Organic Mood Disorder Associated With the HAIR-AN Syndrome Theodore R. Levin, M.D. Thomas R. Terrell, M.D. Alan Stoudemire, M.D.

The HAIR-AN

syndrome

hyperandrogenism,

thosis

is characterized

insulin

nigricans.

resistance,

The authors

report

T

by and acan-

the first

case

of an organic mood disorder associated with this condition that improved markedly in response to ovarian suppression with oral contraceptives. The proposed

pathophysiology

of this syndrome

discussed. (The

Journal

Neurosciences

of Neuropsychiatry 1992;

4:51-54)

and

Clinical

is also

he

syndrome

tance,

and

of

hyperandrogenism,

acanthosis

insulin

nigricans

resis-

(HAIR-AN)

is an

unusual logies.

endocnnologic triad with several possible etioThe hyperandrogenism is primarily ovarian in origin and commonly results from ovarian hyperthecosis or polycystic ovary disease (PCOD). The insulin resistance is usually subclinical, and acanthosis nigricans (AN), characterized by brown to black hyperpigmentation of the epidermis usually in the axilla, groin, umbfficus, nipples, and intertnginous areas, develops following prolonged exposure of the epidermal epithelium to high levels of circulating insulin.’2 Although this syndrome has been described in the medical and gynecological literature, to our knowledge it has not been described in association

with

any

psychiatric

disorders.

We

present

the case of a patient with a chronic organic mood disorder (depressed type) in association with the HAIR-AN syndrome in which the depression responded to ovarian suppression

CASE

with

oral

contraceptives.

REPORT

A 37-year-old chiatry unit lated a long

divorced female presented for evaluation of refractory history of depressed mood

Received August 30, 1990; revised November ary 25, 1991. From the Medical Psychiatric Hospital, and the Department of Psychiatry, of Medicine, Atlanta, Georgia. Address Stoudemire, Clifton

Psychiatry Road,

Copyright

JOURNAL

OF

NEUROPSYCHIATRY

N.E., © 1992

Section, Atlanta,

American

CA

5th

Floor,

to our medical psydepression. She rebeginning at age 9 or 5, 1990; accepted FebruUnit, Emory University Emory University School reprint requests to Dr. Emory

Central

Clinics,

1365

30322. Psychiatric

Press,

Inc.

51

HAIR-AN

SYNDROME

10 (associated suicide at age retrospect the pression were (OCs). At age rhea resulted

AND MOOD

DISORDER

with the onset of menses). She had attempted 11 and again at age 17. She reported that in only periods in her life that were free of dewhen she was also taking oral contraceptives 14 a gynecological evaluation for oligomenorin her taking these agents for the first time. Dur-

ing a 5-year marriage in her early twenties she also took OCs. During the 10 years following the birth of her son she did not take OCs and had a fairly constant level of depression with occasional fluctuations. She was hospitalized once for psychotic depression, approximately 3 years prior to the current admission, following a suicide attempt. She had been severely depressed and suffered from insomnia and nightmares. During the last 10 years she had been under the

continuing care of an outpatient psychiatrist. The patient had suffered from oligomenorrhea intermittently throughout her adult life. Five years before this admission she began to gain weight steadily, gaining more than 40 pounds. She developed hirsutism, acne, and deepening of her voice. She was given an isolated diagnosis of AN eight months prior to this admission. Six months prior to admission she was referred to an endocrinologist for evaluation of her irregular menses, obesity, and hirsutism. Laboratory studies at that time showed a mildly elevated baseline 24-hour urinary free cortisol of 204-228 j.tg/24h (normal 20-84 tg/24h), 17-hydroxycorticosteroids pg/mI

(17-OHCS) 35.5 mg/24h (normal 3-10), ACTH 40 (normal 0-130 pg/ml), elevated testosterone of 92 ng/dl (normal 10-80 ng/dl), and a normal dehydroepiandrosterone sulfate (DHEA-S) level. She suppressed her urinary free cortisol, 17-OHCS, and ACTH production to undetectable levels promptly within 24 hours of low dose dexamethasone, effectively ruling out Cushing’s disease. MRI of the sella turcica and abdominal CT scan examination of adrenal glands were within normal limits.The mildly elevated baseline cortisol production was hypothesized at that time to be possibly secondary to a cyclical variant of Cushing’s disease or secondary to depression. She was discharged on 0.25 mg dexamethasone per day to suppress androgen production, regulate menses, and decrease facial hair. Three months prior to admission to our unit she developed another severe depression in the absence of obvious external stressors. Symptoms included insomnia, decreased energy, anhedonia, apathy, and decreased libido. Her local psychiatrist had tried her on several medications in an attempt to treat her anxiety, depression, and insomnia. On admission she was taking bupropion, amitriptyline, buspirone, and lithium in addition to the 0.25 mg dexamethasone noted above. On physical exam she was obese, with a noncentripetal fat distribution. Signs of AN were prominent over the nape of her neck, between the webs of her fingers, and on her heels. She was hirsute, with prominent facial hair and hair on her linea alba. She had mild temporal balding. Her abdomen was obese with pale striae. There was no clitoromegaly present on pelvic exam, and no adnexal masses or cysts were apparent on bimanual examination. The rest of the physical exam was within normal limits. Laboratory studies revealed random glucose of 142 mg/dl, urinary free cortisol of 66 tg/24h (normal range), total testos-

