TISSUE-SELECTIVE ESTROGEN COMPLEX

The tissue-selective estrogen complex (TSEC) of conjugated estrogen (CE) and the

selective estrogen receptor modulator (SERM), bazedoxifene (BZA), is FDAapproved for the treatment of VMS and the prevention of osteoporosis in

postmenopausal women with a uterus. The CE component of this agent reduces VMS

and prevents bone loss whereas the estrogen-antagonistic properties of BZA in the

breast and uterus mitigate the effects of estrogen on these tissues, eliminating the need

for concurrent progestogen.

68 Although not approved for this indication, studies

suggest that CE/BZA improves symptoms of vaginal atrophy.

69 Clinical trials have

demonstrated that CE/BZA produces fewer bleeding events and breast symptoms than

the traditional combination of CE/MPA.

68 This agent is an alternative for women

with a uterus who are unable or unwilling to use EPT due to adverse effects.

NONHORMONAL AGENTS

CASE 51-1, QUESTION 6: L.K. returns 3 months later. Her hot flushes and night sweats resolved with

EPT, but she experienced worsening of her migraine headaches, so she discontinued HT. Her hot flushes

recurred soon thereafter. What alternative therapies are available for the management of L.K.’s symptoms?

p. 1035

p. 1036

Table 51-4

Nonhormonal Agents for the Management of Vasomotor Symptoms

70–73

,

91

Drug

Recommended

Dosage Adverse Reactions Reported

Serotonergic Antidepressants

Citalopram (Celexa) 10–30 mg Dry mouth, ↓ libido, rash/hives, insomnia,

somnolence, bladder spasm, palpitations,

arthralgias

Desvenlafaxine (Pristiq) 50–100 mg Asthenia, chills, anorexia, nausea, vomiting,

constipation, diarrhea, dizziness, nervousness,

mydriasis, dry mouth

Escitalopram (Lexapro) 10–20 mg Dizziness, lightheadedness, nausea, vivid dreams,

increased sweating

Fluoxetine (Prozac) 10–20 mg Nausea, dry mouth

Paroxetine hydrochloride (Paxil, Paxil

CR)

10–20 mg

12.5–25 mg (CR)

Headache, nausea, insomnia, drowsiness

Paroxetine mesylate

a

(Brisdelle) 7.5 mg

Sertraline (Zoloft) 50 mg Nausea, fatigue/malaise, diarrhea,

anxiety/nervousness

Venlafaxine (Effexor, Effexor XR) 37.5–75 mg

37.5–150 mg XR

Dry mouth, ↓ appetite, nausea, constipation,

possible increase in blood pressure at higher

doses

Antiseizure Agents

Gabapentin (Neurontin) 900 mg, possibly up

to 2,400 mg

Somnolence, fatigue, dizziness, rash, palpitations,

peripheral edema

Pregabalin (Lyrica) 150–300 mg Dizziness, sleepiness, weight gain, cognitive

difficulty

Antihypertensive Agents

Clonidine PO: 0.05–0.15 mg

TD: 0.1 mg/24 hour

Headache, dry mouth, drowsiness

Skin reaction/itching (patch only), risk of rebound

HTN if stopped abruptly

aFDA-approved for the management of vasomotor symptoms.

HTN, hypertension; PO, orally; TD, transdermally.

Nonhormonal agents, including serotonergic antidepressants and antiepileptic

agents, are modestly effective in reducing hot flush frequency and severity. (Table

51-4) Decreased estrogen levels are thought to regulate endorphin concentrations in

the hypothalamus thereby affecting serotonin and norepinephrine levels in the

thermoregulatory area of the hypothalamus.

70

In clinical trials of serotonergic

antidepressants, relief of vasomotor symptoms was seen at lower doses and with a

more rapid onset than is seen for their antidepressant effects.

71,72 Venlafaxine and

paroxetine, the most studied agents, are considered the drugs of choice; other

selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake

inhibitors are considered second-line agents.

72 Low-dose paroxetine mesylate is

FDA-approved for the treatment of vasomotor symptoms; the dose of 7.5 mg is lower

than that required for the treatment of psychiatric disorders.

