Chapter 11

The Thyroid Gland in Gynaecology


The importance of the thyroid gland in gynaecological endocrinology is reflected by the fact that it has been mentioned in almost all chapters in this book. It produces triiodyothyronine (T3), thyroxine (T4) and calcitonin. Its effects span from intrauterine fetal life to the postmenopausal period. It is involved with development, growth, reproduction, and general body homeostasis in all age groups. Beside the endocrine effects which will be discussed in more details in this chapter, T4 and T3 have metabolic and cardiovascular effects. The metabolic ones involve rapid cellular uptake of glucose, increase glycolysis and gluconeogenesis, boost lipid mobilisation increasing free fatty acids levels, promote protein synthesis and increase the number and size of mitochondria in most cells. They also increase the basal metabolic rate, oxygen consumption by most tissues, as well as heat production. Other important metabolic effects include enhancement of intestinal glucose transport, and reduction of plasma cholesterol level, mainly low density lipoproteins. A detrimental effect on low-density lipoprotein cholesterol has been shown even in subclinical hypothyroidism (1). The cardiovascular properties involve both genomic and non genomic effects. They increase heart rate with reduced isovolumic relaxation time, and increase left ventricular ejection fraction and cardiac output (2). They also increase the sympathetic nervous system tone. On the other hand calcitonin is produced by the parafollicular or C- cells and is involved with the regulation of calcium metabolism. It counteracts the effect of the parathyroid hormone and reduces calcium blood level. This effect is utilised clinically for long-term treatment of postmenopausal patients with osteoporosis to reduce the risk of vertebral fractures.

Thyroid gland dysfuncion usually, but not always presents during the reproductive years in women. It is the second most common female endocrinopathy (3), following polycystic ovary syndrome. Accordingly, gynaecologists cannot possibly avoid seeing patients with thyroid disease. Both hypo-and-hyperthyroidism can be insidious without any thyroid gland enlargement, which usually leads to delayed diagnosis and treatment. Furthermore, they can present for the first time during pregnancy. The prevalence of hypothyroidism varies between 2-4% during the reproductive years, with autoimmune thyroid disease being the most common cause. Hyperthyroidism is less common in this age group. Many patients may have subclinical hypothyroidism, with or without thyroid peroxidase antibodies. The diagnosis of this entity is usually made in asymptomatic women with normal free thyroxine (T4), but thyroid stimulating hormone level (TSH) >5.0 mIU/L, though a figure of 2.5 mIU/L has been advocated by many authorities. It was reported by McDermott and Ridgway in 2001 (4) that 13.7% of these patients had different symptoms usually seen in patients with overt hypothyroidism. The list included dry skin (28%), poor memory (24%), slow thinking (22%), muscle weakness (22%), fatigue (18%), muscle cramps (17%), cold intolerance (15%), puffy eyes (12%), constipation (8%) and hoarseness (7%). These are vague symptoms, and were seen in 12.1% of the euthyroid women involved in the same study. More information about this subject will be discussed later on in this chapter.


The fetal thyroid gland

During its early intrauterine life, the fetus depends entirely on maternal thyroid hormones for its development, growth and survival. Maternal thyroid hormones play an essential role in the development of the fetal brain. This is affected through the placenta which regulates the amounts of thyroid hormones reaching the fetus, depending on its stage of development (5). Significant amounts of thyroxine have been found in fetal tissues before the fetal thyroid gland starts functioning, reflecting its importance in fetal development even at this early stage of development. Accordingly, any maternal thyroid dysfunction, or abnormality with the placental transport mechanism can lead to fetal compromise especially of the fetal brain, and developmental delay in children after birth. These changes may be seen even in mild hypothyroid cases, but their severity is directly related to the severity of the condition itself. The placenta lacks the ability to boost the transfer of maternal thyroid hormones into the fetus in pathological conditions of thyroid hormone deficiency (5).

