快樂小藥師 Im pharmacist nichts glücklich

Hormones and the intrinsic characteristics of the hair follicle determine the quality of hair growth. Vellus hairs are fine, unpigmented hairs that cover most of the body before puberty. Pubertal androgens promote the conversion of these vellus hairs to coarser, pigmented terminal hairs. The level and duration of exposure to androgens, the local 5-alpha-reductase activity, and the intrinsic sensitivity of the hair follicle to androgen action determine the extent of conversion from vellus to terminal hair. However, some terminal hair growth is androgen-independent (eg, scalp, eyebrows, lashes).^[3]

The development of terminal hair or reversion back to a vellus pattern may not be immediately evident because of the characteristics of the hair cycle. This cycle has 2 phases that include active hair growth (anagen phase) and a resting period (telogen phase), which follows the anagen phase. During the resting period, the hair shaft separates from the dermal papillae at the follicle base, and no further growth takes place. Eventually, growth restarts and the new hair shaft formed by the reactivated papillae pushes the old hair out. The cycle may take months to complete, and this causes a delay in hair growth response to changes in the androgen milieu.

Dihydrotestosterone is the androgen that acts on the hair follicle to produce terminal hair. This hormone is derived from both the bloodstream and local conversion of a precursor, testosterone. The local production of dihydrotestosterone is determined by 5-alpha-reductase activity in the skin. Differences in the activity of this enzyme may explain why women with the same plasma levels of testosterone can have different degrees of hirsutism.

Frequency

United States

Hirsutism affects approximately 10% of women in the United States.

International

The prevalence rates of hirsutism in northern Europe are similar to those in the United States; in other places, rates are not known with certainty.

Mortality/Morbidity

The mortality and morbidity of hirsutism are determined by the underlying cause.

• Most women with idiopathic hirsutism have no associated mortality or morbidity.
• On the other extreme, a small number of women may have malignant disease with a grave prognosis.

Race

Ethnic origin significantly affects terminal hair growth in healthy women.

• Northern, fair-skinned Europeans have the least amount of terminal hair, whereas southern European, dark-skinned Mediterranean women have the greatest amount of terminal hair.
• The difference in the racial patterns of normal terminal hair growth may be related to genetic differences of 5-alpha-reductase activity in the skin.
• With the exception of congenital adrenal hyperplasia (CAH), the prevalence of diseases that cause hyperandrogenism and hirsutism has not been shown to differ among persons of different races.

Sex

As a medical problem, hirsutism predominates in women.

• Although hirsutism can occur in men, it is more difficult to recognize because of the wide variability of healthy male terminal hair growth.
• Hirsutism in prepubertal children occurs equally between sexes, is usually a sign of precocious puberty, and may signify a serious underlying disease.

This discussion focuses on adult women.

Age

The age of onset of hirsutism depends on the etiology. Most forms of nonneoplastic hirsutism become evident around puberty. This includes polycystic ovary syndrome (PCOS), CAH, and idiopathic hirsutism.

Hirsutism and acne are shown in the image below.

• Hirsutism severity and rate of progression

  • The history of a benign form of hirsutism is usually characterized by pubertal onset with slow progression over many years. This is often true of hirsutism with PCOS.
  • When a history of rapid severe hirsutism or other signs of virilization are obtained, an androgen-secreting tumor is a possibility.
• Adrenarche and puberty

  • Because the development of pubic hair depends on adrenal androgens, early development points toward CAH.
  • In contrast, ovarian hyperandrogenism is associated with normal adrenarche and delayed menarche or irregular menses.

The most important goal in the clinical evaluation of a patient with hirsutism is to rule out significant underlying disease. To do this, seek to understand the cause of hyperandrogenism, if this is present.

• Excess androgens can be from either an exogenous or an endogenous source.

  • An exogenous source of androgens can usually be elicited by history findings; however, surreptitious androgen use has been reported in female athletes, especially those at a high level of competition.
  • Endogenous androgens originate from either the adrenal cortex or the ovary. Therefore, the evaluation of androgen excess can focus on disorders of these 2 glands. The principal possibilities are tumors of the ovary or the adrenal cortex, Cushing syndrome, CAH, and PCOS. Idiopathic hirsutism is the most common etiology, but it is a diagnosis of exclusion. Therefore, seek other causes first.
• The initial task in the evaluation of hirsutism via the physical examination is to quantitate the disorder.^[4] This task requires that terminal hair, which depends on androgen, be differentiated from vellus hair, which is androgen-independent.

  • Vellus hair is fine, soft, and nonpigmented. An excess of vellus hair (hypertrichosis) is associated with metabolic disorders (eg, hyperthyroidism, anorexia nervosa, porphyria) and with some medications (eg, phenytoin, diazoxide, minoxidil, glucocorticoids, cyclosporine, hexachlorobenzene).
  • By contrast, terminal hair is coarse, curly, and pigmented. Because small amounts of terminal hair are normal in women, quantitation is important.
• The most widely accepted method of quantitation uses the Ferriman and Gallwey scale. However, use care because this method has significant interobserver variability. In this approach, hair growth is judged in each of 11 androgen-sensitive areas.

