Cushing Syndrome (Hypercortisolism)

Essentials of Diagnosis

 Central obesity, muscle wasting, thin skin, hirsutism, purple striae.

 Psychological changes.

 Osteoporosis, hypertension, poor wound healing.

 Hyperglycemia, glycosuria, leukocytosis, lymphocytopenia, hypokalemia.

 Elevated serum cortisol and urinary free cortisol. Lack of normal suppression by
dexamethasone.

General Considerations

The term Cushing "syndrome" refers to the manifestations of excessive corticosteroids,

commonly due to supraphysiologic doses of corticosteroid drugs and rarely due to spontaneous
production of excessive corticosteroids by the adrenal cortex. Cases of spontaneous Cushing
syndrome are rare (2.6 new cases yearly per million population) and have several possible
causes.

About 40% of cases are due to Cushing "disease," by which is meant the manifestations of
hypercortisolism due to ACTH hypersecretion by the pituitary. Cushing disease is caused by a
benign pituitary adenoma that is typically very small (< 5 mm) and usually located in the anterior
pituitary (98%) or in the posterior pituitary (2%). It is at least three times more frequent in
women than men.

About 10% of cases are due to nonpituitary ACTH-secreting neoplasms (eg, small cell lung
carcinoma), which produce excessive amounts of ectopic ACTH. Hypokalemia and
hyperpigmentation are commonly found in this group.

About 15% of cases are due to ACTH from a source that cannot be initially located.

About 30% of cases are due to excessive autonomous secretion of cortisol by the adrenals—
independently of ACTH, serum levels of which are usually low. Most such cases are due to a
unilateral adrenal tumor. Benign adrenal adenomas are generally small and produce mostly
cortisol; adrenal carcinomas are usually large when discovered and can produce excessive
cortisol as well as androgens, with resultant hirsutism and virilization. ACTH-independent
macronodular adrenal hyperplasia can also produce hypercortisolism due to the adrenal cortex
cells' abnormal stimulation by hormones such as catecholamines, argininevasopressin, serotonin,
hCG/LH, or gastric inhibitory polypeptide; in the latter case, hypercortisolism may be
intermittent and food dependent and serum ACTH may not be completely suppressed. Pigmented
bilateral adrenal macronodular adrenal hyperplasia is a rare cause of Cushing syndrome in
children and young adults; it may be an isolated condition or part of the Carney complex.

Clinical Findings

Symptoms and Signs

Patients with Cushing syndrome usually have central obesity with a plethoric "moon
face," "buffalo hump," supraclavicular fat pads, protuberant abdomen, and thin extremities;
oligomenorrhea or amenorrhea (or erectile dysfunction in the male); weakness, backache, and
headache; hypertension; osteoporosis; avascular bone necrosis; and acne and superficial skin
infections (see illustration). Patients may have thirst and polyuria (with or without glycosuria),
renal calculi, glaucoma, purple striae (see photograph) (especially around the thighs, breasts, and
abdomen), and easy bruisability. Wound healing is impaired. Mental symptoms may range from
diminished ability to concentrate to increased lability of mood to frank psychosis. Patients are
susceptible to opportunistic infections.

Fig.

Typical findings in Cushing syndrome. (Reproduced, with permission, from McPhee SJ et al

[editors]: Pathophysiology of Disease: An Introduction to Clinical Medicine, 2nd ed. Originally
published by Appleton & Lange. Copyright © 1997 by The McGraw-Hill Companies, Inc.)

Fig.

Axillary pigmented striae of Cushing syndrome preoperatively. (Courtesy of C Grunfeld.)

Laboratory Findings

Glucose tolerance is impaired as a result of insulin resistance. Polyuria is present as a result of

increased free water clearance; diabetes mellitus with glycosuria may worsen it. Patients with
Cushing syndrome often have leukocytosis with relative granulocytosis and lymphopenia.
Hypokalemia may be present, particularly in cases of ectopic ACTH secretion.

Tests for Hypercortisolism

The easiest screening test for Cushing syndrome is the dexamethasone suppression test:
dexamethasone 1 mg is given orally at 11 pm and serum is collected for cortisol determination at
about 8 am the next morning; a cortisol level < 5 mcg/dL (< 135 nmol/L, fluorometric assay) or
< 2 mcg/dL (< 54 nmol/L, high-performance liquid chromatography [HPLC] assay) excludes
Cushing syndrome with some certainty. However, 8% of established patients with pituitary
Cushing disease have dexamethasone-suppressed cortisol levels < 2 mcg/dL. Therefore, when
other clinical criteria suggest hypercortisolism, further evaluation is warranted even in the face of
normal dexamethasone-suppressed serum cortisol. Antiseizure drugs (eg, phenytoin,
phenobarbital, primidone) and rifampin accelerate the metabolism of dexamethasone, causing a
lack of cortisol suppression by dexamethasone. Estrogens—during pregnancy or as oral
contraceptives or ERT—may also cause lack of dexamethasone suppressibility.