The fetal hypothalamo-pituitary-thyroid axis starts functioning by the 12th week and is fully developed by the 16th week of intrauterine fetal life. The level of free thyroxine usually reaches adult levels by 16 weeks of fetal life, and continues to increase with gestational age. Similarly thyroid stimulating hormone (TSH) reaches adult levels by the 20th week, and peaks by the time of birth (6). The fetus becomes more dependent on its own thyroid hormones during the second half of the pregnancy. Assessment of fetal thyroid function has been made possible with cordocentesis, as documented by Thorpe Beeston and Nicolaides in 1993 (7). Administration of thyroid releasing hormone to pregnant women showed rapid increase in the level of fetal TSH from the 25th weeks of pregnancy. Fetal TSH levels have been found to be higher in hypoxic growth retarded fetuses, anaemic fetuses from red cell isoimmunized pregnancies, and chromosomally abnormal fetuses especially those with trisomy 21. These changes were agreeable with previous results reported by the same group two years earlier (8). Higher levels of TSH and lower T4 and free T4 were detected in fetal blood from small for gestational age, than those with appropriate weight at a comparable age. They also reported significant associations between increased TSH level and low T4, and the degrees of fetal hypoxia and acidaemia respectively.


Thyroid function during pregnancy

There is almost 30-50% increased demand for thyroid hormones during pregnancy. This may not be fulfilled if the thyroid gland is dysfunctional. Beside the increased metabolic needs, certain biochemical changes occur during pregnancy which increase the demand for more thyroxine production:

·   Increased production of oestrogens by the placenta during pregnancy increases the hepatic production of thyroxine binding globulin (TBG) which results in lower levels of free T4.

·     There is increased renal blood flow, glomerular filtration rate and loss of iodine in urine starting from early pregnancy.

·   There is increased stimulation of the thyroid gland during the first trimester by the high levels of human chorionic gonadotrophin, which has thyrotrophic effect.

·   Changes in peripheral metabolism of thyroid hormones occur during pregnancy under the effect of placental type 3 iodothyronin deiodinase.

The relationship between maternal hypothyroidism and fetal brain development is well documented. Children born to women with untreated or inefficiently managed hypothyroidism had lower IQ levels. They also had more difficulty in schools, compared to other unaffected siblings. Such impairment may occur even after mild or even subclinical maternal hypothyroidism as reported by Pope and Glinoer in 2003 (9). In general, the more severe the maternal condition, the worse the fetal and newborn outcome. Women living in parts of the world deficient in iodine, and without iodine supplementation are also at risk. The ideal situation will be for all women to start their pregnancies in a well-compensated thyroid function. This is especially so since the increased demand for thyroxine was evident as early as the 5th week of gestation, as shown by patients already on thyroxine replacement therapy (10). This increased demand was shown to start even earlier in patients who conceived after in vitro fertilisation treatment. This is due to the high level of oestrogens which usually follows controlled ovarian hyperstimulation with gonadotrophins. There is a parallel increase in the level of TBG as well, with significant reduction in the level of free T4. Oestrogen levels as high as those seen during the mid trimester of pregnancy (4000 – 6000 pg/ml) have been reported in these cases by the time of human chorionic gonadotrophin injection (11). This will put a strong argument in favour of screening women at risk of having subclinical hypothyroidism with TSH and free T4 before controlled ovarian hyperstimulation is started. The group includes patients with personal or family history of autoimmune disorders including vitiligo, past history of thyroid disease, lipid disorders and chronic anovulation. Regular screening of these women during pregnancy can be useful as well. On a different subject, a detrimental effect of hypothyroidism on maternal blood pressure has also been recorded. Pre-eclamptic patients had significantly elevated TSH level, and those with low total T4 / total T3 ratio had significantly higher plasma urate concentration (12).

There is immense controversy regarding the role of subclinical hypothyroidism with or without thyroid peroxidase antibodies on human reproduction. More evidence has now been published showing that both conditions could be associated with infertility, early pregnancy loss, and preterm labour. Furthermore, women with thyroid peroxidase antibodies are liable to develop postpartum thyroiditis (13). Nevertheless, it is generally known that an association does not always mean causation. In a recent report, Duliére et al in 2009 (14) recommended that thyroid peroxidase antibodies positive pregnant women should be supplemented with 50 µg / day of thyroxine, unless the TSH level is < 1.0 mIU/L.

