Here are my recommendations for the 56 year old woman with subclinical hypothyroidism: 1. Her diagnosis is subclinical hypothyroidism based on an elevated TSH of 7.1 and normal free T4. 2. Given her age (56), fatigue, and 3-4 lb weight gain, I would recommend a trial of levothyroxine therapy. Treatment is reasonable for patients with TSH >10 or positive thyroid antibodies, which she does not have data for. However, treatment may modestly improve her lipids and symptoms. 3. She should be monitored every 6 months with TSH checks to ensure her TSH is maintained between 0.5-2.0 and that she does not

1. Thyroid Disease in Women:
Common Dilemmas
David F. Gardner, M.D.
Professor of Medicine
Division of Endocrinology
Virginia Commonwealth Univ.
School of Medicine

2. I have no conflicts of interest
to report.

3. Five Questions:
 Should women routinely be screened for
thyroid disease?
 Should women with subclinical
hypothyroidism receive any treatment?
 What is a normal TSH level?
 How should hypothyroidism in pregnancy
be managed?
 What is appropriate thyroid hormone
replacement rx in hypothyroid women?

4. Case 1:
A 46 year old woman comes to your office for
her yearly check-up. She has no complaints
and physical examination is normal. You are
about to send her to the lab, when she asks if
you are going to do any thyroid tests. She
recently read that all women should be
“screened” for possible thyroid disease. What
do you do now?

5. Question 1:
Should a serum TSH be a routine
component of the periodic health
examination in women?

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

7. Consensus Statements:
 US Preventive Services Task Force:
Recommends screening only in newborns
 Expert Panel (JAMA, Jan 04): There is insufficient
evidence to support population-based screening.
 American College of Ob-Gyn: No guidelines
regarding testing in woman pre-conception or
during pregnancy
 American College of Physicians: Screening of
women >50 “may be indicated”
 ATA (JAMA, 2000): Adults should be screened
for thyroid dysfunction with a serum TSH
beginning at age 35 and every 5 years thereafter

8. Institute of Medicine evaluation of the
advisability of covering TSH
measurements in Medicare patients:
After analyzing available evidence and
doing a cost-benefit analysis, the IOM
found the evidence for a benefit of
screening to be lacking, and therefore
determined that coverage for screening
should not be provided as a Medicare
benefit . (2003)

9. Joint Statement of AACE, ATA and
Endocrine Society:
Potential benefits of early detection and treatment
of thyroid dysfunction outweigh the potential side
effects that could result from early detection and
therapy…. Therefore, we favor screening for
subclinical thyroid dysfunction in adults, including
pregnant women and those contemplating
pregnancy.
Thyroid, January, 2005

10. Are there subsets of asymptomatic
women who should be screened?:
 Women over the age of 60
 Women with other autoimmune disorders,
including Type 1 diabetes
 Women with a strong family history of
thyroid disease
 Women with hypercholesterolemia
 Women with psychiatric disorders
 Women taking lithium, amiodarone, or
interferon-alpha

11. Are there subsets of women who should
be screened?:
 Women with prior history of thyroid disease
 Women planning pregnancy or soon after
conception
 Women who have had previous head and
neck irradiation
 Women with MS or primary pulmonary
hypertension
 Women with Down or Turner syndromes

12. Case 2:
A 56 year old woman presents with a question regarding
recent thyroid studies. “Screening” labwork by her Ob-
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
feels well, but does report some fatigue, and a 3-4 lb
weight gain in the last year. Examination is normal and
she appears clinically euthyroid. She understands that a
high TSH indicates hypothyroidism and wants to know if
she should be started on a thyroid supplement.
What’s the diagnosis and should she be treated?

13. The diagnosis is subclinical
hypothyroidism:
 Elevated serum TSH concentration and
normal serum thyroid hormone levels in an
apparently asymptomatic patient
 Prevalence is 5-10% in general population,
with women over 60 having a prevalence as
high as 15-20%
 Most commonly due to autoimmune thyroid
disease

14. Question 2:
Should women with subclinical
hypothyroidism be treated with
l-thyroxine?

15. Biondi & Cooper, Endocrine Reviews, 2008

16. What are the clinical consequences
subclinical hypothyroidism?:
 Progression to overt hypothyroidism
 Abnormal lipids
 Increased risk of cardiovascular
disease
 Neuropsychiatric symptoms