70 Studies have shown that

paroxetine mesylate is effective in decreasing the severity and frequency of

vasomotor symptoms. Dosing should be initiated at the lowest effective dose (Table

51-4); this can be increased after 2 to 3 weeks if the patient has an inadequate

response. Patients should be advised not to discontinue therapy abruptly to avoid

withdrawal symptoms. Commonly seen side effects of nonhormonal agents are listed

i n Table 51-4. Of particular concern in postmenopausal women is the risk for

anorgasmia and loss of libido; similar sexual dysfunction may also occur as a result

of menopause. Patients should be advised to discuss the problem with their care

provider if it occurs and is bothersome. The antiepileptic drug gabapentin has been

shown in multiple studies to decrease hot flushes through an unidentified mechanism.

The therapeutic effect occurs at a dose of 900 mg/day with an onset within 4 weeks

of initiation of treatment. To minimize side effects, dosing should be initiated at 300

mg daily and titrated up in 300-mg/day increments as tolerated. Although one study

showed benefit with 2,400 mg/day, the optimal dose of gabapentin for hot flushes is

unknown.

71,73

Paroxetine mesylate 7.5 mg daily can be tried in L.K. If her symptoms are not

improved after 2 to 3 weeks, the dose can be titrated up to a maximum dose of 25 mg

daily.

Genitourinary Atrophy

SIGNS AND SYMPTOMS

CASE 51-2

QUESTION 1: B.L., a 57-year-old woman, presents with a complaint of persistent vaginal dryness and

irritation as well as pain associated with intercourse. She has tried vaginal lubricants, which help with

intercourse-related pain but do not relieve her daily vaginal symptoms. She experienced menopause at age 50,

which was accompanied by moderate hot flushes for 2 to 3 years that have since resolved without intervention.

She denies symptoms of urinary incontinence. She does not smoke. On physical examination, her labia minora

have a pale, dry appearance, and the labia majora appear flattened. Her vagina is small with a pale, dry

epithelium. What is causing B.L.’s condition?

B.L. appears to be experiencing symptoms associated with genitourinary atrophy.

Estrogen is the dominant hormone of vaginal physiology. With the postmenopausal

loss of estrogen production, the vagina decreases in size and loses its rugal pattern.

The mucosa becomes pale, thin, and dry, and vaginal blood flow decreases. A

decrease in Lactobacillus production of lactic acid leads to an increase in vaginal pH

to 5.0 or greater (compared with a

p. 1036

p. 1037

premenopausal pH of 3.5–4.5).

18,74,75 These changes make the vagina more

susceptible to infection from bacterial colonization and localized trauma secondary

to intercourse. Unlike hot flushes, vaginal atrophy does not abate with time since

menopause.

Symptoms of atrophic vaginitis include dryness, itching, pain, and dyspareunia

(painful coitus). About 10% to 40% of postmenopausal women experience

symptoms; however, only 7% of patients report these symptoms to their provider.

74

Postmenopausal women who engage in regular coital activity have less atrophic

vaginal changes compared with those of similar age and estrogen levels who do not

have regular intercourse.

TREATMENT

CASE 51-2, QUESTION 2: What would be an appropriate regimen for B.L. to decrease her vaginal

symptoms?

Nonhormonal Treatment

First-line treatment includes vaginal moisturizers (e.g., Replens), which adhere to the

vaginal mucosa, can improve vaginal symptoms but do not reverse atrophy.

75,76

Personal lubricants (e.g., KY jelly or liquid) can be used for women experiencing

dyspareunia related to vaginal atrophy. Patients report symptom relief within 3

months of continuous treatment. Nonhormonal treatments used for vasomotor

symptoms do not improve vaginal atrophy symptoms.

18,74,75

Ospemifene (Osphena) is a vaginal tissue-specific estrogen agonist/antagonist.

Ospemifene 60 mg once a day has demonstrated significant improvement in

dyspareunia and vaginal atrophy. Duration should be restricted to the shortest amount

of time possible based on patient’s goals. Although ospemifene does not contain

estrogen, it does have estrogen agonist effects and postmenopausal women with an

intact uterus should be placed on progestin therapy as well. Serious adverse effects

include increased risk of endometrial cancer and cardiovascular disorders.

77

Localized Estrogen Treatment

Estrogen therapy reverses vaginal epithelial thinning, decreases the vaginal pH, and

improves the symptoms of vaginal atrophy. Vaginal estrogen therapy has been shown

to be more effective than systemic oral estrogen therapy, resulting in 80% to 90%

response of vaginal atrophy.