In contrast, subclinical hyperthyroidism during pregnancy has fewer clinical consequences, and no treatment is usually required (15). On the other hand, Grave’s disease is rare during pregnancy, and may affect 0.1-0.4 pregnant women, usually during the first trimester and/or after delivery. Fetal hyperthyroidism may follow passage of the related TSH receptor antibodies through the placenta. The treatment plan for patients with hyperthyroidism, and those with nodular goitre at the time of initial diagnosis should be arranged with a medical endocrinologist; whereas management of hypothyroidism can be arranged locally.


Endocrine effects of thyroid dysfunction

Hypothyroidism

Thyroid gland hormones play an important role in modulating the hypothalamo-pituitary-ovarian axis function, which could be affected negatively in cases of thyroid gland dysfunction. Thyroxine has receptors at the level of the ovaries (16), and has also been shown to exert a direct effect on granulosa cells function (17). Such direct action has been documented previously by Channing et al in 1981 (18), in cultured granulosa cells. They showed that thyroxine augmented the action of gonadotrophins on granulosa cell luteinisation and secretion of progesterone. Histologically, women with high TSH were shown to have reduced progesterone effect at the level of the endometrium, with higher incidence of out of phase biopsies than women with normal TSH (19). On the direct hormonal side, hypothyroidism is associated with high prolactin levels due to the secondary increased production of TRH, which stimulates prolactin production. This can have a direct effect on the hypothalamus affecting the pulsatile release of gonadotrophin hormones releasing hormone (GnRH). This in turn can lead to abnormal gonadotrophins production, mainly LH. In severe cases this leads to disruption of the hypothalamo-pituitary-ovarian axis, with resultant anovulation, and occasionally abnormal uterine bleeding. Furthermore, secondary hyperprolactinaemia can have direct effects on the gonadotrophs and ovaries, at post receptors level. The LH surge is usually first to be affected leading to abnormal ovulation with a short or inadequate luteal phase. This can lead to polymenorrhoea, heavy menstruation or even infertility in the long term. The long-standing effect in severe cases is hypoestrogenic amenorrhoea, which can affect bone density as well. Other secondary effects of hyperprolactinaemia can be seen in the adrenal glands, through direct inhibition of adrenal enzymes. One example is reduction in the activity of 3ß-ol dehydrogenase. This will result in reduced incorporation of the D5 precursors into the D4 pathways, resulting in increased production of DHEA which is converted peripherally into more potent androgens. The other enzyme mostly quoted to be affected by hyperprolactinaemia is 21-hydroxylase.

Low thyroxine levels also lead to reduced hepatic production of sex hormone binding globulin (SHBG), reducing the binding sites for androgens and oestradiol. This leads to decreased total plasma concentration of testosterone and oestradiol, with an increase in their free fractions. There is usually decreased metabolic clearance rate of androgens, despite their increased peripheral aromatisation to oestrone (20). This can also occur at the level of the hypothalamus leading to abnormal GnRH pulse production, with disrupted gonadotrophins secretion. Occasionally, basal production of gonadotrophins is not affected, but a blunt or delayed response of LH to GnRH is seen in patients with hypothyroidism (21, 22). This alteration in the level of gonadotrophins is restored back to normal following medication with thyroxine, and achievement of euthyroid state (23). At the level of the ovaries, high free androgens can reduce oocytes maturation capacity, and granulosa cell mitotic activity. They also reduce FSH and LH receptors as well as the activity of the aromatase enzyme, with ultimate anovulation and development of polycystic ovaries. Androgens also have detrimental effects at the level of endometrium.


Effects of hypothyroidism

The diagnosis and management of neonatal and childhood thyroid diseases are the domain of paediatricians and paediatric endocrinologists, and are beyond the remit of this chapter. Suffice to say that fetal hypothyroidism does not affect the development of the reproductive tract, whilst untreated congenital hypothyroidism can lead to dwarfism, mental retardation, and lack of sexual maturation. The effect of hypothyroidism on pubertal development has already been discussed in Chapter 2. Starting before the age of puberty, hypothyroidism can delay the onset of pubertal development. In a few cases isosexual precocious puberty follows stimulation of the pituitary gonadotrophs by the increased level of TRH, leading to increased production of gonadotrophins, mainly LH. This point should be considered when dealing with patients presenting with abnormal pubertal development.

