Gerasimos E. Krassas
The reproductive system has been suggested to be relatively resistant to the effects of thyroid dysfunctions. This view has been challenged by recent evidence, although most of the consequences are minor and reversible. However, the reproductive sequelae of thyroid disease are by no means trivial, particularly because the prevalence of thyroid dysfunction is high in the general population (1). The incidence of thyroid disease including thyrotoxicosis is far more common in women than in men. Whether this is directly or indirectly related to the hormonal status of women remains uncertain.
REPRODUCTIVE EFFECTS OF THYROTOXICOSIS IN THE FEMALE
For a better understanding of the effect of thyrotoxicosis on the female reproductive system, a brief review of the normal development and physiology of the female reproductive system follows.
Fetal and Neonatal Periods
In human fetuses, gonadotropin-releasing hormone (GnRH) cells are found in the olfactory placode in embryonic week 5.5, although a majority of GnRH cells originate in the olfactory pit at embryonic week 6.0 to 6.5. GnRH cells enter the forebrain through the terminal nerve by embryonic week 6.5, and they migrate into the hypothalamus by embryonic week 9.0 (2).
Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are detectable in the human pituitary by embryonic week 10, and their content increases until embryonic weeks 25 to 29. The pituitary starts to release gonadotropins (Gns) into the general circulation by embryonic weeks 11 to 12. Circulating Gns reach peak levels at midgestation, and subsequently both LH and FSH levels decline during late gestation (3). This peak in Gn levels may be causally related to the maximal development of follicles. The gonadotropes in human fetuses respond to GnRH by releasing LH and FSH both in vivo and in vitro (4). A sex difference in Gn levels is seen during midgestation. Pituitary content and circulating concentrations of LH and FSH in female fetuses are higher than those in male fetuses (5). Because circulating testosterone levels are higher in male fetuses as compared with circulating estrogen levels in female fetuses during midgestation, both the sex difference in Gn levels and the decrease in Gn levels toward late gestation in fetuses are attributed to the development of the negative feedback mechanism by the gonadal steroid hormones from the fetal gonads as well as from the placenta (6).
In female neonates, LH levels are only slightly elevated during the first few months of life, but FSH levels are high for the first 5 months (7). After the first 6 months of life, circulating levels of FSH, LH, and gonadal steroids are all low, and the hypothalamo-pituitary-gonadal system enters a quiescent stage until the time of puberty.
The Period at the Onset of and During Puberty
Puberty is defined as the transient period between childhood and adulthood during which reproductive function is reached. During this period the secondary sexual characteristics appear, the adolescent growth spurt occurs, the gonads start to produce mature gametes (sperm or oocytes) capable of fertilization, and major psychological changes occur.
Low levels of Gns during the childhood years are thought to result from exquisite sensitivity of the hypothalamic–pituitary axis (the so-called gonadostat), which remains suppressed despite extremely low levels of circulating gonadal steroids. The prepubertal gonadostat is 6 to 15 times more sensitive to estrogen than is the adult feedback mechanism (8). In addition to the gonadal steroid-dependent highly sensitive negative feedback system, a steroid-independent mechanism for inhibitory control of central nervous system responses is also operative, because Gn levels also decline in the absence of a gonad and in children with Turner's syndrome (8). Although the pineal gland has been proposed to be an inhibitor of Gn secretion in the human, neither the pineal gland nor melatonin has a major inhibitory effect on the gonadostat (8). GnRH is critical for the initiation of puberty. Grumbach and Styne (6) suggest that a gonadal steroid-dependent GnRH increase also occurs at the onset of puberty, since smaller amounts of gonadal steroids are effective in suppressing FSH and LH levels in prepubertal children than in adults. It is possible during the juvenile period in humans that a small amount of GnRH released from the hypothalamus is capable of maintaining the minimum levels of Gn secretion, which is susceptible to the negative feedback effect of steoid hormones. Before the onset of puberty, LH and FSH levels are low, but a highly sensitive assay indicates that circulating LH and FSH levels in prepubertal children are pulsatile, with slightly higher values at night than morning (9). In both boys and girls, preceding the physical signs of puberty, LH and FSH levels become elevated, pulsatility of these hormones becomes more pronounced, and the nocturnal increase in Gn release is enhanced (9,10). Both pulse frequency and amplitude of LH release increase at this stage as well (9). FSH increases early in puberty, with LH following (11). Before puberty the plasma FSH/LH ratio is greater than 1, whereas at the end of puberty the ratio is reversed. At menopause the FSH/LH ratio again becomes greater than 1 (12). During puberty the pituitary becomes more sensitive to infusions of GnRH, and the LH and FSH responses to GnRH increase in age-dependent increments (13). Three major developments characterize the approach of puberty: (a) adrenarche, the onset of adrenal androgen secretion; (b) decreased sensitivity of the gonadostat to feedback control by gonadal steroids, leading to activation or disinhibition of the GnRH neurosecretory neurons in the medial basal hypothalamus, with a consequent increase in pituitary Gn release; and (c) gonadarche, the enhancement of estrogen secretion by the ovary and the onset of ovulatory cycles.