52

terone of 39 tg/dl and DHEA-S of 65 j.tg/dl (both normal range). Prolactin was 15 ng/ml (normal). Her oral glucose tolerance testresults were abnormal, and she had a serum insulin of 194 mU/ml at 30 minutes (normal 1-25 mU/mI) and serum insulin of greater than 400 mU/ml (normal 1-25 mU/mi) at 120 minutes. Ultrasound and CT scanning of the pelvis showed normal ovaries. The remainder of her metabolic studies (SMA-18, T4, T3-RIA, TSH, B,2, and urinalysis) were within normal limits. All psychotropic medications

were stopped,

and the dexamethasone

was stopped

upon

admission. Consultation with reproductive endocrinology consultants led to the diagnosis of the HAIR-AN syndrome. The patient was begun on OCs, and her depression began to improve within several weeks. At 2 months following discharge the patient was doing well, with complete resolution of her depression and a weight loss of 25 pounds.

DISCUSSION This

patient

sion

but

range, sion

was

had

which by

clearly

clinically

was

than

supports

believed

to be an effect

The

normal

and her

glucose

levels

to insulin

depression.

ovarian

function

Acanthosis monly

have

nigricans

described

been

pathies.’

and

and

therefore

described.

Type

creased associated

binding with

with

types

of

binding

the

The fact

HAIR-AN

have

sup-

decreased

her

may be an associand depression, but

resistance,

most

com-

hyperandrogenism,

of endocrino-

resistance

insulin

have

resistance

of insulin to its receptor. Type non-organ-specific autoimmune

of insulin

was (with

occurred

would

a spectrum insulin

A is severe

that results in autoantibodies receptor. Type C represents normal

There

with

test

of antidepressants)

OCs

insulin

suppres-

insulin). depression

The

in association

associated Three

of the

between

circulating levels of androgens. ation between hyperandrogenemia the link is as yet unidentified.

admis-

normal

resistance

of circulating

association

on

in the tolerance

her only relief from OCs (in the absence

a possible

syndrome

testosterone

secondary

that historically while taking

pressed

total

dexamethasone. abnormal

higher

hyperandrogenic

a serum

circulating a post-receptor

with

been de-

B is often disease

to the insulin defect with

to its receptor.’

Hyperandrogenism is associated with AN more often than was previously thought. Barbieri and Ryan2 report that 1% to 3% of hyperandrogenic females may have the HAIR-AN syndrome. More recently, as many as 29% of hyperandrogenic women have been reported to have AN.3 The most common ated with HAIR-AN

types of ovarian pathology associare PCOD and ovarian hypertheco-

sis. Androgen-secreting out in these patients.4

neoplasms Laboratory

VOLUME

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#{149} NUMBER

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onstrate elevated ovarian androgens (testosterone, androstenedione) with normal adrenal androgens (DHEA, DHEA-S). It should be noted that the severity of insulin resistance often parallels the degree of androgen excess.2 Patients with HAIR-AN syndrome rarely show signs or symptoms of diabetes mellitus. As in our patient, often the insulin resistance is documented only by an abnormal glucose tolerance test with higher than normal levels of circulating insulin. Patients often have adequate beta islet cell reserve and respond to insulin resistance by secreting higher than normal levels of insulin. Barbieri and Ryan2 have proposed a pathophysiologic mechanism to account for this syndrome, ifiustrated in Figure 1. In their hypothesis, the primary abnormality is the insulin resistance. Patients do not develop the signs or symptoms of diabetes mellitus because of adequate beta islet cell reserves of insulin. They usually hypersecrete insulin in response to a glucose challenge and therefore have increased circulating insulin levels. In patients with adequate islet cell reserve, this insulin resistance produces marked hyperinsulinemia, and other abnormalities are secondary to this phenomenon. Insulin is hypothesized to stimulate receptors for ovarian insulin-like growth factor (IGF-I) or for other members of the family of insulin-like growth factors. Binding to these receptors The

has

a mitogenic

(trophic)

hyperandrogenemia

so increases the positive feedback

severity

that

subsequently

on the

mgricans

menstrual

secretion, function. er,

and These

develops

over

and

to be an

periods.

