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
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.
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
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.
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
· 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.
effects of thyroid dysfunction
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
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).
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).
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
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.
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.
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).
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.
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
- 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
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
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
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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