An increase in secretion of adrenal androgens (adrenarche) occurs before maturation of Gn secretion. A variety of hormones have been proposed for the initiation of adrenarche, but evidence for the role of a hormone other than corticotropin remains elusive (14). As a consequence of increased FSH, the plasma level of 17-β-estradiol (E2) increases progressively throughout puberty (11). Serum inhibin levels increase in parallel with FSH levels during puberty in girls (15). When inhibin levels reach those of adults, the inhibin-FSH negative feedback relationship is established. The factors that regulate the onset of gonadarche are thought to be initiated by a decreased sensitivity of the gonadostat to circulating levels of steroid hormones. Another hypothesis for the initiation of puberty involves loss of neuronal inhibition or enhanced neuronal stimulation (6).
There are few data on the effects of excess thyroid hormone on the fetal development of the female reproductive tract. It has been shown that small doses of thyroid hormone given to young female mice resulted in the early attainment of sexual maturity with an early opening of the vagina and onset of estrous cycles (16). The ovaries of these mice revealed multiple corpora lutea and follicles. In contrast, the administration of large doses of thyroxine (T4) to the neonatal rat resulted in a delay in vaginal opening and first estrous (17). Due to the short period of administration (5 days), which was followed by a period of hypothyroidism, it is uncertain whether the excess T4 or the subsequent hypothyroidism caused the delay in sexual maturation. In the adult female rat, administration of T4 in high doses resulted in long periods of diestrus with few mature follicles or corpora lutea (18). Moreover, the administration of excess thyroid hormone has been reported to produce an increase or no change in pituitary LH and a decrease in serum LH (19). A synergistic effect of thyroid hormone with FSH to stimulate differentiation of porcine granulosa cells has also been found (20).
Thyroid hormone receptors have been found in the uterus (21). Thus, changes in the uterus would be expected to occur after administration of thyroid hormone. Excess thyroid hormone given to mice produces thickened endometria. Moreover, administration of T4 decreased estradiol uptake and retention by the rat uterus (22). Finally, a reduced uterine response to estrogen in thyrotoxic rats was reported (23).
In pregnancy it was shown that excess thyroid hormone is deleterious to pregnancy and could cause abortion and neonatal death, perhaps through a direct effect on trophoblastic function (24). However, mild thyrotoxicosis was found to help in the maintenance of implantation of delayed blastocysts and an increase in litter size (23).
Thyrotoxicosis results in increased levels of sex hormone–binding globulin (SHBG) synthesized in the liver. Also, plasma estrogen levels may be two- or threefold higher in hyperthyroid than in normal women during all phases of the menstrual cycle (25). 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 E2 is decreased in hyperthyroidism and is thought to be largely due to increased binding of E2 to SHBG (26).
Changes also occur in circulating androgen metabolism in hyperthyroid women. Mean plasma levels of testoster one and androstenedione increase (27). The production rate of testosterone and androstenedione are significantly elevated in hyperthyroid women in comparison with normal females. The conversion ratio of androstenedione to estrone, as well as testosterone to E2, is increased in hyperthyroid women (28).
