Thyroid Disease in Women:Thyroid Disease in Women:Common DilemmasCommon Dilemmas

David F. Gardner, M.D.David F. Gardner, M.D.

Professor of MedicineProfessor of MedicineDivision of EndocrinologyDivision of Endocrinology

Virginia Commonwealth Univ.Virginia Commonwealth Univ.School of MedicineSchool of Medicine

I have no conflicts of interest I have no conflicts of interest to report.to report.

Five QuestionsFive Questions::

Should women routinely be screened for Should women routinely be screened for thyroid disease?thyroid disease?

Should women with subclinical Should women with subclinical hypothyroidism receive any treatment?hypothyroidism receive any treatment?

What is a normal TSH level?What is a normal TSH level? How should hypothyroidism in pregnancy How should hypothyroidism in pregnancy

be managed?be managed? What is appropriate thyroid hormone What is appropriate thyroid hormone

replacement rx in hypothyroid women? replacement rx in hypothyroid women?

Case 1Case 1::

A 46 year old woman comes to your office for A 46 year old woman comes to your office for her yearly check-up. She has no complaints her yearly check-up. She has no complaints and physical examination is normal. You are and physical examination is normal. You are about to send her to the lab, when she asks if about to send her to the lab, when she asks if you are going to do any thyroid tests. She you are going to do any thyroid tests. She recently read that all women should be recently read that all women should be “screened” for possible thyroid disease. What “screened” for possible thyroid disease. What do you do now?do you do now?

Question 1Question 1::

Should a serum TSH be a routine Should a serum TSH be a routine component of the periodic health component of the periodic health examination in women?examination in women?

Is a serum TSH the best screening Is a serum TSH the best screening test?test?

Yes!! With the exception of the rare Yes!! With the exception of the rare patient with secondary hypothyroidism, patient with secondary hypothyroidism, a serum TSH is the best screening test a serum TSH is the best screening test for both hyperthyroidism and for both hyperthyroidism and hypothyroidism.hypothyroidism.

Consensus StatementsConsensus Statements::

US Preventive Services Task ForceUS Preventive Services Task Force: : Recommends screening only in newbornsRecommends screening only in newborns

Expert Panel (JAMA, Jan 04)Expert Panel (JAMA, Jan 04): There is insufficient : There is insufficient evidence to support population-based screening. evidence to support population-based screening.

American College of Ob-GynAmerican College of Ob-Gyn: No guidelines : No guidelines regarding testing in woman pre-conception or regarding testing in woman pre-conception or during pregnancyduring pregnancy

American College of PhysiciansAmerican College of Physicians: Screening of : Screening of women >50 “may be indicated”women >50 “may be indicated”

ATA (JAMA, 2000)ATA (JAMA, 2000): Adults should be screened : Adults should be screened for thyroid dysfunction with a serum TSH for thyroid dysfunction with a serum TSH beginning at age 35 and every 5 years thereafterbeginning at age 35 and every 5 years thereafter

Institute of Medicine evaluation of the Institute of Medicine evaluation of the advisability of covering TSH advisability of covering TSH measurements in Medicare patients:measurements in Medicare patients:

After analyzing available evidence and After analyzing available evidence and doing a cost-benefit analysis, the IOM doing a cost-benefit analysis, the IOM found the evidence for a benefit of found the evidence for a benefit of screening to be lacking, and therefore screening to be lacking, and therefore determined that coverage for screening determined that coverage for screening should not be provided as a Medicare should not be provided as a Medicare benefit . (2003)benefit . (2003)

Joint Statement of AACE, ATA and Joint Statement of AACE, ATA and Endocrine Society:Endocrine Society:

Potential benefits of early detection and treatment Potential benefits of early detection and treatment of thyroid dysfunction outweigh the potential side of thyroid dysfunction outweigh the potential side effects that could result from early detection and effects that could result from early detection and therapy…. Therefore, we favor screening for therapy…. Therefore, we favor screening for subclinical thyroid dysfunction in adults, including subclinical thyroid dysfunction in adults, including pregnant women and those contemplating pregnant women and those contemplating pregnancy. pregnancy.