It is more usual for gynaecologists to see patients with hypothyroidism presenting with menstrual dysfunction. This can be in the form of polymenorrhoea, menorrhagia, oligomenorrhoea or even amenorrhoea. Excessive bleeding can be due to altered hepatic production of factor VII, VIII, IX and XI (24). The reported incidence of menstrual irregularities in women with hypothyroidism declined over the years. Figures of 50-70% were quoted previously, but a figure of 23.4% has been recently quoted in a group of 171 patients by Krassas in 2000 (25). These differences may be a reflection of the early diagnosis of these problems in recent years, before they became severe enough to adversely affect the HPO axis. Accordingly, thyroid indices should be investigated in all women who present with menstrual dysfunction. All the biochemical / endocrine changes associated with hypothyroidism, mentioned before, can also result in involuntary infertility. The exact incidence of this problem is difficult to ascertain, as infertility clinics’ statistics do not represent the exact population prevalence. Furthermore, the problem is confounded by the fact that symptomatic hypothyroid patients are usually treated in primary care clinics. This may occur even before infertility becomes an issue. Moreover, such treatment restores normal fertility in most patients. The issue here will be antenatal monitoring instead.

The situation is even more difficult with subclinical hypothyroid cases, because of the differences in the criteria used by different authors to reach a diagnosis, mainly the upper normal TSH cut-off level. More cases of subclinical hypothyroidism were diagnosed when a TRH stimulation test was used rather than a basal TSH level. In a different approach, Raber et al used the TRH stimulation test to follow the reproductive performance of patients with mild hypothyroidism already on thyroxine medication. Patients who never achieved a basal TSH <2.5 mIU/L or TRH stimulated TSH <20 mIU/L had lower conception rate in a 5 year follow up study (26). Furthermore, they also reported more frequent miscarriages in women with higher basal TSH levels. Many cases of subclinical hypothyroidism were associated with ovulatory dysfunction, with a prevalence of 1-4% in infertile patients. In one study, Bohnet et al (27) reported improvement of luteal serum progesterone, and 20% pregnancy rate after treating women with subclinical hypothyroidism with levothyroxine in a daily dose of 50 µg. The problem regarding the association of subclinical hypothyroidism and infertility has been plagued by the lack of well designed randomized and controlled clinical trials as suggested by Poppe et al in 2007 (28). However, there is enough evidence to show that patients with subclinical hypothyroidism are more vulnerable during induction of ovulation and controlled ovarian hyperstimulation for assisted reproduction treatment. The increased oestradiol level increases TBG production as mentioned previously, and reduces free T4 level, inducing a state of hypothyroidism especially during conception cycles. A similar effect can be induced by HRT, and by using the combined oral contraceptive pill for family planning or cycle control for abnormal uterine bleeding. Even women with normal thyroid gland function may show high TSH and total thyroxine blood levels in these circumstances. Nevertheless, the free T4 fraction will be unaffected. In previous years, free thyroxine index was used to investigate thyroid status during pregnancy and in women using HRT or oral contraceptives, because of the high oestrogen-induced TBG levels. It was obtained by multiplying total T4 times T3 uptake. This has been replaced nowadays by direct measurement of the free T4 fraction.

On a different note, care should be taken when investigating tubal patency in patients with subclinical hypothyroidism, as they are at risk of developing clinical hypothyroidism after hysterosalpingoraphy, using oil–soluble iodinated contrast medium (lipiodol) (29).