Akande and Hockaday (29) found that the mean LH levels in both the follicular and luteal phases of the menstrual cycle are significantly higher in hyperthyroid women than in normal women. We found similar results when we studied women in the middle of the luteal phase of the cycle (30). Zahringer et al. (31) studied seven women with Graves' disease and six controls, sampling blood every 10 minutes for an 8-hour period. This was done in the early follicular phase of the menstrual cycle. They found that LH secretion was increased. Pulsatile characteristics of LH and FSH secretion (frequency, peak, shape) did not differ in patients when compared with controls (31). However, LH peaks may be absent in patients with amenorrhea. Serum LH levels decrease to normal after a few weeks of treatment with antithyroid drugs (32). Baseline FSH levels may be increased, although data on this are limited (30,33); however, some reports claim that FSH levels are normal in thyrotoxic women (31,34). The mechanism for the increase in serum LH and FSH in hyperthyroid women is unclear. Tanaka et al.(33) reported that hyperthyroxinemia results in an augmented Gn response to GnRH. Others, however, have been unable to confirm this finding (34).
We investigated 37 thyrotoxic women, all of reproductive age with normal periods and the same number of age- and weight-matched euthyroid controls. In all patients and controls, LH, FSH, and prolactin (PRL) levels were measured before and 30 and 60 minutes after a combined administration of thyrotropin-releasing hormone (TRH) and GnRH. In all patients, the same procedure was repeated 4 months after the initiation of antithyroid drugs, while the patients were euthyroid. We found that the Gn response was increased before treatment and remained slightly increased 4 months after treatment in comparison with controls (30). Moreover, no significant change in PRL secretion has been found (30,31). Usually, all these biochemical abnormalities are corrected after treatment.
Clinical Signs and Symptoms of the Reproductive System in Thyrotoxicosis
Children born with neonatal Graves' disease have no defects in the reproductive system that can be related to the pathologic entity. Hyperthyroidism occurring before puberty has been reported to delay sexual maturation and the onset of menses. However, others have reported no significant effect of hyperthyroidism on the age of menarche. Saxena et al. (35) found that in hyperthyroid girls the mean age of menarche was slightly advanced over that of their control population without thyroid disease.
Amenorrhea was one of the earlier of the known clinical changes associated with hyperthyroidism, as reported by von Basedow in 1840 (36). Since then, amenorrhea has been frequently reported, as well as a number of other changes in the menstrual cycle, including oligomenorrhea, hypomenorrhea, and anovulation. Biochemical and hormonal abnormalities, nutritional disturbances, and emotional upheavals associated with hyperthyroidism may, individually or in combination, be the cause of the menstrual disturbances.
Much confusion exists among physicians about the definition of different terms used to characterize menstrual abnormalities. It should be remembered that oligomenorrhea, polymenorrhea, and amenorrhea define the duration of the menstrual cycle, whereas hypomenorrhea, hypermenorrhea, and menorrhagia define the amount of menstrual flow. Thus, oligomenorrhea was identified when the interval between two periods was more than 35 days, polymenorrhea less than 21 days, and amenorrhea in women with previously normal periods when there was no menstruation for more than 3 months (37,38). Hypomenorrhea was arbitrarily defined when there was more than a 20% decrease in menstrual flow, hypermenorrhea when there was more than a 20% increase in menstrual flow in comparison with the previous periods, and menorrhagia as heavy menstrual bleeding (1).
The frequency of menstrual abnormalities in more recent studies is not the same as in earlier series. Thus, Benson and Dailey (39) found that of 221 hyperthyroid patients, 58% had oligomenorrhea or amenorrhea, and 5% had polymenorrhea. This is in general agreement with findings in older studies, such as those of Goldsmith et al.(40). Tanaka et al. (33) found that 8 of 41 thyrotoxic patients had amenorrhea and 15 had hypomenorrhea. More recently, Joshi et al. (41) found menstrual irregularities in 64.7% of hyperthyroid women in India, compared with 17.2% among healthy controls. These irregularities sometimes preceded identified thyroid dysfunction. We found irregular cycles in only 46 (21.5) of 214 thyrotoxic patients. Twenty-four of them had hypo-, 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. Although these findings indicate that menstrual disturbances in thyrotoxicosis are 2.5 times more frequent than in the normal population, they are still lower than has previously been described and support our notion that due to better medical care and public awareness, thyroid disturbances are diagnosed much earlier when the symptoms are still mild (42).
We also found that smoking aggravates the development of menstrual disturbances in thyrotoxicosis. Fifty percent of the thyrotoxic patients with abnormal menstruation were smokers, compared with 19% of the thyrotoxic patients with normal periods. We also found that patients with menstrual disturbances had higher total T4levels 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, for which no such correlation was found (42).