Patients with an abnormal dexamethasone suppression test require further investigation, which
includes a 24-hour urine collection for free cortisol and creatinine. An abnormally high 24-hour
urine free cortisol (or free cortisol to creatinine ratio of > 95 mcg cortisol/g creatinine) helps
confirm hypercortisolism. A misleadingly high urine free cortisol excretion occurs with high
fluid intake. In pregnancy, urine free cortisol is increased, while 17-hydroxycorticosteroids
remain normal and diurnal variability of serum cortisol is normal. Carbamazepine and
fenofibrate cause false elevations of urine free cortisol when determined by HPLC.

A midnight serum cortisol level > 7.5 mcg/dL is indicative of Cushing syndrome and
distinguishes it from other conditions associated with a high urine free cortisol (pseudo-Cushing
states; see Differential Diagnosis, below). Requirements for this test include being in the same
time zone for at least 3 days, being without food for at least 3 hours, and having an indwelling
intravenous line established in advance for the blood draw.

Due to the inconvenience of obtaining a midnight blood specimen for serum cortisol, late-night
salivary cortisol assays are useful. Salivary cortisol kits can be ordered at
www.acllaboratories.com. Using enzyme-linked immunosorbent assay (ELISA), midnight
salivary cortisol levels are normally < 0.15 mcg/dL (4.0 nmol/L). Midnight salivary cortisol
levels that are consistently > 0.25 mcg/dL (7.0 nmol/L) are considered very abnormal. The late-
night salivary cortisol test has a high sensitivity and specificity for Cushing syndrome, but false-
positive and false-negative tests have occurred.

Interestingly, hypercortisolism without Cushing syndrome can occur in several conditions, such
as severe depression, anorexia nervosa, alcoholism, and familial cortisol resistance. (See
Differential Diagnosis, below.)

Finding the Cause of Hypercortisolism

Once hypercortisolism is confirmed, a plasma or serum ACTH is obtained. It must be collected

properly in a plastic tube on ice and processed quickly by a laboratory with a reliable, sensitive
assay. A level of ACTH below about 20 pg/mL indicates a probable adrenal tumor, whereas
higher levels are produced by pituitary or ectopic ACTH-secreting tumors.

Localizing Techniques

In ACTH-dependent Cushing syndrome, MRI of the pituitary demonstrates a pituitary lesion in

about 50% of cases. Premature cerebral atrophy is often noted. When the pituitary MRI is normal
or shows a tiny (< 5 mm diameter) irregularity that may be incidental, selective catheterization of
the inferior petrosal sinus veins draining the pituitary is performed. ACTH levels in the inferior
petrosal sinus that are more than twice the simultaneous peripheral venous ACTH levels are
indicative of pituitary Cushing disease. Inferior petrosal sinus sampling is also done during CRH
administration, which ordinarily causes the ACTH levels in the inferior petrosal sinus to be over
three times the peripheral ACTH level when the pituitary is the source of ACTH.

When inferior petrosal sinus ACTH concentrations are not above the requisite levels, a search for
an ectopic source of ACTH is undertaken. Location of ectopic sources of ACTH commences
with CT scanning of the chest and abdomen, with special attention to the lungs (for carcinoid or
small cell carcinomas), the thymus, the pancreas, and the adrenals. In patients with ACTH-
dependent Cushing syndrome, chest masses should not be assumed to be the source of ACTH,
since opportunistic infections are common, so it is prudent to biopsy a chest mass to confirm the
pathologic diagnosis prior to resection.

CT scanning fails to detect the source of ACTH in about 40% of patients with ectopic ACTH
secretion. 111In-octreotide (OCT, somatostatin receptor scintigraphy) scanning is also useful in
detecting occult tumors. A low-dose scan with 6 mCi OCT is used first; a high-dose scan with 12
mCi OCT may be used if the low-dose scan gives equivocal results. 18FDG-PET scanning is not
usually helpful. Some ectopic ACTH-secreting tumors elude discovery, necessitating bilateral
adrenalectomy. The ectopic source of ACTH should continue to be sought, since they may
become detectable by OCT or CT scanning at a later date.

In non-ACTH-dependent Cushing syndrome, a CT scan of the adrenals can localize the adrenal
tumor in most cases (see CT scan).

Fig.

Adrenal CT scans in Cushing syndrome. A: Patient with ACTH-dependent Cushing syndrome.

The adrenal glands are not detectably abnormal by this procedure. The curvilinear right adrenal
(black arrow) is shown posterior to the inferior vena cava (v) between the right lobe of the liver
and the right crus of the diaphragm. The left adrenal (white arrow) has an inverted Y appearance
anteromedial to the left kidney (k). B: A 3-cm left adrenal adenoma (white arrow) is shown
anteromedial to the left kidney (k). (Reproduced, with permission, from Korobkin MT et al:
Computed tomography in the diagnosis of adrenal disease. Am J Roentgenol 1979;132:231.)

