All about of thyroid functions

Thyroid Function

What are the fallacies of reports of T4 highly recommended by endocrinologist? Surprised to know that Free T4 may be fallacious-Why such comments by Dr Pal!!!? Let us face the facts & pl let me know if U have any objections to my reasoning: : Measurements of free serum T₄ and T₃ are complicated by the low levels of free hormone in systemic circulation, with only 0.02% to 0.03% of T₄ and 0.2% to 0.3% of T₃ circulating in the unbound state .Of the T₄ and T₃ in circulation, approximately 70% to 75% is bound to TBG, 10% to 15% attached to prealbumin, 10% to 15% bound to albumin, and a minor fraction (<5%) is bound to lipoprotein.

Then should we order for “Total thyroid measurements” ?? No not at all. Because  are dependent on levels of TBG, which are variable and affected by many conditions such as pregnancy, oral contraceptive pill use, estrogen therapy, hepatitis, and genetic abnormalities of TBG. Thus, assays for the measurement of free T₄ and T₃ are more clinically relevant than measuring total thyroid hormone levels.

There are many different laboratory techniques to measure estimated free serum T₄ and T₃. These methods invariably measure a portion of free hormone that is dissociated from the in vivo protein bound moiety. This is of little clinical significance assuming the same proportions are measured for all assays and considered in the calibration of the assay.. The T₃ resin uptake test in an example of one laboratory method used to estimate free T₄ in the serum. The T₃ resin uptake (T₃ RU) determines the fractional binding or radiolabeled T₃, which is added to a serum sample in the presence of a resin that competes with TBG for T₃ binding. The binding capacity of TBG in the sample is inversely proportional to the amount of labeled T₃ bound to the artificial resin. Therefore, a low T₃ resin uptake indicates high TBG T₃ receptor site availability and implies high circulating TBG levels.

The free T₄ index (FTI) is obtained by multiplying the serum T₄ concentration by the T₃ resin uptake percentage, yielding an indirect estimate of the levels of free T₄:

T₃ RU% X T₄ total= free T₄ index.

A high T₃ RU percentage indicates reduced TBG receptor site availability and high free T₄ index and thus hyperthyroidism, whereas a low T₃ resin uptake percentage is a result of increased TBG receptor site binding and thus hypothyroidism. Equilibrium dialysis and ultrafiltration techniques may be used to determine the free T4 directly.  Free T4 and T3 may also be determined by radioimmunoassay.

How relevant is Free T4?? Most available laboratory methods used for determining estimations or free T4 are able to correct for moderate variations in serum TBG but are prone to error in the setting of large variations of serum TBG, when endogenous T4 antibodies are present, and in the setting of inherent albumin abnormalities .

Because most disorders of hyperthyroidism and hypothyroidism are related to dysfunction of the thyroid gland and TSH levels are sensitive to excessive or deficient levels of circulating thyroid hormone, TSH levels are used to screen for these disorders.

 What about TSH? Unlike hCG assay dilemma due to phantom hCG Current  thyrotropin or TSH sandwich immunoassays are extremely sensitive and capable of differentiating low-normal from pathologic or iatrogenically subnormal values and elevations. Q. 1. Stump the Endocrinologists with your own knowledge :- Well  if U refer yor Pt to an  endocrinologist she will  be offered an appointment after 6 months!  Am  I right my dear members?? Out of  six commonly  available tests (excluding thyroid  USG & radioactive I uptake) – If, as a clinician  you are allowed to prefer number of thyroid tests as minimum as possible  which parameter  you  will  U  bank most? Ans:-Of all the several parameters used for assessing   thyroid functions like i) TSH, ii) ft4,iii) Ft3, iv) TPO (thyroid peroxidase antibodies, v) antibodies to the thymoglobulin  & lastly vi)  TSH receptor stimulating antibodies the most helpful for the clinician is TSH estimation . This index is most cost effective. ,

Q.2.:-Any other feather on the cap of TSH? Because most disorders of hyperthyroidism and hypothyroidism are related to dysfunction of the thyroid gland and TSH levels are sensitive to excessive or deficient levels of circulating thyroid hormone, TSH levels are used to screen for these disorders.