Thyroid autoantibodies

Euthyroid patients with thyroid peroxidase antibodies will be discussed separately in this section. Autoimmune thyroid antibodies are found in 5-10% of women within the reproductive period, and make the most common autoimmune disorder in women. Such autoantibodies are more often associated with infertility in patients with endometriosis (30) and polycystic ovary syndrome (31). Furthermore, the pattern in most studies showed increased incidence of such autoimmune antibodies in infertile women compared to parous controls with a relative risk of 2.1 (27). The most dramatic association of these autoantibodies has been with pregnancy outcome and postpartum thyroiditis. This subject is still shrouded with controversy, but more evidence now points toward a detrimental association. Most work showed normal pregnancy rates in patients with thyroid autoantibodies. Nonetheless, increased incidence of early pregnancy loss has also been documented in these cases. Miscarriage rate figures of 53% and 23% were reported for patients with and without thyroid autoantibodies respectively, following assisted reproduction treatment cycles (32). Three to five folds increase in miscarriage rates have also been reported in euthyroid patients with thyroid autoantibodies (33, 34). This risk was independent of the presence of anti nuclear or anti cardiolipin antibodies for miscarriages in spontaneously pregnant women (35, 36). Furthermore, Abbassi-Ghanavati et al in 2010 have reported a detrimental effect of antithyroid peroxidase antibodies on the placenta (37). They documented threefold higher placental abruption rate in antibodies positive (1.0%) compared to antibodies negative pregnant women (0.3%).

An association between thyroid autoantibodies and reduced thyroid reserve has been shown, with a tendency of these patients to become hypothyroid during pregnancy and controlled ovarian hyperstimulation. Higher levels of TSH and lower levels of free T4 have been reported in patients after controlled ovarian hyperstimulation, in comparison to pre-treatment levels (38). Furthermore, significantly higher TSH and lower free T4 levels were seen during the first 10 weeks of pregnancy in women with thyroid autoantibodies compared to antibodies negative women (39). These endocrine changes figured in one of the three theories used to explain the increased risk of early pregnancy loss in patients with thyroid autoantibodies by Kaprara and Krassas in 2008 (40). Another hypothesis suggested that the presence of such antibodies was just a reflection of a more generalised autoimmune problem which resulted in fetal tissues rejection. The third hypothesis suggested that women with thyroid antibodies usually conceived at an older age than others who had no autoantibodies, because of the related infertility. Consequently, the increased risk of age should be taken into consideration in these cases. Many arguments have been put forward in support of each of these different theories, which are beyond the remit of this chapter. However, it was evident that there were no contradictions between these 3 hypotheses. They might be variably functional together or separately in different individuals, to different degrees. It remains to be said that the real pathophysiological association between thyroid autoantibodies and early pregnancy miscarriages awaits further clarification. Reduction of thyroid reserve in patients with thyroid peroxidase antibodies is further demonstrated by a relative risk of 12.9 for developing long-term thyroid dysfuncion if a patient developed postnatal hypothyroidism as well. This relative risk reached 32 in patients who also showed hypoechoic thyroid changes on ultrasound scans (41).

Various reports documented contradictory outcome following thyroxine medication during pregnancy on the miscarriage rate in euthyroid women with thyroid autoantibodies. This was true even for the same investigators as a beneficial effect was reported when larger numbers of patients were re-examined (42, 43). Negro et al reported miscarriage rates of 3.5% and 13.8%, and premature delivery rates of 7.0% and 22.4% in the thyroxine treated and untreated groups respectively; p<.05 (43). On the whole, some beneficial effects for thyroxine treatment on pregnancy outcome have been shown, but further work needs to be done to establish this fact beyond any doubts. This is especially so for pregnancies that followed assisted reproduction treatment, as the strain on the thyroid gland had already started during controlled ovarian hyperstimulation with gonadotrophins.


