Reporter and Curator: Dr. Sudipta Saha, Ph.D.
Increasing evidence derived from experimental and clinical studies suggests that the hypothalamic–pituitary–thyroid axis (HPT) and the hypothalamic–pitutitary–ovarian axis (HPO) are physiologically related and act together as a unified system in a number of pathological conditions. The suggestion that specific thyroid hormone receptors at the ovarian level might regulate reproductive function, as well as the suggested influence of estrogens at the higher levels of the HPT axis, seems to integrate the reciprocal relationship of these two major endocrine axes. Both hyper- and hypothyroidism may result in menstrual disturbances. In hyperthyroidism the most common manifestation is simple oligomenorrhea. Anovulatory cycles are very common. Increased bleeding may also occur, but it is rare. Hypothyroidism in girls can cause alterations in the pubertal process; this is usually a delay, but occasionally it can result in pseudoprecocious puberty. In mature women hypothyroidism usually is associated with abnormal menstrual cycles characterized mainly by polymenorrhea, especially anovulatory cycles, and an increase in fetal wastage.
Thyrotoxicosis and the female reproductive system
Increased sex hormone-binding globulin (SHBG) concentration is characteristic of hyperthyroidism so much so that this globulin is used as a test of thyroid function, reflecting the tissue response to the thyroid hormones. Serum levels of estradiol and testosterone should thus be interpreted with this fact in mind because their total amounts are increased out of proportion to the free levels. Also, women with thyrotoxicosis have a decrease in the metabolic clearance rates of testosterone and of estradiol, an increase in the 5α/5β-reduced metabolites in the urine, and an increase in catechol estrogens in the urine at the expense of estriol and other 16-hydroxylated estrogen metabolites. Southern et al. have found an increase in the peripheral aromatization of androgens to estrogens in some thyrotoxic women. Other studies, however, did not confirm these findings and suggested that any increase in the peripheral aromatization of androgens is likely to be due to an increase in the peripheral blood flow and and not to the direct effect of T4 on the aromatase complex. One of the earliest clinical changes observed in thyrotoxicosis was the occurrence of amenorrhea, which was first reported in 1840. Amenorrhea has been reported frequently since then, but a number of other changes in menstrual cycles have been noted, including anovulation, oligomenorrhea, and menometrorrhagia, which is more common in hypothyroidism. Whether these changes are due to a direct action of T4 on the ovary and uterus or on the pituitary and hypothalamus or both is uncertain. The effect of T4 on fertility is less well established, although the disturbances in menstrual cycles will obviously disturb fertility. With therapy, the menstrual cycles return to their regular pattern for the individual. 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 seen on the hypothalamic–pituitary axis with alterations in gonadotropin release and also in the circulating levels of SHBG, which alter steroid metabolism or biologic activity. These effects produce the variable clinical picture seen in women with thyrotoxicosis.
Hyperthyroidism and physical development
Children born with neonatal Graves’ disease have no defects in the reproductive system that can be related to this disease. Physical development is normal, however, and skeletal growth is often accelerated without a modification of final height. The delay in puberty may be related to the impact of thyrotoxicosis on body composition (i.e., decreased percentage of body fat), which is thought to be related to the onset of puberty and menarche. Rarely, thyrotoxicosis may occur in children in association with polyostotic fibrous dysplasia, cafe au lait pigmentation, and precocious puberty (McCune-Albright syndrome). Precosity has been described in one-third of the affected girls; and large, unilateral follicular cysts may be present and presumably are responsible for the sexual precocity of the gonadotropin-independent type. Thyrotoxicosis results from single or multiple thyroid adenomas.
Hyperthyroidism and menstrual cycle
Thyrotoxicosis occurring before puberty has been reported to delay sexual maturation and the onset of menses, although Saxena did note that, in thyrotoxic girls, the mean age of menarche was slightly advanced over that of their control population without endocrine disease. The association of thyrotoxicosis and precocity in this disorder appears to be coincidental. Although ovulatory menstrual cycles occur in women with thyrotoxicosis, menstrual disturbances are common. Therefore, the possibility of pregnancy should be considered in an amenorrheic thyrotoxic woman. This is important because many of these women may receive treatment with radioactive iodine, which is contraindicated in pregnancy. Oligomenorrhea is the most common abnormality, and it may progress to amenorrhea, first described in the classic study by von Basedow. Polymenorrhea is distinctly less frequent, in comparison to its occurrence in hypothyroidism. The frequency of these menstrual disorders varies in different series. Benson and Dailey found that out of 221 hyperthyroid patients 58% had oligomenorrhea or amenorrhea and 5% polymenorrhea. This is in general agreement with other older studies such as those of Goldsmith et al. More recently, in India Joshi et al. found menstrual irregularities in 64.7% of hyperthyroid women, compared to 17.2% of healthy controls. These irregularities sometimes preceded thyroid dysfunction. However, Krassas et al. found irregular cycles in only 21.5% out of 214 thyrotoxic patients. These discrepant results may be attributed to either genetic and other factors or to more delayed diagnosis in India than in Greece. The weight loss and psychologic disturbances (primarily anxiety) seen in thyrotoxicosis may also contribute to sexual dysfunction. Thyrotoxic women frequently present with increased LH, FSH, and estrogen levels; and the gonadotropin response to gonadotropin releasing hormone (GnRH) is increased, although the mid-cycle LH peak may be reduced or absent.
