Thomas D. Geracioti Jr, MD

Hypothyroidism—even when occult or subclinical—can cause subtle or frank changes in energy, mood, anxiety level, or cognition. Some patients’ affective symptoms remit with thyroid hormone replacement or with antidepressants only after a euthyroid state is established.

To help you recognize hypothyroidism in patients presenting with psychiatric illnesses and provide effective treatment, this article describes:

• hypothyroidism’s signs and symptoms
• primary and subclinical hypothyroidism, thyroiditis, central hypothyroidism, and thyroid hormone resistance
• laboratory screening for thyroid dysfunction in patients with psychiatric symptoms.

Overlapping clinical signs

Thyroid hormone is required for the metabolic activity of every cell in the body. When patients experience symptoms related to abnormal functioning of the hypothalamic-pituitary-thyroid axis (Figure), psychiatrists often are the first professionals they consult.

Diagnosis of thyroid disorders is based on biochemical and clinical data (Box 1),¹ which might not be congruent. Clinical symptoms of hypothyroidism, for example, are notoriously variable. Severe biochemical hypothyroidism may be associated with mild clinical symptoms, whereas mild biochemical hypothyroidism may be associated with severe symptoms.²

Patients with thyroid disturbance and psychiatric symptoms most often are diagnosed with a depressive-spectrum syndrome. Most common are:

• atypical depression (which may present as dysthymia)
• bipolar spectrum syndrome (including manic-depression, mixed mania, bipolar depression, rapid-cycling bipolar disorder, cyclothymia, and premenstrual syndromes)
• borderline personality disorder
• or psychotic disorder (typically paranoid psychosis).

Psychiatric symptoms of hypothyroidism (Table 1) are often prominent or even primary. Patients commonly show:

• impaired attention, concentration, learning, and memory
• psychomotor slowing
• and/or mental dullness.

Table 1

Hypothyroidism’s psychiatric signs and symptoms

Box 1

Figure Thyroid hormone regulation: The hypothalamic-pituitary-thyroid axis

Thyroid-stimulating hormone (TSH, thyrotropin) released into circulation by the pituitary stimulates the thyroid to synthesize and release thyroid hormone, including triiodothyronine (T3) and thyroxine (T4). TSH is regulated by hypothalamic elaboration of thyrotropin-releasing hormone (TRH), which stimulates TSH release in a dose-dependent manner. Negative feedback from T3 and T4 downregulates TRH gene expression and restrains the pituitary from responding to TSH. Most T3—the active hormone—is formed in circulation or in target tissues by deiodination of T4 by selenium-containing enzymes.

Illustration for Current Psychiatry by Rich LaroccoThe degree of impairment may depend on the patient’s normal functional level. For example, a well-educated patient of mine with thyroiditis-related hypothyroidism reported word-finding difficulties. Instead of asking her husband to take a bottle of wine from the rack, she asked him to take a bottle of wine from the “thing.”

Loss of vitality, fatigue, lethargy, hypersomnia (especially if sleep apnea is present), and depressed mood also are commonly seen.

Depressive symptoms. Hypothyroid patients usually meet several criteria for a major depressive episode—such as concentration difficulties, lassitude, low libido, and sometimes pessimism or sadness—and symptoms improve after sustained thyroid hormone replacement therapy.³ Women with mild hypothyroidism who screen negative for a psychiatric syndrome show statistically significant mood improvement and improved verbal fluency after 6 months of levothyroxine replacement therapy.⁴

In some patients with no clear evidence of a biochemical or clinical thyroid disorder, mood symptoms nevertheless respond to thyroid hormone augmentation of antidepressants.⁵

Anxiety symptoms. Occasionally thyroid dysfunction is seen in patients with anxiety disorders, including panic disorder, agoraphobia, social phobia, performance anxiety, post-traumatic stress disorder, and generalized anxiety disorder.⁶

It may seem counterintuitive, but hypothyroidism is probably as common as hyperthyroidism in extremely anxious patients. Both hypoand hyperthyroidism are seen much more often in patients with panic-level anxiety than in the general population.

In a sample of 144 consecutive female psychiatric patients with a lifetime history of panic disorder and/or agoraphobia:

• 27% had a history of thyroid disorder
• 17% had hypothyroidism
• 8% had hyperthyroidism.⁷

Hypothyroid symptoms. Associated symptoms of hypothyroidism (Table 2) may include cold intolerance, lack of or reduced perspiration, dry skin, constipation, lethargy, psychomotor slowness, and subjective paresthesias and muscle pains. Edema is often present. The face typically is swollen or “puffy” in the morning, but by evening the lower legs (and not the face) are edematous.

Deep tendon reflexes usually relax slowly after initial stimulation. Vascular resistance is increased, but hypertension is not usual. Noradrenergic systems become more active in a compensatory, counter-regulatory manner; however, bradycardia—when present—is sometimes profound. Weight gain can occur but often is conspicuously absent.

Severe hypothyroidism presents with paradoxical tremendous agitation, paranoia, and aggressiveness. The skin is leathery, and facies are characteristically rough. Myxedema is fairly common, even in high-functioning patients. I have seen only one case of so-called “myxedema madness;” the female patient’s hyperarousal, yelling, cursing, grossly poor cognitive ability, and loosely conceived paranoid delusions are unforgettable.

Galactorrhea (related to hyperprolactinemia) can be a symptom of severe hypothyroidism, presumably from increased hypothalamic thyrotropin-releasing hormone (TRH) drive. TRH is the main known secretagogue for pituitary prolactin secretion. Infertility, oligomenorrhea, or amenorrhea could be part of the hypothyroid clinical picture.

Other symptoms. Macroglossia and hypertrophy of the uvula are possible; in a recent report, dysarthria resulting from these oral changes was the only presenting symptom of a hypothyroid man.⁸ Dysarthria promptly corrected after levothyroxine replacement.

Hypothyroidism is a primary cause of central sleep apnea caused by dysfunction of ventilatory control and/or reduction in airway aperture.

Table 2

Hypothyroidism’s other signs and symptoms

Causes of thyroid disorders

Primary hypothyroidism results from thyroid gland failure. The many causes include iodine deficiency, but most cases of adult-onset or acquired hypothyroidism are attributed to autoimmune thyroiditis. In primary hypothyroidism, low serum T4 and/or T3 are seen in combination with elevated serum TSH. Circulating free T4 diminishes sooner than free T3 does as the body attempts to preserve active hormone levels. In turn, total T4 and T3 diminish sooner than free hormone concentrations. A compensatory increase in pituitary-elaborated TSH is seen as the brain and pituitary attempt to stimulate the thyroid to produce adequate thyroid hormone.

In subclinical hypothyroidism, circulating free thyroid hormone concentrations are within the normal laboratory range (typically in the lower range), but TSH is elevated. TSH concentrations >3.0 mIU/mL call for repeat or follow-up biochemistry and clinical correlation.

The decision to treat subclinical hypothyroidism with thyroid hormone replacement is less controversial in psychiatry than in endocrinology. Psychiatric patients with subclinical hypothyroidism—especially those with incomplete responses to psychotropic therapy—should usually be treated with thyroid hormone (Box 2).¹

Free T3 levels in the lower 20% of the laboratory’s normal range are cause for pause in a patient with a mood or psychotic disorder and any of hypothyroidism’s clinical stigmata, even if thyroxine and TSH concentrations are normal.

Thyroiditis is characterized by thyroid gland inflammation. The thyroid may be painful or nonpainful, enlarged, fleshy, goitrous, normal in size, or atrophic and fibrotic (especially late in the course).

Postulated precipitants include viruses and other infectious agents, vaccines, iodine excess, lithium therapy (Box 3),⁹ tobacco smoke, environmental chemicals or toxins, irradiation, and—arguably—cortically-mediated (psychological) stress in vulnerable individuals.

Clinically, thyroiditis syndromes often have a long prodromal phase, wax and wane in severity, have an insidious and sometimes silent course, and can be serially associated with hyperthyroidism (especially early in the course), euthyroidism, or hypothyroidism (especially late in the course). Most thyroiditis syndromes appear to resolve spontaneously, but many become chronic or show evidence of subtle thyroid dysfunction years after the first occurrence or diagnosis.

Most presentations are nonspecific; symptoms may be limited to lethargy, fatigue, and depression. Increased antithyroid antibody titers have been linked with psychotic and depressive syndromes in borderline personality disorder.¹⁰

In early thyroiditis, thyroxine and triiodothyronine secretion is often elevated, with low or suppressed TSH. However, antithyroid antibody production is associated with a significantly increased risk of eventual subclinical or frank hypothyroidism. Permanent hypothyroidism develops eventually in at least one-half of women with histories of postpartum thyroiditis.¹¹

Central hypothyroidism stems from TSH deficiency. Both pituitary thyrotrophic failure and hypothalamic failure—secondary and tertiary hypothyroidism, respectively—are considered central (or “secondary”). Hypothyroidism of pituitary and hypothalamic origins are lumped together as “central” because it is often very difficult to differentiate these pathologies.

Thyroid hormone resistance, in which end-organ or cellular resistance to thyroid hormone signals is seen, is an increasingly recognized syndrome in clinical medicine. The typical case is an euthyroid or hypothyroid individual with elevated T4 and T3 and nonsuppressed or even frankly elevated TSH. Inappropriately elevated TSH combined with high thyroid hormone levels also can be seen in TSH-secreting pituitary tumors, although the clinical picture in this case is one of hyperthyroidism.

Thyroid hormone resistance ranges from euthyroid and clinically transparent to profoundly hypothyroid, and different organs in the same patient may show different sensitivities to thyroid hormone. Clinical features vary, depending on the strength of thyroid hormone resistance.

Early emergence of resistance (as would be expected in someone with an inherited thyroid hormone receptor abnormality) leads to developmental problems, including:

• short stature
• mental or learning disabilities (including attention deficits).

In a study of 18 families with strong history of generalized resistance to thyroid hormone, 70% of affected children met diagnostic criteria for attention-deficit/hyperactivity disorder.¹²

Box 2

Box 3

Laboratory screening

TSH and thyroid hormones. The basic thyroid screen is a combination of serum levels of TSH (“sensitive TSH”) and free thyroid hormones.