ThyroidThyroid, January, 2005, January, 2005

Are there subsets of asymptomatic Are there subsets of asymptomatic women who should be screened?:women who should be screened?:

Women over the age of 60Women over the age of 60 Women with other autoimmune disorders, Women with other autoimmune disorders,

including Type 1 diabetesincluding Type 1 diabetes Women with a strong family history of Women with a strong family history of

thyroid diseasethyroid disease Women with hypercholesterolemiaWomen with hypercholesterolemia Women with psychiatric disordersWomen with psychiatric disorders Women taking lithium, amiodarone, or Women taking lithium, amiodarone, or

interferon-alphainterferon-alpha

Are there subsets of women who shouldAre there subsets of women who should be screened?be screened?::

Women with prior history of thyroid diseaseWomen with prior history of thyroid diseaseWomen planning pregnancy or soon after Women planning pregnancy or soon after

conception conception Women who have had previous head and Women who have had previous head and

neck irradiationneck irradiationWomen with MS or primary pulmonary Women with MS or primary pulmonary

hypertensionhypertensionWomen with Down or Turner syndromesWomen with Down or Turner syndromes

Case 2Case 2::

A 56 year old woman presents with a question regarding A 56 year old woman presents with a question regarding recent thyroid studies. “Screening” labwork by her Ob-recent thyroid studies. “Screening” labwork by her Ob-Gyn showed a TSH of 7.1 uU/ml (0.35-5.5). A Gyn showed a TSH of 7.1 uU/ml (0.35-5.5). A subsequent free T4 was 1.3 ng/dl (normal 0.8-1.8). She subsequent free T4 was 1.3 ng/dl (normal 0.8-1.8). She feels well, but does report some fatigue, and a 3-4 lb feels well, but does report some fatigue, and a 3-4 lb weight gain in the last year. Examination is normal and weight gain in the last year. Examination is normal and she appears she appears clinicallyclinically euthyroid. She understands that a euthyroid. She understands that a high TSH indicates hypothyroidism and wants to know if high TSH indicates hypothyroidism and wants to know if she should be started on a thyroid supplement. she should be started on a thyroid supplement.

What’s the diagnosis and should she be treated? What’s the diagnosis and should she be treated?

The diagnosis is subclinical The diagnosis is subclinical hypothyroidismhypothyroidism::

Elevated serum TSH concentration and Elevated serum TSH concentration and normal serum thyroid hormone levels in an normal serum thyroid hormone levels in an apparently asymptomatic patientapparently asymptomatic patient

Prevalence is 5-10% in general population, Prevalence is 5-10% in general population, with women over 60 having a prevalence as with women over 60 having a prevalence as high as 15-20%high as 15-20%

Most commonly due to autoimmune thyroid Most commonly due to autoimmune thyroid diseasedisease

Question 2Question 2::

Should women with subclinical Should women with subclinical hypothyroidism be treated with hypothyroidism be treated with l-thyroxine? l-thyroxine?

Biondi & Cooper, Endocrine Reviews, 2008Biondi & Cooper, Endocrine Reviews, 2008

What are the clinical consequences What are the clinical consequences subclinical hypothyroidism?:subclinical hypothyroidism?:

Progression to overt hypothyroidismProgression to overt hypothyroidism

Abnormal lipidsAbnormal lipids

Increased risk of cardiovascular diseaseIncreased risk of cardiovascular disease

Neuropsychiatric symptomsNeuropsychiatric symptoms

What is the likelihood of progression What is the likelihood of progression to overt hypothyroidism?to overt hypothyroidism?::

There is significant risk, particularly inThere is significant risk, particularly in1. Older patients (>60)1. Older patients (>60)2. Patients with positive thyroid antibodies2. Patients with positive thyroid antibodies3. Women—in one study 3. Women—in one study annualannual rate of rate of progression to overt hypothyroidism was 4.3%progression to overt hypothyroidism was 4.3%

in women with +TPO antibodies, 3.0% if no ab’s in women with +TPO antibodies, 3.0% if no ab’s 4. Patients with TSH>104. Patients with TSH>105. Patients with prior history of radioactive 5. Patients with prior history of radioactive

iodine treatment or thyroid surgeryiodine treatment or thyroid surgery

On the other hand,On the other hand, in some in some patients with SCHypo, thepatients with SCHypo, theTSH will spontaneously return TSH will spontaneously return into the normal range (4-30% in into the normal range (4-30% in different series)—i.e. no rush to different series)—i.e. no rush to start thyroxine therapy. start thyroxine therapy.