74 For vaginal symptoms alone, low-dose vaginal

estrogen is the preferred treatment.

74 The available products (Table 51-2) appear to

be equivalent in restoring vaginal cytology and pH and relieving symptoms of vaginal

dryness, pruritus, and dyspareunia; product selection should be based on patient

preference.

74 Vaginal creams and tablets are initiated with once-daily dosing; after

symptoms have resolved, the patient should be switched to maintenance dosing of

once- or twice-weekly administration. The low-dose vaginal ring releases a constant

dose of estrogen for 90 days.

The most common adverse effects of vaginal estrogens are vaginal irritation and

bleeding and breast tenderness. Based on limited studies, the risk of endometrial

hyperplasia from low-dose vaginal estrogen is small, and the addition of a

progestogen is generally considered unnecessary.

74,78 Women at high risk for

endometrial cancer, using higher than usual doses of vaginal estrogen, or

experiencing vaginal bleeding during intravaginal ET, should be evaluated for

endometrial hyperplasia.

74

Because B.L. has not had relief with nonhormonal therapy, localized ET such as

conjugated estrogen, 1 g of 0.625 mg/g cream, applied vaginally once daily is

appropriate. After her symptoms have resolved, the dose can be decreased to a

maintenance regimen of twice-weekly administration.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

after the reference.

Key References

Carroll DG, Kelley KW. Use of antidepressants for management of hot flashes. Pharmacotherapy. 2009;29:1357.

(73)

MacBride MB et al. Vulvovaginal atrophy. Mayo Clin Proc. 2010;85:87. (75)

McBane SE et al. Use of compounded bioidentical hormone therapy in menopausal women: an opinion statement

of the Women’s Health Practice and Research Network of the American College of Clinical Pharmacy.

Pharmacotherapy. 2014;34:410. (51)

Mintziori G et al. EMAS position statement: non-hormonal management of menopausal vasomotor symptoms.

Maturitas. 2015;81:410. (91)

Mirkin S et al. Conjugated estrogen/bazedoxifene tablets for the treatment of moderate-to-severe vasomotor

symptoms associated with menopause. Womens Health (Lond). 2014;10:135. (68)

North American Menopause Society. The 2012 hormone therapy position statement of The North American

Menopause Society. Menopause. 2012;19:257. (27)

The North American Menopause Society (NAMS) 2013 Symptomatic Vulvavaginal Atrophy Advisory Panel.

Management of symptomatic vulvo-vaginal atrophy: 2013 position statement of The North American Menopause

Society. Menopause. 2013;20(9):888–902. (74)

Santen RJ et al. Executive summary: postmenopausal hormone therapy: an Endocrine Society Scientific Statement.

J Clin Endocrinol Metab. 2010;95(7, Suppl 1):S1. (33)

Simon JA et al. Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms: two randomized controlled

trails. Menopause. 2013;20(10):1027–1035. (70)

Vuvojic S et al. EMAS position statement: managing women with premature ovarian failure. Maturitas. 2010;67:91.

(44)

Key Websites

European Menopause and Andropause Society. http://www.emas-online.org/home.

NAMS: The North American Menopause Society. http://www.menopause.org.

Women’s Health Initiative. https://www.whi.org/SitePages/WHI%20Home.aspx.

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p. 1037

Thyroid function tests are essential to confirm the presence of thyroid

disorders but can be altered by acute and chronic illness and certain

drugs. Thyrotropin (TSH) is the most accurate indicator of

euthyroidism.

Case 52-1 (Questions 1, 2),

Case 52-2 (Question 1),

Case 52-3 (Question 1),

Case 52-4 (Question 1),

Case 52-5 (Question 5),

Case 52-23 (Question 1),

Case 52-24 (Question 1),

Table 52-1 and 52-7 Figure

52-1 and 52-2

Thyroid hormone deficiency can cause a goiter and hypothyroid

symptoms including myxedema coma, heart failure, and hyperlipidemia.

The most common cause of hypothyroidism is Hashimoto’s thyroiditis.