TSH has a circadian rhythm, with a nocturnal surge amounting to a 50% to 200% increase over daytime levels, beginning at around 6 to 8 PM. Peak TSH pulsatile activity and levels are seen after sleep begins—usually after midnight—with trough levels and fewest TSH pulses in late morning and early afternoon.^13,14 This rhythm implies that the most accurate TSH measurement may be obtained by drawing blood in the morning before 9 AM. I have seen subclinical hypothyroidism missed when clinicians relied on afternoon TSH levels.

In general medicine, TSH alone frequently is used as a routine screening tool. In psychiatric practice, however, I recommend supplementing TSH with free T3 and free T4 because thyroid system dysfunction is frequent in psychiatric syndromes. If laboratory costs are a concern, free T4 with TSH usually suffices for initial screening.

Although the unbound, free fractions of T3 and T4 are of primary interest, total T4 and total T3 are necessary to assess the thyroid gland’s synthetic capacity. When clinical evidence suggests abnormal thyroid hormone function, order repeated or serial biochemical testing. Marginal biochemical results also mandate repeat thyroid function studies, expanded to include:

• total thyroid hormone concentrations (ideally T4 and T3)
• antithyroid antibodies
• serum cholesterol
• prolactin.

Antithyroid antibodies. Obtain antithyroglobulin and antithyroid microsomal antibody titers if:

• thyroid hormone indices are abnormal or marginal—in either direction
• or the patient now has, has had, or has a family history of autoimmune-mediated symptoms, such as lupus erythematosus or rheumatoid arthritis.

Negative or low antithyroid autoantibody titers do not rule out thyroiditis as a cause of hypothyroidism, as these titers are most likely to be generated during periods of active inflammation.

Many autoantibodies react with thyroid-related elements. Most clinical laboratories can quantify antibodies directed against thyroid peroxidase—also called antimicrosomal antibodies—and thyroglobulin. The presence of these antibodies is associated with thyroid inflammation and a risk of progression to thyroid failure and hypothyroidism.

Other laboratory findings of hypothyroidism include hypercholesterolemia, mild hyperprolactinemia, and types of anemia (including iron-deficiency anemia with low ferritin levels).

Related resources

• American Thyroid Association. www.thyroid.org.
• Dunn JT. Guarding our nation’s thyroid health. J Clin Endocrinol Metab 2001;872:486-8.
• Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med 2003;348:2646-55.
• Sullivan GM, Mann JJ, Oquendo MA, et al. Low cerebrospinal fluid transthyretin levels in depression: correlations with suicidal ideation and low serotonin function. Biol Psychiatry 2006;60(5):500-6.

Hypothyroidism—even when occult or subclinical—can cause subtle or frank changes in energy, mood, anxiety level, or cognition. Some patients’ affective symptoms remit with thyroid hormone replacement or with antidepressants only after a euthyroid state is established.

To help you recognize hypothyroidism in patients presenting with psychiatric illnesses and provide effective treatment, this article describes:

• hypothyroidism’s signs and symptoms
• primary and subclinical hypothyroidism, thyroiditis, central hypothyroidism, and thyroid hormone resistance
• laboratory screening for thyroid dysfunction in patients with psychiatric symptoms.

Overlapping clinical signs

Thyroid hormone is required for the metabolic activity of every cell in the body. When patients experience symptoms related to abnormal functioning of the hypothalamic-pituitary-thyroid axis (Figure), psychiatrists often are the first professionals they consult.

Diagnosis of thyroid disorders is based on biochemical and clinical data (Box 1),¹ which might not be congruent. Clinical symptoms of hypothyroidism, for example, are notoriously variable. Severe biochemical hypothyroidism may be associated with mild clinical symptoms, whereas mild biochemical hypothyroidism may be associated with severe symptoms.²

Patients with thyroid disturbance and psychiatric symptoms most often are diagnosed with a depressive-spectrum syndrome. Most common are:

• atypical depression (which may present as dysthymia)
• bipolar spectrum syndrome (including manic-depression, mixed mania, bipolar depression, rapid-cycling bipolar disorder, cyclothymia, and premenstrual syndromes)
• borderline personality disorder
• or psychotic disorder (typically paranoid psychosis).

Psychiatric symptoms of hypothyroidism (Table 1) are often prominent or even primary. Patients commonly show:

• impaired attention, concentration, learning, and memory
• psychomotor slowing
• and/or mental dullness.

Table 1

Hypothyroidism’s psychiatric signs and symptoms

Box 1

Figure Thyroid hormone regulation: The hypothalamic-pituitary-thyroid axis

Thyroid-stimulating hormone (TSH, thyrotropin) released into circulation by the pituitary stimulates the thyroid to synthesize and release thyroid hormone, including triiodothyronine (T3) and thyroxine (T4). TSH is regulated by hypothalamic elaboration of thyrotropin-releasing hormone (TRH), which stimulates TSH release in a dose-dependent manner. Negative feedback from T3 and T4 downregulates TRH gene expression and restrains the pituitary from responding to TSH. Most T3—the active hormone—is formed in circulation or in target tissues by deiodination of T4 by selenium-containing enzymes.

Illustration for Current Psychiatry by Rich LaroccoThe degree of impairment may depend on the patient’s normal functional level. For example, a well-educated patient of mine with thyroiditis-related hypothyroidism reported word-finding difficulties. Instead of asking her husband to take a bottle of wine from the rack, she asked him to take a bottle of wine from the “thing.”

Loss of vitality, fatigue, lethargy, hypersomnia (especially if sleep apnea is present), and depressed mood also are commonly seen.

Depressive symptoms. Hypothyroid patients usually meet several criteria for a major depressive episode—such as concentration difficulties, lassitude, low libido, and sometimes pessimism or sadness—and symptoms improve after sustained thyroid hormone replacement therapy.³ Women with mild hypothyroidism who screen negative for a psychiatric syndrome show statistically significant mood improvement and improved verbal fluency after 6 months of levothyroxine replacement therapy.⁴

In some patients with no clear evidence of a biochemical or clinical thyroid disorder, mood symptoms nevertheless respond to thyroid hormone augmentation of antidepressants.⁵

Anxiety symptoms. Occasionally thyroid dysfunction is seen in patients with anxiety disorders, including panic disorder, agoraphobia, social phobia, performance anxiety, post-traumatic stress disorder, and generalized anxiety disorder.⁶

It may seem counterintuitive, but hypothyroidism is probably as common as hyperthyroidism in extremely anxious patients. Both hypoand hyperthyroidism are seen much more often in patients with panic-level anxiety than in the general population.

In a sample of 144 consecutive female psychiatric patients with a lifetime history of panic disorder and/or agoraphobia:

• 27% had a history of thyroid disorder
• 17% had hypothyroidism
• 8% had hyperthyroidism.⁷

Hypothyroid symptoms. Associated symptoms of hypothyroidism (Table 2) may include cold intolerance, lack of or reduced perspiration, dry skin, constipation, lethargy, psychomotor slowness, and subjective paresthesias and muscle pains. Edema is often present. The face typically is swollen or “puffy” in the morning, but by evening the lower legs (and not the face) are edematous.

Deep tendon reflexes usually relax slowly after initial stimulation. Vascular resistance is increased, but hypertension is not usual. Noradrenergic systems become more active in a compensatory, counter-regulatory manner; however, bradycardia—when present—is sometimes profound. Weight gain can occur but often is conspicuously absent.

Severe hypothyroidism presents with paradoxical tremendous agitation, paranoia, and aggressiveness. The skin is leathery, and facies are characteristically rough. Myxedema is fairly common, even in high-functioning patients. I have seen only one case of so-called “myxedema madness;” the female patient’s hyperarousal, yelling, cursing, grossly poor cognitive ability, and loosely conceived paranoid delusions are unforgettable.

Galactorrhea (related to hyperprolactinemia) can be a symptom of severe hypothyroidism, presumably from increased hypothalamic thyrotropin-releasing hormone (TRH) drive. TRH is the main known secretagogue for pituitary prolactin secretion. Infertility, oligomenorrhea, or amenorrhea could be part of the hypothyroid clinical picture.

Other symptoms. Macroglossia and hypertrophy of the uvula are possible; in a recent report, dysarthria resulting from these oral changes was the only presenting symptom of a hypothyroid man.⁸ Dysarthria promptly corrected after levothyroxine replacement.

Hypothyroidism is a primary cause of central sleep apnea caused by dysfunction of ventilatory control and/or reduction in airway aperture.

Table 2

Hypothyroidism’s other signs and symptoms

Causes of thyroid disorders

Primary hypothyroidism results from thyroid gland failure. The many causes include iodine deficiency, but most cases of adult-onset or acquired hypothyroidism are attributed to autoimmune thyroiditis. In primary hypothyroidism, low serum T4 and/or T3 are seen in combination with elevated serum TSH. Circulating free T4 diminishes sooner than free T3 does as the body attempts to preserve active hormone levels. In turn, total T4 and T3 diminish sooner than free hormone concentrations. A compensatory increase in pituitary-elaborated TSH is seen as the brain and pituitary attempt to stimulate the thyroid to produce adequate thyroid hormone.

In subclinical hypothyroidism, circulating free thyroid hormone concentrations are within the normal laboratory range (typically in the lower range), but TSH is elevated. TSH concentrations >3.0 mIU/mL call for repeat or follow-up biochemistry and clinical correlation.

The decision to treat subclinical hypothyroidism with thyroid hormone replacement is less controversial in psychiatry than in endocrinology. Psychiatric patients with subclinical hypothyroidism—especially those with incomplete responses to psychotropic therapy—should usually be treated with thyroid hormone (Box 2).¹

Free T3 levels in the lower 20% of the laboratory’s normal range are cause for pause in a patient with a mood or psychotic disorder and any of hypothyroidism’s clinical stigmata, even if thyroxine and TSH concentrations are normal.

Thyroiditis is characterized by thyroid gland inflammation. The thyroid may be painful or nonpainful, enlarged, fleshy, goitrous, normal in size, or atrophic and fibrotic (especially late in the course).

Postulated precipitants include viruses and other infectious agents, vaccines, iodine excess, lithium therapy (Box 3),⁹ tobacco smoke, environmental chemicals or toxins, irradiation, and—arguably—cortically-mediated (psychological) stress in vulnerable individuals.

Clinically, thyroiditis syndromes often have a long prodromal phase, wax and wane in severity, have an insidious and sometimes silent course, and can be serially associated with hyperthyroidism (especially early in the course), euthyroidism, or hypothyroidism (especially late in the course). Most thyroiditis syndromes appear to resolve spontaneously, but many become chronic or show evidence of subtle thyroid dysfunction years after the first occurrence or diagnosis.

