Gerasimos E. Krassas
Hypothyroidism affects the reproductive system in women more than in men. Clinicians have long recognized that thyroid diseases in general and hypothyroidism in particular in premenopausal women are often associated with menstrual abnormalities. A review of the physiology of the female reproductive system from fetal to adult life is given in Chapter 39.
REPRODUCTIVE EFFECTS OF HYPOTHYROIDISM IN FEMALES
In the rat, fetal hypothyroidism results in small ovaries deficient in lipid and cholesterol (1). Propylthiouracil (PTU)-induced hypothyroidism or thyroidectomy of sexually immature rats results in delayed vaginal opening and sexual maturation, smaller ovaries and follicles than in controls (2), and poorly developed uteri and vaginas. When adult female rats are made hypothyroid, their estrous cycles become irregular and their ovaries become atrophic (3,4). Also, an enhanced response to human chorionic gonadotropin (hCG) with the development of large cystic ovaries but few corpora lutea have also been described in hypothyroid rats (5). In the mature female rat, hypothyroidism does not result in sterility, but it does interfere with gestation, especially in the first half of pregnancy (6), with resorption of the embryo and subsequent reduction in litter size and an increase in stillbirths (7). Ruh et al (8) reported increased estradiol (E2) binding in the uteri of hypothyroid rats, which has not been confirmed by others (9).
In sheep, fetal hypothyroidism does not interfere with reproductive tract development. The uterus in hypothyroid sheep shows endometrial hyperplasia and smooth muscle hypertrophy, perhaps related to the prolonged estrous noted in hypothyroid ewes (10).
Women with hypothyroidism have decreased rates of metabolic clearance of androstenedione and estrone and an increase in peripheral aromatization (11). The 5α/5β ratio of the metabolites of androgens is decreased in hypothyroid women, and there is an increase in the excretion of 2-oxygenated estrogens (12). The binding activity of sex hormone–binding globulin (SHBG) in plasma is decreased, which results in decreased plasma concentrations of both testosterone and E2, but their unbound fractions are increased. The alterations in steroid metabolism disappear when the euthyroid state is restored (13).
Gonadotropin levels are usually normal (14). However, blunted or delayed luteinizing hormone (LH) response to gonadotropin-releasing hormone (GnRH) has been reported in some female patients with hypothyroidism (15,16). When there is a delayed LH response, the serum prolactin (PRL) concentration may be increased (17). This may be due to the fact that hypothalamic thyrotropin-releasing hormone (TRH) increases the secretion of both thyrotropin (TSH) and PRL. Galactorrhea may occur. These disturbances usually disappear after thyroxine (T4) administration (17).
Effects of Hypothyroidism in Early Life
The reproductive tract appears to develop normally in cretins; thus, hypothyroidism during fetal life does not appear to interfere with the normal development of the reproductive tract. Hypothyroidism in prepubertal years generally leads to short stature and may result in a delay in sexual maturation (18). An interesting syndrome, described by Kendle (19) and Van Wyk and Grumbach (20), may be seen occasionally; it is characterized by precocious menstruation, galactorrhea, and sella enlargement in girls with juvenile hypothyroidism. This is probably due to a “spillover” effect, because TSH, PRL, follicle-stimulating hormone (FSH), and LH are all glycoproteins and may have interlapping actions. However, axillary and public hair are usually not affected because there is no pubertal increase in the adrenal production of androgen precursors (18). Therapy with T4 in proper dosage results in prompt alleviation of the symptomatology.
Menstrual Function and Fertility
In women of fertile age, hypothyrodism results in changes in cycle length and amount of bleeding (i.e., oligomenorrhea and amenorrhea, polymenorrhea, and menorrhagia). The latter is probably due to estrogen breakthrough bleeding secondary to anovulation (21). Defects in hemostasis, such as the decreased levels of factors VII, VIII, IX, and XI that may occur in hypothyroidism, may also contribute to polymenorrhea and menorrhagia (22).