Case 52-5 (Question 1),

Case 52-8 (Question 2),

Case 52-9 (Question 2),

Case 52-10 (Question 1),

Case 52-11 (Questions 1, 2),

Case 52-12 (Question 1),

Case 52-13 (Question 1),

Case 52-20 (Question 1),

Tables 52-2 and 52-3

Generic or branded levothyroxine (L-thyroxine) is the preparation of

choice for optimal correction of hypothyroidism. Triiodothyronine (T3

)-

containing preparations are not necessary because thyroxine (T4

) is

converted to T3

.

Case 52-5 (Question 2),

Case 52-6 (Question 1),

Case 52-10 (Question 2),

Tables 52-4 and 52-8

The signs and symptoms of hypothyroidism can be corrected by the

administration of l-thyroxine on an empty stomach at average oral

replacement dosages of 1.6 to 1.7 mcg/kg/day or intravenously. Dosing

is altered by weight, comorbidities, and drug interactions.

Case 52-5 (Questions 3–5),

Case 52-7 (Question 1),

Case 52-8 (Question 1),

Case 52-9 (Question 1),

Case 52-10 (Question 2),

Case 52-11 (Question 3),

Table 52-4, 52-8 and 52-9

The signs and symptoms of hyperthyroidism mimic those of adrenergic

excess (e.g., tachycardia, tremors, thyroid storm), but symptoms in the

elderly may be absent (“apathetic”). Graves’ disease, a common cause

Case 52-14 (Questions 1, 2),

Case 52-15 (Question 1),

Case 52-21 (Questions 1, 2),

of hyperthyroidism, can be complicated by ophthalmopathy. Case 52-22 (Questions 1, 2),

Table 52-5 and 52-6, Figure

52-3

Management of hyperthyroidism includes thioamides, iodides, radioactive

iodine, and surgery. β-Blockers can provide symptomatic relief of

hyperthyroid symptoms.

Case 52-15 (Questions 2–9,

12), Case 52-16 (Question

1),

Case 52-19 (Questions 1, 2),

Case 52-20 (Question 1),

Case 52-22 (Question 2),

Table 52-10

p. 1038

p. 1039

Methimazole is preferable to propylthiouracil except during the first

trimester of pregnancy and during thyroid storm. Thioamide toxicity

includes gastrointestinalsymptoms, rash, agranulocytosis, and hepatitis.

Case 52-15 (Questions 4–8,

10, 11),

Case 52-18 (Question 1)

Both hypothyroidism and hyperthyroidism can alter metabolism of

coadministered medications (e.g., digoxin, warfarin).

Case 52-14 (Questions 2, 3)

The management of subclinical hypothyroidism and hyperthyroidism

should be individualized.

Case 52-12 (Question 1),

Case 52-17 (Question 1)

Certain drugs (e.g., amiodarone, interferon, lithium, tyrosine kinase

inhibitors) can

cause thyroid disorders.

Case 52-23 (Question 1),

Case 52-24 (Question 1),

Table 52-2 and 52-6

OVERVIEW

Thyroid disease, including hypothyroidism, hyperthyroidism, and nodular disease, is

common, affecting 5% to 15% of the general population. Women are affected 3 to 4

times more than men. Triiodothyronine (T3

) and thyroxine (T4

) are the two

biologically active thyroid hormones produced by the thyroid gland. The

hypothalamic thyrotropin-releasing hormone (TRH) stimulates release of thyrotropin

(i.e., thyroid-stimulating hormone [TSH]) from the pituitary in response to low

circulating levels of thyroid hormone. TSH in turn promotes hormone synthesis and

release by increasing thyroid activity. High circulating thyroid hormone levels block

further production by inhibiting TSH release (negative feedback). As the serum

concentrations of thyroid hormone decrease, the hypothalamic-pituitary centers again

become responsive by releasing TRH and TSH (Fig. 52-1).

T3

is 4 times more potent than T4

, the major circulating hormone secreted by the

thyroid. About 80% of the total daily T3 production results from the peripheral

deiodination of T4

to T3 Approximately 35% to 40% of secreted T4

is converted

peripherally to T3

; another 45% of secreted T4 undergoes peripheral conversion to

inactive reverse T3

(rT3

). Certain drugs and diseases can modify the conversion rate

of T4

to T3 and reduce the serum T3

levels (Table 52-1

1,2

; see Case 52-1, Question

2).