Most presentations are nonspecific; symptoms may be limited to lethargy, fatigue, and depression. Increased antithyroid antibody titers have been linked with psychotic and depressive syndromes in borderline personality disorder.¹⁰

In early thyroiditis, thyroxine and triiodothyronine secretion is often elevated, with low or suppressed TSH. However, antithyroid antibody production is associated with a significantly increased risk of eventual subclinical or frank hypothyroidism. Permanent hypothyroidism develops eventually in at least one-half of women with histories of postpartum thyroiditis.¹¹

Central hypothyroidism stems from TSH deficiency. Both pituitary thyrotrophic failure and hypothalamic failure—secondary and tertiary hypothyroidism, respectively—are considered central (or “secondary”). Hypothyroidism of pituitary and hypothalamic origins are lumped together as “central” because it is often very difficult to differentiate these pathologies.

Thyroid hormone resistance, in which end-organ or cellular resistance to thyroid hormone signals is seen, is an increasingly recognized syndrome in clinical medicine. The typical case is an euthyroid or hypothyroid individual with elevated T4 and T3 and nonsuppressed or even frankly elevated TSH. Inappropriately elevated TSH combined with high thyroid hormone levels also can be seen in TSH-secreting pituitary tumors, although the clinical picture in this case is one of hyperthyroidism.

Thyroid hormone resistance ranges from euthyroid and clinically transparent to profoundly hypothyroid, and different organs in the same patient may show different sensitivities to thyroid hormone. Clinical features vary, depending on the strength of thyroid hormone resistance.

Early emergence of resistance (as would be expected in someone with an inherited thyroid hormone receptor abnormality) leads to developmental problems, including:

• short stature
• mental or learning disabilities (including attention deficits).

In a study of 18 families with strong history of generalized resistance to thyroid hormone, 70% of affected children met diagnostic criteria for attention-deficit/hyperactivity disorder.¹²

Box 2

Box 3

Laboratory screening

TSH and thyroid hormones. The basic thyroid screen is a combination of serum levels of TSH (“sensitive TSH”) and free thyroid hormones.

TSH has a circadian rhythm, with a nocturnal surge amounting to a 50% to 200% increase over daytime levels, beginning at around 6 to 8 PM. Peak TSH pulsatile activity and levels are seen after sleep begins—usually after midnight—with trough levels and fewest TSH pulses in late morning and early afternoon.^13,14 This rhythm implies that the most accurate TSH measurement may be obtained by drawing blood in the morning before 9 AM. I have seen subclinical hypothyroidism missed when clinicians relied on afternoon TSH levels.

In general medicine, TSH alone frequently is used as a routine screening tool. In psychiatric practice, however, I recommend supplementing TSH with free T3 and free T4 because thyroid system dysfunction is frequent in psychiatric syndromes. If laboratory costs are a concern, free T4 with TSH usually suffices for initial screening.

Although the unbound, free fractions of T3 and T4 are of primary interest, total T4 and total T3 are necessary to assess the thyroid gland’s synthetic capacity. When clinical evidence suggests abnormal thyroid hormone function, order repeated or serial biochemical testing. Marginal biochemical results also mandate repeat thyroid function studies, expanded to include:

• total thyroid hormone concentrations (ideally T4 and T3)
• antithyroid antibodies
• serum cholesterol
• prolactin.

Antithyroid antibodies. Obtain antithyroglobulin and antithyroid microsomal antibody titers if:

• thyroid hormone indices are abnormal or marginal—in either direction
• or the patient now has, has had, or has a family history of autoimmune-mediated symptoms, such as lupus erythematosus or rheumatoid arthritis.

Negative or low antithyroid autoantibody titers do not rule out thyroiditis as a cause of hypothyroidism, as these titers are most likely to be generated during periods of active inflammation.

Many autoantibodies react with thyroid-related elements. Most clinical laboratories can quantify antibodies directed against thyroid peroxidase—also called antimicrosomal antibodies—and thyroglobulin. The presence of these antibodies is associated with thyroid inflammation and a risk of progression to thyroid failure and hypothyroidism.

Other laboratory findings of hypothyroidism include hypercholesterolemia, mild hyperprolactinemia, and types of anemia (including iron-deficiency anemia with low ferritin levels).

Related resources

• American Thyroid Association. www.thyroid.org.
• Dunn JT. Guarding our nation’s thyroid health. J Clin Endocrinol Metab 2001;872:486-8.
• Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med 2003;348:2646-55.
• Sullivan GM, Mann JJ, Oquendo MA, et al. Low cerebrospinal fluid transthyretin levels in depression: correlations with suicidal ideation and low serotonin function. Biol Psychiatry 2006;60(5):500-6.

Hypothyroidism—even when occult or subclinical—can cause subtle or frank changes in energy, mood, anxiety level, or cognition. Some patients’ affective symptoms remit with thyroid hormone replacement or with antidepressants only after a euthyroid state is established.

To help you recognize hypothyroidism in patients presenting with psychiatric illnesses and provide effective treatment, this article describes:

• hypothyroidism’s signs and symptoms
• primary and subclinical hypothyroidism, thyroiditis, central hypothyroidism, and thyroid hormone resistance
• laboratory screening for thyroid dysfunction in patients with psychiatric symptoms.

Overlapping clinical signs

Thyroid hormone is required for the metabolic activity of every cell in the body. When patients experience symptoms related to abnormal functioning of the hypothalamic-pituitary-thyroid axis (Figure), psychiatrists often are the first professionals they consult.

Diagnosis of thyroid disorders is based on biochemical and clinical data (Box 1),¹ which might not be congruent. Clinical symptoms of hypothyroidism, for example, are notoriously variable. Severe biochemical hypothyroidism may be associated with mild clinical symptoms, whereas mild biochemical hypothyroidism may be associated with severe symptoms.²

Patients with thyroid disturbance and psychiatric symptoms most often are diagnosed with a depressive-spectrum syndrome. Most common are:

• atypical depression (which may present as dysthymia)
• bipolar spectrum syndrome (including manic-depression, mixed mania, bipolar depression, rapid-cycling bipolar disorder, cyclothymia, and premenstrual syndromes)
• borderline personality disorder
• or psychotic disorder (typically paranoid psychosis).

Psychiatric symptoms of hypothyroidism (Table 1) are often prominent or even primary. Patients commonly show:

• impaired attention, concentration, learning, and memory
• psychomotor slowing
• and/or mental dullness.

Table 1

Hypothyroidism’s psychiatric signs and symptoms

Box 1

Figure Thyroid hormone regulation: The hypothalamic-pituitary-thyroid axis

Thyroid-stimulating hormone (TSH, thyrotropin) released into circulation by the pituitary stimulates the thyroid to synthesize and release thyroid hormone, including triiodothyronine (T3) and thyroxine (T4). TSH is regulated by hypothalamic elaboration of thyrotropin-releasing hormone (TRH), which stimulates TSH release in a dose-dependent manner. Negative feedback from T3 and T4 downregulates TRH gene expression and restrains the pituitary from responding to TSH. Most T3—the active hormone—is formed in circulation or in target tissues by deiodination of T4 by selenium-containing enzymes.

Illustration for Current Psychiatry by Rich LaroccoThe degree of impairment may depend on the patient’s normal functional level. For example, a well-educated patient of mine with thyroiditis-related hypothyroidism reported word-finding difficulties. Instead of asking her husband to take a bottle of wine from the rack, she asked him to take a bottle of wine from the “thing.”

Loss of vitality, fatigue, lethargy, hypersomnia (especially if sleep apnea is present), and depressed mood also are commonly seen.

Depressive symptoms. Hypothyroid patients usually meet several criteria for a major depressive episode—such as concentration difficulties, lassitude, low libido, and sometimes pessimism or sadness—and symptoms improve after sustained thyroid hormone replacement therapy.³ Women with mild hypothyroidism who screen negative for a psychiatric syndrome show statistically significant mood improvement and improved verbal fluency after 6 months of levothyroxine replacement therapy.⁴

In some patients with no clear evidence of a biochemical or clinical thyroid disorder, mood symptoms nevertheless respond to thyroid hormone augmentation of antidepressants.⁵

Anxiety symptoms. Occasionally thyroid dysfunction is seen in patients with anxiety disorders, including panic disorder, agoraphobia, social phobia, performance anxiety, post-traumatic stress disorder, and generalized anxiety disorder.⁶

It may seem counterintuitive, but hypothyroidism is probably as common as hyperthyroidism in extremely anxious patients. Both hypoand hyperthyroidism are seen much more often in patients with panic-level anxiety than in the general population.

In a sample of 144 consecutive female psychiatric patients with a lifetime history of panic disorder and/or agoraphobia:

• 27% had a history of thyroid disorder
• 17% had hypothyroidism
• 8% had hyperthyroidism.⁷

Hypothyroid symptoms. Associated symptoms of hypothyroidism (Table 2) may include cold intolerance, lack of or reduced perspiration, dry skin, constipation, lethargy, psychomotor slowness, and subjective paresthesias and muscle pains. Edema is often present. The face typically is swollen or “puffy” in the morning, but by evening the lower legs (and not the face) are edematous.

Deep tendon reflexes usually relax slowly after initial stimulation. Vascular resistance is increased, but hypertension is not usual. Noradrenergic systems become more active in a compensatory, counter-regulatory manner; however, bradycardia—when present—is sometimes profound. Weight gain can occur but often is conspicuously absent.

Severe hypothyroidism presents with paradoxical tremendous agitation, paranoia, and aggressiveness. The skin is leathery, and facies are characteristically rough. Myxedema is fairly common, even in high-functioning patients. I have seen only one case of so-called “myxedema madness;” the female patient’s hyperarousal, yelling, cursing, grossly poor cognitive ability, and loosely conceived paranoid delusions are unforgettable.

Galactorrhea (related to hyperprolactinemia) can be a symptom of severe hypothyroidism, presumably from increased hypothalamic thyrotropin-releasing hormone (TRH) drive. TRH is the main known secretagogue for pituitary prolactin secretion. Infertility, oligomenorrhea, or amenorrhea could be part of the hypothyroid clinical picture.

