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Acne vulgaris is the most commonly treated skin condition . Prompt and appropriate treatment of acne is essential. Because acne primarily occurs during adolescence, when self-image is being formed, even a mild case can have a profound effect on psychosocial development and performance in school. Moderate to severe acne, with its attendant scarring, can cause significant disfigurement that persists throughout life and affects career choice and employability. In the past 30 years, however, considerable understanding of the pathogenesis of acne has been achieved, leading to the development of rational, effective, and safe treatments.

Acne affects persons of all ages, but adolescents and young adults are the most frequently affected. Acne may occur in children as young as eight years and often occurs in those 10 to 12 years of age. Contrary to popular expectation, acne does not always resolve by the end of the teenage years. In fact, it may persist into the 40s, and in women, its onset may not occur until the mid-20s. Acne occurs in boys more frequently than in girls.

Acne is a disease of the pilosebaceous unit. Each pilosebaceous unit consists of a hair follicle and a sebaceous gland that drains directly into the hair follicle. To explain the pathogenesis of acne to patients and to dispel the many myths about the disease, the physician must have a basic understanding of the anatomy and physiology of the pilosebaceous unit.

Human facial skin has three functional and morphological varieties of pilosebaceous units-vellus follicles, terminal follicles, and sebaceous follicles . The vellus hair grows from the orifice of an inconspicuous but otherwise completely developed follicle. Compared with the size of the follicle, the sebaceous gland is large. In contrast, the terminal follicle produces a fully developed hair, such as a beard hair. This hair is thick and stiff and has a diameter almost the size of that of the follicle. Terminal follicles are larger than vellus follicles, but the larger number of vellus follicles on the face contributes significantly to the production of surface lipids.
The sebaceous follicle is huge compared with its barely perceptible hair, which may not even protrude from the follicular opening. The sebaceous gland is also large and is multilobulated. The coincidence of a large follicle, a small and insignificant hair, and a well-developed sebaceous gland makes an ideal setting for the development of an acne lesion because debris can easily accumulate to produce comedones. The accumulation of debris that can occur in sebaceous follicles does not occur in terminal follicles, at least in part because of the mechanical properties and size of the hairs in the terminal follicles. Indeed, acne is primarily a disease of sebaceous follicles. The distribution of sebaceous follicles on the face, earlobes, neck, shoulders, and V-shaped areas of the upper central chest and back corresponds to that of acne.

The hair follicle is an epidermal tubular sac in the dermis. It is completely lined with stratified epithelium that is contiguous with the surface, or interfollicular, epithelium. The various regions of the hair follicle have both structural and functional significance.

The lower part of the follicle, or inferior segment, extends from the deepest part of the hair follicle to the insertion point of the arrector pili muscle. The inferior segment contains the hair bulb and the hair matrix, which is the germinative epitheli um that gives rise to the hair shaft. This part of the hair follicle is present only in follicles with growing (anagen) hairs and is absent in follicles with resting (telogen) hairs.

The middle part of the follicle, or isthmus, extends from the insertion point of the arrector pili muscle to the opening of the sebaceous gland. Its upper extent is also defined by the disintegration of the inner root sheath, which functions as a mold for the forming hair.

The upper part of the follicle, or infundibulum, is divided into two regions. The acroinfundibulum contains epithelium with properties like those of surface epidermis. The infrainfundibulum, which lines most of the length of this segment of the hair follicle, differs morphologically and functionally from the acroinfundibulum and is where the pathognomonic microcomedo of acne develops. This stratified epithelium gives rise to fully differentiated cornified cells that normally are shed into the hair follicle canal and carried to the surface by the flow of sebum. Abnormalities of the epidermis of the follicular infrainfundibulum result in increased production and decreased shedding of these cornified cells and are currently considered the primary cause of acne.

The function of the sebaceous gland is to secrete sebum, a complex mixture of lipids. The sebaceous gland, like all of the epidermal appendages, arises from primordial cells contained in the fetal epidermis. At about eight weeks of gestation, focal areas of thickening of the primitive epidermis form above foci of mesenchymal cells in the dermis. Downward growth of epidermal cells results in the formation of the primordial hair follicles. The sebaceous gland arises from a bulge in the epithelium of the hair follicle above the level of the insertion of the arrector pili muscle. The rapid development of this structure in the fetus is driven by maternal androgenic hormones.