Lipids in Subclinical HypothyroidismLipids in Subclinical Hypothyroidism::

Relationship is controversialRelationship is controversialSeveral cross-sectional studies show Several cross-sectional studies show

increased TC and LDL-Cincreased TC and LDL-CLikelihood of abnormality is greater in Likelihood of abnormality is greater in

patients with TSH>10patients with TSH>10

Walsh et al. Busselton Health Study. Walsh et al. Busselton Health Study. Clin Endocrinol, 2005.Clin Endocrinol, 2005.Cross-Sectional Data:Cross-Sectional Data:

NN LDL-Chol (mmol/L)LDL-Chol (mmol/L)

Euthyroid Controls 1906 Euthyroid Controls 1906 3.5 3.5++1.01.0SCHypo SCHypo 119 119 4.1 4.1++1.2* 1.2* SCHypo (TSH>10.0) 23 SCHypo (TSH>10.0) 23 4.3 4.3++1.3**1.3** *p<0.01 vs. controls *p<0.01 vs. controls**p<0.001 vs. controls**p<0.001 vs. controls

Does treatment of SCHypo have Does treatment of SCHypo have beneficial effect on lipidsbeneficial effect on lipids::

Villar et al. (Cochrane Data Base Rev, Villar et al. (Cochrane Data Base Rev, 2007) - meta-analysis of 12 clinical trials: 2007) - meta-analysis of 12 clinical trials: no effectno effect of T4 rx on total, LDL, HDL of T4 rx on total, LDL, HDL cholesterol, triglyceridescholesterol, triglycerides

In In sixsix other randomized trials, comparing other randomized trials, comparing T4 with placebo, there T4 with placebo, there waswas significant significant lowering of LDL and total cholesterol lowering of LDL and total cholesterol

Meier et al. JCEM, 2001Meier et al. JCEM, 2001

Summary of SCHypo and LipidsSummary of SCHypo and Lipids::

There is a consistent but modest There is a consistent but modest association of SCHypo with increased association of SCHypo with increased total and LDL cholesteroltotal and LDL cholesterol

Correction of SCHypo has modest Correction of SCHypo has modest expected effect of decreasing LDL and expected effect of decreasing LDL and total cholesteroltotal cholesterol

Is there increased risk of Is there increased risk of cardiovascular disease in cardiovascular disease in subclinical hypothyroidism?subclinical hypothyroidism?

Biondi & Cooper, Endo Rev, 2008Biondi & Cooper, Endo Rev, 2008::

In some epidemiological studies the In some epidemiological studies the risk of CHD was increased in young risk of CHD was increased in young and middle-aged patients but not in and middle-aged patients but not in elderly patients with SCHypo. Indeed, elderly patients with SCHypo. Indeed, SCHypo appeared to exert a SCHypo appeared to exert a protective cardiovascular effect in protective cardiovascular effect in patients older than 85.patients older than 85.

Copyright ©2008 The Endocrine Society

Biondi, B. et al. Endocr Rev 2008;29:76-131

FIG. 4. Hypothetical relationship between age and effect of SHypo on cardiovascular disease

Biondi & Cooper, Endo Rev, 2008Biondi & Cooper, Endo Rev, 2008:: There is no evidence that treatment of There is no evidence that treatment of subclinical hypothyroidism has any subclinical hypothyroidism has any impact on the risk of developing CHD impact on the risk of developing CHD or on all-cause and cardiovascular or on all-cause and cardiovascular mortality! Perhaps, treatment should mortality! Perhaps, treatment should be avoided in the very elderly be avoided in the very elderly (Gussekloo et al.).(Gussekloo et al.).

Neuropsychiatric SymptomsNeuropsychiatric Symptoms

Critical questions areCritical questions are::

1. Do patients with SCHypo truly have1. Do patients with SCHypo truly have more symptoms than age-matched more symptoms than age-matched euthyroid controls? euthyroid controls?