Q .3.Acknowledging the fact that TSH test is most effective but is this test is full proof for diagnosing hypo or hyperthyroidism? The answer is no; Acknowledging the facts that firstly 1) Current thyrotropin or TSH sandwich immunoassays are extremely sensitive and capable of differentiating low-normal from pathologic or iatrogenically subnormal values and elevations. & 2) that TSH measurements provide the best way to screen for thyroid dysfunction and accurately predict thyroid hormone dysfunction but its sensitivity is about 80% of cases.

Q.4. We should be very cautious while interpreting the values of TSH!!! What are the problem or pitfall if the clinician concerned is a bit casual or relies too much on TSH values. The question or clinical dilemma is “Should we order for TSH alone, particularly when pt can afford and or clinical suspicion is strong?

Q.4. Old men talk too much!! Which state my dear meber belong to ? Dilemma in reference values of TSH in diff regions of India!!! -How best to determine normal basal value of TSH ? Who will standardize in reference to dietary total iodine intake including I present in drinking water.?  Let us first be aware how the “Reference values for TSH” –i.e. population specific TSH in a given geographical area traditionally estimated & standardized as percentile? It is based on the central 95% of values for healthy individuals, and some controversy exists regarding the upper limit of normal. The clinicians should realize and keep in mind that “Values in the upper limit of normal”à  may predict future thyroid disease .In a longitudinal study, women with positive thyroid antibodies (TPOAbs or TgAbs), the prevalence of hypothyroidism at follow-up was 12.0% (when baseline TSH was 2.5 mU/L or less, 55.2% for TSH between 2.5 and 4.0mU/L, and 85.7% for TSH above 4.0 mU/L.

Q. 5. Gynaecologists must know internal medicine too.:  Q, .5.  What else, as a clinician ,we should be aware off? Anything else that should be kept in the back of our mind?  Physicians ordering TSH should be aware of its limitations. Because in following clinical conditions TSH levels may false alter albeit temporarily .Such clinical situations ate 1) in the setting or acute illness, 2)  central hypothyroidism,3)  the presence of heterophile antibodies, and 4)  TSH autoantibodies. .

Q. 6. Prof S Pal. :-Are you a voting booth agent for TSH? Why not to insist on estimation of active form thyroid hormone i.e. FT3? 02% to 0.03% of T₄ and 0.2% to 0.3% of T₃ circulating in the unbound state .Of the T₄ and T₃ in circulation, approximately 70% to 75% is bound to TBG, 10% to 15% attached to prealbumin   , 10% to 15% bound to albumin, and a minor fraction (<5%) is bound to lipoprotein. Assuch TSH is a better market except possibly in early preg and other 5 clinical conditions as sated earlier?

As a gynecologist U may not know location of  uterus or cervix but must be aware of ABC of immunology!!! Now . Q.7. What happens when heterophile antibodies are present? In the setting of heterophile antibodies or even in TSH autoantibodies (SCH-subclinical hypothyroidism), TSH values will be falsely elevated.

Q.8Having acquired knowledge on “internal medicine “ & “immunology” now be acquainted with biochemistry of sialylation of TSH, FSH hCG molecules!!!  . What happens in cases of central hypothyroidism, decreased “sialylation of TSH”, This increased sialylation results in a longer half-life and a reduction in bioactivity, Therefore  TSH levels may be elevated or normal when the patient remains clinically hypothyroid in states of central hypothyroidism, and successful treatment is often associated with low or undetectable TSH levels.

Q.9. Back to immunology again :- What are the antigens present in the thyroid gland capable of producing auto antibodies? Such are 1)  thyroglobulin, (Tg), 2) second  antigen called- Thyroid peroxidase(TPO), & lastly the third known 3) antigen called TSH receptor .Antibodies can be evoked against all these three antigens in own body and we must analyze  such  report of antibody titer in a meaningful way.