  • The grade for each area ranges from 0 (no terminal hair) to 4 (frankly virile).
  • The body areas used to grade hirsutism are (1) the upper lip, (2) chin, (3) chest, (4) leg, (5) thigh, (6) upper arm, (7) forearm, (8) upper back, (9) lower back, (10), upper abdomen, and (11) lower abdomen.
  • Areas such as the axilla and pubis are not included because terminal hair grows in these places at normal androgen levels in women.
  • The total score correlates roughly with the elevation of androgen levels. A woman with a score of 8 or higher is considered to have hirsutism. Most women who seek medical attention for the disorder have scores of 15 or higher. Normal scores have also been established for Turkey (up to 11) and Thailand (up to 3 on the modified Ferriman and Gallwey scale).
• In women with moderate-to-severe hirsutism (score >15), seek additional signs of hyperandrogenism, including (1) temporal hair recession, (2) oily skin, (3) masculine voice, (4) well-developed musculature, (5) enlargement of the clitoris (>35 mm² in surface area), (6) irregular menses, and (7) psychological changes (eg, heightened libido, aggressiveness).
• The degree to which these clinical factors are present suggests the level of androgen overproduction and, thus, helps to determine the degree of concern for the presence of an underlying disease.
• The extent of the evaluation for the cause of hirsutism is greater in women who have more severe clinical evidence of masculinization.
• A thorough abdominal and pelvic examination is important in patients with hirsutism because more than half of androgen-secreting adrenal and ovarian tumors are palpable.
• Examine the skin for acanthosis nigricans, a manifestation of insulin resistance.
• Women with hirsutism are usually obese, with increased waist-hip ratios, and are thought to be at an increased risk for atherosclerosis and coronary heart disease. They also have increased bone mineral density scores at the hip and spine. These increases correlate with higher levels of serum free testosterone and estrogen.

Multiple diseases can cause hyperandrogenism and hirsutism. The etiologic forms of hirsutism include endocrine-related, idiopathic, medication-related, and miscellaneous. Endocrine-related causes include adrenocortical disorders and ovarian disorders.

• Tumors, Cushing syndrome, and CAH are the adrenocortical causes.

  • Adrenal tumors: Adrenocortical tumors are almost always malignant in patients who present with hirsutism. These tumors are usually large and are associated with a very poor prognosis.
  • Cushing syndrome: In most instances, Cushing syndrome is caused by glucocorticoid therapy. Because pure glucocorticoids have no androgenic activity, the treatment rarely produces hirsutism. Instead, glucocorticoid therapy is one of the causes of hypertrichosis (see Physical), resulting in vellus hair growth, especially on the face. Thus, excess growth of terminal hair in a patient with the clinical stigmata of Cushing syndrome suggests that the syndrome has an endogenous origin, ie, a pituitary tumor that secretes adrenocorticotropin hormone (ACTH), an adrenal tumor that secretes both cortisol and androgens, or an ectopic tumor that secretes ACTH. The pituitary tumor is the most likely possibility. Cushing syndrome, as a cause of hirsutism, is diagnosed based on the presence of dexamethasone that fails to suppress both androgens and cortisol.
  • CAH: CAH is actually a family of defects in 1 of 5 enzymes that are responsible for the biosynthesis of cortisol. The resulting cortisol deficiency heightens the secretion of ACTH and thereby leads to adrenal cell proliferation. However, only 3 of these defects can produce hirsutism—21-hydroxylase (most frequent), 3 β -hydroxysteroid dehydrogenase (less frequent), and 11-β -hydroxylase deficiency (least frequent). If CAH is considered, an ACTH-stimulation test is indicated, which is a search for exaggerated quantities of the precursors of cortisol. The stimulation test is required because baseline elevation of these steroids may be in the reference range. Hyperandrogenism in CAH can cause infertility, but dexamethasone therapy in this setting may induce ovulation. Two important reasons for the diagnosis of CAH are that specific therapy is availableand genetic counseling may be necessary.
  • Women with both CAH (21-hydroxylase deficiency) and Cushing syndrome have been described with particularly severe hirsutism.
• Tumors (malignant or benign) and PCOS are the ovarian causes of hirsutism.