2. Does treatment with thyroxine 2. Does treatment with thyroxine ameliorate symptoms? ameliorate symptoms?

Canaris et al.: Colorado Thyroid Disease Canaris et al.: Colorado Thyroid Disease Prevalence Study, Arch Int Med, 2000Prevalence Study, Arch Int Med, 2000::

Cross-sectional study of 25,862 Cross-sectional study of 25,862 participants in statewide health fairparticipants in statewide health fair

Responses to a hypothyroid Responses to a hypothyroid symptoms questionnaire were symptoms questionnaire were recorded in 2336 patients with recorded in 2336 patients with SCHypoSCHypo

Compared with euthyroid controls, patients Compared with euthyroid controls, patients with SCHypo significantly more often with SCHypo significantly more often reported symptoms, as follows:reported symptoms, as follows:

Dry skin (28%, p<0.001)Dry skin (28%, p<0.001) Poor memory (24%, p<0.001)Poor memory (24%, p<0.001) Slow thinking (22%, p<0.001)Slow thinking (22%, p<0.001) Muscle weakness (22%, p<0.001)Muscle weakness (22%, p<0.001) Fatigue (18%, p<0.01)Fatigue (18%, p<0.01) Muscle cramps (17%, p<0.001)Muscle cramps (17%, p<0.001) Cold intolerance (15%, p<0.001)Cold intolerance (15%, p<0.001) Puffy eyes (12%, p<0.05)Puffy eyes (12%, p<0.05) Constipation (8%, p<0.05)Constipation (8%, p<0.05)

Many other studies do Many other studies do notnot support an association of support an association of SCHypo with any symptoms!SCHypo with any symptoms!

Bell et al., 2007Bell et al., 2007::

Community-based x-sectional study of Community-based x-sectional study of 1423 “non-healthcare-seeking 1423 “non-healthcare-seeking women”—mean age 54women”—mean age 54

Utilized Short-Form 36 (SF-36) and Utilized Short-Form 36 (SF-36) and Psychological General Well-Being Index Psychological General Well-Being Index (PGWI) to evaluate health-related QOL(PGWI) to evaluate health-related QOL

SCHypo defined as TSH > 4.0SCHypo defined as TSH > 4.0

Clin Endocrinol, 66:548, 2007

Bell et al., 2007Bell et al., 2007::

There were no differences between There were no differences between women with SCHypo (n=80) and age-women with SCHypo (n=80) and age-matched euthyroid controls (n=240) in matched euthyroid controls (n=240) in terms of:terms of:– Anti-depressant useAnti-depressant use– PGWI score PGWI score – SF-36 mental composite scoreSF-36 mental composite score– SF-36 physical composite scoreSF-36 physical composite score

The presence of symptoms in The presence of symptoms in patients with SCHypo remains patients with SCHypo remains controversial, and symptoms, controversial, and symptoms, when present are non-specific. when present are non-specific.

Biondi & Cooper, Endo Rev, 2008

Does treatment improve signs Does treatment improve signs and symptoms of hypothyroidism, and symptoms of hypothyroidism, quality of life, and psychometric quality of life, and psychometric tests in patients with SCHypo?tests in patients with SCHypo?

At least 12 placebo-controlled At least 12 placebo-controlled studies have addressed these studies have addressed these issues and the results are issues and the results are conflicting!conflicting!

Summary: Treatment of Summary: Treatment of Subclinical HypothyroidismSubclinical Hypothyroidism::

No studies have demonstrated an adverse No studies have demonstrated an adverse effect from correction of subclinical effect from correction of subclinical hypothyroidismhypothyroidism

Patients with serum TSH > 10 uU/mL Patients with serum TSH > 10 uU/mL appear to derive the greatest benefits from appear to derive the greatest benefits from treatmenttreatment

Adverse effects of therapy are only related Adverse effects of therapy are only related to cost and overtreatment--in one study of to cost and overtreatment--in one study of 339 elderly patients on T4 rx, 339 elderly patients on T4 rx, 41%41% had low had low TSH levels (Somwaru, JCEM, 2009)TSH levels (Somwaru, JCEM, 2009)

It seems reasonable to recommend It seems reasonable to recommend therapy for the following patients:therapy for the following patients:

TSH>10 uU/mlTSH>10 uU/mlPositive thyroid autoantibodiesPositive thyroid autoantibodiesLipid abnormalitiesLipid abnormalitiesPsychiatric patients, especially those Psychiatric patients, especially those

with depression/bipolar disorderswith depression/bipolar disordersHistory of radioactive iodine History of radioactive iodine

treatment or previous thyroid surgerytreatment or previous thyroid surgery

It seems reasonable to recommend It seems reasonable to recommend therapy for the following patients:therapy for the following patients:

Pregnant womenPregnant womenWomen with infertilityWomen with infertility““Younger” patients (<60-70 y/o), Younger” patients (<60-70 y/o),

especially those with cardiovascular especially those with cardiovascular risk factors (DM, dyslipidemia, risk factors (DM, dyslipidemia, hypertension, smoking, etc.)hypertension, smoking, etc.)

Avoid therapy in the “oldest” oldAvoid therapy in the “oldest” old

All patients with subclinical All patients with subclinical hypothyroidism hypothyroidism notnot receiving treatment must be closely treatment must be closely monitored for the development monitored for the development of overt hypothyroidism.of overt hypothyroidism.

Case 3:Case 3:

A 46 year old woman presents to your office for follow-A 46 year old woman presents to your office for follow-up of her longstanding hypothyroidism. She is taking l-up of her longstanding hypothyroidism. She is taking l-thyroxine 125 ug/d, and reports that she is feeling thyroxine 125 ug/d, and reports that she is feeling “pretty well”, except for some fatigue and a 5 lb weight “pretty well”, except for some fatigue and a 5 lb weight gain over the last year. Physical examination is normal. gain over the last year. Physical examination is normal. Thyroid studies are as follows:Thyroid studies are as follows:

Free T4Free T4 1.2 ng/ml (0.8-1.8)1.2 ng/ml (0.8-1.8)TSHTSH 4.84.8 uU/ml (0.35-5.5) uU/ml (0.35-5.5)

Should you make any changes in her dose of thyroid Should you make any changes in her dose of thyroid hormone replacement?hormone replacement?

Question 3Question 3::

What is the normal TSH reference What is the normal TSH reference range and what level of TSH should be range and what level of TSH should be targeted in the treatment of hypothyroid targeted in the treatment of hypothyroid patients? patients?

What level of TSH should be targeted?What level of TSH should be targeted?::

Simple answer: TSH within the normal range Simple answer: TSH within the normal range for the assay utilized—usually 0.35 – 5.5 mIU/Lfor the assay utilized—usually 0.35 – 5.5 mIU/L

BUT….there is now accumulating body of BUT….there is now accumulating body of evidence that the upper limit of normal for most evidence that the upper limit of normal for most assays is too high and appropriate upper limit assays is too high and appropriate upper limit could becould be as low as 2.5 – 3.0 mIU/L. as low as 2.5 – 3.0 mIU/L.

This is based on studies that rigorously exclude This is based on studies that rigorously exclude subjects with even the mildest degrees of subjects with even the mildest degrees of thyroid failure in determining the normal rangethyroid failure in determining the normal range

Studies addressing normal TSH range:Studies addressing normal TSH range:

Bjoro et al. (Eur J Endocrinol, 2000): Norway, Bjoro et al. (Eur J Endocrinol, 2000): Norway, Upper limits of normal: men Upper limits of normal: men 3.43.4; women ; women 3.63.6

Kratzsch et al. (Clin Chem, 2005): Germany, Kratzsch et al. (Clin Chem, 2005): Germany, Normal range: Normal range: 0.30 – 3.630.30 – 3.63

NHANES III (JCEM, 2002): United States, NHANES III (JCEM, 2002): United States, Normal range: Normal range: 0.45 – 4.120.45 – 4.12

Jensen et al. (Clin Chem Lab Med, 2004): Jensen et al. (Clin Chem Lab Med, 2004): Denmark, Normal range: Denmark, Normal range: 0.58 - 4.070.58 - 4.07

Hamilton et al. (JCEM, 2008): United States, Hamilton et al. (JCEM, 2008): United States, Normal range: Normal range: 0.55 - 4.100.55 - 4.10

TSH distribution progressively shifts TSH distribution progressively shifts toward higher concentrations in older toward higher concentrations in older populations:populations: TSH ULNTSH ULNAge 20-29Age 20-29 3.56 3.56Age 60-69Age 60-69 4.33 4.33Age 70-79Age 70-79 5.90 5.90Age >80Age >80 7.49 7.49

Surks & Hollowell. JCEM, 2007Surks & Hollowell. JCEM, 2007

ConclusionsConclusions::

The prevalence of subclinical The prevalence of subclinical hypothyroidism may be significantly hypothyroidism may be significantly overestimated unless an age-specific overestimated unless an age-specific range for TSH is used.range for TSH is used.