Other symptoms. Macroglossia and hypertrophy of the uvula are possible; in a recent report, dysarthria resulting from these oral changes was the only presenting symptom of a hypothyroid man.⁸ Dysarthria promptly corrected after levothyroxine replacement.

Hypothyroidism is a primary cause of central sleep apnea caused by dysfunction of ventilatory control and/or reduction in airway aperture.

Table 2

Hypothyroidism’s other signs and symptoms

Causes of thyroid disorders

Primary hypothyroidism results from thyroid gland failure. The many causes include iodine deficiency, but most cases of adult-onset or acquired hypothyroidism are attributed to autoimmune thyroiditis. In primary hypothyroidism, low serum T4 and/or T3 are seen in combination with elevated serum TSH. Circulating free T4 diminishes sooner than free T3 does as the body attempts to preserve active hormone levels. In turn, total T4 and T3 diminish sooner than free hormone concentrations. A compensatory increase in pituitary-elaborated TSH is seen as the brain and pituitary attempt to stimulate the thyroid to produce adequate thyroid hormone.

In subclinical hypothyroidism, circulating free thyroid hormone concentrations are within the normal laboratory range (typically in the lower range), but TSH is elevated. TSH concentrations >3.0 mIU/mL call for repeat or follow-up biochemistry and clinical correlation.

The decision to treat subclinical hypothyroidism with thyroid hormone replacement is less controversial in psychiatry than in endocrinology. Psychiatric patients with subclinical hypothyroidism—especially those with incomplete responses to psychotropic therapy—should usually be treated with thyroid hormone (Box 2).¹

Free T3 levels in the lower 20% of the laboratory’s normal range are cause for pause in a patient with a mood or psychotic disorder and any of hypothyroidism’s clinical stigmata, even if thyroxine and TSH concentrations are normal.

Thyroiditis is characterized by thyroid gland inflammation. The thyroid may be painful or nonpainful, enlarged, fleshy, goitrous, normal in size, or atrophic and fibrotic (especially late in the course).

Postulated precipitants include viruses and other infectious agents, vaccines, iodine excess, lithium therapy (Box 3),⁹ tobacco smoke, environmental chemicals or toxins, irradiation, and—arguably—cortically-mediated (psychological) stress in vulnerable individuals.

Clinically, thyroiditis syndromes often have a long prodromal phase, wax and wane in severity, have an insidious and sometimes silent course, and can be serially associated with hyperthyroidism (especially early in the course), euthyroidism, or hypothyroidism (especially late in the course). Most thyroiditis syndromes appear to resolve spontaneously, but many become chronic or show evidence of subtle thyroid dysfunction years after the first occurrence or diagnosis.

Most presentations are nonspecific; symptoms may be limited to lethargy, fatigue, and depression. Increased antithyroid antibody titers have been linked with psychotic and depressive syndromes in borderline personality disorder.¹⁰

In early thyroiditis, thyroxine and triiodothyronine secretion is often elevated, with low or suppressed TSH. However, antithyroid antibody production is associated with a significantly increased risk of eventual subclinical or frank hypothyroidism. Permanent hypothyroidism develops eventually in at least one-half of women with histories of postpartum thyroiditis.¹¹

Central hypothyroidism stems from TSH deficiency. Both pituitary thyrotrophic failure and hypothalamic failure—secondary and tertiary hypothyroidism, respectively—are considered central (or “secondary”). Hypothyroidism of pituitary and hypothalamic origins are lumped together as “central” because it is often very difficult to differentiate these pathologies.

Thyroid hormone resistance, in which end-organ or cellular resistance to thyroid hormone signals is seen, is an increasingly recognized syndrome in clinical medicine. The typical case is an euthyroid or hypothyroid individual with elevated T4 and T3 and nonsuppressed or even frankly elevated TSH. Inappropriately elevated TSH combined with high thyroid hormone levels also can be seen in TSH-secreting pituitary tumors, although the clinical picture in this case is one of hyperthyroidism.

Thyroid hormone resistance ranges from euthyroid and clinically transparent to profoundly hypothyroid, and different organs in the same patient may show different sensitivities to thyroid hormone. Clinical features vary, depending on the strength of thyroid hormone resistance.

Early emergence of resistance (as would be expected in someone with an inherited thyroid hormone receptor abnormality) leads to developmental problems, including:

• short stature
• mental or learning disabilities (including attention deficits).

In a study of 18 families with strong history of generalized resistance to thyroid hormone, 70% of affected children met diagnostic criteria for attention-deficit/hyperactivity disorder.¹²

Box 2

Box 3

Laboratory screening

TSH and thyroid hormones. The basic thyroid screen is a combination of serum levels of TSH (“sensitive TSH”) and free thyroid hormones.

TSH has a circadian rhythm, with a nocturnal surge amounting to a 50% to 200% increase over daytime levels, beginning at around 6 to 8 PM. Peak TSH pulsatile activity and levels are seen after sleep begins—usually after midnight—with trough levels and fewest TSH pulses in late morning and early afternoon.^13,14 This rhythm implies that the most accurate TSH measurement may be obtained by drawing blood in the morning before 9 AM. I have seen subclinical hypothyroidism missed when clinicians relied on afternoon TSH levels.

In general medicine, TSH alone frequently is used as a routine screening tool. In psychiatric practice, however, I recommend supplementing TSH with free T3 and free T4 because thyroid system dysfunction is frequent in psychiatric syndromes. If laboratory costs are a concern, free T4 with TSH usually suffices for initial screening.

Although the unbound, free fractions of T3 and T4 are of primary interest, total T4 and total T3 are necessary to assess the thyroid gland’s synthetic capacity. When clinical evidence suggests abnormal thyroid hormone function, order repeated or serial biochemical testing. Marginal biochemical results also mandate repeat thyroid function studies, expanded to include:

• total thyroid hormone concentrations (ideally T4 and T3)
• antithyroid antibodies
• serum cholesterol
• prolactin.

Antithyroid antibodies. Obtain antithyroglobulin and antithyroid microsomal antibody titers if:

• thyroid hormone indices are abnormal or marginal—in either direction
• or the patient now has, has had, or has a family history of autoimmune-mediated symptoms, such as lupus erythematosus or rheumatoid arthritis.

Negative or low antithyroid autoantibody titers do not rule out thyroiditis as a cause of hypothyroidism, as these titers are most likely to be generated during periods of active inflammation.

Many autoantibodies react with thyroid-related elements. Most clinical laboratories can quantify antibodies directed against thyroid peroxidase—also called antimicrosomal antibodies—and thyroglobulin. The presence of these antibodies is associated with thyroid inflammation and a risk of progression to thyroid failure and hypothyroidism.

Other laboratory findings of hypothyroidism include hypercholesterolemia, mild hyperprolactinemia, and types of anemia (including iron-deficiency anemia with low ferritin levels).

Related resources

• American Thyroid Association. www.thyroid.org.
• Dunn JT. Guarding our nation’s thyroid health. J Clin Endocrinol Metab 2001;872:486-8.
• Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med 2003;348:2646-55.
• Sullivan GM, Mann JJ, Oquendo MA, et al. Low cerebrospinal fluid transthyretin levels in depression: correlations with suicidal ideation and low serotonin function. Biol Psychiatry 2006;60(5):500-6.

When a patient exhibits depressed mood, low energy, anxiety, insomnia, and low libido, do you consider major depression related to testosterone deficiency? Psychiatrists who don’t look for hypogonadism may miss a reversible cause of depression, especially in patients whose affective symptoms don’t respond to antidepressants.

Evidence is revealing how below-normal androgen levels may affect behavior and psychopathology in both men and women. This article describes:

• possible causes and effects of hypogonadism
• how to recognize and treat depression related to testosterone deficiency
• which lab tests provide the most clinically useful measures of testosterone
• potential benefits and adverse effects of testosterone replacement therapy.

Low testosterone and depression

Testosterone deficiency is particularly common in men with treatment-resistant depression. In one study, hypogonadism (total AMtestosterone contrations ≤350 ng/dL) was detected in 24 (43%) of 56 middle-aged men with treatment-resistant depression.¹

Table 1

Signs and symptoms of testosterone deficiency

Symptoms. Although most depressed patients are not hypogonadal, testosterone deficiency can cause depressed mood, low self-confidence, timidity, fearfulness, irritability, low libido, and impaired sexual function in men^1-6 and most likely in women.⁷

Conversely, robust androgen secretion usually promotes good mood, self-confidence, boldness, dominant behavior, and strong libido. Men’s normally higher testosterone levels may relate to this sex’s lower frequency of depression and generally more violent aggression, compared with women.

Increased male aggression is associated with elevated gonadal steroid levels—from overelaboration of endogenous hormone or, more commonly, use of exogenous anabolic steroids.⁸ Less well-appreciated is that testosterone deficiency in men is frequently associated with irritability,⁹ particularly in response to stress. Correcting testosterone deficiency can improve control of hostile feelings and lead to higher self-esteem and less impulsivity.²

In general, correcting hypogonadism improves mood in men,^10,11 including those with refractory depression.^1,12

Depression in women. Evidence is conflicting and limited on a possible link between testosterone deficiency and depression in women. Psychological well-being in postmenopausal women given exogenous estrogens appears to improve when low-dose testosterone is added. In a recent placebo-controlled trial, testosterone cream, 10 mg/d—sufficient to bring total testosterone to the upper normal range—significantly improved mood in premenopausal women with low libido.¹³

Diagnosing hypogonadism

Hypogonadism is usually diagnosed by clinical and biochemical findings. Testosterone deficiency’s common signs and symptoms are shown in Table 1. Treated diabetes and obesity are significantly related to testosterone deficiency, as are—to a lesser extent—headaches, age >60, not smoking, treated asthma, low dominance rating, and sleeping <5 hr/night.¹⁴

Laboratory evaluation. Measuring total serum testosterone concentrations in blood withdrawn before 9 AMis a useful initial screen for testosterone deficiency. Circulating testosterone concentrations show diurnal variation in both sexes, with higher levels in early morning—typically 7 to 8 AM—and lowest levels in the evening—typically 7 to 8 PM. Morning concentrations of serum and salivary testosterone decline an average 50% to 60% from zenith to nadir.

Box

Total testosterone includes protein-bound and unbound testosterone and is a good measure of testosterone synthesis (Box).¹⁵ Normal circulating total testosterone levels are:

• 325 to 1,000 ng/dL in men
• 25 to 90 ng/dL in women (approximately 10% of male levels).