Table 31.10 Thyroid Autoantigens
Antigen	Location	Function
Thyroglobulin (Tg)	Thyroid	Thyroid hormone storage
Thyroid peroxidase (TPO) (microsomal antigen)	Thyroid	Transduction of signal from TSH
TSH receptor (TSHR)	Thyroid, lymphocytes, fibroblasts, adipocytes (including retro-orbital), and cancers	Transduction of signal from TSH
Na+/l- symporter (NIS)	Thyroid, breast, salivary or lacrimal gland, gastric or colonic mucosa, thymus, pancreas	ATP-driven uptake of l- along with Na+

TSH, thyroid-stimulating hormone; ATP, adenosine triphosphate

Immunologic Abnormalities

Many antigen-antibody reactions affecting the thyroid gland can be detected. Antibodies to TgAb, the TSH receptor (TSHRAb), TPOAb, the sodium iodine symporter (NISAb), and to thyroid hormone were identified and implicated in autoimmune thyroid disease states .A number of recognized thyroid autoantigens. Antibody production to thyroglobulin depends on a breach in normal immune surveillance .The incidence of thyroid autoantibodies in various autoimmune thyroid disorders is shown in Antithyroglobulin antibodies are predominantly in the noncomplement fixing, polycolonal, immunoglobulin-G (IgG) class. Antithyroglobulin antibodies are found in 35% to 60% of patients with hypothyroid autoimmune thyroiditis, 12% to 30% of patients with Graves disease, and 3% of the general population .,Antithyroglobulin antibodies are associated with acute thyroiditis, nontoxic goiter, and thyroid cancer .

Previously referred to as anti-microsomal antibodies, TPO antibodies are directed against thyroid peroxidase and are found in Hashimoto thyroiditis, Graves’s disease, and postpartum thyroiditis. The antibodies produced are characteristically cytotoxic, complement-fixing IgG antibodies. In patients with thyroid autoantibodies, 99% will have positive anti-TPO antibodies, whereas only 36% will have positive antithyroglobulin antibodies, making anti-TPO a more sensitive test for autoimmune thyroid disease.

 Anti-TPO antibodies are present in 80% to 90% of patients with hypothyroid autoimmune thyroiditis, 45% to 80% of patients with Graves’s disease, and 10% to 15% of the general population, these antibodies can cause artifact in the measurement of thyroid hormone levels. Antithyroid peroxidase antibodies are used clinically in

Table 31.11 Prevalence of Thyroid Autoantibodies and their Role in Immunopathology
Antibody	General Population	Hypothyroid Autoimmune Thyroiditis	Graves Disease
Antithyroglobulin (TgAb)	3%	35%-60%	12%-30%
Anti-microsomal thyroid peroxidase (TPOAb)	10%-15%	80%-99%	45%-80%
Anti-TSH receptor (TSHRAb)	1%-2%	6%-60%	70%-100%
Anti-Na/l symporter (NISAb)	0%	25%	20%

TSH, thyroid-stimulating hormone.

Table 31.12 Nomenclature of Anti-TSH Receptor Antibodies
Abbreviation	Term	Assay Used	Refers To
LATS	Long-acting thyroid stimulator	In vivo assay of stimulation of mouse thyroid	Original description of serum molecule able to stimulate mouse thyroid; no longer used
TSHRAb, TRAb	TSHR antibodies	Competitive and functional  assays described below	All antibodies recognizing the TSH receptor (includes TBII (competitive), and TSI, TBI and TNI (functional) based on assay method
TBII	TSHR-binding inhibitory immunoglobulin	Competitive binding assays with TSH	Antibodies able to compete with TSH for TSH receptor binding irrespective of biologic activity
TSI (also TSAb)	TSHR-stimulating immunoglobulins	Competitive and functional bioassays of TSH receptor activation	Antibodies able to block TSH receptor binding, induce cAMP production and nonclassical signaling cascades
TBI (also TSBAb, TSHBAb	TSHR stimulation-blocking antibodies	Functional bioassays of TSH receptor activation	Antibodies able to block TSH receptor binding, induce cAMP production with +/- effects on nonclassical cascades
TNI	TSHR nonbinding immunoglobulin	Binding and functional assays	No TSH binding, no effect on cAMP levels and variable effects on nonclassical cascades

TSH, thyroid-stimulating hormone.

 the diagnosis of Graves disease, the diagnosis of chronic autoimmune thyroiditis, in conjunction with TSH testing as a means to predict future hypothyroidism in subclinical hypothyroidism, and to assist in the diagnosis of autoimmune thyroiditis in euthyroid patients with goiter or nodules (348).