Thyrotoxicosis in women has been linked with reduced fertility, although most thyrotoxic women remain ovulatory according to the results of endometrial biopsies (40). Joshi et al. (41) found that 3 (5.8) of 52 thyrotoxic women 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 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 periods. We remeasured progesterone levels at the same phase of the cycle, 4 months after the initiation of therapy with antithyroid when they were euthyroid. We found that progesterone levels were decreased before treatment in comparison with controls and were not restored 4 months after carbimazole therapy (43). Because endometrial biopsies were not performed, however, we are unable to reach final conclusions.
Thyrotoxicosis during and after pregnancy is discussed in detail in Chapters 27 and 80.
In summary, thyrotoxicosis occurring in prepubertal girls may result in slightly delayed menarche. In adult women, the effects of thyrotoxicosis on the reproductive system are present at the hypothalamic pituitary level with alterations in Gn release and in the circulating levels of SHBG, which result in alterations in sex steroid metabolism or their biologic activity. The variable clinical symptoms seen in women with thyrotoxicosis are the consequence of these alterations.
REPRODUCTIVE EFFECTS OF THYROTOXICOSIS IN THE MALE
Although the effects of hyper- and hypothyroidism on female gonadal function are well established (1), controversies exist regarding the impact of these diseases on male reproduction. This is due mainly to the clinical irrelevance of signs and symptoms related to male gonadal function, as compared with the systemic effects of hyper- and hypothyroidism, which results in the lack of well-controlled clinical studies. For a better understanding of the effect of thyrotoxicosis on the male reproductive system, a brief review of the normal physiology is followed.
The Male Reproductive System from Fetal to Adult Life
Male gonadal differentiation begins at 7 week of gestation, with organization of the gonadal blastema into interstitium and germ cell–containing testicular cords. Primitive Sertoli's cells and spermatogonia become visible within the cords, while the epithelium differentiates to form the tunica albuginea (44). Leydig's cells derived from the undifferentiated interstitium are visible by the end of the eighth week of gestation and are capable of androgen synthesis at this time. By 14 weeks of gestation these cells make up as much as 50% of the cell mass, but as the tubules develop they account for a smaller percentage of the tissue. The fetal testes grow from approximately 20 mg at 14 weeks of gestation to 800 mg at birth; at 5 to 6 months they descend into the inguinal canal in association with the epididymis and the ductus deferens (44). Testicular secretion of testosterone in the fetus reaches a peak late in the first trimester and then declines until parturition (45). The fetal testis also produces antimüllerian hormone, which causes dedifferentiation of the müllerian duct system in the male fetus (46). In the first year of life, there is a transient increase in testosterone, after which the testis remains relatively quiescent until the onset of puberty. The pulsatile secretion of GnRH causes pulsatile secretion of Gns. Plasma levels of LH and FSH in the fetus increase after the establishment of the hypothalamic–pituitary portal system until midgestation and then decrease toward term as inhibitory control begins to function; mean levels of fetal plasma FSH are higher in females than in males (47). During the first two years after birth, plasma levels of LH and FSH increase intermittently to adult values and occasionally higher, and then they remain low until puberty.
In the adult male, GnRH and the Gns are secreted in discrete pulses. The secretory pulses of LH occur at a frequency of 8 to 14 pulses per 24 hours and vary in magnitude (48). Pulsatile secretion of FSH is temporally coupled to that of LH but is lower in amplitude (49). The secretion of LH is controlled by the negative feedback action of gonadal steroids on the hypothalamus and the pituitary. Both testosterone and E2 can effect this inhibition. Testosterone can be converted to E2 in the brain and the pituitary, but on the basis of the results of many studies the two hormones are thought to act independently (50,51). LH stimulates the Leydig's cells to secrete testosterone and, to a minor extend, E2 (52). Also, LH appears to govern testicular aromatization in the Leydig's cells. In the normal adult male, testosterone, dihydrotestosterone (DHT), and to some extend E2 circulate in the plasma bound in part to SHBG, which synthesized in the liver (53). Thyroxine increases serum SHBG levels (53,54). Sex hormones bound to SHBG are inactive and appear not to be readily metabolized (53). The unbound sex hormones or those bound to albumin are biologically active. The testosterone concentration in the testes is maintained at a high concentration relative to serum by androgen-binding protein secreted by the Sertoli's cells under the influence of FSH. The high intratesticular concentration of testosterone may be necessary for normal Sertoli's cell function or may play a role in spermatogenesis or sperm transport (55). In certain tissues, especially the prostate, circulating testosterone enters the cell and is metabolized to more active products, especially DHT, through the action of the enzyme 5α-reductase II. In other tissues, 5α-reductase I is the major isoenzyme (56). Although DHT is the active androgen in some areas, testosterone itself is an active androgen in some tissues that lack the enzyme, like muscle. There is a decline in testicular function due to age (57), although the interplay of lifestyle and disease processes probably plays a role (58).