The gland is fully functional well before birth. This hypothesis is supported by the presence of the vernix caseosa, a cheesy substance composed of sebum and adherent cornified cells, on the skin of newborns and by the occurrence of neonatal acne, a fine papulopustular eruption on the faces of newborns. The sebaceous glands regress by three to six months of age and remain small and minimally active until early puberty; at that time, androgenic hormones stimulate the glands to enlarge, differentiate, and secrete sebum.

Androgenic hormones play the dominant role in regulating sebaceous gland activity. Circulating androgens arising from both the gonads and the adrenal glands are complemented by the peripheral conversion of testosterone to dihydrotestosterone in the sebaceous gland. The source redundancy and peripheral conversion of androgenic hormones may partly explain why consistent elevations of serum androgens are not observed in patients with acne .

Sebum consists principally of triglycerides, wax esters, and squalene. The composition of sebum differs from that of epidermal surface lipids in that some of the triglycerides in sebum have been hydrolyzed to free fatty acids. It was once thought that free fatty acids play a central role in the pathogenesis of acne; this hypothesis was supported by considerable circumstantial evidence. However, topical application of potent inhibitors of bacterial lipases, which rapidly inhibit the formation of free fatty acids, has since been shown to alter neither the sebum secretion rate nor the number of lesions. It is now thought that free fatty acids play a minimal role in the pathogenesis of acne.

The earliest lesion of acne is the microcomedo. It is clinically inapparent but is easily seen under the microscope as a concretion of keratinocytes, sebum, and colonies of bacteria in the follicular infundibulum. The microcomedo forms as a result of accelerated proliferation of keratinocytes in the follicular infundibulum and increased adherence of differentiated cornified cells. Continued aggregation of cornified cells leads to widening of the follicular infundibulum and production of a closed comedo. The hyperkeratosis may then extend to and dilate the follicular opening, forming an open comedo that permits the discharge of sebum and cornified cells; alternatively, the follicular wall ruptures, leading to the appearance of inflammatory papules and pustules.

Androgens are essential in the pathogenesis of acne. Many studies have reported endocrine abnormalities in patients with acne, but only a small proportion of women with acne exhibit signs of excessive androgen production, such as male pattern alopecia and hirsutism, or symptoms of significant menstrual dysfunction. In patients with mild acne, circulating levels of androgens are usually normal and peripheral conversion is increased, whereas in patients with severe acne, circulating levels of androgens are also elevated.

Although the severity of acne correlates with the rate of sebum production, acne is primarily a disease of the follicular infundibulum. How sebum excretion is related to abnormalities of the follicular infundibulum is unclear.

The organisms that colonize sebum-rich skin are Propionibacterium acnes, Micrococcus and Staphylococcus species, aerobic coryneform bacteria, and species of the yeast genus Malassezia (formerly called Pityrosporum). However, the importance of these organisms in the pathogenesis of acne vulgaris, once dogma, is now debated.

Several observations support the hypothesis that Propionibacterium species play an important role in the pathogenesis of acne. Antibiotics have been successfully used for decades to treat acne. In addition, increased skin colonization occurs at puberty and is associated with increased sebum production and with the development of acne. Finally, the emergence of antibiotic-resistant strains of Propionibacterium is associated with clinical exacerbation of disease.

Other observations support the hypothesis that microbial colonization plays little or no role in the pathogenesis of acne. Although the density of the microbial flora in patients with acne differs significantly from that in patients with normal skin, the severity of acne is not correlated with the number of organisms. In addition, comedonal acne and inflammatory acne occur in patients with follicles from which viable organisms cannot be recovered; conversely, Propionibacterium species can be found in the follicles of both normal patients and those with acne. Proponents of this hypothesis also point out that the well-documented efficacy of antibiotics in the management of acne may be caused by the anti-inflammatory properties of these drugs and their ability to inhibit protein synthesis and extracellular enzymes, not their antimicrobial activity.