Autoimmune Thyroid Disease

The case cited by Dr Pal is a case of  with subfertility problem who is on neomercazole Ry for 5 yrs. She   is an autoimmune thyroid disorder which however, represents the combined effects of the multiple thyroid autoantibodies .The various antigen-antibody reactions result in the wide clinical spectrum of these disorders.

Q.10.           about foetus if she conceives on neomercazole?? Well, there is  a definite threat for “transplacental transmission of some of these immunoglobulins” & secondly of ingested antithyroid drugs like neomercazole  in which she is better(In fact she was never switched  over  to PPU-prpolylthiouracil . All these may, but not always affect thyroid function in the fetus. The presence of autoimmune thyroid disorders, particularly Graves’s disease, is associated with other autoimmune conditions: Hashimoto thyroiditis, Addison disease, ovarian failure, rheumatoid arthritis, Sjogren syndrome, diabetes mellitus (type 1), vitiligo, pernicious anemia, myasthenia gravis, and idiopathic thrombocytopenic purpura. Foetus may have some other prtrobelm unrelated to affection of thyroid fauntion possibly. Such association are  with the development of autoimmune thyroid disorders include 1) low birth weight,2)  iodine excess and deficiency, selenium deficiency, parity, oral contraceptive pill use, reproductive age span, fetal microchimerism, stress, seasonal variation, allergy, smoking, radiation damage to the thyroid, and viral and bacterial infections Now coming to SCH:-Recommendations for Testing and Treatment

Overt and subclinical hypothyroidism are defined as an elevated TSH with a low T₄ and an elevated TSH and normal T₄, respectively, using appropriate patient ranges (nonpregnant and pregnant). A number of professional organizations published various recommendations for thyroid function assessment via a TSH in women. Because of the long interval from development of disease to diagnosis, the nonspecific nature of symptoms, and the potential adverse neonatal and maternal outcomes associated with untreated hypothyroidism in pregnancy, the American Association of Clinical Endocrinologists (AACE) recommended screening women prior to conceiving or at the first prenatal appointment .

The AACE also recommended screening for the presence of hypothyroidism in patients with type 1 diabetes mellitus (threefold increased risk of postpartum thyroid dysfunction and 33% prevalence overall), patients taking lithium therapy (35% prevalence), and consideration of testing in patients presenting with infertility (>12% prevalence) or depression (10% to 12% prevalence), as these populations are at an increased risk of hypothyroidism . A screening TSH was recommended in women starting at the age of 50 because of the increased prevalence of hypothyroidism in this population . Thyroid function testing at 6-month intervals was recommended for patients taking amiodarone, as hyperthyroidism or hypothyroidism occurs in 14% to 18% of these patients . Any woman with a history of postpartum thyroiditis should be offered annual surveillance of thyroid function, as 50% of these patients will develop hypothyroidism within 7 years of diagnosis .

Because there is a high prevalence of hypothyroidism in women with Turner and Down syndrome, an annual check of thyroid function is recommended for these patients .