Selenium and thyroid function

Many articles have been published in recent years regarding the importance of selenium in relation to thyroid function. A positive correlation was reported between selenium blood levels and the volume of the thyroid gland (44). Its importance stems from the fact that selenoproteins play an important role in the redox system, and for enzymatic reduction of hydro-peroxidase in the thyroid gland, thus protecting it from excessive hydrogen peroxide and reactive free oxygen species (45, 46). Furthermore, selenium dependent enzymes have modifying effects on the immune system (47), especially on the development of autoimmune thyroid disorders (44). In addition, selenium deficiency during pregnancy and the puerperium may trigger postpartum thyroiditis (45). Similarly, many articles have also demonstrated reduction in thyroid peroxidase antibodies (48 - 50), as well as well as improvement in mood and general wellbeing (51) following selenium medication. Supplementation during pregnancy and the postpartum period reduced thyroid inflammatory activity and the incidence of hypothyroidism as reported by Negro et al in 2007 (49). Withdrawal of supplementation resulted in sharp drop in selenium blood level, and marked increase in the level of the thyroid peroxidase antibodies (50). This is a an important subject as supplementation of women with subclinical hypothyroidism and peroxidase positive euthyroid women with daily doses of 100 – 200 µg of selenium may help in slowing down the progress of the disease. However, unlike levothyroxine medication, selenium supplementation during pregnancy did not reduce the incidence of preterm deliveries as reported by a recent Cochrane database review (52).


Effects of hyperthyroidism

Hyperthyroidism is defined as a TSH concentration <0.10 mIU/L with an elevated free T4 level (53). It may affect 2% of women between the ages of 20 and 50 years. The majority of cases are due to Grave’s disease, with 15-20% caused by nodular goitre (54). Uncontrolled thyroxine medication can be an important factor as well. Hyperthyroidism leads to increased hepatic production of SHBG, as well as blood haemostatic factors. Such hypercoagulable state is evident even in patients with subclinical hyperthyroidism (55), which is generally diagnosed when TSH levels are persistently <0.10 mIU/L with normal free T4 concentration. Thyroxine also modifies GnRH pulsatility, and increases the sensitivity of the pituitary gland to GnRH stimulation. This may result in increased production of gonadotrophins by the pituitary gland, mainly LH. Consequently, there is increased production of testosterone and androstenedione by the ovaries. There is also reduced clearance of oestradiol leading to a hyperoestrogenic state with hyperthyroidism. The final outcome is 2-3 fold increased production of oestradiol during both the follicular and luteal phases of the menstrual cycle. Despite these biochemical changes, many women with hyperthyroidism ovulate regularly, as shown by endometrial biopsies (56). Nonetheless, they have low luteal phase serum progesterone, despite having regular menstruation. As for hypothyroidism, the quoted incidence of menstrual irregularities in women with hyperthyroidism declined over the yeas for the same reason. A figure of 21.5% has been quoted within a group of 214 thyrotoxic patients by Krassas in 2000 (57).

Information regarding the prevalence of infertility in women with hyperthyroidism is not readily available. A figure of 5.8% has been reported by Joshi et al in 1993 (58). Menstrual irregularities were reported in 22% of hyperthyroid patients, with hypomenorrhoea and polymenorrhoea being the most common (52% and 32% respectively). The prevalence of hypomenorrhoea reflects the increased concentration of the clotting factors alluded to before. Such menstrual abnormalities were 2.5 times more common in hyperthyroid patients in comparison to a control group (59). Patients usually respond well to treatment with carbimazole, but it should not be used by women who are planning to get pregnant. Propylthiouracil should be prescribed instead, as it is safer to use during pregnancy. Management of hyperthyroidism should be agreed with a medical endocrinologist, who should set the general management plan. Normal ovulatory function may not resume quickly, despite correction of the blood TSH and free T4 levels. The effect of hyperthyroidism on the pituitary gland may take longer time to correct. These patients may still show exaggerated LH production by the pituitary gland in response to GnRH stimulation test, for many weeks after initiating treatment with carbimazole, and the correction of the peripheral biochemical blood picture.

It is usually easy to diagnose overt hyperthyroidism because of the associated symptoms of weight loss, sweating, tremors, palpitations and occasionally eye signs. Nonetheless, many women may live with subclinical hyperthyroidism without being aware of its existence. The incidence of subclinical hyperthyroidism has been reported as 1.5% in the general population (59, 60). Accordingly, the condition should be kept in mind in gynaecology clinics when dealing with patients presenting with menstrual irregularities, especially hypomenorrhoea or polymenorrhoea. This is especially so in the presence of high blood levels of FSH, LH and oestradiol. On the other hand, subclinical hyperthyroidism is less detrimental during pregnancy and treatment does not improve pregnancy outcome, with an increased risk of fetal exposure to antithyroid drugs.