Testosterone assays are usually insensitive in the lower concentration ranges. This makes establishing testosterone deficiency difficult in women.

When total testosterone level is equivocal or low, repeat total testosterone levels once or twice and measure free testosterone, which is the biologically active form. More than 95% of circulating testosterone is bound to plasma proteins, including SHBG and albumin. Also measure free testosterone during the initial screen when you suspect testosterone deficiency.

In cycling women, sex hormone concentrations spike during ovulation and are low when the follicular phase begins. Although longitudinal evaluation is more accurate, the more practical crosssectional screen (AMblood) in the late follicular or late luteal phase is usually adequate.

Evaluating women taking oral contraceptives is biochemically straightforward, as exogenous estrogen suppresses ovarian sex hormone production and induces steady testosterone concentrations.

Postmenopausal women can be screened for sex hormone concentrations on virtually any morning, although perimenopausal women (within 5 years of last menstrual period) are, like premenopausal women, best studied longitudinally. DHEA and DHEA-S concentrations are perhaps more important to measure in women than in men because these sex steroids are responsible for a comparatively much larger component of circulating testosterone in women.

Follow-up tests. If testosterone deficiency is established, measure circulating pituitary hormones LH, FSH, and prolactin to determine if hypogolnadism is primary (gonadal) or secondary to another abnormality (of the brain or pituitary):

• Elevated LH and/or FSH levels are seen in primary hypogonadism, as the pituitary attempts to compensate for poorly functioning or sluggish gonads by increasing their stimulation.
• Diminished or inappropriately normal LH levels during testosterone deficiency (when high levels should be seen) are consistent with central or secondary hypogonadism.
• A combination of primary and secondary hypogonadism is common with advanced age.

Measure serum prolactin concentrations when evaluating hypogonadism because hyperprolactinemia is a common cause.

If the patient is testosterone-deficient, also assess other endocrine systems. If one fails or becomes inflamed, other glands or hormone systems often show insufficiency or inflammation as well, perhaps because of a common pathologic process. Circulating testosterone levels may be normal or elevated in testosterone insensitivity or hyposensitivity syndromes.

Correcting deficiency

Testosterone deficiency can often be corrected without using androgens, such as by changing or supplementing a medication.

Hyperprolactinemia is a common cause of central hypogonadism and testosterone deficiency in psychiatric patients, often as an adverse effect of psychotropics (particularly antipsychotics). Hyperprolactinemia suppresses GnRH and, in turn, LH and gonadal synthesis of testosterone. Hyperprolactinemia depresses libido and causes infertility in both sexes and amenorrhea in women.

Medication changes can usually correct psychotropic-induced hyperprolactinemia. Elevated prolactin levels from other causes (such as a pituitary prolactinoma) usually respond to dopamine agonists such as bromocriptine or cabergoline.

Zinc deficiency can lower testosterone levels. Zinc is highly enriched in the testes and prostate, where it accumulates via a zinc uptake system. The cerebral cortex is also zinc-enriched.

Zinc’s recommended daily allowance (RDA) is 15 mg for men and 12 mg for women. Mild zinc deficiency is common, affecting, for example, about 30% of healthy older men in Detroit¹⁶ and many depressed patients.¹⁷

Remarkably, dietary zinc restriction (to one-third of the RDA) in healthy young men reduces serum testosterone levels by 75% after 5 to 6 months. Conversely, giving a zinc supplement, 30 mg/d, to marginally zinc-deficient older men nearly doubled their serum testosterone concentrations after 6 months.¹⁸

Because serum zinc concentrations do not reliably reflect zinc status, the most expedient clinical approach is to supplement with the RDA—found in widely available multivitamins. Zinc is generally considered low-risk for toxicity, although high doses should be avoided. Much is unknown about zinc’s role in the CNS, where it apparently can be neuroprotective or neurotoxic.

Androgen suppressants. Cholesterol-lowering agents—whether they inhibit cholesterol biosynthesis or absorption—can sometimes lower serum androgen levels. Included are antihyperlipidemic pharmaceuticals and plant sterols that compete with cholesterol for gut absorption. Plant sterols such as beta-sitosterol are marketed as cholesterol-lowering food supplements.

Volatile and fatty oils of the saw palmetto berry (Seranoa repens or Sabal serrulata)—a frequently used over-the-counter phytotherapy for benign prostatic hypertrophy—have antiandrogen properties. They inhibit 5-alpha reductase types I and II, reducing testosterone’s conversion to dihydrotestosterone.¹⁹ Flaxseed oil (linseed oil), another over-the-counter herbal supplement, also may alter testosterone levels.

Table 2

Recommended testosterone-replacement preparations

Exogenous glucocorticoids suppress DHEA release by negative feedback suppression of adrenocorticotropic hormone (ACTH) at the anterior pituitary. To protect against sex hormone deficiency, give DHEA in replacement doses whenever more than a few glucocorticoid doses are given. This applies particularly to postmenopausal women, in whom DHEA is the major source of circulating androgens.

Testosterone replacement

Preliminary data suggest that correcting testosterone deficiency in depressed men can have an antidepressant effect, especially in men who respond inadequately to standard antidepressants. Moreover, like antidepressants, testosterone replacement therapy can induce hypomania or mania in some individuals.

Depression and/or anxiety associated with sustained, irreversible serum testosterone deficiency—usually with other signs of testosterone deficiency (Table 1)—is the major psychiatric indication for testosterone replacement. Borderline biochemical testosterone deficiency and psychiatric symptoms in a “treatment-resistant” patient—especially one at risk for suicide—may justify an empirical testosterone replacement trial. Do not continue such a trial indefinitely without compelling reasons, however, because gonadal function recovery can be delayed for months after even a 12-week testosterone trial.²⁰

Recommended agents for testosterone replacement are shown in Table 2. In men, testosterone preparations are normally used to increase testosterone levels. In women, I prescribe DHEA (discussed below). In young men and women with secondary hypogonadism, pulsatile use of gonadotropins may be necessary to induce spermatogenesis or ovulation—interventions outside the scope of psychiatric practice.

Contraindications to androgen replacement include hyperandrogenism, prostate cancer, antisocial personality, current mania, pedophilia, hypersexuality, and any psychiatric syndrome characterized by violent or predatory behavior. Pregnant patients (or women without a reliable birth control method) should not receive testosterone. Use caution when replacing androgens in patients with benign prostatic hypertrophy, hypomania, or a history of mania or hypomania.

An antidepressant response to adequate exogenous testosterone (enough to raise free testosterone levels to mid-normal range) is generally seen within 4 weeks. If psychological improvement is not observed, testosterone replacement may still prove beneficial if reversing hypogonadism improves the efficacy of subsequent antidepressants.

Dosage forms for men. Transdermal testosterone patches are normally applied to clean, dry skin on the upper arms, abdomen, thigh, or back and rotated among sites to avoid dermal irritation. When the nonscrotal patch is applied at night, testosterone concentrations mimic the circadian pattern seen in young men without causing supraphysiologic transients.²¹

Testosterone gel is applied every morning—also in a rotating manner—to clean, dry, intact skin and allowed to dry. Absorption is rapid, with measurable testosterone increases within 30 minutes. Approximately 10% of the testosterone is absorbed, delivering 5 to 10 mg/d into the circulation after 5 to 10 grams of gel (containing 50 to 100 mg of testosterone) is applied. Steady-state concentrations are achieved within 2 to 3 days, so dosages can be adjusted quickly.

Some patients regard 10 grams of gel as too messy to apply comfortably. Testosterone gel residuals can be washed from the skin with soap and water. Prolonged coated-skin contact with another person, such as a sex partner, can increase testosterone concentrations in the untreated individual.

Oral testosterone is absorbed poorly (often requiring high dosages) and cleared rapidly (half-life: 10 to 100 minutes). Only 10-mg capsules of methyltestosterone preparations are readily available—a dose too small for most men and too large for women. Many pharmacists can formulate other dosages for individual patients. Twice-daily doses are often used. Gum irritation and altered taste can occur when using buccal mucoadhesive testosterone.

Oil-based testosterone injections (such as IM testosteroneenanthate) are absorbedslowly and cannot reproduce normal circadian testosterone rhythms and concentrations. In some cases, however, the long-acting effectsof IM testosteroneare beneficial.

DHEA acutely increases testosterone and estrogens in both men and women after a single physiologic dose. During maintenance DHEA replacement, however, clinically significant increases in both sex hormones are seen only in women. DHEA is preferred to increase testosterone levels in women, as it is converted to appropriate proportions of androgens and estrogens by endogenous steroidogenic enzymes.

Table 3

Potential adverse effects of testosterone replacement therapy

DHEA, which occurs in yams, is available over-the-counter as a “food supplement” or “nutritional supplement.” However, many of these preparations, which are not regulated by the FDA, are unreliable because of poor quality control.²²

Aromatase inhibitors were developed as antibreastcancer agents but also may treat testosterone deficiency. Testosterone administration increases circulating estrogens because testosterone is metabolized by the enzyme aromatase to estradiol. Aromatase inhibitors may prevent excessive estradiol levels—and associated adverse effects, such as gynecomastia—that are sometimes seen during testosterone replacement therapy in men. Available aromatase inhibitors include anastrozole, exemestane, and letrozole.

Potential adverse effects

Short-term testosterone replacement is generally low-risk. Acne is the most common adverse effect (Table 3).

The incidence of adverse events increases as testosterone concentrations are elevated above the normal range. For example, about 5% of men experience a manic or hypomanic arousal within 2 to 6 weeks of induced supraphysiologic testosterone levels.⁸

Gonadal suppression. Exogenous testosterone (or high-dose DHEA) suppresses endogenous gonadal function in men and premenopausal women. When a sustained course of exogenous androgens is discontinued, gonadal suppression usually does not reverse completely for several months or longer.

Prostatic hypertrophy, commonly considered to be testosterone driven, may be a risk of testosterone replacement therapy. Emergent urinary retention during testosterone replacement therapy has been reported, so use caution when giving testosterone to men with prostatic hypertrophy.

Barring evidence to the contrary, testosterone therapy is contraindicated in patients with prostate cancer. Baseline and post-treatment prostate-specific antigen measures are recommended.