Alternatively, the Endocrine Society’s clinical practice guidelines regarding the management of thyroid dysfunction during pregnancy and postpartum recommends targeted screening for the following individuals: history of thyroid disorder, family history of thyroid disease, goiter, thyroid autoantibodies, clinical signs or symptoms of thyroid disease, autoimmune disorders, infertility, head and/or neck radiation, and preterm delivery .The American Congress of Obstetricians and Gynecologists accepted these recommendations for TSH testing .Because of the (i) potentially significant neurologic affects on the fetus and other adverse pregnancy events; (ii) physiologic rise in TBG and the TSH-like activity of hCG in pregnancy, and (iii) potential for the targeted screening groups to have overt or subclinical hypothyroidism defined by the reference ranges for pregnancy (TSH <2.5, 3.1 and 3.5 μIU/mL for the first, second, and third trimesters, respectively), targeted maternal testing for hypothyroidism is encouraged. The targeted screening protocol allows that 30% of subclinical hypothyroidism cases may be missed. According to these recommendations, preconceptionally diagnosed hypothyroid women (overt or subclinical) should have their T₄ dosage adjusted such that the TSH value is less than 2.5 μIU/mL before pregnancy. The T₄ dosage in women already on replacement will routinely require a dose escalation (30% to 50%) at 4 to 6 weeks gestation in order to maintain a TSH value less than 2.5μIU/mL.

Pregnant women with overt hypothyroidism should be normalized as rapidly as possible to maintain TSH at less than 2.5 and 3 μIU/mL in the first, second, and third trimesters, respectively. Euthyroid women with thyroid autoantibodies are at risk of hypothyroidism and should have TSH careening in each trimester.

 After delivery, hypothyroid women need a reduction in T₄ dosage used pregnancy. Because subclinical hypothyroidism is associated with adverse outcomes for mother and the fetus, T₄ replacement is recommend.

Hashimoto Thyroiditis

Hashimoto thyroiditis, or chronic lymphocytic thyroiditis, was firstdescribed in 1912 by Dr. Hakaru Hashimoto. Hashimoto thyroiditis can manifest as hyperthyroidism, hypothyroidism, euthyroid goite, or diffuse goiter. High levels of antimicrosomal and antithyroglobulin antibody are usually present, and TSHRAb may be present . Typically, glandular hypertrophy is found, but atrophic forms are also present.

What are the three classic types of autoimmune injure are found in Hashimoto thyroiditis: (i) complement-mediated cytotoxicity, (ii) antibody-dependent cell-mediated cytotoxicity, and (iii) stimulation or blockade of hormone receptors, which result in hypo-or hyperfunction or growth The histologic picture of Hashimoto thyroiditis includes cellular hyperplasia, disruption or follicular cells, and infiltration of the gland y lymphocytes, monocytes, and plasma cells. Occasionally, adjacent lymphadenopathy may be noted. Some epithelial cells are enlarged and demonstrate oxyphilic changes in the cytoplasm (Askanazy cells or Hurthle cells, which are not specific to this disorder). The interstitial cells show fibrosis and lymphocytic infiltration. Graves disease and Hashimoto thyroiditis may cause very similar histologic findings manifested by a similar mechanism of injury.

Treatment of Hashimoto Disease as is in this case seeking fertility enhancing TR ??

Thyroxine replacement is initiated in patients with clinically overt hypothyroidism or subclinical hypothyroidism with a goiter. Regression of gland size usually does not occur, but treatment often prevents further growth of the thyroid gland. Treatment is recommended for patients with subclinical hypothyroidism in the setting or a TSH greater than 10mIU/L on repeat measurements, pregnant patients, a strong habit of tobacco use, signs or symptoms associated with thyroid failure, or patients with severe hyperlipidemia  .

All pregnant patients with an elevated TSH level should be treated with levothyroxine. Treatment does not slow progression of the disease. The initial dosage of levothyroxine may be as little as 12.5 μg per day up to up to a full replacement dose. The mean replacement dosage of levothyroxine is 1.6 μg/kg or body weight per day, although the dosage varies greatly between patients .Aluminum hydroxide (antacids), cholestyramine, iron, calcium, and sucralfate may interfere with absorption. Rifampin and sertraline hydrochloride may accelerate the metabolism of levothyroxine is nearly 7 days; therefore, nearly 6 weeks of treatment are necessary before the effects of a dosage change can be evaluated.