The thyroid gland and menopause

The incidence of thyroid disease increases with age, more so in women than men. The prevalence of overt and subclinical conditions in postmenopausal women has been reported as 2.4% and 23.2%, respectively by Schindler in 2003 (61). Within the subclinical group, 73.8% were hypothyroid and 26.2% hyperthyroid, as reported by the same author who recommended routine screening of thyroid function during the climacteric period.

The importance of thyroid gland dysfunction during the postmenopausal period is related to the following three points:

1.  Many symptoms of thyroid gland dysfunction are similar to hypoestrogenic ones, and can be missed accordingly. A long list includes memory loss, depression, neuromuscular complaints, loss of energy, dry skin, cognitive impairment in hypothyroid patients, and vasomotor symptoms with hyperthyroidism. All these symptoms can be seen even with mild thyroid dysfunction.

2. Many cases of thyroid dysfunction are subclinical, and both the doctor and the patient may not be aware of the condition. Accordingly, there is real danger of converting a subclinical case of hypothyroidism into an overt one by prescribing HRT.

3. Thyroid dysfunction at this age group is associated with different health risks including cardiac problems and osteoporosis. Increased cardiac risks are related to increased serum cholesterol and low density lipoprotein cholesterol, as well as reduced levels of high density lipoprotein. The most common symptom related to subclinical hyperthyroidism in this age group is cardiac arrhythmia, and 15% may develop thromboembolic complications. An adjusted hazard ratio of 1.98 was reported for atrial fibrillation in 65 year old women with subclinical hyperthyroidism in comparison to a normal control group (62). A population based study published by Parle et al in 2001 (63) showed 2-3 folds increased mortality in women aged 60 years or older with subclinical hyperthyroidism within 2-5 years after a single measurement of low TSH. Yet again, in another population based study involving older women with an average age of 69 years, Hak et al (64) found subclinical hypothyroidism to be a strong indicator or risk factor for atherosclerosis and myocardial infarction, with odd ratios of 1.7 and 2.3 respectively. The association was even stronger for thyroid autoantibodies positive women with subclinical hypothyroidism. The corresponding odd ratios for atherosclerosis and myocardial infarction were 1.9 and 3.1 respectively. On the other hand, a significant increase in osteoporosis risk is related to hyperthyroidism, both clinical and subclinical. This stresses the need for strict control of the hyperthyroid state, and for oestrogen replacement therapy to counteract this detrimental effect.

It is evident by now that both overt and subclinical thyroid dysfunctions could pose significant health related issues on postmenopausal women. The involvement of gynaecologists in well woman and postmenopausal management clinics dictates that thorough knowledge of this information is essential. There is reduced need for thyroxine with advanced age. Accordingly, care should be taken when prescribing thyroxine, because of the age related increased incidence of cardiovascular diseases. Accordingly, a small starting dose of 25 µg / day should be used, when indicated. The dose can be increased slowly with equivalent amounts every few weeks to avoid cardiovascular complications. Similarly, overdosing with thyroxine can lead to osteoporosis. The situation is rather reversed with HRT. Oestrogen medication though beneficial for both the acute and late menopausal symptoms, it can convert patients with subclinical hypothyroidism into clinical cases. In return, the thyroxine dose may need to be increased for patients already on medication. All this information stresses the need to ascertain thyroid function and cardiovascular status before starting such medications in patients at risk of clinical or subclinical hypothyroidism or hyperthyroidism. Though treatment of patients with subclinical thyroid dysfunction is controversial, it has been recommended that such treatment should be considered in women with TSH ≥10 mIU/L, symptomatic women with subclinical hypothyroidism and TSH value <10 mIU/L, and in women with subclinical hyperthyroidism who have TSH level <0.1 mIU/L (65).


