Case-base Presentation of Connective Tissue Systems Course April 25, 2002 Richard A. Clark, MD Professor of Dermatology and Medicine Chair of Dermatology

A 17-year old white female comes to Dermatology for evaluation of severe acne that began shortly after menarche at age 13. She has tried many topical medications as well as a 6 month course of tetracycline without success. Currently she uses a benzyl peroxide wash in the morning, 13-cis retinoic acid solution before bedtime and minocycline 100 mg BID. There has been little or no improvement on this regimen. The mother, who is with the patient, is quite concerned about the effect of the patient’s acne on her general well-being. She reports that her daughter eats incessantly, has difficulty sleeping, does poorly in school and “hangs-out” with the wrong crowd. Family history is significant for obesity and type 2 diabetes. The patient denies the use of systemic medications or recreational drugs other than those taken for acne. She uses heavy make-up to cover her acne. On review of systems the patient admits to very irregular and infrequent menses. Sometimes she bleeds profusely but usually the bleeding is minimal. No pain is associated with her menses.

On examination the patient is markedly obese (5’3”, 210 lbs), has increase facial hair in the beard area and has moderately severe papular/pustular acne over the face, chest and upper back. No are apparent today although the patient claims that she does get cysts on occasion. She has striae around the axillary vault, over the abdomen and

upper thighs. Both the patient and mother insist on treatment with systemic Figure from AAD slide set. isotretinoin.

A. What needs to be discussed?

B. What tests are needed and why?

C. What treatment options might be considered?

A. What needs to be discussed?

There are several issues that need to be discussed with this patient. First, the patient admits to using heavy make-up to cover her acne. Acne cosmetica occurs in individuals who are enthusiastic users of cosmetics over many years. It is important in this patient to take a detailed history about the use of moisturizers, foundation creams, cleansers, toners, anti-wrinkle creams, hair care products, and sunscreens. The connection between cosmetic usage and acne is often overlooked by patients. Afflicted individuals may frequently rotate from one cosmetic counter to another. These patients often use very heavy make-up to mask lesions. Irritants found in many products can aggravate acne without being comedogenic. Many different chemicals found in cleansers, soaps, astringents, and toners can enhance the activity of comedogenic substances. A trial period off all cosmetics would be a reasonable starting point in this patient.

It is also important to get a detailed menstrual history including age at menarche, the regularity of menstrual cycles, pregnancies, and oral contraceptive history. The time course of symptoms also needs to be carefully elucidated. All medications that the patient takes need to be documented. Many drugs can cause , which needs to be differentiated from . In addition, a detailed history of all nutritional supplements, herbal products, and over the counter medications must be obtained.

Lastly, a careful family history needs to be obtained. Familial history of hirsutism, acne, menstrual irregularity, infertility, early cardiovascular disease, and obesity are all indicators of a familial tendency toward chronic anovulation, which includes polycystic ovary syndrome (PCOS).

B. What tests are needed and why?

Several tests are needed for the evaluation of this patient. There are a number of conditions that should be considered in the evaluation of a relative androgen excess and chronic anovulation. Adrenal and ovarian tumors can secrete large amounts of androgens and could be the etiology in this case. However, the increase in androgens caused by such tumors usually results in a rapid onset of symptoms and extremely high levels of androgens. Cushing's’syndrome is another condition that can cause androgen excess and chronic anovulation. An overnight dexamethasone suppression test or 24-hour urine test for free cortisol may need to be done. There are also late- onset forms of congenital adrenal hyperplasia that can result in a relative androgen excess and chronic anovulation.

Steroid hormones are produced in two tissues. Therefore, the adrenal cortex and ovaries must be carefully worked up in patients with clinical signs of androgen excess along with anovulation. Dehydroepiandrosterone, DHEAS, and androstenedione are androgenic steroids produced by the adrenal cortex. All three are very weak androgens, but they each can be converted in the periphery to testosterone. Interestingly, adrenal androgens can also be converted in the liver and adipose tissue to estrogenic compounds. The ovary produces testosterone and androstenedione. Laboratory evaluation is vital in the work up of patients with anovulation and hyperandrogenism.