Hypothyroidism and the female reproductive system
Production of SHBG is decreased in hypothyroidism. As a result, serum estradiol and testosterone concentrations are reduced, although free levels of these hormones remain normal. The metabolism of both androgens and estrogens is also altered in hypothyroidism. Androgen secretion is decreased, and the metabolic transformation of testosterone shifts toward androstenedione rather than androsterone, the reverse of that seen in hyperthyroidism. With respect to estradiol and estrone, hypothyroidism favors metabolism of these steroids via 16α-hydroxylation over 2-oxygenation, resulting in increased formation of estriol at the expense of 2-hydroxyestrone and its derivative, 2-methohyestrone. The alterations in steroid metabolism disappear when the euthyroid state is restored. Serum FSH and LH values are usually normal, but the midcycle FSH and LH surge may be blunted or absent. In postmenopausal women, serum FSH and LH concentrations may be somewhat lower than expected, and the response to GnRH may be reduced. The anovulation is reflected in the frequent finding of aproliferative endometrium on endometrial biopsy. TRα-1 and TRβ-1 receptors have been found in follicular fluid. Earlier work indicated that thyroxine enhanced the action of gonadotropins on luteinization and progestin secretion by cultured granulosa cells, and it has been recently noted 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 TSH. The defects in hemostasis reported in hypothyroidism, such as decreased levels of factors VII, VIII, IX, and XI, may also contribute to the pathogenesis of polymenorrhea. 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. Recent studies indicate these events may be less common but that gestational hypertension occurs often in pregnant women with untreated hypothyroidism. Pregnancy occurring in women with myxedema has been reported to be uncommon, but this is somewhat hard to document and may be the result of anovulation. The use of L-thyroxine is not helpful in treating euthyroid patients for infertility, menstrual irregularity, or the premenstrual syndrome. Some myxedematous women will present with amenorrhea and galactorrhea and elevated serum prolactin concentrations. Thus, thyroid evaluation should be an essential part of the work-up in any person with galactorrhea. If hypothyroidism is the cause, the amenorrhea and galactorrhea and elevated serum prolactin will disappear promptly with thyroxine therapy. There is an increased incidence of Hashimoto’s thyroiditis in individuals with Turner’s syndrome, and, although a chromosomal linkage between autoimmune disease and the X chromosome has been suggested, this has not been confirmed. Inherited abnormalities in serum TBG are X-linked, and patients with Turner’s syndrome may have low serum TBG values. Women with hypothyroidism have decreased metabolic clearance rates of androstenedione and estrone and increased peripheral aromatization. The ratio of 5α/5β metabolites of androgens is decreased in hypothyroid women, and there is an increase in the excretion of estriol and a decrease in the excretion of 2-hydroxyestrone and its derivative 2-methoxyestrone.
Hypothyroidism and physical development
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. Hypothyroidism in prepubertal years generally leads to short stature and may lead to a delay in sexual maturity.
Hypothyroidism and the menstrual cycle
An interesting syndrome described by Kendle and Van Wyk and Grumbach occurs not infrequently: it is characterized by precocious menstruation, galactorrhea, and sella enlargement in girls with juvenile hypothyroidism. The cause is thought to be an overlap in the pituitary production of TSH and gonadotropins, with the latter causing early ovarian secretion of estrogens and subsequent endometrial stimulation with vaginal bleeding. Prolactin levels are elevated, leading to galactorrhea. The estrogen and progesterone response of the ovary to human chorionic gonadotropin is increased, possibly from prolactin induction of ovarian LH receptors. In this way hyperprolactinemia may sensitize the ovaries to the low circulating gonadotropin levels present prepubertally. However, there is no pubertal increase in the adrenal production of androgen precursors, so that axillary and pubic hair are usually not apparent. Therapy with thyroxine in proper dosage results in prompt alleviation of the symptoms. In adult women, hypothyroidism results in changes in cycle length and amount of bleeding and has been reported in association with the ovarian hyperstimulation syndrome.108 In an Indian study, 68.2% of hypothyroid women had menstrual abnormalities, compared to 12.2% of healthy controls. Menorrhagia is a frequent complaint and is probably due to estrogen breakthrough bleeding secondary to anovulation, which is frequent in severe hypothyroidism. Some investigators have reported a high incidence of thyroid hypofunction in women with premenstrual syndrome. Most of the thyroid disease was subclinical hypothyroidism, defined as an augmented response of TSH to TRH. Many of the affected women were reported to have complete relief of premenstrual syndrome (PMS) symptoms with L-T4 therapy.
Source References:
http://www.ncbi.nlm.nih.gov/pubmed/10818393
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