Acne occurs on the skin of the face, upper back, and upper chest, a distribution that corresponds to the distribution of sebaceous follicles. Occasionally, lesions may be more widespread. Acne is frequently but not always associated with seborrhea, or excessive oiliness of the skin. The lesions are polymorphic, consisting of open and closed comedones, erythematous papules, pustules, nodules, cysts, and scars of various morphological types.

The diagnostic clinical lesion, the comedo, contains keratinized cells, sebum, and some bacteria. Comedones may be present in open or closed follicles , but inflammatory lesions tend to develop around closed comedones.

The open comedo, or blackhead, is the most recognizable morphological sign of acne, but its presence is not required for the diagnosis. Open comedones are visible concretions that are 0.5 to 2.0 mm in diameter. They take several weeks to develop. It was once thought that their black color was caused by oxidized fatty acids, but studies have convincingly demonstrated that it is caused by the presence of melanin. When the comedo is removed by the application of steady, gentle pressure, it can be seen to be a greasy, wormlike excrescence with a gray-white color.

Closed comedones are probably much more common than open comedones in patients with acne but are much more difficult to detect on clinical examination. The closed comedo is a barely palpable whitish papule that is 0.1 to 2.0 mm in diameter and that lies just below the surface of the skin. The follicular orifice may be hardly visible. If these lesions do not become inflamed, they resolve spontaneously in a few weeks to a few months.

The inflammatory lesions of acne begin as follicular papules that may develop into pustules or as nodules that may evolve into cysts . The papules are reddish and vary in size and consistency. Papules often appear to arise on clinically normal skin, but in almost all cases, a closed comedo was previously present. The lesions are an average of about 4 mm in diameter. If papules do not evolve into pustules, they resolve, leaving an erythematous macule and, ultimately, normal skin or an abnormally pigmented macule.

Pustules may be tender and surmount an erythematous papule or macule. Superficial pustules usually run their course and dry up in less than a week. Deep pustules are more common in patients with more severe cases of acne. These lesions are almost always tender and take two to six weeks to resolve.

As papules and pustules resolve, they may leave areas of hyperpigmentation and hypopigmentation that are of special cosmetic significance in dark-skinned patients. Areas of hyperpigmentation may require more than a year to resolve. Although scarring is usually associated with deeper nodular and cystic lesions, scarring may also be a sequela of less inflammatory, more superficial papules and pustules.

Nodules are very deep seated lesions that are often 1 cm or larger in diameter and that vary in consistency from firm to fluctuant. Occasionally, several lesions appear to coalesce; these lesions are often painful. Cysts, which are fairly uncommon, may reach a size of several centimeters in diameter. These lesions may coalesce and form boggy sinuses with multiple openings to the surface; this condition is called acne conglobata . The lesions of acne conglobata resolve with noticeable scarring.

Because scarring is associated with both the superficial and the deep inflammatory lesions of acne, early and aggressive medical intervention should be instituted for patients with these lesions. Fortunately, acne scars undergo physiologic remodeling for months and years after the acne has become quiescent. This fact should be stressed to patients who are concerned about the cosmetic appearance of their scars. Scars may be either hypertrophic and associated with increased amounts of collagen or atrophic and associated with some tissue loss. Each type of scar presents unique therapeutic challenges.

Atrophic scars are characterized as so-called ice-pick scars, fibrotic scars, or elastolytic scars. Ice-pick scars usually occur on the cheeks and forehead. The lesions are small and irregular, jagged, or polygonal and have very sharp, steep sides. Some have a distinctive fibrotic component that does not allow the scar to be stretched. Fibrotic scars are depressed craters that have smoother borders merging into normal skin and shallower sides; they are generally larger than ice-pick scars. Small elastolytic scars occur in a follicular distribution, but larger elastolytic scars are associated with such destruction of the dermis that a follicular origin is not apparent. The epidermis has a thin cigarette-paper appearance, and the dermis has a distinctive softness on palpation, as if it were absent. Occasionally, the dermis bulges outward under a thin, atrophic epidermis; this pattern of scarring occurs because of loss of integrity of the elastin network in the dermis.

The lesions of acne vulgaris fall into three basic clinical patterns-comedonal, papulopustular, and nodulocystic. Therapy is directed by the type and severity of the lesions.

In comedonal acne, the predominant lesions are open and closed comedones. A few small inflammatory papules and pustules may be present.