T4 exists in the circulation as 0.03% free (active) and 99.97% protein-bound

(inactive), primarily to thyroxine-binding globulin (TBG). This affinity for plasma

proteins accounts for T4

’s slow metabolic degradation and long half-life (t1/2

) of 7

days. T3

is less strongly bound to plasma proteins (99.7%); with about 0.3% free.

The lower protein-binding affinity of T3 accounts for its threefold greater metabolic

potency and its shorter t1/2 of 1.5 days.

Hypothyroidism is a clinical syndrome that results from a deficiency of thyroid

hormone. The prevalence of hypothyroidism is 1.4% to 2% in women and 0.1% to

0.2% in men and is increased in persons older than 60 years, to 6% of women and

2.5% of men. Hypothyroidism can be caused by either primary (thyroid gland) or less

commonly, by secondary (hypothalamic-pituitary) malfunction.

Hashimoto’s thyroiditis, an autoimmune disorder, is the most common cause of

primary hypothyroidism and appears to have a strong genetic predisposition. The

pathogenesis of Hashimoto’s thyroiditis results from an impaired immune

surveillance, causing dysfunction of normal suppressor T lymphocytes and excessive

production of thyroid antibodies by plasma cells (differentiated B lymphocytes). The

destruction of thyroid cells by circulating thyroid antibodies produces an underlying

defect or block in the intrathyroidal, organobinding of iodide. The typical

presentation is hypothyroidism and goiter (thyroid gland enlargement), but patients

can present with hypothyroidism and no goiter, with euthyroidism and goiter, or

rarely (<5%) with hyperthyroidism (Hashitoxicosis).

Other common causes of hypothyroidism, including drug induced, are presented in

Table 52-2

3–24

The clinical presentation, physical findings, and laboratory abnormalities of overt

hypothyroidism are summarized in Table 52-3. Myxedema coma is a medical

emergency resulting from longstanding, uncorrected hypothyroidism (see Case 52-

10). Patients with myxedema coma can present with hypothermia, confusion, coma,

carbon dioxide retention, hypoglycemia, hyponatremia, and ileus. Hypothyroid

symptoms increase with the severity of the hypothyroidism except in the older

patient, who often presents with minimal or atypical symptoms. Patients with

subclinical hypothyroidism might have few or no symptoms. Laboratory findings that

are diagnostic for overt hypothyroidism include elevated TSH and low free thyroxine

(FT4

) levels; for subclinical or early hypothyroidism, the findings are an elevated

TSH and normal FT4

levels.

Levothyroxine (L-thyroxine), at an oral replacement dosage of 1.6 to 1.7

mcg/kg/day administered on an empty stomach, is the preferred thyroid replacement

preparation. Several brand name and less costly generic preparations are

interchangeable in most patients. Older patients, and those with severe

hypothyroidism, and cardiac disease may require minute T4 doses initially to avoid

cardiac toxicity (Table 52-4); complete reversal of hypothyroidism might not be

indicated or possible. In myxedema coma, an intravenous (IV) L-thyroxine (e.g., 400

mcg × 1) loading dose is necessary to reduce the high mortality rate. In subclinical

hypothyroidism (see Case 52-12), T4

replacement therapy is beneficial in those with

TSH >10 IU/mL.

Figure 52-1 Regulation of thyroid hormone secretion. Release of thyroid hormones is controlled by the

hypothalamic–pituitary–thyroid axis. Dashed lines represent negative feedback.

p. 1039

p. 1040

Table 52-1

Factors that can Significantly Alter Thyroid Function Tests in Euthyroid

Patients

Factors Drugs/Situations

↑ TBG Binding Capacity

↑ TT4 Estrogens,

1,2

tamoxifen,

55

raloxifene

54

↑ TT3 Oral contraceptives

21

Normal TSH Heroin

53

Normal FT4

I, FT4 Methadone maintenance

53

Normal FT3

I, FT3 Genetic ↑ in TBG

Clofibrate

Active hepatitis

31

↓ TBG Binding Capacity/Displacement T4 from Binding Sites

↓ TT4 Androgens

21

↓ TT3 Salicylates,

21,45,46 disalcid,

46

salsalate

46

Normal TSH High-dose furosemide

Normal FT4

I, FT4

↓ TBG synthesis-cirrhosis/hepatic failure

Normal FT3

I, FT3 Nephrotic syndrome

21,31

Danazol

21,31

Glucocorticoids

21,31,59

↓ Peripheral T4 → T3 Conversion

↓ TT3 PTU

Normal TT4 Propranolol

200

Normal FT4

I, FT4 Glucocorticoids

21,33,59

Normal TSH

↓ Pituitary and Peripheral T4 → T3

↓ TT3 Iodinated contrast media (e.g., ipodate)