Differential Diagnosis

Alcoholic patients can have hypercortisolism and many clinical manifestations of Cushing
syndrome. Regular use of the "party drug" gamma hydroxybutyrate (GHB, sodium oxybate) has
been reported to cause reversible ACTH-dependent Cushing syndrome. Depressed patients also
have hypercortisolism that can be nearly impossible to distinguish biochemically from Cushing
syndrome but without clinical signs of Cushing syndrome. Some adolescents develop violaceous
striae on the abdomen, back, and breasts; these are known as "striae distensae" and are not
indicative of Cushing syndrome. Cushing syndrome can be misdiagnosed as anorexia nervosa
(and vice versa) owing to the muscle wasting and extraordinarily high urine free cortisol levels
found in anorexia. Patients with severe obesity frequently have an abnormal dexamethasone
suppression test, but the urine free cortisol is usually normal, as is diurnal variation of serum
cortisol. Patients with familial cortisol resistance have hyperandrogenism, hypertension, and
hypercortisolism without actual Cushing syndrome. In patients with familial partial
lipodystrophy type I, central obesity and a moon facies develop, along with thin extremities due
to atrophy of subcutaneous fat. However, these patients' muscles are strong and may be
hypertrophic, distinguishing this condition from Cushing syndrome. Patients receiving
antiretroviral therapy for HIV-1 infection frequently develop partial lipodystrophy with thin
extremities and central obesity with a dorsocervical fat pad ("buffalo hump") that may mimic
Cushing syndrome.

Complications

Cushing syndrome, if untreated, produces serious morbidity and even death. The patient may
suffer from any of the complications of hypertension or of diabetes. Susceptibility to infections is
increased. Compression fractures of the osteoporotic spine and aseptic necrosis of the femoral
head may cause marked disability. Nephrolithiasis and psychosis may occur. Following bilateral
adrenalectomy for Cushing disease, a pituitary adenoma may enlarge progressively, causing local
destruction (eg, visual field impairment) and hyperpigmentation; this complication is known as
Nelson syndrome.

Treatment

Cushing disease is best treated by transsphenoidal selective resection of the pituitary adenoma.
After pituitary surgery, the rest of the pituitary usually returns to normal function; however, the
pituitary corticotrophs remain suppressed and require 6–36 months to recover normal function.
Hydrocortisone or prednisone replacement therapy is necessary in the meantime. Patients who do
not have a remission (or who have a recurrence) should be treated by bilateral laparoscopic
adrenalectomy. Another treatment option for patients with ACTH-secreting pituitary tumors is
stereotactic pituitary radiosurgery (gamma knife or cyberknife), which normalizes urine free
cortisol in two-thirds of patients within 12 months. Conventional radiation therapy results in a
23% cure rate.

Pituitary radiosurgery can also be used to treat Nelson syndrome, the progressive enlargement of
ACTH-secreting pituitary tumors following bilateral adrenalectomy. Patients who are not
surgical candidates may be given a trial of ketoconazole in doses of about 200 mg orally every 6
hours; liver enzymes must be monitored for progressive elevation.

Adrenal neoplasms secreting cortisol are resected laparoscopically. The contralateral adrenal is
suppressed, so postoperative hydrocortisone replacement is required until recovery occurs.
Metastatic adrenal carcinomas may be treated with mitotane; ketoconazole or metyrapone can
help suppress hypercortisolism in unresectable adrenal carcinoma. The
thiazolidinedione rosiglitazone has slowed the growth of adrenal carcinomas in-vitro, but clinical
trials are lacking.

Ectopic ACTH-secreting tumors should be located, when possible, and surgically resected. If that
cannot be done, laparascopic bilateral adrenalectomy is recommended. Medical treatment with
ketoconazole or metyrapone (or both) may partially suppress the hypercortisolism; however,
metyrapone may exacerbate female virilization. The somatostatin analog octreotide, given
parenterally, suppresses ACTH secretion in about one-third of such cases.

Patients who are successfully treated for Cushing syndrome typically develop "cortisol
withdrawal syndrome," even when given replacement corticosteroids for adrenal insufficiency.
Manifestations can include hypotension, nausea, fatigue, arthralgias, myalgias, pruritus, and
flaking skin. Increasing the hydrocortisone replacement to 30 mg twice orally daily can improve
these symptoms; the dosage is then reduced as tolerated.

Prognosis

Patients with Cushing syndrome from a benign adrenal adenoma experience a 5-year survival of
95% and a 10-year survival of 90%, following a successful adrenalectomy. Patients with Cushing
disease from a pituitary adenoma experience a similar survival if their pituitary surgery is
successful. However, transsphenoidal surgery incurs a failure rate of about 10–20%, often due to
the adenoma's ectopic position or invasion of the cavernous sinus. Those patients who have a
complete remission after transsphenoidal surgery have about a 15–20% chance of recurrence
over the next 10 years. Patients with failed pituitary surgery may require pituitary radiation
therapy, which has its own morbidity. Bilateral adrenalectomy is often complicated by infection;
recurrence of hypercortisolism may occur as a result of growth of an adrenal remnant stimulated
by high levels of ACTH. The prognosis for patients with ectopic ACTH-producing tumors
depends on the aggressiveness and stage of the particular tumor. Patients with ACTH of
unknown source have a 5-year survival rate of 65% and a 10-year survival rate of 55%. Patients
with adrenal carcinoma have a median survival of 7 months.
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Hirsutism & Virilization

Essentials of Diagnosis

 Hirsutism, acne, menstrual disorders.