Other risks in men. Men occasionally develop gynecomastia during testosterone replacement, perhaps because of testosterone aromatization to estradiol. Beyond increased hematocrit levels and associated problems, testosterone’s cardiovascular risks are unclear. Testosterone deficiency also has been linked to increased atherosclerosis risk in older men.²³

Risks in women. Overtreating women with testosterone (DHEA) can promote hirsutism (including facial hair), loss of hair on scalp, voice lowering, clitoromegaly, breast regression, and muscle hypertrophy.

Related resources

• Daly RC, Su T-P, Schmidt PJ, et al. Cerebrospinal fluid and behavioral changes after methyltestosterone administration. Arch Gen Psychiatry 2001;58:172-7.
• Davis S. Testosterone deficiency in women.J Reprod Med2 001; 46(3 suppl):291-6.
• Rohr UD. The impact of testosterone imbalance on depression and women’s health. Maturitas 2002;41(1 suppl):S25-S46.
• Mantzoros CS, Georgiadis EI. Contribution of dihydrotestosterone to male sexual behaviour. BMJ 1995;310:1289-91.

Drug brand names

• Methyltestosterone (oral) • Android, Methitest, Testred, Virilon
• Testosterone (buccal) • Striant
• Testosterone (gel) • AndroGel, Testim
• Testosterone (transdermal) • Androderm, Testoderm
• Testosterone enanthate (IM injection) • Delatestryl

Disclosure

Dr. Geracioti reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

When a patient exhibits depressed mood, low energy, anxiety, insomnia, and low libido, do you consider major depression related to testosterone deficiency? Psychiatrists who don’t look for hypogonadism may miss a reversible cause of depression, especially in patients whose affective symptoms don’t respond to antidepressants.

Evidence is revealing how below-normal androgen levels may affect behavior and psychopathology in both men and women. This article describes:

• possible causes and effects of hypogonadism
• how to recognize and treat depression related to testosterone deficiency
• which lab tests provide the most clinically useful measures of testosterone
• potential benefits and adverse effects of testosterone replacement therapy.

Low testosterone and depression

Testosterone deficiency is particularly common in men with treatment-resistant depression. In one study, hypogonadism (total AMtestosterone contrations ≤350 ng/dL) was detected in 24 (43%) of 56 middle-aged men with treatment-resistant depression.¹

Table 1

Signs and symptoms of testosterone deficiency

Symptoms. Although most depressed patients are not hypogonadal, testosterone deficiency can cause depressed mood, low self-confidence, timidity, fearfulness, irritability, low libido, and impaired sexual function in men^1-6 and most likely in women.⁷

Conversely, robust androgen secretion usually promotes good mood, self-confidence, boldness, dominant behavior, and strong libido. Men’s normally higher testosterone levels may relate to this sex’s lower frequency of depression and generally more violent aggression, compared with women.

Increased male aggression is associated with elevated gonadal steroid levels—from overelaboration of endogenous hormone or, more commonly, use of exogenous anabolic steroids.⁸ Less well-appreciated is that testosterone deficiency in men is frequently associated with irritability,⁹ particularly in response to stress. Correcting testosterone deficiency can improve control of hostile feelings and lead to higher self-esteem and less impulsivity.²

In general, correcting hypogonadism improves mood in men,^10,11 including those with refractory depression.^1,12

Depression in women. Evidence is conflicting and limited on a possible link between testosterone deficiency and depression in women. Psychological well-being in postmenopausal women given exogenous estrogens appears to improve when low-dose testosterone is added. In a recent placebo-controlled trial, testosterone cream, 10 mg/d—sufficient to bring total testosterone to the upper normal range—significantly improved mood in premenopausal women with low libido.¹³

Diagnosing hypogonadism

Hypogonadism is usually diagnosed by clinical and biochemical findings. Testosterone deficiency’s common signs and symptoms are shown in Table 1. Treated diabetes and obesity are significantly related to testosterone deficiency, as are—to a lesser extent—headaches, age >60, not smoking, treated asthma, low dominance rating, and sleeping <5 hr/night.¹⁴

Laboratory evaluation. Measuring total serum testosterone concentrations in blood withdrawn before 9 AMis a useful initial screen for testosterone deficiency. Circulating testosterone concentrations show diurnal variation in both sexes, with higher levels in early morning—typically 7 to 8 AM—and lowest levels in the evening—typically 7 to 8 PM. Morning concentrations of serum and salivary testosterone decline an average 50% to 60% from zenith to nadir.

Box

Total testosterone includes protein-bound and unbound testosterone and is a good measure of testosterone synthesis (Box).¹⁵ Normal circulating total testosterone levels are:

• 325 to 1,000 ng/dL in men
• 25 to 90 ng/dL in women (approximately 10% of male levels).

Testosterone assays are usually insensitive in the lower concentration ranges. This makes establishing testosterone deficiency difficult in women.

When total testosterone level is equivocal or low, repeat total testosterone levels once or twice and measure free testosterone, which is the biologically active form. More than 95% of circulating testosterone is bound to plasma proteins, including SHBG and albumin. Also measure free testosterone during the initial screen when you suspect testosterone deficiency.

In cycling women, sex hormone concentrations spike during ovulation and are low when the follicular phase begins. Although longitudinal evaluation is more accurate, the more practical crosssectional screen (AMblood) in the late follicular or late luteal phase is usually adequate.

Evaluating women taking oral contraceptives is biochemically straightforward, as exogenous estrogen suppresses ovarian sex hormone production and induces steady testosterone concentrations.

Postmenopausal women can be screened for sex hormone concentrations on virtually any morning, although perimenopausal women (within 5 years of last menstrual period) are, like premenopausal women, best studied longitudinally. DHEA and DHEA-S concentrations are perhaps more important to measure in women than in men because these sex steroids are responsible for a comparatively much larger component of circulating testosterone in women.

Follow-up tests. If testosterone deficiency is established, measure circulating pituitary hormones LH, FSH, and prolactin to determine if hypogolnadism is primary (gonadal) or secondary to another abnormality (of the brain or pituitary):

• Elevated LH and/or FSH levels are seen in primary hypogonadism, as the pituitary attempts to compensate for poorly functioning or sluggish gonads by increasing their stimulation.
• Diminished or inappropriately normal LH levels during testosterone deficiency (when high levels should be seen) are consistent with central or secondary hypogonadism.
• A combination of primary and secondary hypogonadism is common with advanced age.

Measure serum prolactin concentrations when evaluating hypogonadism because hyperprolactinemia is a common cause.

If the patient is testosterone-deficient, also assess other endocrine systems. If one fails or becomes inflamed, other glands or hormone systems often show insufficiency or inflammation as well, perhaps because of a common pathologic process. Circulating testosterone levels may be normal or elevated in testosterone insensitivity or hyposensitivity syndromes.

Correcting deficiency

Testosterone deficiency can often be corrected without using androgens, such as by changing or supplementing a medication.

Hyperprolactinemia is a common cause of central hypogonadism and testosterone deficiency in psychiatric patients, often as an adverse effect of psychotropics (particularly antipsychotics). Hyperprolactinemia suppresses GnRH and, in turn, LH and gonadal synthesis of testosterone. Hyperprolactinemia depresses libido and causes infertility in both sexes and amenorrhea in women.

Medication changes can usually correct psychotropic-induced hyperprolactinemia. Elevated prolactin levels from other causes (such as a pituitary prolactinoma) usually respond to dopamine agonists such as bromocriptine or cabergoline.

Zinc deficiency can lower testosterone levels. Zinc is highly enriched in the testes and prostate, where it accumulates via a zinc uptake system. The cerebral cortex is also zinc-enriched.

Zinc’s recommended daily allowance (RDA) is 15 mg for men and 12 mg for women. Mild zinc deficiency is common, affecting, for example, about 30% of healthy older men in Detroit¹⁶ and many depressed patients.¹⁷

Remarkably, dietary zinc restriction (to one-third of the RDA) in healthy young men reduces serum testosterone levels by 75% after 5 to 6 months. Conversely, giving a zinc supplement, 30 mg/d, to marginally zinc-deficient older men nearly doubled their serum testosterone concentrations after 6 months.¹⁸

Because serum zinc concentrations do not reliably reflect zinc status, the most expedient clinical approach is to supplement with the RDA—found in widely available multivitamins. Zinc is generally considered low-risk for toxicity, although high doses should be avoided. Much is unknown about zinc’s role in the CNS, where it apparently can be neuroprotective or neurotoxic.

Androgen suppressants. Cholesterol-lowering agents—whether they inhibit cholesterol biosynthesis or absorption—can sometimes lower serum androgen levels. Included are antihyperlipidemic pharmaceuticals and plant sterols that compete with cholesterol for gut absorption. Plant sterols such as beta-sitosterol are marketed as cholesterol-lowering food supplements.

Volatile and fatty oils of the saw palmetto berry (Seranoa repens or Sabal serrulata)—a frequently used over-the-counter phytotherapy for benign prostatic hypertrophy—have antiandrogen properties. They inhibit 5-alpha reductase types I and II, reducing testosterone’s conversion to dihydrotestosterone.¹⁹ Flaxseed oil (linseed oil), another over-the-counter herbal supplement, also may alter testosterone levels.

Table 2

Recommended testosterone-replacement preparations

Exogenous glucocorticoids suppress DHEA release by negative feedback suppression of adrenocorticotropic hormone (ACTH) at the anterior pituitary. To protect against sex hormone deficiency, give DHEA in replacement doses whenever more than a few glucocorticoid doses are given. This applies particularly to postmenopausal women, in whom DHEA is the major source of circulating androgens.

Testosterone replacement

Preliminary data suggest that correcting testosterone deficiency in depressed men can have an antidepressant effect, especially in men who respond inadequately to standard antidepressants. Moreover, like antidepressants, testosterone replacement therapy can induce hypomania or mania in some individuals.

Depression and/or anxiety associated with sustained, irreversible serum testosterone deficiency—usually with other signs of testosterone deficiency (Table 1)—is the major psychiatric indication for testosterone replacement. Borderline biochemical testosterone deficiency and psychiatric symptoms in a “treatment-resistant” patient—especially one at risk for suicide—may justify an empirical testosterone replacement trial. Do not continue such a trial indefinitely without compelling reasons, however, because gonadal function recovery can be delayed for months after even a 12-week testosterone trial.²⁰

Recommended agents for testosterone replacement are shown in Table 2. In men, testosterone preparations are normally used to increase testosterone levels. In women, I prescribe DHEA (discussed below). In young men and women with secondary hypogonadism, pulsatile use of gonadotropins may be necessary to induce spermatogenesis or ovulation—interventions outside the scope of psychiatric practice.

