ovulation (45).

The use of radioiodine in the management of hyperthyroidism and thyroid cancer in female patients of reproductive age
Studies on pregnancy outcomes and offspring of patients previously treated with 131| for thyroid carcinoma failed to reveal any significant 131|-related effects (49-53). In one recent study, Schlumberger et al. (54) presented data on 2,113 pregnancies conceived after exposure to 30-100 mCi of 131| given for thyroid cancer or thyroid remnant ablation. The incidences 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. 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| is low and of no clinical significance. Fertility in the long term is not disturbed and 131I treatment is not contraindicated for this reason. Nevertheless, it should be avoided for at least one year after exposure to 131|, because of the increased risk of miscarriages (55). Following therapeutic administration of 131| to the mother, breastfeeding should be discontinued immediately (56-58).


  Hyperthyroidism appears to cause sperm abnormalities (mainly reduction in motility), which reverse after restoration of euthyroidism.
  Radioiodine therapy for thyroid cancer may cause transient reductions in sperm count and motility, but there appears to be little risk of permanent effects provided that the cumulative dose is less than 14 GBq.
  The effects of hypothyroidism on male reproduction appear to be more subtle than those of hyperthyroidism and reversible. Severe, prolonged hypothyroidism in childhood may be associated with permanent abnormalities in gonadal function.
  Hyperthyroidism is associated with menstrual disturbances in female patients, mainly hypomenorrhoea and polymenorrhoea. The frequency and pattern in contemporary studies is at variance with views expressed in classic thyroid textbooks.
  Hypothyroidism may cause oligomenorrhoea, amenorrhoea, hypo- and hypermenorrhoea/menorrhagia. Severe hypothyroidism is commonly associated with diminished libido and failure of ovulation. The frequency of these disturbances is much lower than findings of older similar studies.
  The incidences of stillbirth, preterm birth, low birth weight, congenital malformation, and death during the first year of life are similar between pregnancies conceived before and after 131I therapy for thyroid cancer. Pregnancy should be avoided for at least one year after the 131I. Therapeutic administration of 131I should be followed by immediate cessation of breastfeeding.


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