When papules and pustules are the predominant lesions, however, larger numbers of P. acnes organisms in the skin lesions and evidence of follicular wall degeneration and rupture are present. Papulopustular acne leads to scarring and requires prompt and aggressive intervention.

Nodulocystic acne comprises a broad spectrum of clinical presentations. It includes patients with a few nodules and cysts on the face; those with widespread nodules and cysts on the face, chest, and back; those with pyoderma faciale (the presence of eruptive, suppurating lesions on the face, a condition that usually occurs in women); those with acne conglobata and those with acne fulminans .

The disease name acne is subjected to more modifiers than are nearly all of the other disease names in medicine. All of the variants of acne are characterized by comedones, papules and pustules, or inflammatory nodules and cysts , but they clearly fall outside the spectrum of acne vulgaris; one variant, hidradenitis suppurativa, is probably not even very closely related to acne vulgaris. Each variant has its own clinical features and recommended treatment .

Milia, the tiny inclusion cysts that arise when vellus follicles are obstructed, may erupt in substantial numbers on the forehead and chest, mimicking acne. They differ from epidermal inclusion cysts only in size. They frequently occur around the eyes and are distinguished from closed comedones by the absence of a visible follicular ostium. Treatment consists of opening the cysts and expressing the contents.

This eruption, which usually occurs on the trunk, appears as inflammatory papules but is not unequivocally associated with hair follicles. Some areas of vague erythema may be marked by regularly spaced, clearly follicular papules. When pus is expressed from a suppurating lesion, Gram's stain reveals the characteristic gram-positive budding yeast. Treatment consists of shampooing with topical selenium sulfide, applying topical imidazole antifungal drugs, or taking oral ketoconazole.

Perioral dermatitis is a monomorphous, acnelike eruption that occurs on the lower part of the face and that typically occurs in women. It is often associated with the use of fluorinated topical steroids on that part of the body. A narrow zone adjacent to the vermilion is often spared. Treatment consists of discontinuance of the fluorinated topical steroid (usually by tapering it and eventually substituting a lower-potency nonfluorinated topical steroid for it) and administration of topical or oral tetracycline or topical metronidazole.

Rosacea consists of inflammatory papules and pustules, telangiectasia or central facial flushing, and sebaceous gland hyperplasia. Although the eruption usually occurs in persons older than 30 years, differentiating it from acne vulgaris by other characteristics may be very difficult. Rhinophyma, consisting of profound hyperplasia of the sebaceous glands on the nose and chronic lymphedema caused by destruction of the facial lymphatics by inflammation in the deep dermis, may occur. The flushing and telangiectasia of rosacea are exacerbated by consumption of hot liquids, such as coffee, or of alcohol. Treatment consists of removal of exacerbating factors and the administration of topical or oral tetracycline, topical hydrocortisone, or topical metronidazole.

In eliciting the history, the physician should ask about the patient's age at onset of acne and the history of disease progression; whether seasonal variation or aggravation by stress occurs; the patient's occupation and exposure to foreign substances; the patient's history of skin disease, especially that of dry skin or atopic dermatitis; the patient's propensity to scar; and the patient's general health, especially his or her endocrine, hepatic, and renal function. Women should be asked about their cosmetic use, premenstrual flares, pregnancy status and menstrual history, symptoms of virilization, previous endocrine evaluations, and use of oral contraceptive agents and their effect on acne. The physician should obtain a detailed list of the over-the-counter and prescription topical and systemic agents that the patient is taking for acne and other medical problems and should pay special attention to potential drug interactions. Understanding the details of previous treatments and their successes and failures helps the physician judge the potential success of future therapies and assess the patient's frustration with efforts to control the condition.

On physical examination, the physician should make note of the types of current lesions (open or closed comedones, papules, pustules, nodules, or cysts), types of residual lesions (including postinflammatory hyperpigmentation or hypopigmentation), and types of scars. An unusual distribution of lesions should lead the physician to search for extrinsic causal factors. For example, acne on only the left side of the neck ("fiddler's neck") may occur in violinists; that on only the forehead and chin may occur in football players. Chloracne may occur behind the ears as a result of exposure to chlorinated hydrocarbon compounds such as tetrachlorodibenzodioxin, and pomade acne may occur where the hair comes in contact with facial skin. Acne mechanica, caused by various orthopedic or prosthetic appliances or football shoulder pads, should be suspected when eruptions occur on the back and shoulders but nowhere else or on amputation stumps.