249–253

↑ TT4 Amiodarone

3,12,17

↑ TSH (transient) Non-thyroidal illness

37,39,254

↑ FT4

I

↑ T4 Clearance by Enzyme Induction/↑ Fecal Loss

a

↓ TT4 Phenytoin

47,48

↓ FT4

I Phenobarbital

47

Normal or ↓ FT4 Carbamazepine

47–52

Normal or ↓ TT3 Cholestyramine, colestipol

127

Normal or ↑ TSH Rifampin

47

Bexarotene

20

↓ TSH Secretion

Dopamine

21,31 dobutamine

255

Levodopa

21 cabergoline

256

Glucocorticoids

21,33,59

Bromocriptine

21,33 Pramipexole

58,59 Ropinirole

58,59

Octreotide

32

Metformin

60,61

Bexarotene

10

↑ TSH Secretion

Metoclopramide

21,31,33

Domperidone

21,31,33

aCan also cause hypothyroidism in patients receiving levothyroxine therapy.

FT3

, free triiodothyronine; FT4

, free thyroxine; FT3

I, free triiodothyronine index; FT4

I, free thyroxine index; PTU,

propylthiouracil; T3

, triiodothyronine; T4

, thyroxine; TBG, thyroxine-binding globulin; TSH, thyroid-stimulating

hormone; TT3

, total triiodothyronine; TT4

, total thyroxine.

Table 52-2

Causes of Hypothyroidism

Non-goitrous (No Gland Enlargement)

Primary Hypothyroidism (Dysfunction of the Gland)

Idiopathic atrophy

Iatrogenic destruction of thyroid

Surgery

Radioactive iodine therapy

X-ray therapy

Postinflammatory thyroiditis

Cretinism (congenital hypothyroidism)

Secondary Hypothyroidism

Deficiency of TSH because of pituitary dysfunction

Deficiency of TRH because of hypothalamic dysfunction

Goitrous Hypothyroidism (Enlargement of Thyroid Gland)

Dyshormonogenesis: defect in hormone synthesis, transport, or action

Hashimoto’s thyroiditis

Congenital cretinism: maternally induced

Iodide deficiency

Natural goitrogens: rutabagas, turnips, cabbage

Drug-Induced

Aminoglutethimide

21

Amiodarone

3,12,17

Bexarotene

10,20

Ethionamide

18

Iodides and iodide-containing preparations

16

Rifampin

22

Tyrosine kinase inhibitors (e.g., imatinib, sunitinib, sorafenib)

8,9,14,19

Interleukin

11,23

Interferon-α

6,7,15,24

Lithium

4,5,13

Thiocyanates, phenylbutazone, sulfonylureas

21

TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.

The goal of therapy is to reverse the signs and symptoms of hypothyroidism and

normalize the TSH and FT4

levels. Some improvement of hypothyroid symptoms is

often evident within 2 to 3 weeks of starting T4

therapy. Over-replacement of T4

(i.e.,

suppressed serum concentrations of TSH) is associated with osteoporosis and

cardiac toxicity. The optimal T4

replacement dosage must be administered for

approximately 6 to 8 weeks to achieve steady-state levels. Medications that interfere

with T4 absorption (e.g., iron, aluminum-containing products, some calcium

preparations [e.g., carbonate], cholesterol resin phosphate binders, and raloxifene)

should be separated by at least 4 hours from concomitant T4 administration.

p. 1040

p. 1041

Table 52-3

Clinical and Laboratory Findings of Primary Hypothyroidism

Symptoms Physical Findings Laboratory

General: weakness, tiredness,

lethargy, fatigue

Thin brittle nails ↓ TT4

Cold intolerance Thinning of skin ↓ FT4

I

Headache Pallor ↓ FT4

Loss of taste/smell Puffiness of face, eyelids ↓ TT3

Deafness Yellowing of skin ↓ FT3

I

Hoarseness Thinning of outer eyebrows ↑ TSH

No sweating Thickening of tongue Positive antibodies (in

Hashimoto’s)