Hypothyroidism appears to be associated with decreased fertility resulting from disruption in ovulation, and thyroid autoimmune disease is associated with an increased risk of pregnancy loss with or without overt thyroid dysfunction .A meta-analysis of case-control and longitudinal studies performed since 1990 reveals a possible association between miscarriage and thyroid antibodies wi6th an odds ratio of 2.73 (95% CI, 2.20 – 3.40). This association may be explained by a heightened autoimmune state affecting the fetal allograft or a slightly higher age of women with antibodies compared with those without antibodies (0.7 + 1 year, p <.001) (342). Studies suggest that early subclinical hypothyroidism may be associated with menorrhagia (383).

Severe primary hypothyroidism is associated with menstrual irregularities in 23% of women, with oligomenorrhea being the most common (382). Reproductive dysfunction in hypothyroidism may be caused by a decrease in the binding activity of sex hormone-binding globulin, resulting in increased estradiol and free testosterone and from hyperprolactinemia .The increase in prolactiin levels is the result of enhanced sensitivity of the prolactin-secreting cells to TRH (with elevated TRH seen in primary hypothyroidism) and defective dopamine turnover resulting in hyperprolactinemia (348-387). Hyperprolactinemia-induced luteal phase defects are associated with less severe forms of hypothyroidism .Replacement therapy appears to reverse the hyperprolactinemia and correct ovulatory defects .

Combined thyroxine and triiodothyronine therapy is no more effective than thyroxine therapy alone, and patients with hypothyroidism should be treated with thyroxine alone .

Clinical Characteristics and Diagnosis

The class is triad in Graves disease consists of exophthalmos, goiter, and hyperthyroidism.

The symptoms associated with Graves disease include frequent bowel movements, heat intolerance, irritability, nervousness, heart palpitations, impaired fertility, vision changes, sleep disturbances, tremor, weight loss, and lower extremity swelling. Physical findings may include lid lag, notender thyroid enlargement (two to four times normal), onycholysis, dependent lower extremity edema, palmar erythema, proptosis, staring gaze, and thick skin. A cervical venous bruit and tachycardia may be noted. The tachycardia does not respond to increased vagal tone produced with a Valsalva maneuver. Severe cases may demonstrate acropachy, chemosis, clubbing, dermopathy, exophthalmos with ophthalmoplegia, follicular conjunctivitis, pretibial, myxedema, and vision loss.

Approximately 40% of patients with new onset of Graves disease and many of those previously treated have elevated T₃ and normal T₄ levels. Abnormal T₄ or T₃ results are often caused by protein binding changes rather than altered thyroid function; therefore assessment of free T₄ and free T₃ is indicated in conjunction with TSH. In Graves, the TSH levels are suppressed, and levels may remain undetectable for some time even after the initiation of treatment. Thyroid autoantibodies, including TSI, may be useful during pregnancy to more accurately predict fetal risk of thyrotoxicosis /Autonomously functioning benign thyroid neoplasms that exhibit

Table 31.14 Potential Causes of Hyperthyroidism

Factitious hyperthyroidism

Graves disease

Metastatic follicular cancer

Pituitary hyperthyroidism

Postpartum thyroiditis

Silent hyperthyroidism (low radioiodine uptake)

Struma ovarii

Subacute thyroiditis

Toxic multinodular goiter

Toxic nodule

Tumors secreting human chorionic gonadotropin (molar pregnancy, choriocarcinoma)

a similar clinical picture include toxic adenomas and toxic multinodular goiter. A radioactive iodine uptake thyroid scan may help differentiate these two conditions from Graves disease. Rare conditions resulting in thyrotoxicosis include metastatic thyroid carcinoma causing thyrotoxicosis, amiodarone induced thyrotoxicosis, iodine induced thyrotoxicosis, postpartum thyroiditis, a TSH-secreting pituitary adenoma, an hCG- secreting chofiocarcinoma, struma ovarii, and “de Quervan’s” or sbuacute thyroiditis .Factitious ingestion of thyroxine or desiccated thyroid should be considered in patients with eating disorders. Patients with thyrotoxicosis factitia demonstrate elevated T₃ and T₄ suppressed TSH, and a low serum thyroglobulin level, whereas other causes of thyroiditis and thyrotoxicosis demonstrate high levels of thyroglobulin. Potential causes of hyperthyroidism are listed in

Antithyroid  Drugs

Antithyroid drugs of the thioamide class include propylthiouracil (PTU) and methimazole. Low doses of either agent block the secondary coupling reactions that form T₃ and T₄ from MIT and DIT. At higher doses, they also block iodination of tyrosy1 residues in thyroglobulin, Propylthiouracil additionally blocks the peripheral conversion of T4 to T3. Approximately one-third of patients treated by this approach alone go into remission and become euthyroid .