Excessive muscularity may suggest that the patient is surreptitiously using anabolic steroids; the presence of monomorphous pustules may suggest the use of lithium carbonate, the use of corticosteroids, or gram-negative folliculitis. In women, the presence of nodulocystic acne should trigger an examination for other signs of virilization; that of ulcerations and excoriations, an examination for excoriated acne; and excessive use of layered cosmetics, an examination for acne cosmetica. The physician should be alert to the presence of xerosis (dry skin), atopic dermatitis, eczema, or photosensitivity because the presence of these conditions may preclude the use of some topical treatments.

Treatment of acne can be directed at achieving any of four major goals: removal of the existing comedones and prevention of new ones, reduction of the amount of sebum synthesized by the sebaceous glands, reduction of the numbers of P. acnes organisms, and reduction of the inflammatory response to follicular rupture, thereby reducing or preventing scarring. Therapeutic agents that achieve one or more of these four goals may be used singly or in combination as appropriate for the clinical situation.

Patients should be instructed to routinely cleanse the skin with mild soap and water before applying topical agents. Patients should also be told that a response to treatment, however aggressive, will not occur immediately. It is incumbent on the physician to know and anticipate some of the problems associated with acne treatment and when results can be expected so that the patient can be appropriately counseled. Acne will be many patients' first experience with a chronic medical problem; the physician must take special care to communicate clearly and set realistic goals to achieve good compliance and a favorable outcome. The many myths about acne should be addressed and dispelled .

The management of a patient with acne vulgaris depends on the numbers, kinds, and distribution of lesions present (i.e., a correct assessment of the type of acne vulgaris an assessment of the patient's likely sensitivity to irritation; and an assessment of the patient's propensity to scar. A so-called cookbook approach to acne management will not succeed; sound clinical judgment is required. Although topical and systemic treatments may be used alone or in combination, combination therapy provides distinct advantages except in very mild or very severe cases.

The three basic topical treatments used in patients with acne vulgaris are retinoids, benzoyl peroxide, and antibiotics. Each has benefits for selected patients and problems associated with its use.

Mechanism of action Tretinoin is comedolytic. It decreases the cohesiveness of follicular epithelial cells and increases the mitotic rate and turnover of follicular epithelium, effects that contribute to the extrusion of comedones. Tretinoin treatment also prevents new comedo formation and thereby indirectly prevents the evolution of more inflammatory and potentially scarring lesions. Although the thinning of the cornified cell layer of the interfollicular epithelium effected by tretinoin renders the epidermis more susceptible to irritation, it also allows better penetration of adjunctive topical agents such as benzoyl peroxide (see below).

Formulations Tretinoin is available in a gel base in concentrations of 0.01 percent and 0.025 percent; in a cream base (hydrophilic cream) in concentrations of 0.1 percent, 0.05 percent, and 0.025 percent; and in solution (0.05 percent). The solution is more drying than the gels, and the gels are more drying than the creams.

Indications Tretinoin is used as monotherapy for comedonal acne; if tolerated, it can be used in conjunction with other modalities for other clinical forms of acne.

Mechanism of action Benzoyl peroxide is an antibac terial agent that decreases the number of P. acnes organisms by about 2.0 log₁₀ in 48 hours. Benzoyl peroxide also may reduce the number of comedones and have a slight direct anti-inflammatory effect.

Formulations Benzoyl peroxide is available in numerous over-the-counter and prescription formulations. The acetone- or alcohol-based formulations are more irritating and drying but possibly more effective than the water-based formulations. It is commonly available in strengths of 2.5 percent, 5.0 percent, and 10.0 percent, but there is little evidence to support a therapeutically important dose-response relation at these concentrations. Most practitioners recommend beginning with a lower concentration of a water-based formulation to prevent the potentially severe skin irritation and peeling induced by the higher concentrations.