 Virilization: increased muscularity, androgenic alopecia, deepening of the voice,

clitoromegaly.

 Rarely, a palpable pelvic tumor.

 Urinary 17-ketosteroids and serum DHEAS and androstenedione elevated in adrenal

disorders; variable in others.

 Serum testosterone is often elevated.

General Considerations

Hirsutism is defined as excessive terminal hair growth that appears in a male pattern in women.
Hirsutism is frequently quantitated according to the Ferriman-Gallwey scale, which grades the
presence of androgen sensitive hair from 0 (no hair) to 4 (virile) in 9 areas of the body
(maximum score = 36). About 5% of reproductive age women are hisute, with Ferriman-Gallwey
scores 8.

Etiology

Hirsutism may be idiopathic or familial or be caused by the following disorders: polycystic ovary
syndrome (PCOS), steroidogenic enzyme defects, neoplastic disorders or rarely by medications,
acromegaly, or ACTH-induced Cushing disease.
Idiopathic or Familial

Most women with hirsutism or androgenic alopecia have no detectable hyperandrogenism.

Patients often have a strong familial predisposition to hirsutism that may be considered normal in
the context of their genetic background. Such patients may have elevated serum levels of
androstenediol glucuronide, a metabolite of dihydrotestosterone that is produced by skin in
cosmetically unacceptable amounts.

Polycystic Ovary Syndrome (Hyperthecosis, Stein–Leventhal Syndrome)

PCOS is a common functional disorder of the ovaries, affecting about 4–6% of premenopausal
women in the United States and accounting for at least 50% of all cases of hirsutism associated
with elevated testosterone levels. It is familial and transmitted as a modified autosomal dominant
trait. Affected women have elevated serum testosterone or free testosterone levels. Affected
women have signs of androgen excess, including hirsutism, acne, and male-pattern thinning of
scalp hair. About 50% of affected women have oligomenorrhea or amenorrhea with anovulation.
Despite the syndrome's name, the presence of ovarian cysts is not helpful diagnostically and is
actually a misnomer, since about 30% of women with PCOS do not have cystic ovaries and 25–
30% of normal menstruating women have cystic ovaries. Obesity and high serum insulin levels
(due to insulin resistance) contribute to the syndrome in 70% of women. The serum LH:FSH
ratio is often > 2.0. Both adrenal and ovarian androgen hypersecretion are commonly present.
Women with PCOS have a 35% risk of depression, compared with 11% in age-matched controls.
Diabetes mellitus is present in about 13% of cases. Untreated women with amenorrhea have a
slightly increased risk of endometrial carcinoma. Hypertension and hyperlipidemia are often
present, increasing the risk of cardiovascular disease. Women frequently regain normal menstrual
cycles with aging.

Steroidogenic Enzyme Defects

Baby girls with "classic" 21-hydroxylase deficiency have ambiguous genitalia and may become
virilized unless treated with corticosteroid replacement; about 50% of such patients have
clinically evident mineralocorticoid deficiency (salt-wasting) as well.

About 2% of patients with adult-onset hirsutism have been found to have a partial defect in
adrenal 21-hydroxylase, whose phenotypic expression is delayed until adolescence or adulthood;
such patients do not have salt-wasting. Polycystic ovaries and adrenal adenomas are more likely
to develop in these women.

Some rare patients with hyperandrogenism and hypertension have 11-hydroxylase deficiency.
This is distinguished from cortisol resistance by high cortisol serum levels in the latter and by
high serum 11-deoxycortisol levels in the former.

Patients with an XY karyotype and a deficiency in 17 -hydroxysteroid dehydrogenase-3

or a deficiency in 5 -reductase-2 may present as phenotypic girls in whom virilization

develops at puberty.

Neoplastic Disorders

Ovarian tumors are very uncommon causes of hirsutism (0.8%) and include arrhenoblastomas,
Sertoli-Leydig cell tumors, dysgerminomas, and hilar cell tumors. Adrenal carcinoma is a rare
cause of Cushing syndrome and hyperandrogenism that can be quite virilizing. Pure androgen-
secreting adrenal tumors occur very rarely; about 50% are malignant.

Rare Causes of Hirsutism

Acromegaly and ACTH-induced Cushing syndrome can cause hirsutism. Maternal virilization
during pregnancy may occur as a result of a luteoma of pregnancy, hyperreactio luteinalis, or
polycystic ovaries. In postmenopausal women, diffuse stromal Leydig cell hyperplasia is a rare
cause of hyperandrogenism. Aquired hypertrichosis lanuginosa is manifested by the appearance
of diffuse fine lanugo hair growth on the face and body along with stomatologic symptoms; the
disorder is usually associated with an internal malignancy, especially colorectal cancer, and may
regress after tumor removal. Pharmacologic causes include minoxidil, cyclosporine, phenytoin,
anabolic steroids, diazoxide, and certain progestins.