More precisely, Goldsmith et al (23) found that 8 (80%) of 10 patients with primary myxedema had menstrual disturbances. Specifically, one patient had amenorrhea, five had clinical metropathia hemorrhagica, and two had menorrhagia. Benson and Dailey (24) studied the menstrual pattern in hyperthyroidism and subsequent posttherapy hypothyroidism. Menorrhagia, polymenorrhea, or both were noted in 18 (58.6%) of 31 women during the period of decreased thyroid function subsequent to specific therapy for hyperthyroidism.
Scott and Mussey (25) found that 28 (56%) of 50 hypothyroid patients had menstrual irregularities, mainly metrorrhagia or menorrhagia, alone or combined. Joshi et al (26) found that 15 (68.2%) of 22 patients with hypothyroidism had menstrual irregularities in comparison with 6 (12.2%) of 49 controls. Of those, 8 had oligohypomenorrhea, 2 amenorrhea, and 5 polymenorrhea and menorrhagia.
In a recent study (21), we found that 40 (23.4%) of 171 hypothyroid women had irregular cycles. Of those, 17 had oligomenorrhea, 6 hypomenorrhea, 5 amenorrhea, and 12 hypermenorrhea/menorrhagia. None had polymenorrhea or hypermenorrhea. For the purpose of the study, 214 normal controls with similar age and body mass index were investigated concerning their menstrual history. We found that only 18 (8.4%) had irregular periods. 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 in previous similar studies. Furthermore, we found that the main menstrual irregularity in these patients was oligomenorrhea (42.5%), which is also inconsistent with what is generally believed. Moreover, as expected, patients with more severe hypothyroidism had higher TSH levels. Although there was a tendency for patients with higher serum TSH levels to have more menstrual disturbances, these differences were not statistically significant. Finally, we found that thyroid antibodies are unimportant in the development of menstrual abnormalities in hypothyroidism. The fewer menstrual abnormalities in these more recent studies may be attributed to genetic and other factors among the populations studied or to the more delayed diagnosis of hypothyroidism in the earlier studies, which would result in a more severe clinical picture in the newly diagnosed patient.
In women, severe hypothyroidism is commonly associated with diminished libido and failure of ovulation (23). Hypothyroid women who become pregnant have more fetal wastage (27). Ovulation and conception can occur in mild hypothyroidism, but in the past those pregnancies that did occur were often associated with abortions in the first trimester, stillbirths, or prematurity (28,29). Recent studies indicate that these events may be less common but that gestational hypertension often occurs in pregnant women with untreated hypothyroidism (30). Data from two studies indicate that large medical centers are likely to care for one or two women each year who are hypothyroid at the time that they become pregnant (31,32), and a report of a screening study described an incidence rate of 0.4% in pregnant women (33). Hyperprolactinemia resulting from long-standing primary hypothyroidism has been implicated in ovulatory dysfunction ranging from inadequate corpus luteal progesterone secretion when mildly elevated (34) to oligomenorrhea or amenorrhea when circulating PRL levels are high. Adequate thyroid supplementation restores PRL levels and normalizes ovulatory function. In some cases the latter may be delayed (35).
Goldsmith et al (23) reported that 7 of 10 patients with myxedema had no evidence of ovulation and one demonstrated inadequate corpus luteum effect. The anovulation was reflected in the frequent finding of a proliferative endometrium on endometrial biopsy. All 7 patients had menstrual irregularities. Joshi et al (26) found that only 1 of 16 patients with hypothyroidism was infertile.
Bohnet et al (36) investigated 150 unselected women 25 to 34 years of age with long-standing (>2 years) primary or secondary infertility due to anovulation or luteal insufficiency. A 400-µg TRH test was performed in all. In patients with subclinical hypothyroidism, a PRL stimulation test (metoclopramide) was done. They found that subclinical hypothyroidism may be of greater clinical importance in infertile women with menstrual disorders—especially when the luteal phase is inadequate—than is usually thought. They concluded that a TRH stimulation test in such patients should be mandatory. This was also confirmed in a recent study (37) reporting that mean serum TSH levels and antithyroid peroxidase antibodies were higher among women with infertility compared with controls. It must be emphasized, however, that the use of T4 is not helpful in treating euthyroid patients for infertility or menstrual irregularity.