Indications Benzoyl peroxide is used as monotherapy for mild to moderate inflammatory acne, but synergistic effects are obtained when it is used in conjunction with topical tretinoin and possibly when it is used in conjunction with topical or oral antibiotics.

Mechanism of action Topical antibiotics suppress the growth of P. acnes and thereby decrease the likelihood of follicular rupture and the intensity of the subsequent inflammatory response.

Formulations Topical preparations of tetracycline, meclocycline, erythromycin, clindamycin, and a combination of erythromycin and benzoyl peroxide are available. All of these preparations use an alcohol-containing vehicle and thus tend to be drying and irritating. Although topical tetracycline administered twice daily is as effective as oral tetracycline, 250 mg, administered twice daily, few comparison studies have been performed and a clear dose-response relation has not been established.

Indications Topical antibiotics are used as monotherapy for mild to moderate inflammatory acne, but the best results are obtained when a topical antibiotic is combined with other topical treatments such as tretinoin.

Mechanism of action Treatment with oral antibiotics reduces the number of P. acnes organisms but decreases neither the rate of sebum secretion nor the number of comedones. Oral antibiotics have well-documented nonantimicrobial properties that have been thought to play a role in the management of acne; the importance of these properties remains to be defined.

Therapeutic options and dosing Tetracycline (250 to 500 mg twice daily) is commonly prescribed. It is lipophilic and therefore becomes concentrated in sebum, and it has few side effects. Tetracycline-resistant strains of P. acnes do not emerge even after years of use. Erythromycin (250 to 500 mg twice daily) is equally effective, but gastrointestinal side effects often limit the use of this drug. The second-generation tetracyclines minocycline and doxycycline (50 to 100 mg daily or twice daily) offer certain advantages, such as being better absorbed with food and having a greater bioavailability that permits once-daily dosing. Laboratory monitoring is not cost-effective even when long periods of oral antibiotic therapy are anticipated.

Indications Systemic antibiotics are used as therapy for moderate to severe inflammatory acne or for inflammatory acne that does not respond to other measures.

Short courses of trimethoprim-sulfamethoxazole (80 mg of trimethoprim and 400 mg of sulfamethoxazole) or an oral cephalosporin are occasionally beneficial in the short-term management of patients who have acne that is unresponsive to conventional antibiotic treatment. Most of these patients are eventually given isotretinoin .

Because closed comedones are the precursors of the inflammatory acne lesions that cause scarring, as many as possible should be removed mechanically. Closed comedones should be opened with an 18- to 20-gauge needle. The opening of a comedo extractor should be placed over the open or just-opened comedo. Direct uniform pressure should then be applied over the opening of the follicle until the comedo is extruded.

Suppurating acne lesions are disfiguring and often quite painful. Intralesional corticosteroid injections promptly relieve pain and suppress the inflammatory reaction. The skin should be cleansed with an alcohol swab. Triamcinolone diacetate (10 mg/ml for intralesional use) should be diluted with saline or lidocaine to 3 to 5 mg/ml and mixed thoroughly before it is injected. The injection should be given through the thinnest portion of the top of and directly into the suppurating lesion. Only 0.05 to 0.2 ml of the suspension, or just enough to make the overlying skin blanch because of distention, should be injected into each inflammatory lesion.

Success in treating patients with acne does not occur automatically; the sympathy and interest of the physician play a key role in obtaining a good result. Acne is often the patient's first encounter with a chronic medical condition, and the treatment programs are complex. Treatment failures are often related to the patient's noncompliance, failure on the physician's part to impart instructions clearly, or failure on the physician's part to understand the patient's social situation and correctly assess the patient's ability to comply. Providing concise written and oral instructions that are suited to the patient's level of medical sophistication is essential. At follow-up evaluations, the original therapeutic plan should be compared point by point with the steps the patient has actually taken.

The treatment failures not related to compliance are usually caused by five other factors:

1. The patient is taking medication that is exacerbating the acne or making it resistant to treatment. The use of medications such as carbamazepine, phenytoin, androgenic steroids, anabolic steroids, corticosteroids, and lithium may have been overlooked in the first clinical encounter.

2. The female patient has an underlying endocrine problem that must be addressed. A limited endocrine and gynecologic evaluation may be appropriate.