17. What is the likelihood of progression
to overt hypothyroidism?:
There is significant risk, particularly in
1. Older patients (>60)
2. Patients with positive thyroid antibodies
3. Women—in one study annual rate of
progression to overt hypothyroidism was 4.3%
in women with +TPO antibodies, 3.0% if no ab’s
4. Patients with TSH>10
5. Patients with prior history of radioactive
iodine treatment or thyroid surgery

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

19. Lipids in Subclinical Hypothyroidism:
 Relationship is controversial
 Several cross-sectional studies show
increased TC and LDL-C
 Likelihood of abnormality is greater in
patients with TSH>10

20. Walsh et al. Busselton Health Study.
Clin Endocrinol, 2005.
Cross-Sectional Data:
N LDL-Chol (mmol/L)
Euthyroid Controls 1906 3.5+1.0
SCHypo 119 4.1+1.2*
SCHypo (TSH>10.0) 23 4.3+1.3**
*p<0.01 vs. controls
**p<0.001 vs. controls

21. Does treatment of SCHypo have
beneficial effect on lipids:
 Villar et al. (Cochrane Data Base Rev,
2007) - meta-analysis of 12 clinical trials:
no effect of T4 rx on total, LDL, HDL
cholesterol, triglycerides
 In six other randomized trials, comparing
T4 with placebo, there was significant
lowering of LDL and total cholesterol

22. Meier et al. JCEM, 2001

23. Summary of SCHypo and Lipids:
 There is a consistent but modest
association of SCHypo with increased
total and LDL cholesterol
 Correction of SCHypo has modest
expected effect of decreasing LDL and
total cholesterol

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

26. Biondi & Cooper, Endo Rev, 2008:
In some epidemiological studies the
risk of CHD was increased in young
and middle-aged patients but not in
elderly patients with SCHypo. Indeed,
SCHypo appeared to exert a
protective cardiovascular effect in
patients older than 85.

27. FIG. 4. Hypothetical relationship between age and effect of SHypo on cardiovascular
disease
Biondi, B. et al. Endocr Rev 2008;29:76-131
Copyright ©2008 The Endocrine Society

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

29. Neuropsychiatric Symptoms
Critical questions are:
1. Do patients with SCHypo truly have
more symptoms than age-matched
euthyroid controls?
2. Does treatment with thyroxine
ameliorate symptoms?

30. Canaris et al.: Colorado Thyroid Disease
Prevalence Study, Arch Int Med, 2000:
 Cross-sectional study of 25,862
participants in statewide health fair
 Responses to a hypothyroid
symptoms questionnaire were
recorded in 2336 patients with
SCHypo

31. Compared with euthyroid controls, patients
with SCHypo significantly more often
reported symptoms, as follows:
 Dry skin (28%, p<0.001)
 Poor memory (24%, p<0.001)
 Slow thinking (22%, p<0.001)
 Muscle weakness (22%, p<0.001)
 Fatigue (18%, p<0.01)
 Muscle cramps (17%, p<0.001)
 Cold intolerance (15%, p<0.001)
 Puffy eyes (12%, p<0.05)
 Constipation (8%, p<0.05)

32. Many other studies do not
support an association of
SCHypo with any symptoms!

33. Bell et al., 2007:
 Community-based x-sectional study of
1423 “non-healthcare-seeking
women”—mean age 54
 Utilized Short-Form 36 (SF-36) and
Psychological General Well-Being Index
(PGWI) to evaluate health-related QOL
 SCHypo defined as TSH > 4.0
Clin Endocrinol, 66:548, 2007

34. Bell et al., 2007:
 There were no differences between
women with SCHypo (n=80) and age-
matched euthyroid controls (n=240) in
terms of:
– Anti-depressant use
– PGWI score
– SF-36 mental composite score
– SF-36 physical composite score

35. The presence of symptoms in
patients with SCHypo remains
controversial, and symptoms,
when present are non-specific.
Biondi & Cooper, Endo Rev, 2008

36. Does treatment improve signs
and symptoms of hypothyroidism,
quality of life, and psychometric
tests in patients with SCHypo?
At least 12 placebo-controlled
studies have addressed these
issues and the results are
conflicting!