Hyperthyroidism in Gestational Trophoblastic Disease and Hyperemesis Gravidarum

Because of the weak TSH-like activity of hCG, conditions with levels of hCG, such as molar pregnancy, may be associated with biochemical and clinical hyperthyroidism. Symptoms regress with removal or the abnormal trophoblastic  tissue and resolution of elevated levels of hCG. In a similar fashion, when hyperemesis gravidarum is associated with high levels of hCG, mile biochemical and clinical features of hyperthyroidism may be seen . Thyroid Function in Pregnancy

Physicians should be aware of the changes in thyroid physiology during pregnancy. Pregnancy is associated with reversible changes in thyroid physiology that should be noted before diagnosing thyroid abnormalities for pregnancy associated changes in TBG, total T_4, hCG, TSH, and free T₄) .

hypothyroidism Women with a history of hypothyroidism often require increased thyroxine replacement during pregnancy, and patients should have thyroid function tests performed at the first prenatal visit and during each trimester thereafter. Evidence suggests that optimal fetal and infant neurodevelopmental outcomes may require careful titration of replacement thyroxine that meets the frequently .increased requirements of pregnancy Reproductive Effects of Hyperthyroidism

High levels of TSAb (TSI) in women with Graves disease are associated with fetal-neonatal hyperthyroidism .Despite both the inhibition and elevation of gonadotropins seen in thyrotosicosis, most women remain ovulatory and fertile .severe thyrotoxicosis can result in weight loss, menstrual cycle irregularities, and amenorrhea. An increased risk of spontaneous abortion is noted in women with thyrotoxicosis. An increased incidence of congenital anomalies, particularly choanal atresia and possibly aplasia cutis, can occur in the offspring of women treated with methimazole .

Autoimmune hyperthyroid Graves disease may improve spontaneously, in which case antithyroid drug therapy may be reduced or stopped. TSHRAb production may persist for several years after radical radioactive iodine therapy or surgical treatment for hyperthyroid Graves disease. In this circumstance, there is a risk of exposing a fetus to TSHRAb.

Fetal-neonatal hyperthyroidism is observed in 2% to 10% of pregnancies occurring in mothers with a current or previous diagnosis of Graves disease, secondary to the transplacental passageof maternal TSHRAb. This is a serious condition with a 16% neonatal mortality rate and a risk of intrauterine fetal death, stillbirth, and skeletal developmental abnormalities, such as craniosynostosis. Caution against overtreatment with antithyroid medication is warranted, as these medications may cross the placenta in sufficient quantities to induce fetal goiter.  Guidelines for TSHRAb testing during pregnancy in women with previously treated Graves disease. Fetal goiters and the associated fetal hypo-or hyperthyroid status were diagnosed accurately in mothers with Graves disease using a combination of fetal ultrasonography of the thyroid with Doppler, fetal heart rate monitoring, bone maturation, and maternal TSHRAb and antithyroid drug status .

Postpartum Thyroid Dysfunction

Postpartum thyroid dysfunction is much more common than recognized; it is often difficult to diagnose because its symptoms appear 1 to 8 months postpartum and are often confused with postpartum depression and difficulties adjusting to the demands of the neonate and infant. Postpartum thyroiditis appears to be caused by the combination of a rebounding immune system in the postpartum state and the presence of thyroid autoantibodies. Histologically,

Table 31.15 Guidelines for TSHRAb Testing During Pregnancy with Previously Treated Graves Disease

In the woman with antecedent Graves disease in remission after ATD treatment, the risk for fetal-neonatal hyperthyroidism is negligible, and systematic measurement of TSHRAb is not necessary.