Clinical Findings

Symptoms and Signs

Modest androgen excess from any source increases sexual hair (chin, upper lip, abdomen, and
chest) and increases sebaceous gland activity, producing acne. Menstrual irregularities,
anovulation, and amenorrhea are common. If androgen excess is pronounced, defeminization
(decrease in breast size, loss of feminine adipose tissue) and virilization (frontal balding,
muscularity, clitoromegaly, and deepening of the voice) occur. Virilization implicates the
presence of an androgen-producing neoplasm.

Hypertension may be seen in rare patients with Cushing syndrome, adrenal 11-hydroxylase
deficiency, or cortisol resistance syndrome.

A pelvic examination may disclose clitoromegaly or ovarian enlargement that may be cystic or
neoplastic.

Laboratory Testing and Imaging

Serum androgen testing is mainly useful to screen for rare occult adrenal or ovarian neoplasms.
Some general guidelines are presented here, though exceptions are common.
Serum is assayed for total testosterone and free testosterone. A serum testosterone level > 200
ng/dL or free testosterone > 40 ng/dL indicates the need for pelvic examination and ultrasound. If
that is negative, an adrenal CT scan is performed.

Most radioimmunoassays and ELISA for testosterone are inaccurate below serum testosterone
levels of 300 ng/dL. The more accurate testosterone assays rely upon extraction and
chromatography, followed by mass spectrometry or immunoassay. Free testosterone is best
measured by calculation, using accurate assays for testosterone and sex hormone binding
globulin.

A serum androstenedione level > 1000 ng/dL also implicates an ovarian or adrenal neoplasm.

Patients with milder elevations of serum testosterone or androstenedione usually are treated with
an oral contraceptive.

Patients with very elevated serum DHEAS (> 700 mcg/dL) have an adrenal source of androgen.
This usually is due to adrenal hyperplasia and rarely to adrenal carcinoma. An adrenal CT scan is
performed.

No firm guidelines exist as to which patients (if any) with hyperandrogenism should be screened
for "late-onset" 21-hydroxylase deficiency. The evaluation requires levels of serum 17-
hydroxyprogesterone to be drawn at baseline and at 30–60 minutes after the intramuscular
injection of 0.25 mg of cosyntropin (ACTH1–24). This test should ideally be done during the
follicular phase of a woman's menstrual cycle. Patients with congenital adrenal hyperplasia will
usually have a baseline 17-hydroxyprogesterone level over 300 ng/dL or a stimulated level over
1000 ng/dL.

Patients with any clinical signs of Cushing syndrome should receive a screening test. (See
Cushing Syndrome.)

Serum levels of FSH and LH are elevated if amenorrhea is due to ovarian failure. An LH:FSH
ratio > 2.0 is common in patients with PCOS. On abdominal ultrasound, about 25–30% of
normal young women have polycystic ovaries, so the appearance of ovarian cysts on ultrasound
is not helpful.

Virilizing tumors of the ovary can usually be detected by pelvic ultrasound or MRI. However,
small virilizing ovarian tumors may not be detectable on imaging studies; selective venous
sampling for testosterone may be used for diagnosis in such patients.

Treatment

Postmenopausal women with severe hyperandrogenism should undergo laparoscopic bilateral

oophorectomy (if CT scan of the adrenals and ovaries is normal), since small hilar cell tumors of
the ovary may not be visible on scans. Girls with hyperandrogenism due to classic salt-wasting
congenital adrenal hyperplasia may be treated with laparoscopic bilateral adrenalectomy. Any
drugs causing hirsutism are stopped.

Spironolactone may be taken in doses of 50–100 mg orally twice daily on days 5–25 of the
menstrual cycle or daily if used concomitantly with an oral contraceptive. Hyperkalemia or
hyponatremia is uncommon.

Cyproterone acetate is a potent antiandrogen with progestational activity. A dose of 2 mg orally

is effective. An oral contraceptive is usually prescribed also. Cyproterone is not available in the
United States but is available elsewhere as the progestin element in an oral contraceptive (Diane-
35: ethinyl estradiol 35 mcg with cyproterone acetate 2 mg). Side effects may include fatigue,
nausea, depression, or hyperlipidemia.

Finasteride inhibits 5 -reductase, the enzyme that converts testosterone to active

dihydrotestosterone in the skin. Given as 2.5-mg doses orally daily, it provides modest reduction
in hirsutism over 6 months—somewhat less than that achieved with spironolactone. Finasteride
is ineffective for androgenic alopecia in women. Side effects are rare.

Flutamide inhibits testosterone binding to androgen receptors and also suppresses serum
testosterone. It is given orally in a dosage of 250 mg/d for the first year and then 125 mg/d for
maintenance. Used with an oral contraceptive, it appears to be more effective than spironolactone
in improving hirsutism, acne, and male pattern baldness. Women with congenital adrenal
hyperplasia who take replacement hydrocortisone, experience decreased renal cortisol clearance
when treated with flutamide, resulting in lower hydrocortisone dosage requirements;
corticosteroid replacement doses should be reduced when flutamide is added for treatment of
hirsutism. Hepatotoxicity has been reported but is rare.