37. Summary: Treatment of
Subclinical Hypothyroidism:
 No studies have demonstrated an adverse
effect from correction of subclinical
hypothyroidism
 Patients with serum TSH > 10 uU/mL
appear to derive the greatest benefits from
treatment
 Adverse effects of therapy are only related
to cost and overtreatment--in one study of
339 elderly patients on T4 rx, 41% had low
TSH levels (Somwaru, JCEM, 2009)

38. It seems reasonable to recommend
therapy for the following patients:
 TSH>10 uU/ml
 Positive thyroid autoantibodies
 Lipid abnormalities
 Psychiatric patients, especially those
with depression/bipolar disorders
 History of radioactive iodine
treatment or previous thyroid
surgery

39. It seems reasonable to recommend
therapy for the following patients:
 Pregnant women
 Women with infertility
 “Younger” patients (<60-70 y/o),
especially those with cardiovascular
risk factors (DM, dyslipidemia,
hypertension, smoking, etc.)
 Avoid therapy in the “oldest” old

40. All patients with subclinical
hypothyroidism not receiving
treatment must be closely
monitored for the development
of overt hypothyroidism.

41. Case 3:
A 46 year old woman presents to your office for follow-
up of her longstanding hypothyroidism. She is taking l-
thyroxine 125 ug/d, and reports that she is feeling
“pretty well”, except for some fatigue and a 5 lb weight
gain over the last year. Physical examination is normal.
Thyroid studies are as follows:
Free T4 1.2 ng/ml (0.8-1.8)
TSH 4.8 uU/ml (0.35-5.5)
Should you make any changes in her dose of thyroid
hormone replacement?

42. Question 3:
What is the normal TSH reference
range and what level of TSH should be
targeted in the treatment of hypothyroid
patients?

43. What level of TSH should be targeted?:
 Simple answer: TSH within the normal range
for the assay utilized—usually 0.35 – 5.5 mIU/L
 BUT….there is now accumulating body of
evidence that the upper limit of normal for most
assays is too high and appropriate upper limit
could be as low as 2.5 – 3.0 mIU/L.
 This is based on studies that rigorously exclude
subjects with even the mildest degrees of
thyroid failure in determining the normal range

44. Studies addressing normal TSH range:
 Bjoro et al. (Eur J Endocrinol, 2000): Norway,
Upper limits of normal: men 3.4; women 3.6
 Kratzsch et al. (Clin Chem, 2005): Germany,
Normal range: 0.30 – 3.63
 NHANES III (JCEM, 2002): United States,
Normal range: 0.45 – 4.12
 Jensen et al. (Clin Chem Lab Med, 2004):
Denmark, Normal range: 0.58 - 4.07
 Hamilton et al. (JCEM, 2008): United States,
Normal range: 0.55 - 4.10

45. TSH distribution progressively shifts
toward higher concentrations in older
populations:
TSH ULN
Age 20-29 3.56
Age 60-69 4.33
Age 70-79 5.90
Age >80 7.49
Surks & Hollowell. JCEM, 2007

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

47. My opinion:
 The upper limit of normal for the
serum TSH concentration is probably
between 3.0 and 4.0 mIU/mL
 A reasonable target TSH for most
patients with primary hypothyroidism
is in the 1.0 – 3.0 mIU/L range

48. Important Caveats:
 Lowering the upper limit of normal for
serum TSH to 2.5-3.0 will result in ~25
million more Americans being diagnosed
with hypothyroidism
 There is no evidence that treating patients
with TSH in 3-5 mIU/L range is beneficial
—in fact, benefits of treating patients with
TSH levels in 5-10 range are
controversial.

49. Case 4:
A 28 year old woman with longstanding
hypothyroidism on l-thyroxine therapy comes
to you to discuss her plans for starting a
family some time in the next 6 months. She
asks if there will be any problems related to
her current treatment with l-thyroxine.

50. Question 4:
What is the potential impact of
pregnancy on thyroxine treatment in
hypothyroid women?

51. Thyroxine replacement during pregnancy:
 The daily dose of thyroxine to maintain
the euthyroid state in pregnancy will
increase in 50-70% of women
 Average dose increase ranges from
20-50%
 Increased T4 requirements may be
apparent as early as 5-6 weeks of
gestation

52. Mean Serum FT4 and TSH before
and during pregnancy (n=25):
Before During
T4 dose (ug/day) 112 112
Serum FT4 (ng/dL) 1.60 0.84
Serum TSH (uU/mL) 1.44 14.1
Kaplan, 1992