Thyroid function should be evaluated during pregnancy to detect an unlikely but possible recurrence. In that case, TSHRAb assay is mandatory.

In the woman with antecedent Graves disease previously treated with radioiodine or thyroidectomy and regardless of the current thyroid status (euthyroidism with or without  thyroxine substitution), TSHRAb should be measured early in pregnancy to evaluate the risk for fetal hyperthyroidism.

If the TSHRAb level is high, careful monitoring of the fetus is mandatory for the early detection of signs of thyroid overstimulation (tachycardia, impaired growth rate, oligohydramnios, goiter). Cardiac echography and measurement of circulatory velocity may be confirmatory. Ultrasonographic measurements of the fetal thyroid have been defined from 20 weeks gestational age but require a well-tranied operator, and thyroid visibility may be hindered because of fetal head position. Color Doppler ultrasonography is helpful in evaluating thyroid hypervascularization. Because of the potential risks of fetal-neonatal hyperthyroid cardiac insufficiency and the inability to measure the degree of hypethyroidism in the mother because of previous thyroid ablation, it may be appropriate to consider direct diagnosis in the fetus. Fetal blood sampling through cordocentesis is feasible as early as 25 to 27 weeks gestation with less than 1% adverse effects (fetal bleeding, bradycardia, infection, spontaneous abortion, in utero death) when performed by experienced clinicians. ATD administration to the mother may be considered to treat the fetal hyperthyroidism.

In the woman with concurrent hyperthyroid Graves disease, regardless of whether it has preceded the onset of pregnancy, ATD treatment should be monitored and adjusted to keep free T₄ in the high-normal range to prevent fetal hypothyroidism and minimize toxicity associated with higher doses of these medications.

TSHR-Ab should be measured at the beginning of the last trimester, especially if the required ATD dosage is high. If the TSHRAb assay is negative or the level low, fetal-neonatal hyperthyroidism is rare. If antibody levels are high (TBII ≥40 U/L or TSAb ≥300%), evaluation of the fetus for hyperthyroidism is required. In this condition, there is usually a fair correlation between maternal and fetal thyroid function such that monitoring the ATD dosage according to the mother’s thyroid status is appropriate for the fetus. In some cases in which a high dose of ATD >20 mg/d of methimazole or >300 mg/d of propylthiouracil [PTU] is necessary, there is a risk of goitrous hypothyroidism in the fetus, which might be indistinguishable from goitrous Graves disease. The correct diagnosis relies on the assay of fetal thyroid hormones and TSH, which allows for optimal treatment.

Antithyroid Antibodies and Disorders of Reproduction

Women who have antithyroid autoantibodies before and after conception appear to be at an increased risk for spontaneous abortion .

Nonorgan-specific antibody production and pregnancy loss are documented in cases of antiphospholipid abnormalities . The concurrent presence of organ-specific thyroid antibodies and nonorgan-specific autoantibody production is not uncommon (429-431). In cases of recurrent pregnancy loss, thyroid autoantibodies may serve as peripheral markers of abnormal T-cell function and further implicate an immune component as the cause of reproductive failure. The clinical implications of these findings in management of patients with recurrent pregnancy loss are not known. Hypothalamic— pituitary (HP) causes of amenorrhea and ovulatory dysfunction

Primary HP amenorrhea is rare. If Kallmann syndrome (congenital HP amenorrhea associated with anosmia or hypo-osmia) is suspected, genetic counseling should be carried out before attempting pregnancy. Secondary HP amenorrhea due to stress, exercise and eating or weight disorders is mediated through the hypothalamic centers for gonadotropin-releasing hormone (GnRH). Treatment should be aimed at correction the underlying condition. Secondary amenorrhea due to pituitary infarction or blood-loss shock (Sheehan’s syndrome) is associated with adrenocorticotropic hormone (ACTH) and thyroid-stimulating hormone (TSH) deficiency, which should be corrected before attempting pregnancy.