Oral

contraceptives,

hypothalamus

the arcuate nucleus areas are anatomically

neuronal

as

neu-

the

changes

can

regulates gonadal close to each oth-

occur

in

both

areas

in

tients

hypersecreting

corticotropin-releasing

that in a pa-

hormone.

The hypothalamus may be the neuroanatomic basis for the association between depression and the HAIR-AN syndrome. The HATR-AN syndrome has been only recently described,2 and the relationship between insulin resistance and hyperandrogenism is complex and poorly understood. We suspect that as more physicians become aware of insulin

resistance

associations

will

hyperandrogenic cluding

FIGURE

among

be

found

hyperandrogenic

between

conditions

a link

lin resistance

between and

and

women,

a wide insulin

resistance,

hyperandrogenism

mood

variety

and/or

of in-

insu-

disorders.

1.Pathogenic

mechanism in patients with the HAIR-AN The insulin resistance and the hyperandrogenemia are the primary disturbances. The severity of the insulin resistance and the hyperandrogenism are correlated. There is a positivefeedback relationship syndrome.

al-

between ism. The

time.

is believed

the

certain animal models of diabetes. It is well accepted the hypothalamic-pituitary-adrenal axis is disrupted substantial group of depressed patients, with many

ovary.

both

epiphenom-

enon, secondary to prolonged exposure of epidermal epithelium to high levels of circulating insulin.2 AN, however, can occur in association with other medical disorders as well, including malignancies (usually adenocarcinomas), Cushing’s syndrome, obesity, acromegaly, and the Stein-Leventhal syndrome. As described earlier, the condition is characterized by brown to black epidermal hyperpigmentation in areas of multiple confluent papilomas that give the skin a velvety surface elevation.5 Several treatments have been employed. First, weight loss is important in obese patients to help decrease the severity of the insulin resistance. Dexamethasone may occasionally suppress ovarian androgen production and regulate

et al.3 propose

et at.

roanatomic location of the disruption of insulin regulation and androgen hypersecretion in this syndrome. The ventromedial hypothalamus putatively regulates insulin

severity of the insulin resistance. This loop leads to a progressive increase in

of the disease

Acanthosis

effect

Dunaif

LEVIN

partic-

those containing 0.035 mg ethinyl estradiol, are for suppressing ovarian androgen production.4 Some authors have reported using ketoconazole in refractory patients to suppress androgen production and reverse hirsutism.6

the insulin acanthosis

the insulin

Adapted

from

Insulin

resistance nigricans

resistance Barbieri

and the hyperandrogenis an epiphenomenon

and the and Ryan.2

of

hyperandrogenism.

Resistance

I Chronically insulin

/ \

Stimulation stromal

increased levels

of ovarian & thecal tissues

ularly useful

JOURNAL

OF

NEUROPSYCHIATRY

Acanthosis

Hyperandrogenemia

Nigricans

53

HAIR-AN

SYNDROME

AND

MOOD

DISORDER

References 1. Atkinson presentations

AB,

Kennedy of the

L, Andrews syndrome

WJ,

of acanthosis

et al:

Diverse

nigricans

endocrine and

resistance.J R Coil Physicians Lond 1989; 23:165-169 2. Barbieri RL, Ryan KJ: Hyperandrogenism, insulin resistance, acanthosis nigricans syndrome: a common endocrinopathy distinct pathophysiologic features. Am I Obstet Gynecol

insulin

and with 1983;

147:90-101

3. Dunaif A, Graf M, Mandeli J, et al:Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance and/or hyperinsulinemia. I Clin Endocrinol Metab 1987; 65:499-507

54

4. Dunaif A: Commentary, in Case Records of the Massachusetts General Hospital Weekly Clinicopathologic Exercises, case 22-1 988: 13 year old girl with secondary amenorrhea, obesity, acanthosis nigricans and hirsutism. N Engi J Med 1988; 318:1449-1457 5. Haynes HA, Fitzpatrick TG: Cutaneous manifestations of internal malignancy, in Harrison’s Principles of Internal Medicine. New York, McGraw-Hill, 1983, pp829-.835 6. Pepper

GM,

Poretzky

L, Gabrilore

JL, et al: Ketoconazole

hyperandrogenism in a patient with insulin sis nigricans. J Clin Endocrinol Metab 1987;

VOLUME

4

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resistance

reverses

and acantho-

65:1047-1052.

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