3. The patient has acquired gram-negative folliculitis or antibiotic-resistant strains of P. acnes. Appropriate cultures and antibiotic or oral retinoid treatment will be required.

When acne is particularly severe and resistant to conventional treatment (see above), the patient may benefit from treatment with isotretinoin or from hormone manipulation.

Indications and patient selection Treatment with isotretinoin may be considered for patients with severe acne who have failed to respond adequately to conventional topical and systemic therapy, patients who have relapsed soon after several courses of oral antibiotic therapy, and patients who are dysmorphophobic. Women of childbearing potential must meet certain additional criteria before being given the drug.

Proper patient selection is essential because isotretinoin is a potent drug that produces significant and severe side effects, especially in women. It has substantial teratogenic potential: teratogenic effects occur in approximately 15 to 45 percent of in utero exposures. Spontaneous abortions occur in an additional 20 to 30 percent of pregnant women. The period of greatest risk is during the first trimester, but the risk persists for at least one month after the drug has been discontinued. The multiple malformation syndrome that most commonly occurs involves the face, central nervous system, and heart. In patients who are carefully selected and monitored, however, isotretinoin has proved to be a successful therapeutic intervention.

Additional criteria for women who are of childbearing potential Before isotretinoin is prescribed for a woman who can become pregnant, the physician must determine that she is capable of understanding and carrying out instructions and of complying with mandatory contraceptive measures. She must then be given oral and written warnings of the hazards of taking isotretinoin during pregnancy and exposing a fetus to the drug. She must also be given oral and written warnings of the risk of possible contraception failure and of the need to use two reliable forms of contraception simultaneously, unless she abstains from sexual in tercourse or has undergone a hysterectomy. She must acknowledge in writing her understanding of these warnings and of the need for using two contraceptive methods. An informed consent statement appropriate for women undergoing isotretinoin treatment is published with the package insert and in the Physicians' Desk Reference.

Therapy with isotretinoin should be begun on the second or third day of the next normal menstrual period. Within one week before therapy is begun, the patient must have negative results on a serum or urine pregnancy test with a sensitivity of at least 50 mIU/ml.

Dosing The normal dosage of isotretinoin is 1.0 mg/kg/day in two divided doses (an oral dosage of 30 mg twice daily for a 60 kg patient). Up to 2.0 mg/kg/day may be given if acne is particularly severe on the trunk or if the patient has responded inadequately to the lower dosage. Lower starting dosages (0.5 mg/kg/day) are effective in controlling acne but are associated with unacceptably high relapse rates when therapy is discontinued. A course of therapy usually lasts for 20 weeks but may be shortened if an excellent response occurs. Isotretinoin treatment is unusual in that patients often continue to improve even after the course of therapy is completed; therefore, patients who have an incomplete response should be followed for about eight weeks before administration of another course of treatment is considered. About 10 to 20 percent of patients who are treated with isotretinoin at 1.0 mg/kg/day will require a second course of treatment.

Few women require endocrine and gynecologic evaluation for acne; at one acne clinic, it was thought that hormone dysfunction accounted for acne in fewer than three percent of the women patients. Even fewer patients are found to have polycystic ovary disease or congenital adrenal hyperplasia as the underlying cause of their acne. Nevertheless, selected patients do benefit from hormone manipulation.

The finding of elevated plasma levels of dehydroepiandrosterone sulfate (DHEAS), the principal androgen secreted by the adrenal gland, or of testosterone, the hormone secreted in small amounts from the ovary, suggests that hormone therapy may be of some benefit. If testosterone levels are elevated, the patient may be treated with an oral contraceptive that contains 50 mg of estrogen. A six- to 12-month course of therapy will be required before any benefit is seen. If DHEAS levels are elevated, the patient may be treated with adrenal-suppressive doses of dexamethasone (0.25 to 0.5 mg/day). Improvement will occur within a few months.

Other women may have severe or resistant acne caused by so-called end-organ sensitivity. In these patients, the sebaceous glands can convert circulating androgens into the biologically much more potent dihydrotestosterone more rapidly than is normal, or the sebaceous glands are, by some means as yet undefined, hyperresponsive to androgenic stimulation. Treatment with spironolactone (150 to 200 mg/day) may be helpful in these patients.