Interpretation of thyroid indices

Within a gynaecology outpatient setup, thyroid gland investigations are usually indicated in patients with abnormal pubertal development, menstrual dysfunction, infertility, recurrent miscarriages, galactorrhoea and high prolactin level, premature ovarian failure, excessive weight gain, and during investigations of symptomatic postmenopausal women. This is especially so in patients with family history of thyroid disease, personal or family history of autoimmune dysfunction, history of thyroid surgery, thyroid enlargement, and in patients with symptoms or signs suggestive of thyroid dysfunction. Serum TSH and free T4 are the basic investigations usually started with. The effect of HRT and oral contraceptives on TSH and total T4 has been alluded to before. In certain cases assessment of free T3 and thyroid peroxidase antibodies will be needed. These indices can be interpreted as follows, as documented by MacFarlane in 2000 (54):

  • Blood tests should be repeated in asymptomatic patients with high TSH level > 10 IU/L and free T4 <10 pmol/L to confirm the diagnosis, guard against laboratory errors and to avoid treatment of patient with transient thyroiditis.
  • Secondary hypothyroidism should be excluded in patients with persistent low free T4 and normal TSH.
  • TSH blood levels > 5 mIU/L with normal free T4 indicate subclinical hypothyroidism in asymptomatic women. These tests should be repeated together with thyroid peroxidase antibodies. Patients with confirmed readings but negative peroxidase antibodies should have regular follow up with similar blood tests. In contrast, patients with similar readings and positive peroxidase antibodies need treatment with thyroxine.
  • High TSH level with normal free T4 in a patient already on thyroxine usually reflects irregular medication. She should be encouraged to take her medication regularly, and to test compliance with further blood tests.
  • Normal free T4 and T3 with undetectable TSH level in a patient taking thyroxine is not an indication to reduce the dose.
  • A normal TSH level usually excludes thyrotoxicosis, except with TSH producing pituitary tumours.
  • Undetectable or low TSH blood level should suggest a diagnosis of thyrotoxicosis, if confirmed with high levels of free T4 and T3. In some cases only T3 level is raised.

At this point it is important to emphasise the need for regular follow up of patients with subclinical hypothyroidism. Within a 10-years follow up period, 34% of 154 women with a similar diagnosis progressed to overt hypothyroidism (66). The most important predictor for such conversion was the presence of thyroid peroxidase antibodies. In a clinical perspective published as early as 2001, McDermott and Ridgway (4) emphasised the clinical importance of this entity and recommended L-thyroxine treatment for symptomatic patients, those with relevant cardiovascular risk factors or goitre, those who tested positive to thyroid peroxidase antibodies, and pregnant women. 


Summary

This chapter has been written with gynaecologists and the gynaecological patients in mind. Women with frank hypo-or-hyperthyroidism are usually diagnosed and managed in-between the primary care unit and a hospital medical endocrinologist. Nevertheless, many patients with thyroid dysfunction present for the first time with gynaecological problems. At the same time, many others will be seen by gynaecologists while under treatment, or had previously been treated for a thyroid problem. The high incidence of hypothyroidism both overt and subclinical in women, and their correlation to disturbed reproductive function dictate that gynaecologists should be aware of the diagnosis and management plan of such patients, both in the pregnant and non-pregnant states. This entails thorough awareness of the several interactions between the HPT axis with the corresponding ovarian and adrenal ones. The effects of exogenous oestrogens including the oral contraceptive pills and HRT, other medications, assisted reproduction treatment and pregnancy on the function of the thyroid gland should be appreciated. Other autoimmune disorders should be kept in mind when dealing with patients with personal or family history of autoimmune thyroid disease. Common autoimmune disorders tend to coexist and cluster in families. The frequency of another autoimmune disorder was reported by Boelaert et al as 9.67% and 14.3% in patients with Grave’s disease and Hashimoto’s thyroiditis, respectively (67). The list included Addison’s disease, vitiligo, coeliac disease, systemic lupus erythematosus and pernicious anaemia. Accordingly, the same authors recommended that patients with autoimmune thyroid disease should be screened for other autoimmune disorders, especially when they present with new or nonspecific symptoms.

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