Hypothyroidism
	Influence of decreased thyroid hormone on the female reproductive tract and ovarian function 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 tract27. Hypothyroidism from infancy, if untreated, leads to sexual immaturity and hypothyroidism beginning before puberty cause, a delay in onset of puberty followed by anovulatory cycles28. Paradoxically, in some cases of juvenile hypothyroidism, precocious puberty and galactorrhoea have been reported29. This is probably due to a "spillover" effect; TSH, PRL, FSH & LH are all glycoproteins and may have interlapping actions30. Women with hypothyroidism have a decrease in the metabolic clearance rates of androstenedione and estrone and an increase in peripheral aromatization31. The 5α/ 5β ratio of the metabolites of androgens is decreased in hypothyroid women, and there is an increase in the excretion of 2-oxyogenated estrogens32. The binding activity of TeBG in plasma is decreased, with the result that the plasma concentrations of both testosterone and estradiol are decreased but their unbound fractions are increased. The alterations in steroid metabolism disappear when the euthyroid state is restored33. Gonadotropin levels usually, are normal28. However, blunted or delay LH response to LRH has been reported in some female patients with hypothyroidism15,34. In the latter, the serum prolactin levels may be increased35. This may be due to the fact that the hypothalamic thyrotropin - releasing hormone (TRH) increases the secretion of both TSH and PRL. Galactorrhoea may occur. Those disturbances usually disappear after thyroxine administration35. Hypothyroidism, menstrual function and fertility In women of fertile age, hypothyroidism results in changes in cycle length and amount of bleeding, i.e. oligo- and amenorrhoea, polymenorrhoea and menorrhagia. The latter is probably due to estrogen breakthrough bleeding secondary to anovulation36. Defects in haemostasis which have been demonstrated in hypothyroidism, such as decreased levels of factors VII, VIII, IX and XI may also contribute to polymenorrhoea and menorrhagia37. More precisely, Goldsmith et al19 found that 8 out of 10 patients with primary myxoedema had menstrual disturbances. Specifically, one patient had amenorrhoea, 5 had clinical metropathia hemorrhagica and 2 had menorrhagia. Benson & Dailey18 studied the menstrual pattern in hyperthyroidism and subsequent posttherapy hypothyroidism. Menorrhagia, polymenorrhoea 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 Mussey38 fount that 28 (56%) out of 50 hypothyroid patients had menstrual irregularities, mainly metrorrhagia or menorrhagia, alone or combined. Joshi et al20 found that 15 (68.2%) out of 22 patients with hypothyroidism had menstrual irregularities in comparison with 6 (12.2%) out of 49 controls. Of those, 8 had oligohypomenorrhoea, 2 amenorrhoea and 5 polymenorrhoea and menorrhagia. In a very recent study36 we 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 (Table 2). For the purpose of the study 214 normal controls with similar age and BMI, were investigated concerning their menstrual history. We found that only 18 (8.4%) had irregular periods. The type of menstrual disturbance is presented in Table 2. Table 2: Number (%) of patients and type of menstrual disturbance in hypothyroid patients before and after thyroxine treatment and in normal controls Type of menstrual disturbance Normal controls (n = 214) Hypothyroid patients (n = 171) Before LT4 After LT4 n % n % n % Oligomenorrhoea 12 67 17 42.5 8 50 Amenorrhoea - - 5 12.5 1 6 Polymenorrhoea 1 5.5 - - - - Hypomenorrhoea 3 16.5 6 15 4 25 Hypermenorrhoea / menorrhagia 2 11 12 30 3 19 Total 18 8.4 40 23.4* 16 9.3 * Statistically significant percentage in comparison with that of normal controls. P < 0.001 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 in these patients was oligomenorrhoea (42.5%) which is also inconsistent with what is generally believed or written in classic thyroid texts27,28. Although there was a tendency for patients with higher 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. These discrepant results may be attributed to either genetic and other factors between the populations studied or to more delayed diagnosis of the disease in earlier era, which resulted in a more severe clinical picture of the newly diagnosed patient. In women, severe hypothyroidism is commonly associated with diminished libido and failure of ovulation19. Hypothyroid women who become pregnant have more fetal wastage39. 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 prematurity40,41. Recent studies indicate these events may be less common but that gestational hypertension occurs often in pregnant women with untreated hypothyroidism42. Data from 2 contemporary studies indicate that large medical centers are likely to care for one or two women each year who are hypothyroid at the time they become pregnant43,44 and a report of a screening study described an incidence rate of 0.4% in pregnant women45. Hyperprolactinemia resulting from long-standing primary hypothyroidism has been implicated in ovulatory dysfunctions, ranging from inadequate corpus luteal progesterone secretion when mildly elevated46, to oligo- or amenorrhoea when circulating PRL levels are high. Adequate thyroid supplementation restores PRL levels and normalizes ovulatory function. In some cases the latter may be delayed47. Goldsmith et al19 reported that 7 out of 10 patients with myxedema had no evidence of ovulation and 1 demonstrated inadequate corpus luteum effect. The anovulation was reflected in the frequent finding of a proliferative endometrium on endometrial biopsy. All the 7 patients had menstrual irregularities. Joshi et al20 found that only 1 out of 16 patients with hypothyroidism had infertility. Bohnet et al48 investigated one hundred and fifty unselected women aged 25-34 years with long-standing (>2 years) primary or secondary infertility due to anovulation or luteal insufficiency. In all of them a 400 µg TRH test was carried out. 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. However, it has to be emphasized that the use of l-thyroxine is not helpful in treating euthyroid patients for infertility or menstrual irregularity. Earlier work indicated that thyroxine enhanced the action of gonadotropins on luteinization and progestin secretion by cultured granulosa cells49 and it has recently been 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 TSH50. These data support the suggestion that women presenting with menstrual irregularities or conception difficulties have to be investigated in depth for thyroid dysfunction before any treatment is being considered.