My opinionMy opinion::

The upper limit of normal for the The upper limit of normal for the serum TSH concentration is probably serum TSH concentration is probably between 3.0 and 4.0 mIU/mLbetween 3.0 and 4.0 mIU/mL

A reasonable target TSH for most A reasonable target TSH for most patients with primary hypothyroidism patients with primary hypothyroidism is in the 1.0 – 3.0 mIU/L rangeis in the 1.0 – 3.0 mIU/L range

Important CaveatsImportant Caveats::

Lowering the upper limit of normal for Lowering the upper limit of normal for serum TSH to 2.5-3.0 will result in ~25 serum TSH to 2.5-3.0 will result in ~25 million more Americans being diagnosed million more Americans being diagnosed with hypothyroidismwith hypothyroidism

There is no evidence that treating patients There is no evidence that treating patients with TSH in 3-5 mIU/L range is beneficialwith TSH in 3-5 mIU/L range is beneficial—in fact, benefits of treating patients with —in fact, benefits of treating patients with TSH levels in 5-10 range are TSH levels in 5-10 range are controversial.controversial.

Case 4Case 4::

A 28 year old woman with longstanding A 28 year old woman with longstanding hypothyroidism on l-thyroxine therapy comes hypothyroidism on l-thyroxine therapy comes to you to discuss her plans for starting a to you to discuss her plans for starting a family some time in the next 6 months. She family some time in the next 6 months. She asks if there will be any problems related to asks if there will be any problems related to her current treatment with l-thyroxine. her current treatment with l-thyroxine.

Question 4Question 4::

What is the potential impact of What is the potential impact of pregnancy on thyroxine treatment in pregnancy on thyroxine treatment in hypothyroid women?hypothyroid women?

Thyroxine replacement during pregnancyThyroxine replacement during pregnancy::

The daily dose of thyroxine to maintain The daily dose of thyroxine to maintain the euthyroid state in pregnancy will the euthyroid state in pregnancy will increase in 50-70% of womenincrease in 50-70% of women

Average dose increase ranges from Average dose increase ranges from 20-50%20-50%

Increased T4 requirements may be Increased T4 requirements may be apparent as early as 5-6 weeks of apparent as early as 5-6 weeks of gestationgestation

Mean Serum FTMean Serum FT44 and TSH before and TSH before

and during pregnancy (n=25):and during pregnancy (n=25):

BeforeBefore DuringDuring

T T44 dose (ug/day) dose (ug/day) 112 112 112 112

Serum FT Serum FT44 (ng/dL) 1.60 (ng/dL) 1.60 0.84 0.84

Serum TSH (uU/mL) 1.44 Serum TSH (uU/mL) 1.44 14.1 14.1

Kaplan, 1992 Kaplan, 1992

RecommendationsRecommendations::

Adjust T4 rx to serum TSH<2.0 prior to Adjust T4 rx to serum TSH<2.0 prior to pregnancypregnancy

Check TSH early in pregnancy—by week 5-6Check TSH early in pregnancy—by week 5-6 Monitor TSH every 5-6 weeks during 1Monitor TSH every 5-6 weeks during 1stst half of half of

pregnancy; less often in 2pregnancy; less often in 2ndnd half of pregnancy half of pregnancy T4 dose adjustments should be based on T4 dose adjustments should be based on

trimester-specific TSH normal ranges—e.g. trimester-specific TSH normal ranges—e.g. normal range in 1normal range in 1stst trimester is 0.10 – 2.5 trimester is 0.10 – 2.5

Separate T4 ingestion by at least 3-4 hours Separate T4 ingestion by at least 3-4 hours from iron supplements, calcium supplements, from iron supplements, calcium supplements, multivitamins, and soy milkmultivitamins, and soy milk