Modest weight gain Peripheral edema ↑ Cholesterol

Muscle cramps, aches, pains Pleural/peritoneal/pericardial

effusions

↑ CPK

Dyspnea ↓ DTRs ↓ Na

Slow speech “Myxedema heart” ↑ LDH

Constipation Bradycardia (↓ HR) ↑ AST

Menorrhagia Hypertension ↓ Hct/Hgb

Galactorrhea Goiter (primary hypothyroidism)

AST, aspartate aminotransferase; CPK, creatinine phosphokinase; DTRs, deep tendon reflexes; Hct, hematocrit;

Hgb, hemoglobin; HR, heart rate; LDH, lactate dehydrogenase; Na, sodium; FT3

I, free triiodothyronine index;

FT4

I, free thyroxine index; FT4

, free thyroxine; TSH, thyroid-stimulating hormone; TT3

, total triiodothyronine; TT4

,

total thyroxine.

Table 52-4

Treatment of Hypothyroidism

Patient

Type/Complications Dose (L-Thyroxine) Comment

Uncomplicated adult 1.6–1.7 mcg/kg/day; 100–125

mcg/day average replacement

dose; usual increment 25 mcg

q6–8wk

2–3 weeks; 4–6 weeks. Reversal of skin and hair

changes may take several months. An FT4

and TSH

should be checked 6–8 weeks after initiation of

therapy because T4

has a half-life of 7 days and three

to four half-lives are needed to achieve steady state.

Levels obtained before steady state can be very

misleading. Because 80% is bioavailable, adjust IV

doses downward. Small changes can be made by

varying dose schedule (e.g., 150 mcg daily except

Sunday).

Elderly ≤1.6 mcg/kg/day (50–100

mcg/day)

Initiate T4

cautiously. Elderly may require less than

younger patients. Sensitive to small dose changes. A

few patients older than 60 years require ≤50 mcg/day.

Cardiovascular

disease (angina,

CAD)

Start with 12.5–25 mcg/day. ↑

by 12.5–25 mcg/day q2–6

weeks as tolerated

These patients are very sensitive to cardiovascular

effects of T4

. Even subtherapeutic doses can

precipitate severe angina, MI, or death. Replace

thyroid deficit slowly, cautiously, and sometimes even

suboptimally.

Long-standing

hypothyroidism (>1

year)

Dose slowly. Start with 25

mcg/day. ↑ by 25 mcg/day q4–6

weeks as tolerated

Sensitive to cardiovascular effects of T4

. Steady state

may be delayed because of ↓ clearance of T4

.

a

Correct replacement dose is a compromise between

prevention of myxedema and avoidance of cardiac

toxicity.

Pregnancy Most will require 45% ↑ in dose Evaluate TSH, TT4

, and FT4

I. normal TSH and

to ensure euthyroidism TT4

/FT4

I in upper normal range to prevent fetal

hypothyroidism. TSH should be no higher than 2.5

microunits/mL during the first trimester and 3.0

microunits/mL in the second and third trimesters

Pediatric (0–3 mo) 10–15 mcg/kg/day Hypothyroid infants can exhibit skin mottling, lethargy,

hoarseness, poor feeding, delayed development,

constipation, large tongue, neonatal jaundice, piglike

facies, choking, respiratory difficulties, and delayed

skeletal maturation (epiphyseal dysgenesis). The

serum T4

should be increased rapidly to minimize

impaired cognitive function. In the healthy term infant,

37.5–50 mcg/day of T4

is appropriate. Dose

decreases with age (Table 52-9).

a

In severely myxedematous patients, steady state may require ≥6 months. In patients who are clinically euthyroid

but have ↑ TT4

and FTI, use TT3

and TSH as guide to dose adjustments.

CAD, coronary artery disease; FT4

, free thyroxine; FT4

I, free thyroxine index; IV, intravenous; MI, myocardial

infarction; q, every; QD, every day; T4

, thyroxine; TSH, thyroid-stimulating hormone; TT4

, total thyroxine.

p. 1041

p. 1042