Although the testicular secretion of E2 is important, the major source of circulating hormone derives from aromatization of testosterone in peripheral tissues, including adipose tissue, muscle, and skin; however, little aromatization appears to occur in the liver (59). These formed estrogens are further metabolized, primarily in the liver, to estriol and the catechol estrogens (60). The hypothalamus and pituitary can aromatize androgens, so it is uncertain whether testosterone itself or the estrogens formed locally from testosterone are the main negative feedback mechanisms for LH release (61). However, there is good evidence that one of the major factors controlling LH release is testosterone itself. Inhibin is a major factor in the control of FSH secretion (62).
Therefore, masculinization in men depends on the actions of both testosterone and DHT. The exact role of E2 is uncertain, but it appears in some processes, like bone formation, to play an important role.
Studies on the effects of alterations in thyroid hormone levels on the reproductive system have been performed extensively in animals (63). Changes from normal have generally resulted in a decrease in fertility and sexual activity. However, the mechanism is not constant throughout all species studied, and the results from different studies disagree. In intact rats, the administration of T4 resulted in a decrease in serum Gn levels (64). In male mice the administration of T4 doses, slightly greater than physiologic, resulted in shortening the time of development and with a tendency toward early maturation (63). However, large doses of thyroid hormone resulted in a decrease in the weights of the testes and seminal vesicles in mice and rabbits (63). In ram lambs, the administration of testosterone resulted in a decrease in testis volume and in an impairment of sexual development, in part due to alteration in LH pulse frequency (65). Studies on the effect of T4 directly on the testes have indicated that there is a minimal change in oxygen consumption when T4 is present in testicular slice incubations (66). Total lipids, cholesterol, and phospholipids in the testes are decreased after administration of excess T4 to mature male rats (67). Testes from rats made thyrotoxic by T4 administration synthesized increased amounts of testosterone (64). There are conflicting data on the effect of T4on spermatogenesis; it would appear that T4 does not exert a direct effect on spermatogenesis in mature rats or rams (68).
Hormonal Changes in Male Thyrotoxicosis
An increase in SHBG is a consistent feature associated with thyrotoxicosis (69) and leads to an increase in circulating levels of total testosterone (69) and reduction in the metabolic clearance rate of testosterone (70). However, the plasma level of free testosterone is usually maintained within the normal range (71), which is in keeping with the lack of clinical consequences of the markedly elevated levels of total testosterone found in thyrotoxicosis. Circulating E2levels are increased in many men with thyrotoxicosis (72), which is partly due to increased bound E2 to SHBG (72). However, an increase in the production rates of estrogens is also observed in some men with thyrotoxicosis, although it is unclear whether this is due to increased production of adrenal androgen precursors (specifically androstenedione) or to other mechanisms (73).
Thyrotoxicosis influences the metabolism of androgens and estrogens, leading to an increase in the excretion of 5α-reduced metabolites and an increase in the α:β ratio (74), although the mechanism for this is uncertain. Peripheral conversion of androgen to estrogen is enhanced in thyrotoxicosis, probably due to changes in peripheral blood flow (73) rather than a direct effect of T4 on the aromatase complex. Furthermore, serum progesterone was reported to be higher in hyperthyroid than in euthyroid men (75), whereas mean basal testosterone bioactivity was lower in thyrotoxic patients when compared with controls (76). The hyperthyroid state also affects estrogen metabolism, and is associated with a marked increase in the excretion of the 2-hydroxyestrogens and a decrease in the excretion of 16α-hydroxyestrogens (77). Thyrotoxic males often present with clinical features that are compatible with exposure to increased estrogen bioactivity (gynecomastia, spider angiomas, and a decrease in libido) (78). Whether this results from alterations in estrogen metabolism, or is a direct effect of hyperthyroxinemia, is unknown.