Thyroid Hormone Early Adjustment in Pregnancy Thyroid Hormone Early Adjustment in Pregnancy (The THERAPY) Trial. Yassa et al., JCEM, 2010(The THERAPY) Trial. Yassa et al., JCEM, 2010

Prospective trial of empiric ~29% Prospective trial of empiric ~29% increase in T4 dose (2 extra tablets per increase in T4 dose (2 extra tablets per week) when pregnancy confirmedweek) when pregnancy confirmed

Intervention significantly reduced risk of Intervention significantly reduced risk of maternal hypothyroidism in 1maternal hypothyroidism in 1stst trimester trimester

Only 2 of 25 women required a dose Only 2 of 25 women required a dose reduction due to over-replacementreduction due to over-replacement

Only 2 of 25 women required a further Only 2 of 25 women required a further dose increasedose increase

Thyroid Hormone Early Adjustment in Pregnancy Thyroid Hormone Early Adjustment in Pregnancy (The THERAPY) Trial. Yassa et al., JCEM, 2010(The THERAPY) Trial. Yassa et al., JCEM, 2010

ConclusionsConclusions– 29% increase in maternal T4 at 29% increase in maternal T4 at

confirmation of pregnancy reduces risk of confirmation of pregnancy reduces risk of maternal hypothyroidism in first trimestermaternal hypothyroidism in first trimester

– Monitoring thyroid function once monthly Monitoring thyroid function once monthly is required through “mid-pregancy”, is required through “mid-pregancy”, ~week 20~week 20

– The protocol appears safe and mimics The protocol appears safe and mimics normal thyroid gestational physiologynormal thyroid gestational physiology

B. What are the adverse effects B. What are the adverse effects of maternal hypothyroidism?of maternal hypothyroidism?

Morbidity Associated with Hypothyroidism Morbidity Associated with Hypothyroidism During PregnancyDuring Pregnancy::

Spontaneous miscarriagesSpontaneous miscarriagesGestational hypertension and Gestational hypertension and

preeclampsiapreeclampsiaPremature deliveryPremature delivery Increased frequency of neonatal ICU Increased frequency of neonatal ICU

admissionsadmissions Increased fetal mortalityIncreased fetal mortality Impaired neuropsychological developmentImpaired neuropsychological development

Children of Children of Children of Children of Treated Untreated Treated Untreated Women with Women with Control Women with Women with Control Hypothyroidism Hypothyroidism Children Hypothyroidism Hypothyroidism Children (N=14) (N=48) (N=124) (N=14) (N=48) (N=124)

Full Scale IQ Score 111 100* 107Full Scale IQ Score 111 100* 107

% with IQ % with IQ <<85 0 19* 585 0 19* 5

Freedom fromFreedom fromdistractibility score 103 97* 102distractibility score 103 97* 102

Verbal IQ score 111 101* 107Verbal IQ score 111 101* 107

Performance IQ score 109 99* 105Performance IQ score 109 99* 105

*P-value *P-value <<0.01 for comparison of untreated vs. control children0.01 for comparison of untreated vs. control children

ConclusionConclusion::

Undiagnosed hypothyroidism in pregnant Undiagnosed hypothyroidism in pregnant women may adversely affect their fetuses; women may adversely affect their fetuses; therefore, screening for thyroid deficiency therefore, screening for thyroid deficiency during pregnancy during pregnancy maymay be warranted. be warranted.

Unresolved IssueUnresolved Issue::

Should Should allall women be screened for women be screened for hypothyroidism prior to or shortly after hypothyroidism prior to or shortly after conception?conception?

  ■■RECOMMENDATION 74RECOMMENDATION 74There is insufficient evidence to recommend There is insufficient evidence to recommend for or against TSH testing for or against TSH testing preconceptionpreconception in in women at high risk for hypothyroidism. women at high risk for hypothyroidism. Level Level I-USPSTFI-USPSTF

  ■■RECOMMENDATION 76RECOMMENDATION 76Serum TSH values should be obtained Serum TSH values should be obtained early in pregnancyearly in pregnancy in women at high in women at high risk for overt hypothyroidismrisk for overt hypothyroidismLevel B-USPSTFLevel B-USPSTF

Case 5Case 5::