Contraindications to androgen replacement include hyperandrogenism, prostate cancer, antisocial personality, current mania, pedophilia, hypersexuality, and any psychiatric syndrome characterized by violent or predatory behavior. Pregnant patients (or women without a reliable birth control method) should not receive testosterone. Use caution when replacing androgens in patients with benign prostatic hypertrophy, hypomania, or a history of mania or hypomania.

An antidepressant response to adequate exogenous testosterone (enough to raise free testosterone levels to mid-normal range) is generally seen within 4 weeks. If psychological improvement is not observed, testosterone replacement may still prove beneficial if reversing hypogonadism improves the efficacy of subsequent antidepressants.

Dosage forms for men. Transdermal testosterone patches are normally applied to clean, dry skin on the upper arms, abdomen, thigh, or back and rotated among sites to avoid dermal irritation. When the nonscrotal patch is applied at night, testosterone concentrations mimic the circadian pattern seen in young men without causing supraphysiologic transients.²¹

Testosterone gel is applied every morning—also in a rotating manner—to clean, dry, intact skin and allowed to dry. Absorption is rapid, with measurable testosterone increases within 30 minutes. Approximately 10% of the testosterone is absorbed, delivering 5 to 10 mg/d into the circulation after 5 to 10 grams of gel (containing 50 to 100 mg of testosterone) is applied. Steady-state concentrations are achieved within 2 to 3 days, so dosages can be adjusted quickly.

Some patients regard 10 grams of gel as too messy to apply comfortably. Testosterone gel residuals can be washed from the skin with soap and water. Prolonged coated-skin contact with another person, such as a sex partner, can increase testosterone concentrations in the untreated individual.

Oral testosterone is absorbed poorly (often requiring high dosages) and cleared rapidly (half-life: 10 to 100 minutes). Only 10-mg capsules of methyltestosterone preparations are readily available—a dose too small for most men and too large for women. Many pharmacists can formulate other dosages for individual patients. Twice-daily doses are often used. Gum irritation and altered taste can occur when using buccal mucoadhesive testosterone.

Oil-based testosterone injections (such as IM testosteroneenanthate) are absorbedslowly and cannot reproduce normal circadian testosterone rhythms and concentrations. In some cases, however, the long-acting effectsof IM testosteroneare beneficial.

DHEA acutely increases testosterone and estrogens in both men and women after a single physiologic dose. During maintenance DHEA replacement, however, clinically significant increases in both sex hormones are seen only in women. DHEA is preferred to increase testosterone levels in women, as it is converted to appropriate proportions of androgens and estrogens by endogenous steroidogenic enzymes.

Table 3

Potential adverse effects of testosterone replacement therapy

DHEA, which occurs in yams, is available over-the-counter as a “food supplement” or “nutritional supplement.” However, many of these preparations, which are not regulated by the FDA, are unreliable because of poor quality control.²²

Aromatase inhibitors were developed as antibreastcancer agents but also may treat testosterone deficiency. Testosterone administration increases circulating estrogens because testosterone is metabolized by the enzyme aromatase to estradiol. Aromatase inhibitors may prevent excessive estradiol levels—and associated adverse effects, such as gynecomastia—that are sometimes seen during testosterone replacement therapy in men. Available aromatase inhibitors include anastrozole, exemestane, and letrozole.

Potential adverse effects

Short-term testosterone replacement is generally low-risk. Acne is the most common adverse effect (Table 3).

The incidence of adverse events increases as testosterone concentrations are elevated above the normal range. For example, about 5% of men experience a manic or hypomanic arousal within 2 to 6 weeks of induced supraphysiologic testosterone levels.⁸

Gonadal suppression. Exogenous testosterone (or high-dose DHEA) suppresses endogenous gonadal function in men and premenopausal women. When a sustained course of exogenous androgens is discontinued, gonadal suppression usually does not reverse completely for several months or longer.

Prostatic hypertrophy, commonly considered to be testosterone driven, may be a risk of testosterone replacement therapy. Emergent urinary retention during testosterone replacement therapy has been reported, so use caution when giving testosterone to men with prostatic hypertrophy.

Barring evidence to the contrary, testosterone therapy is contraindicated in patients with prostate cancer. Baseline and post-treatment prostate-specific antigen measures are recommended.

Other risks in men. Men occasionally develop gynecomastia during testosterone replacement, perhaps because of testosterone aromatization to estradiol. Beyond increased hematocrit levels and associated problems, testosterone’s cardiovascular risks are unclear. Testosterone deficiency also has been linked to increased atherosclerosis risk in older men.²³

Risks in women. Overtreating women with testosterone (DHEA) can promote hirsutism (including facial hair), loss of hair on scalp, voice lowering, clitoromegaly, breast regression, and muscle hypertrophy.

Related resources

• Daly RC, Su T-P, Schmidt PJ, et al. Cerebrospinal fluid and behavioral changes after methyltestosterone administration. Arch Gen Psychiatry 2001;58:172-7.
• Davis S. Testosterone deficiency in women.J Reprod Med2 001; 46(3 suppl):291-6.
• Rohr UD. The impact of testosterone imbalance on depression and women’s health. Maturitas 2002;41(1 suppl):S25-S46.
• Mantzoros CS, Georgiadis EI. Contribution of dihydrotestosterone to male sexual behaviour. BMJ 1995;310:1289-91.

Drug brand names

• Methyltestosterone (oral) • Android, Methitest, Testred, Virilon
• Testosterone (buccal) • Striant
• Testosterone (gel) • AndroGel, Testim
• Testosterone (transdermal) • Androderm, Testoderm
• Testosterone enanthate (IM injection) • Delatestryl

Disclosure

Dr. Geracioti reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

When a patient exhibits depressed mood, low energy, anxiety, insomnia, and low libido, do you consider major depression related to testosterone deficiency? Psychiatrists who don’t look for hypogonadism may miss a reversible cause of depression, especially in patients whose affective symptoms don’t respond to antidepressants.

Evidence is revealing how below-normal androgen levels may affect behavior and psychopathology in both men and women. This article describes:

• possible causes and effects of hypogonadism
• how to recognize and treat depression related to testosterone deficiency
• which lab tests provide the most clinically useful measures of testosterone
• potential benefits and adverse effects of testosterone replacement therapy.

Low testosterone and depression

Testosterone deficiency is particularly common in men with treatment-resistant depression. In one study, hypogonadism (total AMtestosterone contrations ≤350 ng/dL) was detected in 24 (43%) of 56 middle-aged men with treatment-resistant depression.¹

Table 1

Signs and symptoms of testosterone deficiency

Symptoms. Although most depressed patients are not hypogonadal, testosterone deficiency can cause depressed mood, low self-confidence, timidity, fearfulness, irritability, low libido, and impaired sexual function in men^1-6 and most likely in women.⁷

Conversely, robust androgen secretion usually promotes good mood, self-confidence, boldness, dominant behavior, and strong libido. Men’s normally higher testosterone levels may relate to this sex’s lower frequency of depression and generally more violent aggression, compared with women.

Increased male aggression is associated with elevated gonadal steroid levels—from overelaboration of endogenous hormone or, more commonly, use of exogenous anabolic steroids.⁸ Less well-appreciated is that testosterone deficiency in men is frequently associated with irritability,⁹ particularly in response to stress. Correcting testosterone deficiency can improve control of hostile feelings and lead to higher self-esteem and less impulsivity.²

In general, correcting hypogonadism improves mood in men,^10,11 including those with refractory depression.^1,12

Depression in women. Evidence is conflicting and limited on a possible link between testosterone deficiency and depression in women. Psychological well-being in postmenopausal women given exogenous estrogens appears to improve when low-dose testosterone is added. In a recent placebo-controlled trial, testosterone cream, 10 mg/d—sufficient to bring total testosterone to the upper normal range—significantly improved mood in premenopausal women with low libido.¹³

Diagnosing hypogonadism

Hypogonadism is usually diagnosed by clinical and biochemical findings. Testosterone deficiency’s common signs and symptoms are shown in Table 1. Treated diabetes and obesity are significantly related to testosterone deficiency, as are—to a lesser extent—headaches, age >60, not smoking, treated asthma, low dominance rating, and sleeping <5 hr/night.¹⁴

Laboratory evaluation. Measuring total serum testosterone concentrations in blood withdrawn before 9 AMis a useful initial screen for testosterone deficiency. Circulating testosterone concentrations show diurnal variation in both sexes, with higher levels in early morning—typically 7 to 8 AM—and lowest levels in the evening—typically 7 to 8 PM. Morning concentrations of serum and salivary testosterone decline an average 50% to 60% from zenith to nadir.

Box

Total testosterone includes protein-bound and unbound testosterone and is a good measure of testosterone synthesis (Box).¹⁵ Normal circulating total testosterone levels are:

• 325 to 1,000 ng/dL in men
• 25 to 90 ng/dL in women (approximately 10% of male levels).

Testosterone assays are usually insensitive in the lower concentration ranges. This makes establishing testosterone deficiency difficult in women.

When total testosterone level is equivocal or low, repeat total testosterone levels once or twice and measure free testosterone, which is the biologically active form. More than 95% of circulating testosterone is bound to plasma proteins, including SHBG and albumin. Also measure free testosterone during the initial screen when you suspect testosterone deficiency.

In cycling women, sex hormone concentrations spike during ovulation and are low when the follicular phase begins. Although longitudinal evaluation is more accurate, the more practical crosssectional screen (AMblood) in the late follicular or late luteal phase is usually adequate.

Evaluating women taking oral contraceptives is biochemically straightforward, as exogenous estrogen suppresses ovarian sex hormone production and induces steady testosterone concentrations.

Postmenopausal women can be screened for sex hormone concentrations on virtually any morning, although perimenopausal women (within 5 years of last menstrual period) are, like premenopausal women, best studied longitudinally. DHEA and DHEA-S concentrations are perhaps more important to measure in women than in men because these sex steroids are responsible for a comparatively much larger component of circulating testosterone in women.