53. Recommendations:
 Adjust T4 rx to serum TSH<2.0 prior to
pregnancy
 Check TSH early in pregnancy—by week 5-6
 Monitor TSH every 5-6 weeks during 1st half of
pregnancy; less often in 2nd half of pregnancy
 T4 dose adjustments should be based on
trimester-specific TSH normal ranges—e.g.
normal range in 1st trimester is 0.10 – 2.5
 Separate T4 ingestion by at least 3-4 hours
from iron supplements, calcium supplements,
multivitamins, and soy milk

56. Thyroid Hormone Early Adjustment in Pregnancy
(The THERAPY) Trial. Yassa et al., JCEM, 2010
 Prospective trial of empiric ~29%
increase in T4 dose (2 extra tablets per
week) when pregnancy confirmed
 Intervention significantly reduced risk of
maternal hypothyroidism in 1st trimester
 Only 2 of 25 women required a dose
reduction due to over-replacement
 Only 2 of 25 women required a further
dose increase

57. Thyroid Hormone Early Adjustment in Pregnancy
(The THERAPY) Trial. Yassa et al., JCEM, 2010
 Conclusions
– 29% increase in maternal T4 at
confirmation of pregnancy reduces risk of
maternal hypothyroidism in first trimester
– Monitoring thyroid function once monthly
is required through “mid-pregancy”,
~week 20
– The protocol appears safe and mimics
normal thyroid gestational physiology

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

60. Morbidity Associated with Hypothyroidism
During Pregnancy:
 Spontaneous miscarriages
 Gestational hypertension and
preeclampsia
 Premature delivery
 Increased frequency of neonatal ICU
admissions
 Increased fetal mortality
 Impaired neuropsychological development

62. Children of Children of
Treated Untreated
Women with Women with Control
Hypothyroidism Hypothyroidism Children
(N=14) (N=48) (N=124)
Full Scale IQ Score 111 100* 107
% with IQ <85 0 19* 5
Freedom from
distractibility score 103 97* 102
Verbal IQ score 111 101* 107
Performance IQ score 109 99* 105
*P-value <0.01 for comparison of untreated vs. control children

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

64. Unresolved Issue:
Should all women be screened for
hypothyroidism prior to or shortly after
conception?
■RECOMMENDATION 74
There is insufficient evidence to recommend
for or against TSH testing preconception in
women at high risk for hypothyroidism. Level
I-USPSTF

65. ■RECOMMENDATION 76
Serum TSH values should be obtained
early in pregnancy in women at high
risk for overt hypothyroidism
Level B-USPSTF

66. Case 5:
A 52 year old woman returns for follow-up of
longstanding hypothyroidism. She is doing well
on brand-name of l-thyroxine, but she has read
that a combination of T4/T3 is superior to T4
alone and wonders whether that would be a
good idea for her. In addition, at the time of her
last refill, she was told by her pharmacist that
she could save some money by switching to a
generic T4 preparation. What should you tell
her? Thyroid studies done one week prior to
her visit showed a TSH of 1.2 uU/mL.

67. Question 5:
Are all l-thyroxine preparations
therapeutically equivalent? Should
combination T4/T3 preparations be
used?

68. Are all levothyroxine preparations
therapeutically equivalent?
Appropriate studies comparing all
available brand-name and generic
preparations have not been performed,
so a definitive answer is not available!

69. Cost Differences:
Brand Cost of 90 0.1 mg tabs
Synthroid $63.97
Levoxyl 44.97
Generic 25.97
So difference in cost for one year supply
of Synthroid vs. generic = $152
Source: www.drugstore.com

70. Endocrine Society, ATA, AACE
“Best Physician Practices” Guidelines:
 Patients should be maintained on the same
brand name l-thyroxine product
 Change from one brand to another, change
from a brand to a generic product, or change
from one generic to another generic requires
repeat TSH testing in 6-8 weeks
 Small differences in l-thyroxine doses may
have significant adverse clinical outcomes

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

72. Should combination T4/T3
preparations be used?

73. NO!

74. NEJM, 340: 424-429, 1999

75. T4-T3 Therapy vs. T4 Monotherapy for
Hypothyroidism: Meta-Analysis of
Randomized Controlled Trials:
 Included 11 studies with total of 1216 patients
 No difference was found between treatments for
any of the following: depression, anxiety, bodily
pain, fatigue, quality of life, body weight, total and
LDL cholesterol, and triglycerides
 Adverse events did not differ between regimens
 Conclusion: T4 monotherapy should remain the
treatment of choice for hypothyroidism
J Clin Endocrinol Metab, 2006

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