Basal serum Gn concentrations are usually normal. In one study LH and FSH responses to exogenous GnRH were significantly greater in thyrotoxic patients in comparison with patients who were rendered euthyroid (79). A direct effect of thyroid hormone on Gn sensitivity to GnRH has been postulated (79). Other studies have observed an increase in basal serum levels of LH and FSH (31) and hyperresponsiveness to GnRH stimulation (76,80). It has been suggested that the LH elevation could be secondary to changes in sex steroid binding and peripheral metabolism, alterations in the hypothalamic–pituitary feedback, or due to the direct effect of thyroid hormones per se at this level.
All the above changes are fully reversible with restoration of the euthyroid state, and require no other specific treatment.
Spermatogenesis, Fertility, and Thyrotoxicosis
The effect of hyperthyroidism on semen quality has been the subject of only a few studies. Clyde et al. (81) investigated three young men and found that two had marked oligospermia with decreased motility. The third patient had a borderline low sperm count and decreased motility. Kidd et al. (71) studied five patients and found that all had total sperm counts of less than 40 × 106/ mL. In 1992 Hudson and Edwards (82) assessed testicular function in 16 thyrotoxic men. They found that although the mean sperm densities were low, they did not differ significantly from controls. However, the forward progressive sperm motility of thyrotoxic patients was significantly lower than that of normal men. In a more recent study, Abalovich et al. (76) investigated the effect of hyperthyroidism on spermatogenesis in 21 patients; 9 patients (43%) had a low total sperm count, 18 (85.7%) had “grade A” lineal motility defects, and 13 (61.9%) displayed “progressive motility” problems.
In a very recent study (78), 23 thyrotoxic men and 15 healthy controls were studied prospectively. Two semen analyses were obtained for examination before and about 5 months after achievement of euthyroidism either by methimazole alone (14 patients) or iodine 131 plus methimazole (9 patients). Total fructose, zinc, and magnesium concentrations were also measured in seminal plasma of 16 patients. Results in the patients represent the average of the values of the two measurements, whereas in the control group semen analysis was performed only once. Mean semen volume was within the normal range for both patients and controls. Mean sperm density was lower in patients, although the difference compared with controls did not reach statistical significance. Similar observations were made with regard to sperm morphology. However, mean sperm motility was lower in thyrotoxic men than in controls. Following treatment of the thyrotoxicosis, sperm density and motility improved, but sperm morphology did not change. The type of treatment administrated for control of thyrotoxicosis (methimazole alone or 131I plus methimazole) had no impact on sperm counts or morphology. Mean values for semen concentrations of fructose, zinc, and magnesium did not differ between patients and controls, either before or after achievement of euthyroidism, and did not correlate with sperm parameters or with pretreatment thyroid hormone levels (78).
In summary, most of the studies conducted so far have shown that men with thyrotoxicosis have abnormalities in seminal parameters, mainly sperm motility. These abnormalities improve or normalize when patients become euthyroid. Mechanisms that may explain these observations include alterations in sex steroid and Gn concentrations, direct effects of thyroid hormones, effects of thyroid-stimulating immunoglobulins on the testes, or other autoimmune mechanisms associated with Graves' disease.
Radioiodine Treatment for Hyperthyroidism and Reproduction
Radioiodine (131I) is used widely in the diagnosis and treatment of thyroid diseases (83). The notion that radiation is mutagenic and may affect the gonads has raised concern in younger patients regarding its effect on reproductive function. Because the germinal epithelium and particularly the spermatogonia within it are very sensitive to radiation, there is concern that the radiation absorbed by the testes following large doses of radioiodine could result in azoospermia and permanent infertility (84). So far, several studies have reported normal reproductive performance in both male and female juvenile and adult patients with thyrotoxicosis after 131I therapy (85). Many clinicians therefore justifiably use 131I therapy as a first-line treatment for thyrotoxicosis for adults of all ages (1,86). However, given the considerable increase in the risk for thyroid cancer in young children exposed to external radiation, it has been hypothesized that there may be a small increase in the risk for thyroid cancer in young children treated with radioiodine therapy. This theoretic risk is probably highest in children before the age of 5 years and progressively lower in those treated at 5 to 10 and 10 to 20 years of age (87). Until safety long-term data are available for young children, radioiodine treatment in this age group should be administered with caution (88).
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