Follow-up tests. If testosterone deficiency is established, measure circulating pituitary hormones LH, FSH, and prolactin to determine if hypogolnadism is primary (gonadal) or secondary to another abnormality (of the brain or pituitary):

• Elevated LH and/or FSH levels are seen in primary hypogonadism, as the pituitary attempts to compensate for poorly functioning or sluggish gonads by increasing their stimulation.
• Diminished or inappropriately normal LH levels during testosterone deficiency (when high levels should be seen) are consistent with central or secondary hypogonadism.
• A combination of primary and secondary hypogonadism is common with advanced age.

Measure serum prolactin concentrations when evaluating hypogonadism because hyperprolactinemia is a common cause.

If the patient is testosterone-deficient, also assess other endocrine systems. If one fails or becomes inflamed, other glands or hormone systems often show insufficiency or inflammation as well, perhaps because of a common pathologic process. Circulating testosterone levels may be normal or elevated in testosterone insensitivity or hyposensitivity syndromes.

Correcting deficiency

Testosterone deficiency can often be corrected without using androgens, such as by changing or supplementing a medication.

Hyperprolactinemia is a common cause of central hypogonadism and testosterone deficiency in psychiatric patients, often as an adverse effect of psychotropics (particularly antipsychotics). Hyperprolactinemia suppresses GnRH and, in turn, LH and gonadal synthesis of testosterone. Hyperprolactinemia depresses libido and causes infertility in both sexes and amenorrhea in women.

Medication changes can usually correct psychotropic-induced hyperprolactinemia. Elevated prolactin levels from other causes (such as a pituitary prolactinoma) usually respond to dopamine agonists such as bromocriptine or cabergoline.

Zinc deficiency can lower testosterone levels. Zinc is highly enriched in the testes and prostate, where it accumulates via a zinc uptake system. The cerebral cortex is also zinc-enriched.

Zinc’s recommended daily allowance (RDA) is 15 mg for men and 12 mg for women. Mild zinc deficiency is common, affecting, for example, about 30% of healthy older men in Detroit¹⁶ and many depressed patients.¹⁷

Remarkably, dietary zinc restriction (to one-third of the RDA) in healthy young men reduces serum testosterone levels by 75% after 5 to 6 months. Conversely, giving a zinc supplement, 30 mg/d, to marginally zinc-deficient older men nearly doubled their serum testosterone concentrations after 6 months.¹⁸

Because serum zinc concentrations do not reliably reflect zinc status, the most expedient clinical approach is to supplement with the RDA—found in widely available multivitamins. Zinc is generally considered low-risk for toxicity, although high doses should be avoided. Much is unknown about zinc’s role in the CNS, where it apparently can be neuroprotective or neurotoxic.

Androgen suppressants. Cholesterol-lowering agents—whether they inhibit cholesterol biosynthesis or absorption—can sometimes lower serum androgen levels. Included are antihyperlipidemic pharmaceuticals and plant sterols that compete with cholesterol for gut absorption. Plant sterols such as beta-sitosterol are marketed as cholesterol-lowering food supplements.

Volatile and fatty oils of the saw palmetto berry (Seranoa repens or Sabal serrulata)—a frequently used over-the-counter phytotherapy for benign prostatic hypertrophy—have antiandrogen properties. They inhibit 5-alpha reductase types I and II, reducing testosterone’s conversion to dihydrotestosterone.¹⁹ Flaxseed oil (linseed oil), another over-the-counter herbal supplement, also may alter testosterone levels.

Table 2

Recommended testosterone-replacement preparations

Exogenous glucocorticoids suppress DHEA release by negative feedback suppression of adrenocorticotropic hormone (ACTH) at the anterior pituitary. To protect against sex hormone deficiency, give DHEA in replacement doses whenever more than a few glucocorticoid doses are given. This applies particularly to postmenopausal women, in whom DHEA is the major source of circulating androgens.

Testosterone replacement

Preliminary data suggest that correcting testosterone deficiency in depressed men can have an antidepressant effect, especially in men who respond inadequately to standard antidepressants. Moreover, like antidepressants, testosterone replacement therapy can induce hypomania or mania in some individuals.

Depression and/or anxiety associated with sustained, irreversible serum testosterone deficiency—usually with other signs of testosterone deficiency (Table 1)—is the major psychiatric indication for testosterone replacement. Borderline biochemical testosterone deficiency and psychiatric symptoms in a “treatment-resistant” patient—especially one at risk for suicide—may justify an empirical testosterone replacement trial. Do not continue such a trial indefinitely without compelling reasons, however, because gonadal function recovery can be delayed for months after even a 12-week testosterone trial.²⁰

Recommended agents for testosterone replacement are shown in Table 2. In men, testosterone preparations are normally used to increase testosterone levels. In women, I prescribe DHEA (discussed below). In young men and women with secondary hypogonadism, pulsatile use of gonadotropins may be necessary to induce spermatogenesis or ovulation—interventions outside the scope of psychiatric practice.

Contraindications to androgen replacement include hyperandrogenism, prostate cancer, antisocial personality, current mania, pedophilia, hypersexuality, and any psychiatric syndrome characterized by violent or predatory behavior. Pregnant patients (or women without a reliable birth control method) should not receive testosterone. Use caution when replacing androgens in patients with benign prostatic hypertrophy, hypomania, or a history of mania or hypomania.

An antidepressant response to adequate exogenous testosterone (enough to raise free testosterone levels to mid-normal range) is generally seen within 4 weeks. If psychological improvement is not observed, testosterone replacement may still prove beneficial if reversing hypogonadism improves the efficacy of subsequent antidepressants.

Dosage forms for men. Transdermal testosterone patches are normally applied to clean, dry skin on the upper arms, abdomen, thigh, or back and rotated among sites to avoid dermal irritation. When the nonscrotal patch is applied at night, testosterone concentrations mimic the circadian pattern seen in young men without causing supraphysiologic transients.²¹

Testosterone gel is applied every morning—also in a rotating manner—to clean, dry, intact skin and allowed to dry. Absorption is rapid, with measurable testosterone increases within 30 minutes. Approximately 10% of the testosterone is absorbed, delivering 5 to 10 mg/d into the circulation after 5 to 10 grams of gel (containing 50 to 100 mg of testosterone) is applied. Steady-state concentrations are achieved within 2 to 3 days, so dosages can be adjusted quickly.

Some patients regard 10 grams of gel as too messy to apply comfortably. Testosterone gel residuals can be washed from the skin with soap and water. Prolonged coated-skin contact with another person, such as a sex partner, can increase testosterone concentrations in the untreated individual.

Oral testosterone is absorbed poorly (often requiring high dosages) and cleared rapidly (half-life: 10 to 100 minutes). Only 10-mg capsules of methyltestosterone preparations are readily available—a dose too small for most men and too large for women. Many pharmacists can formulate other dosages for individual patients. Twice-daily doses are often used. Gum irritation and altered taste can occur when using buccal mucoadhesive testosterone.

Oil-based testosterone injections (such as IM testosteroneenanthate) are absorbedslowly and cannot reproduce normal circadian testosterone rhythms and concentrations. In some cases, however, the long-acting effectsof IM testosteroneare beneficial.

DHEA acutely increases testosterone and estrogens in both men and women after a single physiologic dose. During maintenance DHEA replacement, however, clinically significant increases in both sex hormones are seen only in women. DHEA is preferred to increase testosterone levels in women, as it is converted to appropriate proportions of androgens and estrogens by endogenous steroidogenic enzymes.

Table 3

Potential adverse effects of testosterone replacement therapy

DHEA, which occurs in yams, is available over-the-counter as a “food supplement” or “nutritional supplement.” However, many of these preparations, which are not regulated by the FDA, are unreliable because of poor quality control.²²

Aromatase inhibitors were developed as antibreastcancer agents but also may treat testosterone deficiency. Testosterone administration increases circulating estrogens because testosterone is metabolized by the enzyme aromatase to estradiol. Aromatase inhibitors may prevent excessive estradiol levels—and associated adverse effects, such as gynecomastia—that are sometimes seen during testosterone replacement therapy in men. Available aromatase inhibitors include anastrozole, exemestane, and letrozole.

Potential adverse effects

Short-term testosterone replacement is generally low-risk. Acne is the most common adverse effect (Table 3).

The incidence of adverse events increases as testosterone concentrations are elevated above the normal range. For example, about 5% of men experience a manic or hypomanic arousal within 2 to 6 weeks of induced supraphysiologic testosterone levels.⁸

Gonadal suppression. Exogenous testosterone (or high-dose DHEA) suppresses endogenous gonadal function in men and premenopausal women. When a sustained course of exogenous androgens is discontinued, gonadal suppression usually does not reverse completely for several months or longer.

Prostatic hypertrophy, commonly considered to be testosterone driven, may be a risk of testosterone replacement therapy. Emergent urinary retention during testosterone replacement therapy has been reported, so use caution when giving testosterone to men with prostatic hypertrophy.

Barring evidence to the contrary, testosterone therapy is contraindicated in patients with prostate cancer. Baseline and post-treatment prostate-specific antigen measures are recommended.

Other risks in men. Men occasionally develop gynecomastia during testosterone replacement, perhaps because of testosterone aromatization to estradiol. Beyond increased hematocrit levels and associated problems, testosterone’s cardiovascular risks are unclear. Testosterone deficiency also has been linked to increased atherosclerosis risk in older men.²³

Risks in women. Overtreating women with testosterone (DHEA) can promote hirsutism (including facial hair), loss of hair on scalp, voice lowering, clitoromegaly, breast regression, and muscle hypertrophy.

Related resources

• Daly RC, Su T-P, Schmidt PJ, et al. Cerebrospinal fluid and behavioral changes after methyltestosterone administration. Arch Gen Psychiatry 2001;58:172-7.
• Davis S. Testosterone deficiency in women.J Reprod Med2 001; 46(3 suppl):291-6.
• Rohr UD. The impact of testosterone imbalance on depression and women’s health. Maturitas 2002;41(1 suppl):S25-S46.
• Mantzoros CS, Georgiadis EI. Contribution of dihydrotestosterone to male sexual behaviour. BMJ 1995;310:1289-91.

Drug brand names

• Methyltestosterone (oral) • Android, Methitest, Testred, Virilon
• Testosterone (buccal) • Striant
• Testosterone (gel) • AndroGel, Testim
• Testosterone (transdermal) • Androderm, Testoderm
• Testosterone enanthate (IM injection) • Delatestryl

Disclosure

Dr. Geracioti reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.