Abnormal Skin Pigmentation
Increased skin pigmentation can be caused by excessive ACTH secretion in Addison's disease and can occur after bilateral adrenalectomy for Cushing's disease (Nelson's syndrome). Pigmentation can be generalized or may be localized to palmar creases, extensor joint surfaces, tongue, nails, belt or bra lines, freckles, or new scars.
Pigmentation of the upper lip, forehead, or malar eminences, known as chloasma, can be caused by pregnancy ("mask of pregnancy"), oral contraceptives, or estrogen replacement therapy.
Acanthosis nigricans presents as velvety brown thickened skin of the neck and axillae. It may be associated with syndromes of severe insulin resistance type A (ovarian dysfunction and hirsutism) or type B (autoimmune). It may also be familial or associated with obesity, acromegaly, or thyroid disease. Acanthosis presenting after age 35 years is often a sign of an underlying malignancy, such as hepatocellular carcinoma.
Pretibial areas of pigmentation are common in diabetes ("diabetic shin spots") as a result of minor trauma or following necrobiosis lipoidica diabeticorum.
Prominent lentigines can be a sign of Carney's complex, an autosomal dominant condition associated with atrial myxomas, schwannomas, and endocrine overactivity (eg, tumors of the thyroid, gonads, or pigmented adrenal nodular hyperplasia). Similar skin pigmentation is seen in Peutz–Jeghers syndrome with an increased risk of intestinal polyposis, adenocarcinoma, breast cancer, and tumors of the gonads and thyroid.
Diffuse hyperpigmentation is seen in POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) syndrome; adrenal insufficiency, hypoparathyroidism, diabetes, osteosclerotic bone lesions, or thiamine deficiency may occur.
Gray-brown ("bronze") hyperpigmentation is caused by hemochromatosis, which can cause endocrine deficiencies such as diabetes mellitus. An orange skin discoloration is characteristic of jaundice and carotenodermia (caused by ingestion of large amounts of carotene in vegetables, seaweed, or vitamin preparations).
Patchy hypopigmentation can be due to vitiligo, a condition sometimes associated with Addison's disease and with other endocrine deficiencies as part of the polyglandular autoimmune syndrome. Hypopigmentation can also be a manifestation of cobalamin deficiency, trisomy 13, and various dermatologic conditions.
Patients undergoing chronic hemodialysis frequently become hyperpigmented, and hypopigmentation has also been reported. Other causes of hyperpigmentation include sprue, malnutrition, HIV infection, and porphyria. Hyperpigmentation may be caused by certain drugs: amiodarone, arsenic, bleomycin, busulfan, clofazimine, hydroxychloroquine, chlorpromazine, doxorubicin (nail beds), imipramine, methimazole, minocycline, niacin, primaquine, propylthiouracil, topical tretinoin, and zidovudine (nails).
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Gynecomastia
Essentials of Diagnosis
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Enlargement of the male breast, often asymmetric or unilateral (see photograph).
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Glandular gynecomastia characterized by tenderness.
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Fatty gynecomastia typically nontender.
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Must be distinguished from tumors or mastitis.
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General Considerations
Gynecomastia refers to a female-appearing male breast. Pubertal gynecomastia is common and the swelling usually subsides spontaneously within a year. Gynecomastia is particularly common in teenagers who are very tall or overweight. Gynecomastia develops in about 50% of athletes who abuse androgens and anabolic steroids. It is seen in Klinefelter's syndrome, which affects 1:500 men. (See section on Klinefelter's syndrome.) Gynecomastia can develop in HIV-infected patients treated with highly active antiretroviral therapy (HAART), especially in men receiving efavirenz or didanosine; breast enlargement resolves spontaneously in 73% of patients within 9 months. Gynecomastia is common among elderly men, particularly when there is associated weight gain. However, it can be the first sign of a serious disorder. Patients with Peutz–Jeghers syndrome are prone to development of gynecomastia caused by testicular tumors.
Clinical Findings
Symptoms and Signs
Gynecomastia is graded according to severity: I, mild; II, moderate; III, severe. Fatty gynecomastia is usually diffuse and nontender. Glandular enlargement beneath the areola may be tender. Pubertal gynecomastia is characterized by tender discoid enlargement of breast tissue 2–3 cm in diameter beneath the areola.
Laboratory Findings
Laboratory measurements of plasma levels of prolactin (PRL) (see Hyperprolactinemia) and the -subunit of human chorionic gonadotropin (-hCG). Detectable levels of -hCG implicate a testicular tumor (germ cell or Sertoli cell) or other malignancy (usually lung or liver). Detectable low levels of serum -hCG (< 5 mU/mL) may be reported in men with primary hypogonadism and high serum luteinizing hormone (LH) levels if the assay for -hCG cross-reacts with LH. Measurements of plasma testosterone and LH are valuable in the diagnosis of primary or secondary hypogonadism. A low testosterone and high LH are seen in primary hypogonadism. High testosterone levels plus high LH levels characterize partial androgen resistance. Serum estradiol is determined but is usually normal; increased levels may result from testicular tumors, increased -hCG, liver disease, obesity, adrenal tumors (rare), true hermaphroditism (rare), or gain of function mutations affecting the aromatase gene (rare). Many estrogens and substances with estrogenic activity are not detected by estradiol assays. Serum thyroid-stimulating hormone (TSH) (sensitive) and free thyroxine (FT4) levels are also determined. A karyotype (for Klinefelter's syndrome) is obtained in men with persistent gynecomastia without obvious cause.
Investigation of unclear cases should include a chest radiograph to search for metastatic or bronchogenic carcinoma. Needle biopsy with cytologic examination may be performed on suspicious areas of male breast enlargement (especially when unilateral or asymmetric) to distinguish gynecomastia from tumor or mastitis.
Treatment
Pubertal gynecomastia often resolves spontaneously within 1–2 years. Drug-induced gynecomastia resolves after the offending drug is removed. Spironolactone can be stopped, with substitution of a selective aldosterone antagonist such as eplerenone. Patients with painful or persistent (> 12 months) gynecomastia may be treated with a 3- to 9-month course of a selective estrogen receptor modulator (SERM; eg, raloxifene or tamoxifen). SERM therapy is much more effective for glandular ("lumpy") gynecomastia than for diffuse fatty gynecomastia. There is some evidence that raloxifene, taken orally in a dose of 60 mg daily, may be the more effective drug. Aromatase inhibitors (eg, letrozole, anastrozole, or exemestane) are marginally effective and should not ordinarily be used for adolescent boys, since long-term therapy may prevent epiphyseal fusion. Surgical correction is reserved for patients with persistent or severe gynecomastia, since results are often disappointing. Endoscopically assisted transaxillary liposuction and subcutaneous mastectomy may produce acceptable results. Generally, it is prudent to treat patients for gynecomastia only when it becomes a troubling and continuing problem for them.
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