Laboratory evaluation by the dermatologist should include a check of plasma free testosterone and DHEAS levels. If these tests are abnormal or if the patient’s condition warrants further evaluation, a referral to endocrinology is appropriate. Tests that may be performed by the endocrinologist include determination of 17-hydroxyprogesterone levels, which are useful for the detection of congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Measurements of serum prolactin and thyroid-stimulating hormone need to be checked as part of the assessment of oligomenorrhea owing to anovulation. An overnight dexamethasone suppression test should be performed by endocrinology in women with physical features of cortisol excess including hypertension, central obesity, facial plethora, easy bruising, striae, and proximal muscle weakness.

Polycystic Ovary Syndrome (PCOS)

Chronic anovulation with estrogen present is commonly referred to a polycystic ovarian disease. However, it is more appropriate to utilize the term polycystic ovary syndrome (PCOS), for it is a syndrome and not a disease. It is characterized by infertility, hirsutism, obesity, and amenorrhea or oligomenorrhea. Three minimal criteria are needed for the diagnosis of PCOS:

1. Menstrual irregularity 2. Evidence of hyperandrogenism, either clinical or biochemical 3. The exclusion of other diseases

Interestingly, the diagnosis of PCOS does not require pelvic ultrasonography. The classic polycystic ovarian morphology is described in 20% to 25% of regularly ovulating normal women, and therefore, the presence of this morpholgy alone is insufficient to make the diagnosis os PCOS. The three major pathophysiologic hyotheses of PCOS implicate LH, insulin, and the ovaries.

C. What treatment options might be considered?

Acne that has a strong hormonal component will often be unresponsive to standard treatments. If standard acne regimens are unsuccessful, alternate therapies need to be tried. Spirinoloactone can be used for acne asscoiated with hyperandrogenism. Spirinolactone is an antiandrogen and aldosterone antagonist. It works by competing with dihydrotestosterone for androgen receptors in the skin. There are randomized, placebo-controlled studies that show 50 to 100% improvement with dosed of 100 to 200 mg/day. However, a Cochrane review of spironolactone treatment for acne fails to demonstrate efficacy.

Cypterone acetate is a progestin with antiandrogenic activity. It has been used successfully in other countries but it is not available in the U.S. Numerous uncontrolled studies have shown benefit in hirsutism and acne with doses of 25 to 100mg/day. Low doses (2mg/d) as part of oral contraceptive pills have been associated with excellent responses in the treatment of acne and are the most common formulation of cyproterone acetate. Flutamide is an androgen receptor blocker used for prostate cancer. It has been used for acne but it has many side effects and there are concerns about potential hepatotoxicity that limit its usefulness.

Oral contraceptive pills can be very useful in acne patients with androgen excess. Systemic retinoids can also be tried. However, this patient would not be a good candidate for Accutane based on her symptoms of depression. Roche includes a package insert with Accutane that clearly warns that the drug “may cause depression, psychosis, and, rarely, suicidal ideation, suicide attempts, and suicide. Discontinuation of Accutane therapy may ge insufficient; further evaluation may be necessary.”

Hirsutism can also be treated with antiandrogens including spirinolactone, cyproterone acetate, and flutamide. Oral contraceptive pills are generally cosidered first line therapy. Combined therapy with OCPs and antiandrogens can be used for severe hirsutism. Other methods of hair removal can be used including shaving, dipilatories, electrolysis, and laser hair removal.

Women with chronic anovulation/PCOS also have many non-dermatological symptoms including menstrual irregularites, weight gain, obesity, insulin resistance, and infertility. There are a multitude of treatment options based on an individual patient’s lifestyle and goals including OCPs, GNRH analogs, ovulation inducing agents, nutritional and weight loss counseling, exercise, laparoscopic ovarian drilling, and insulin sensitizing agents.

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