Earlier work indicated that T4 enhanced the action of gonadotropins on luteinization and progestin secretion by cultured granulosa cells (38). It has recently been reported that in a group of infertile women, those with elevated TSH levels had a higher incidence of out-of-phase biopsies than women with normal serum TSH concentrations (39). These data support the suggestion that women presenting with menstrual irregularities or conception difficulties should be examined in depth for thyroid dysfunction before specific T4 treatment is considered. Hypothyroidism during and after pregnancy is discussed in detail in Chapters 27 and 80.
In summary, contemporary studies have shown that the frequency of menstrual irregularities in hypothyroidism is far less than reported earlier. Moreover, the most common manifestation is oligomenorrhea. Also, hypothyroidism is commonly associated with failure of ovulation. Ovulation and conception can occur in mild hypothyroidism. However, these pregnancies are often associated with abortions, stillbirths, or prematurity. Subclinical hypothyroidism may be of significant clinical importance in infertile women with “unexplained” infertility, and such patients should be investigated in depth for thyroid dysfunction.
REPRODUCTIVE EFFECTS OF HYPOTHYROIDISM IN MALES
Although less common in men than in women, hypothyroidism, whether induced or spontaneous, affects the male reproductive tract in a number of ways, depending in part on the age at onset. A review of the physiology of the male reproductive system from fetal to adult life is given in Chapter 39.
Hypothyroidism, induced or occurring soon after birth, is associated with a marked delay in sexual maturation and development (40). When rats are made hypothyroid with PTU administered from birth to 24 to 26 days of age, testicular size is decreased, Sertoli cell differentiation is retarded, and the time of Sertoli cell proliferation is prolonged (41,42). Transient hypothyroidism also alters the expression of a number of mRNAs in the Sertoli cell (43). Testis size, Sertoli cell number, and sperm production are increased as these rats become older and euthyroid (43). Hardy et al (44) found that Leydig cell numbers are increased, testosterone secretion per cell is decreased, although total testosterone secretion remains the same as controls. FSH and LH levels tend to remain low throughout treatment and recovery periods, whereas inhibin levels are increased (41).
If hypothyroidism persists untreated, there is an arrest of sexual maturity, and libido and ejaculate are absent (45). The interstitial cells of the testis are reduced in number, and the arrested growth of the accessory male sex organs indicates a decrease in the production of testosterone (45). The longer the hypothyroidism persists, the greater the degree of damage to the testes (45), although genetically induced hypothyroidism in male mice is associated with normal fertility (46). In the mature male rat, the induction of hypothyroidism has little effect on the pathology of the testes, spermatogenesis, or serum testosterone concentrations (47), although the LH response to GnRH may be blunted (48). In the adult ram, hypothyroidism is associated with a decrease in testosterone concentration but normal spermatogenesis (49). Thus, it would appear that hypothyroidism can affect the immature, but not the mature, testis.
Hypothyroidism is associated with a decrease in serum total testosterone (50,51). SHBG is usually low (50,52,53). Dehydroepiandrosterone (DHEA), DHEA sulphate, estrogenic metabolites of DHEA (androstenediol and its sulphate), and pregnenolone sulphate are decreased in the serum of men with hypothyroidism compared with normal controls (54). In a prospective study of 10 men with primary hypothyroidism, plasma free testosterone levels were low, and they increased after beginning T4 therapy (55). Gonadotropin levels were not elevated, consistent with a state of hypogonadotropic hypogonadism (55). In addition, a marked decrease in the 5α:5β ratio of the metabolites of androstenedione and testosterone has been reported in hypothyroidism, which is the reverse of that seen in hyperthyroidism (56). A small study of hypothyroid men showed an attenuated LH response to GnRH, which improved after thyroid hormone therapy (52). These findings suggest an effect of hypothyroidism on gonadotropin secretion at the level of the hypothalamus–pituitary. In rare cases of severe prolonged primary hypothyroidism, pituitary hyperplasia may occur, causing multiple pituitary hormone deficiencies, including gonadotropin and corticotropin deficiencies (57,58). Circulating androgenic steroids may also be reduced by hyperprolactinemia caused by hypothyroidism (17,59).