Oral contraceptives stimulate menses (if that is desired) and reduce acne vulgaris, but are less
effective for hirsutism. Contraceptives containing antiandrogen progestins (either desogestrel
0.15 mg or levonorgestrel 0.15 mg) may be more effective for treating hirsutism but are
associated with an increased risk of deep venous thrombosis. Simvastatin, when added to oral
contraceptive therapy, has been reported to further decrease serum free testosterone by 16%,
besides improving patients' serum lipid profiles.

Metformin may improve menstrual function in women with PCOS and amenorrhea or
oligomenorrhea, but is less effective than oral contraceptives. Metformin is not effective in
promoting fertility or in improving hirsutism in women with PCOS. Metformin therapy is
usually given with meals and is started at a dose of 500 mg/d with breakfast for 1 week, then 500
mg with breakfast and dinner for 1 week, then 500 mg with breakfast and 1000 mg with dinner
for 1 week, then 850–1000 mg with breakfast and dinner. The most common side effects are
dose-related gastrointestinal upset and diarrhea. Patients are advised to take the highest tolerated
dosage. Metformin appears to be nonteratogenic. Although metformin reduces insulin resistance,
it does not cause hypoglycemia in nondiabetics. Metformin is contraindicated in renal and
hepatic disease.

Simvastatin has been demonstrated to decrease serum androgen levels in women with PCOS.
One clinical trial that studied women with PCOS who were given simvastatin 20 mg daily for 3
months showed reductions in serum testosterone, cholesterol levels, and acne.

Clomiphene is the treatment of choice for women with PCOS and infertility. Over 6 months,
clomiphene therapy resulted in a 22.5% rate of conception with live births. The rate of pregnancy
with multiple fetuses is 6%.

Women with classic congenital adrenal hyperplasia (21-hydroxylase deficiency) have hirsutism
and adrenal insufficiency that requires glucocorticoid and mineralocorticoid replacement.
However, women with partial "late onset" 21-hydroxylase deficiency do not require hormone
replacement. Treating such women with dexamethasone risks iatrogenic Cushing syndrome and
is not particularly more effective than the other treatments for hirsutism listed below.

Local treatment by shaving or depilatories, waxing, electrolysis, or bleaching should be

encouraged. Eflornithine (Vaniqua 13.9%) topical cream retards hair growth when applied twice
daily to unwanted facial hair; improvement is noted within 4–8 weeks. However, local skin
irritation may occur. Hirsutism returns with discontinuation. Laser therapy (photoepilation) is an
effective treatment for facial hirsutism, particularly for women with dark hair and light skin;
complications include skin hypopigmentation (rare) and hyperpigmentation, which occurs in
20% but usually resolves.

Topical minoxidil 2% solution applied twice daily to a dry scalp, may be used to effectively treat
women with androgenic alopecia. Hypertrichosis is an unwanted side effect of topical minoxidil,
occurring in 3–5% of treated women; it may affect the forehead, cheeks, upper lip, or chin.
Hypertrichosis resolves within 1–6 months after the drug is stopped.

Antiandrogen treatments must be given only to nonpregnant women. Women must be counseled
to take oral contraceptives, when indicated, and avoid pregnancy, since use during pregnancy
causes malformations and pseudohermaphroditism in male infants.

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Primary Aldosteronism

Essentials of Diagnosis

 Hypertension that may be severe or drug-resistant.

 Hypokalemia (in minority of patients) may cause polyuria, polydipsia, muscle weakness.

 Elevated plasma and urine aldosterone levels and low plasma renin level.

General Considerations

Primary aldosteronism (hyperaldosteronism) is common and is believed to account for 5–10% of

all cases of hypertension. Patients of all ages may be affected, but the peak incidence is between
30–60 years. Excessive aldosterone production increases sodium retention and suppresses
plasma renin. It increases renal potassium excretion, which can lead to hypokalemia.
Cardiovascular events are more prevalent in patients with aldosteronism (35%) than in those
with essential hypertension (11%). Primary aldosteronism is most commonly caused by an
adrenal adenoma (Conn syndrome), and unilateral or bilateral adrenal hyperplasia. Bilateral
aldosteronism may be corticosteroid suppressible, due to an autosomal-dominant genetic defect
allowing ACTH stimulation of aldosterone production.

Clinical Findings

Symptoms and Signs

Patients have hypertension that is typically moderate. Some patients have only diastolic
hypertension, without other symptoms and signs. Edema is rarely seen in primary aldosteronism.
About 37% of patients have hypokalemia and may consequently have symptoms of muscular
weakness (at times with paralysis simulating periodic paralysis), paresthesias with frank tetany,
headache, polyuria, and polydipsia.

Laboratory Findings

Screening for hyperaldosteronism is usually with PRA. About 20% of hypertensive patients have
a low PRA, and a significant portion of these patients have primary aldosteronism. Initial
screening can also include both PRA and aldosterone to determine a renin:aldosterone ratio (see
below).