  • Ovarian tumors may be malignant, and the threat can be serious. Androgen-secreting ovarian tumors are a less-serious threat. The most common among them is arrhenoblastoma, which accounts for less than 1% of all ovarian tumors. In patients with this neoplasm, the serum testosterone level is always elevated, and most patients have amenorrhea and a palpable ovarian mass.
  • Gonadoblastomas usually develop in younger persons (aged 10-30 y) who are genetic males with female external genitalia. Nearly half of these tumors are malignant, and many are bilateral. Pelvic examination findings are abnormal because internal female genitalia are absent.
  • Lipoid cell tumors are of 2 histologic types: adrenallike cells (in younger patients) and hilar or Leydiglike cells (in older patients). These tumors are usually palpable but are seldom malignant. Ovarian tumors, which are even less frequently encountered, include dysgerminomas, Brenner tumors, and cystic granulosa-theca cell tumors.
  • PCOS is the most common ovarian disorder associated with hirsutism. Although the cause of PCOS is not known, the etiology is speculated to be multifactorial. By definition, polycystic ovaries have 20 or more subcapsular follicles, which range from approximately 1-15 mm in diameter. The follicles are at various states of atresia, and hyperplasia of the theca interna, the anatomic source of ovarian androgens, is present. However, the basic abnormalities in PCOS are functional, rather than anatomic, in nature. In particular, levels of luteinizing hormone (LH) are tonically elevated (with LH levels higher than those of follicle-stimulating hormone [FSH]).
    • Many women with PCOS have insulin resistance, manifested by acanthosis nigricans and elevated plasma insulin levels. Increased insulin levels have been speculated to stimulate androgen production from the ovarian theca interna cells. An experiment in nature supports this hypothesis; women with PCOS who have a specific genetic mutation that lowers insulin resistance have lower hirsutism scores. In addition, the importance of insulin resistance is emphasized by the therapeutic effect of insulin-sensitizing medications (eg, metformin, thiazolidinediones), which restore normal ovarian androgen production and ovulation.^[5]
    • PCOS usually begins at puberty. The incidence has been estimated to be approximately 5% among adolescent girls and adult women in the United States. As noted, the characteristic endocrine abnormality is an elevation in levels of plasma free testosterone that is not suppressed by dexamethasone; however, as many as 50% of patients also show abnormal adrenal androgen secretion.
• Idiopathic hirsutism is a diagnosis of exclusion.

  • The patient's hirsutism is not caused by well-defined abnormalities such as an androgen-secreting tumor or CAH.
  • The spectrum of clinical presentations ranges from normal menses and mild hirsutism to amenorrhea and signs of virilization, and testosterone levels range from normal to frankly elevated.
  • The hirsutism usually begins at puberty.
  • The disorder is often familial and may be associated with obesity and insulin resistance.
  • Some classification schemes distinguish patients with elevated adrenal androgen levels (dehydroepiandrosterone sulfate [DHEAS]); in these cases, the disorder is called idiopathic adrenal hyperandrogenism.
  • Some patients with idiopathic hirsutism have normal plasma androgen levels. As noted above, the underlying mechanism in these patients may be an increase in androgen sensitivity or in 5-alpha-reductase activity in the skin. Increased activity of the enzyme has been demonstrated based on skin biopsy findings and by a finding of elevated urinary levels of dihydrotestosterone metabolites; however, presently, tests for 5-alpha-reductase activity have been used only in research.
• Miscellaneous causes of hirsutism include other causes of insulin resistance and androgen excess.
• Hypertrichosis should not be confused with hirsutism because hirsutism usually implies hyperandrogenism. Hypertrichosis, on the other hand, usually involves nonandrogenic hair. Hypertrichosis can be caused by porphyria, medications (phenytoin, minoxidil, cyclosporine, diazoxide, corticosteroids, streptomycin, hexachlorobenzene, penicillamine, heavy metals, sodium tetradecyl sulfate, acetazolamide, interferon), and genetic factors.

The most effective strategy for treating hirsutism is to combine systemic therapy, which has a slow onset of effectiveness, with mechanical depilation (shaving, plucking, waxing, depilatory creams).

Systemic therapies directed at hirsutism can be divided into those that decrease ovarian or adrenal androgen production and those that inhibit androgen action in the skin.

Class Summary

OCs inhibit ovarian androgen production and are probably the first choice for young women with hirsutism who do not want to become pregnant. OCs are inexpensive, and they promote regular uterine bleeding. OCs can be used in combination with antiandrogens or other agents. They have a significant failure rate in hirsutism for several reasons. Low-dose OCs and progestin-only minipills fail to suppress ovulation in as many as 50% of women. Ovarian function continues at a variable rate, and ovarian androgens continue to be produced. Second, the progestins in OCs are attenuated derivatives of testosterone and have variable degrees of androgenic activity in women. The degree depends on the type of progestin and, more importantly, on individual susceptibility.

Prednisone (Deltasone, Orasone, Meticorten)

May inhibit ACTH-dependent androgen synthesis through negative feedback.

Dexamethasone (Decadron, AK-Dex, Alba-Dex)

May inhibit ACTH-dependent androgen synthesis through negative feedback.

Lower doses (eg, 0.25 mg) may prove to be effective with fewer adverse effects.

Class Summary

Antiandrogens are used to block androgen action.

Spironolactone (Aldactone)

Decreases testosterone production. Can be combined with OCs for added effects.

Class Summary

These agents are indicated for treatment of benign prostatic hyperplasia and male pattern baldness. An unlabeled use is for the treatment of female hirsutism.

Finasteride (Proscar, Propecia) 

Specific inhibitor of the intracellular enzyme that converts testosterone into the androgen 5-α -dihydrotestosterone. Efficacy in hirsutism is similar to that of spironolactone. To be used only in postmenopausal women with no chance of becoming pregnant.