Effects of Hypothyroidism in Early Life
Congenital hypothyroidism is not associated with abnormal development of the male reproductive tract (40). This is not surprising because small but adequate amounts of maternal thyroid hormones cross the placenta to satisfy fetal demands (60). Maternal hypothyroidism during pregnancy and cretinism are also not associated with abnormal male reproductive tract development (61). When adequately treated with thyroid hormone, boys with congenital hypothyroidism progress through puberty normally and at the appropriate time (62,63). Untreated hypothyroidism in early childhood can result in delay in sexual maturation, which can be reversed by thyroid hormone therapy (64). It has been known for many years that severe juvenile hypothyroidism is associated with precocious pseudopuberty (19,40). External genitalia develop early, but without axillary or pubic hair, and there is often macro-orchidism (65). The serum gonadotropins are usually normal, and serum testosterone is in the prepubertal range. It is proposed that cross-reactivity of TSH with the FSH receptor may be responsible for this rare phenomenon (66).
Spermatogenesis and Fertility
Hypothyroidism is associated with decreased libido (50,52,67) or impotence (50,67). However, little is known about the effects of hypothyroidism on human spermatogenesis and fertility. Griboff (68) investigated five men with primary hypothyroidism who were 30 to 64 years of age. All demonstrated normal sperm counts. However, exposure of semen to room air revealed a rapid drying of the material and loss of sperm motility in two of the five specimens. A study by De la Balze et al (69) investigated six adult male hypothyroid patients 17 to 59 years of age. Thyroid insufficiency had occurred before puberty in five subjects and in childhood in one. All patients demonstrated features of hypogonadotropic hypogonadism. Testicular biopsies revealed histologic abnormalities in all patients. It was concluded that severe and prolonged thyroid insufficiency occurring early in life resulted in moderate failure of pituitary gonadotropins secretion and abnormal testicular biopsy results. Wortsman et al (50) studied eight hypothyroid men 37 to 77 years of age. All patients had evidence of hypogonadism, five were hypergonadotropic, and the remaining three hypogonadotropic. Seven of eight patients had varying degrees of testicular atrophy. Serum testosterone and SHBG concentrations were low in four of the patients. Sperm analyses were not performed. They concluded that abnormalities of gonadal function are common in men with primary hypothyroidism. Corrales Hernandez et al (51) studied spermatogesis in 10 patients with a history of hypothyroidism treated with T4. Hypothyroidism was induced by discontinuation or a decrease of the dose of T4 over at least one spermatogenic cycle. A decrease in seminal volume, progressive forward motility, and cumulative percentage of mobile forms was observed compared with controls. There were no abnormalities in sperm density or percentage of spermatozoa with normal morphology. Induction of hypothyroidism did not lead to seminal changes compared with the same patients when euthyroid. Serum concentrations of testosterone and gonadotropin were normal during the hypothyroid phase. It appears, therefore, that short-term postpubertal hypothyroidism does not cause seminal alterations sufficiently intense to impair male fertility. Jaya Kumar et al (52) studied the reproductive and endocrine function of eight men with primary hypothyroidism during the hypothyroid phase and after achieving euthyroid status with T4 substitution therapy. They found high mean levels of gonadotropins, low serum testosterone, low SHBG, and subnormal testosterone response to hCG. Semen analysis was performed in five of eight patients, but these data were not presented, although the authors claimed that “some improvement in sperm count and motility was observed.”
In summary, the data so far suggest that short-term hypothyroidism in adults has no significant effect on reproductive function. Severe, prolonged hypothyroidism, particularly when the onset occurs in childhood, may impair reproductive function. However, more studies are needed with a larger number of patients to define the effects of hypothyroidism on male reproductive function.
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