Plasma potassium should also be determined in hypertensive individuals. However,

hypokalemia, once thought to be the hallmark of hyperaldosteronism, is present in only 37% of
affected patients: 50% of those with an adrenal adenoma and 17% of those with adrenal
hyperplasia. Proper phlebotomy technique is important to avoid spurious increases in potassium.
The blood should be drawn slowly with a syringe and needle (rather than a vacutainer) at least 5
seconds after tourniquet release and without fist-clenching. Plasma potassium, rather than routine
serum potassium, should be measured in cases of unexpected hyperkalemia, with the separation
of plasma from cells within 30 minutes of collection. Besides hypokalemia, many patients with
primary aldosteronism have metabolic alkalosis with an elevated serum bicarbonate (HCO–3)
concentration.

Testing for primary aldosteronism should be done for all hypertensive patients with
hypokalemia, whether spontaneous or diuretic induced. But since only a minority of affected
patients have hypokalemia, testing should also be considered for normokalemic hypertensive
patients with (1) treatment-resistant hypertension (despite three drugs); (2) severe hypertension:
> 160 mm Hg systolic or > 100 mm Hg diastolic; (3) early-onset hypertension; (4) low-renin
hypertension; (5) hypertension with an adrenal mass; and (6) family history of aldosteronism.

For a patient to be properly tested for primary aldosteronism, certain antihypertensive

medications should ideally be held. Diuretics should be discontinued for 3 weeks.
Dihydropyridine calcium channel blockers can normalize aldosterone secretion, thus interfering
with the diagnosis. -Blockers suppress PRA in patients with essential hypertension. ACE

inhibitors and -blockers are less likely to affect testing. Antihypertensive medications

that have minimal effects on the plasma aldosterone:renin ratio include verapamil, hydralazine,
prazosin, doxazosin, and terazosin. However, it may be impractical to hold or change
antihypertensive medicines; in such cases, testing should proceed.

During the testing period, the patient should have an unrestricted high sodium intake. The patient
should be out of bed for at least 2 hours and seated for 5–15 minutes before the blood draw,
which should preferably be obtained between 8 am and 10 am. Renin is measured as either PRA
or direct renin concentration. Serum aldosterone should ideally be measured with a tandem mass
spectrometry assay.

For patients who have not been receiving diuretics for at least 3 weeks, a plasma renin activity
(PRA) that is normal or elevated makes primary aldosteronism very unlikely. However, a low
plasma renin is insufficient to establish the presence of primary aldosteronism, since many
patients with essential hypertension have a low PRA. A plasma aldosterone:renin ratio is a
sensitive screening test. Plasma aldosterone (ng/dL):PRA (ng/mL/h) ratios < 24 exclude primary
aldosteronism, whereas ratios between 24 and 67 are suspicious and ratios > 67 are very
suggestive of primary aldosteronism. Such elevated ratios are not diagnostic; rather, they indicate
the need to document increased aldosterone secretion with a 24-hour urine collection. Another
problem with the aldosterone:renin ratio is the use of different units and measurements. For
aldosterone, 1 ng/dL converts to 27.7 pmol/L. For renin, a PRA of 1 ng/mL/h (12.8 pmol/L/min)
converts to a direct renin concentration of 5.2 ng/L (8.2 mU/L).

When the aldosterone:renin ratio is high, a 24-hour urine collection is assayed for aldosterone,
free cortisol, and creatinine. A low PRA (< 5 mcg/L/h) with a urine aldosterone over 20 mcg/24 h
indicates primary aldosteronism.

Once primary aldosteronism is diagnosed, unilateral adrenal aldosteronism may be distinguished

from bilateral adrenal aldosteronism by adrenal vein sampling (see below) and by further
biochemical testing. Plasma may be assayed for 18-hydroxycorticosterone; a level > 100 ng/dL is
seen with adrenal neoplasms, whereas levels < 100 ng/dL are nondiagnostic. In addition, a
posture stimulation test may be performed, but this requires overnight hospitalization. The test is
performed by drawing blood for aldosterone at 8 am while the patient is supine after overnight
recumbency and again after the patient is upright for 4 hours. Patients with a unilateral adrenal
adenoma usually have a baseline plasma aldosterone level > 20 ng/dL that does not rise. Patients
with bilateral adrenal hyperplasia typically have a baseline plasma aldosterone level < 20 ng/dL
that rises during upright posture. The accuracy of the posture stimulation test is about 85%.

Imaging

All patients with biochemically confirmed primary aldosteronism require a thin-section CT scan
of the adrenals to screen for a rare adrenal carcinoma. In the absence of a large adrenal
carcinoma, adrenal CT scanning cannot reliably distinguish unilateral from bilateral aldosterone
excess, having a sensitivity of 78% and a specificity of 78% for unilateral aldosteronism.
Therefore, the decision to perform a unilateral adrenalectomy should not be based solely on an
adrenal CT scan. Instead, patients with primary aldosteronism should be considered for a trial of
medical therapy with spironolactone or eplerenone (see below). If medical therapy is ineffective
or if surgery is desired for an apparent adrenal adenoma, further evaluation for surgical
candidacy should be done with laboratory testing (see above). However, since CT scanning and
laboratory testing is often inconclusive, adrenal vein sampling is often required.