A 52 year old woman returns for follow-up of A 52 year old woman returns for follow-up of longstanding hypothyroidism. She is doing well longstanding hypothyroidism. She is doing well on brand-name of l-thyroxine, but she has read on brand-name of l-thyroxine, but she has read that a combination of T4/T3 is superior to T4 that a combination of T4/T3 is superior to T4 alone and wonders whether that would be a alone and wonders whether that would be a good idea for her. In addition, at the time of her good idea for her. In addition, at the time of her last refill, she was told by her pharmacist that last refill, she was told by her pharmacist that she could save some money by switching to a she could save some money by switching to a generic T4 preparation. What should you tell generic T4 preparation. What should you tell her? Thyroid studies done one week prior to her? Thyroid studies done one week prior to her visit showed a TSH of 1.2 uU/mL.her visit showed a TSH of 1.2 uU/mL.

Question 5Question 5::

Are all l-thyroxine preparations Are all l-thyroxine preparations therapeutically equivalent? Should therapeutically equivalent? Should combination T4/T3 preparations be combination T4/T3 preparations be used?used?

Are all levothyroxine preparations Are all levothyroxine preparations therapeutically equivalent?therapeutically equivalent?

Appropriate studies comparing all Appropriate studies comparing all available brand-name and generic available brand-name and generic preparations have not been performed, preparations have not been performed, so a definitive answer is not available!so a definitive answer is not available!

Cost DifferencesCost Differences::

BrandBrand Cost of 90 0.1 mg tabsCost of 90 0.1 mg tabs

Synthroid Synthroid $63.97 $63.97 LevoxylLevoxyl 44.97 44.97 GenericGeneric 25.97 25.97

So difference in cost for one year supply So difference in cost for one year supply of Synthroid vs. generic = $152of Synthroid vs. generic = $152

Source: www.drugstore.com

Endocrine Society, ATA, AACE Endocrine Society, ATA, AACE “Best Physician Practices” Guidelines“Best Physician Practices” Guidelines::

Patients should be maintained on the same Patients should be maintained on the same brand name l-thyroxine productbrand name l-thyroxine product

Change from one brand to another, change Change from one brand to another, change from a brand to a generic product, or change from a brand to a generic product, or change from one generic to another generic requires from one generic to another generic requires repeat TSH testing in 6-8 weeksrepeat TSH testing in 6-8 weeks

Small differences in l-thyroxine doses may Small differences in l-thyroxine doses may have significant adverse clinical outcomeshave significant adverse clinical outcomes

My OpinionMy Opinion::

Use a brand name preparation and Use a brand name preparation and consistently prescribe that brand for a consistently prescribe that brand for a given patient. Any change in brand or given patient. Any change in brand or to a generic requires a follow-up TSH to a generic requires a follow-up TSH in 6-8 weeks.in 6-8 weeks.

Should combination T4/T3 Should combination T4/T3 preparations be used?preparations be used?

NO!NO!

NEJM, 340: 424-429, 1999NEJM, 340: 424-429, 1999

T4-T3 Therapy vs. T4 Monotherapy for T4-T3 Therapy vs. T4 Monotherapy for Hypothyroidism: Meta-Analysis of Hypothyroidism: Meta-Analysis of Randomized Controlled Trials:Randomized Controlled Trials:

Included 11 studies with total of 1216 patients Included 11 studies with total of 1216 patients No difference was found between treatments for No difference was found between treatments for

any of the following: depression, anxiety, bodily any of the following: depression, anxiety, bodily pain, fatigue, quality of life, body weight, total and pain, fatigue, quality of life, body weight, total and LDL cholesterol, and triglyceridesLDL cholesterol, and triglycerides

Adverse events did not differ between regimensAdverse events did not differ between regimens Conclusion: T4 monotherapy should remain the Conclusion: T4 monotherapy should remain the

treatment of choice for hypothyroidismtreatment of choice for hypothyroidism

J Clin Endocrinol Metab, 2006J Clin Endocrinol Metab, 2006

Conclusions from available Conclusions from available studies:studies:

There is insufficient evidence at There is insufficient evidence at this time to support the routine this time to support the routine addition of T3 to T4 replacement addition of T3 to T4 replacement in hypothyroid patients. Results in hypothyroid patients. Results of the Bunevicius study have not of the Bunevicius study have not been confirmed in subsequent been confirmed in subsequent RCT’s.RCT’s.