Adrenal Vein Sampling

Bilateral selective adrenal vein sampling is the most accurate way to determine whether primary
aldosteronism is due to unilateral aldosterone excess, which can be treated by adrenalectomy. It
is indicated only to direct the surgeon to the correct adrenal and should be performed only if
surgery is contemplated. It is particularly useful for patients who are not hypokalemic, who are
over age 40 years, or who have an adrenal adenoma < 1 cm diameter. It is particularly difficult to
catheterize the right adrenal vein. Therefore, the venous samples are assayed for both aldosterone
and cortisol during a cosyntropin (ACTH1–24) infusion to be sure that the sampling has included
both adrenal veins. The procedure has a sensitivity of 95% and a specificity of 100% but only
when performed by an experienced radiologist. The complication rate is 2.5%. Risks can be
minimized if the radiologist avoids adrenal venography and limits the use of contrast.

Screening

Hyperaldosteronism is the most common cause of refractory hypertension in youth and middle-
aged adults. The Endocrine Society’s Clinical Practice Guidelines recommend screening for
hyperaldosteronism in patients who have any of the following: (1) blood pressure > 160/100 mm
Hg; (2) drug-resistant hypertension; (3) hypertension with spontaneous or diuretic-induced
hypokalemia; (4) hypertension with adrenal incidentaloma; (5) hypertension with a family
history of early-onset hypertension or cerebrovascular accident before age 40 years; (6)
hypertension and a first-degree relative with primary aldosteronism.

Differential Diagnosis

The differential diagnosis of primary aldosteronism includes other causes of hypokalemia (see
Chapter 21: Fluid & Electrolyte Disorders) in patients with essential hypertension, especially
diuretic therapy. Chronic depletion of intravascular volume stimulates renin secretion and
secondary hyperaldosteronism. Thus, it is important to discontinue diuretics and ensure adequate
hydration and sodium intake when assessing a patient for primary hyperaldosteronism (see
above).

Excessive ingestion of real licorice (black and derived from anise) or Sambuca (an Italian
liqueur) can cause hypertension and hypokalemia. Licorice and Sambuca contains glycrrhizinic
acid, which has a metabolite that inhibits the adrenal enzyme 11 -hydroxysteroid

dehydrogenase, thereby blocking the production of cortisol and causing accumulation of the
precursor mineralocorticoid deoxycorticosterone. Oral contraceptives may increase aldosterone
secretion in some patients. Renal vascular disease can cause severe hypertension with
hypokalemia; PRA is high, distinguishing it from primary aldosteronism.

Excessive adrenal secretion of other corticosteroids (besides aldosterone) may also cause
hypertension with hypokalemia. This occurs with certain congenital adrenal enzyme disorders
such as P450c11 deficiency (increased deoxycorticosterone with virilization and deficient
cortisol) or P450c17 deficiency (increased deoxycorticosterone, corticosterone, and progesterone
but deficient estradiol and testosterone). P450c17 deficiency results from a defect in the 17-
hydroxylase enzyme in both the adrenal and ovarian steroidogenic pathways. Presenting signs
include hypertension and ambiguous genitalia or primary amenorrhea. Urinary aldosterone
secretion is < 20 mcg/24 h and plasma renin is low in both P450c11 and P450c17 deficiencies.
Primary cortisol resistance can cause hypertension and hypokalemia; renin and aldosterone are
suppressed, while plasma levels of cortisol, ACTH, and deoxycorticosterone are high. Liddle
syndrome is an autosomal dominant cause of hypertension and hypokalemia resulting from
excessive sodium absorption from the renal tubule; renin and aldosterone levels are low.
Thyrotoxicosis and familial periodic paralysis may also present with hypokalemia.
Hyperaldosteronism may rarely be due to a malignant ovarian tumor.

Complications

The incidence of cardiovascular complications from hypertension are higher in primary

aldosteronism than in idiopathic hypertension. Following unilateral adrenalectomy for Conn
syndrome, suppression of the contralateral adrenal may result in temporary postoperative
hypoaldosteronism, characterized by hyperkalemia and hypotension.

Treatment

Conn syndrome (unilateral aldosterone-secreting adrenal adenoma) is treated by laparoscopic

adrenalectomy, though long-term therapy with spironolactone or eplerenone is an option.
Bilateral adrenal hyperplasia is best treated with spironolactone or eplerenone. Spironolactone
also has anti-androgen activity and frequently causes breast tenderness, gynecomastia, or
reduced libido; it is given at initial doses of 12.5–25 mg orally once daily. Eplerenone is
becoming favored for men since it does not have anti-androgen effects; it is usually given at an
initial dose of 25 mg orally twice daily. Eplerenone is metabolized by hepatic CYP 3A4 and
drugs that inhibit or compete for this enzyme may increase serum eplerenone levels excessively.
Blood pressure must be monitored daily when beginning these anti-mineralocorticoid
medications; significant drops in blood pressure have occurred when these drugs are added to
other antihypertensives. Other antihypertensive drugs may also be required. Glucocorticoid-
remediable aldosteronism is very rare but may respond well to suppression with low-dose
dexamethasone.

Prognosis

The hypertension is reversible in about two-thirds of cases but persists or returns in spite of
surgery in the remainder. The prognosis is much improved by early diagnosis and treatment.
Only 2% of aldosterone-secreting adrenal tumors are malignant.

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