Topics in Acne: Hormonal Influences, P acnes Resistance, and Topical Retinoids

/Home/Acne Therapy: Treatments & Cure/Topical Retinoids

Topics in Acne: Hormonal Influences, P acnes Resistance, and Topical Retinoids
Barbara A. Burrall, MD

Acne Pathogenesis
Acne vulgaris is such a common skin disease that it may almost be considered a normal physiologic process in adolescents. Up to 80% to 90% of teens are affected by acne, with approximately 30% requiring treatment.[1,2] Though acne is most commonly observed in the middle to late teens and is more severe in males, acne may persist into the third to fifth decades of life, particularly in women. Clinical lesions consist of comedones, follicular papules, pustules, and nodules usually found on the face, neck, chest, and back.

Acne is a disorder of the pilosebaceous follicle. The predominant early changes involve alterations in keratinization within the follicle. The presence of this denser, compacted keratinous material, as well as the enhanced sebaceous output, which is under hormonal control, is responsible for follicular obstruction and comedo formation.[3] In addition, the follicular bacteria Propionibacterium acnes is the predominant follicular organism and is increased in acne skin. P acnes is responsible for producing enzymatic and chemical agents that promote inflammation. Released enzymes may catalyze the lipolysis of sebum triglycerides to release irritating fatty acids. However, the release of chemotactic factors that recruit polymorphonuclear leukocytes may actually be more important in promoting inflammation that contributes to comedo rupture. Once rupture occurs, the extruded sebaceous and keratinous material is responsible for escalating the inflammatory response substantially.

Acne and Hormones in Women
Diane S. Berson, MD,[4] New York University School of Medicine, New York, NY, discussed hormones and acne and the management of acne in women during the Acne Symposium at the 59th Annual Meeting of the American Academy of Dermatology. Androgens exert their acne-causing activity by stimulating the sebaceous glands and probably promoting follicular hyperkeratosis. In women, androgens are produced in 2 glandular sites (adrenal gland, ovary) and other extraglandular sites (liver, skin, fat). The hypothalamus initiates the cascade leading to stimulation of the adrenals and ovaries by secreting gonadotropin-releasing hormone (GnRH), which acts on the pituitary.[5] Pituitary production of ACTH stimulates the adrenals to produce androstenedione, dehydroepiandrosterone (DHEA) and its sulfated form dehydroepiandrosterone sulfate (DHEAS), and cortisol. Conversely, the pituitary release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) stimulates the ovary to produce androstenedione, testosterone, and estrogens. At extraglandular sites, androstenedione and DHEAS are converted to testosterone. Aromatase located in the skin and fat can further convert testosterone to estradiol and androstenedione to estrone.

The level of sex hormone-binding globulin (SHBG) greatly influences the level of testosterone. Greater than 97% of testosterone is bound to SHBG. SHBG is decreased in obesity and hyperinsulinemia, leading to an increase in free testosterone. SHBG is increased with estrogen treatment, such as oral contraceptives, and in hyperthyroid states leading to a decrease in free testosterone. It is the free testosterone that is available to exert effects on target tissues.

The enzyme 5-alpha reductase, which is located in sebaceous glands and hair follicles, converts testosterone to the more potent dihydrotestosterone (DHT). At target tissues DHT binds to receptors and elicits a variety of effects, including the production of axillary and pubic hair, enlargement of sebaceous glands, temporal hair recession, and stimulation of terminal facial hairs. DHT is the most important hormonal regulator at these sites. 5-alpha reductase is comprised of 2 isoenzymes. Type I predominates in skin, the follicular infundibulum, and the sebaceous gland. Type II predominates in the prostate, scrotum, sweat glands, and inner hair sheath.

Adrenal androgens are increased earlier than those produced at other sites, sometimes by age 6-8. At adrenarche, one may see the development of pubic and axillary hair and an increase in sebum production due to increased DHEAS. At puberty, significant increases in oil production are seen. A variety of conditions are associated with enhanced androgen activity. These include androgen-producing neoplasms, congenital adrenal hyperplasia, and polycystic ovary syndrome (PCOS). Clinical findings associated with these conditions include acne, hirsutism, alopecia, amenorrhea, infertility, obesity, insulin resistance, and deepening of the voice.

Acne in Adult Women
Hormone-related acne in adult women may have its onset or may notably worsen in the adult years. As already noted, acne in women frequently persists beyond the teen years and may persist into middle age. When a cohort of patients older than age 25 was examined, only 3% of men but 12% of women exhibited acne.[6] Adult women frequently notice premenstrual flares of acne, and flares are also induced by stress probably due to adrenal stimulation. Adult women with acne may notice increased oiliness, menstrual irregularities, and, occasionally, facial hirsutism. Many fail standard acne therapy.

The clinical picture demonstrates inflammatory and noninflammatory acne of the lower face, especially the jaw line and chin. In most cases, serum androgens are normal, but there is increased sensitivity at the end organs. However, if the woman has menstrual irregularity, hirsutism, virilization, infertility, or very sudden, late onset of acne, evaluation of the adrenals, ovaries, and pituitary should be undertaken in collaboration with an endocrinologist. Laboratory clues to significant endocrine aberrations include:

* DHEAS > 6000-8000 ng/dL: suggests adrenal tumor

* DHEAS 4000-8000 ng/dL: suggests late-onset congenital adrenal hyperplasia

* Testosterone > 200 ng/dL: suggests ovarian tumor

* Testosterone > 95 ng/dL suggests polycystic ovary syndrome

* LH/FSH > 3/1: suggests polycystic ovary syndrome

Treatment of Acne in Adult Women
Initial treatment of acne in adult women is similar to the treatment of other forms of acne: topical and oral antibiotics, topical benzoyl peroxide, retinoids, or azelaic acid. However, in addition to these modalities, oral contraceptive therapy is highly effective.

Oral contraceptives combine an estrogen with a progestin. The estrogen increases SHBG, thereby decreasing free testosterone. The progestin competitively binds androgen receptors, decreases ovarian testosterone production, inhibits 5-alpha reductase, and may decrease adrenal production of DHEAS. The undesirable side effects of oral contraceptive therapy include nausea, headache, breast tenderness, weight gain, and breakthrough bleeding. However, these symptoms most frequently occur in first-time users and usually resolve with continued use.

Contraindications to the use of oral contraceptives include hypertension, history of stroke, history of thromboembolism, smoking in women older than 35, or a history of breast or uterine cancer. Desirable effects include the regulation of menses, decrease in PMS, decreased acne, decreased hirsutism, decreased bone loss, and decreased ovarian and colorectal cancer.

Currently Used Oral Contraceptives
Most of the currently used oral contraceptives employ ethinyl estradiol as the estrogen, but there are 3 commonly used progestins:

* Desogestrel (Desogen, Ortho-Cept, Mircette)

* Norgestimate (Ortho-Cyclen, Ortho Tri-Cyclen [FDA-approved for acne])

* Levonorgestrel (Alesse)

These contraceptives are particularly useful in women with adult acne because they tend to have minimal effects on weight gain, blood pressure, and lipoprotein metabolism. A trial of oral contraceptives should continue for at least 3 months to adequately evaluate efficacy.

Other Antiandrogens
When the response to oral contraceptives is inadequate, a trial of spironolactone may be considered. Spironolactone blocks the binding of DHT to receptor (decreased sebum production) and decreases ovarian and adrenal androgen synthesis. Spironolactone is useful in hormonal acne, hirsutism, and androgenetic alopecia. The dose range is from 25 to 200 mg per day, given in 2 divided doses. It is usually best to start at 25 mg twice daily and gradually increase by 25 mg twice daily. Side effects include breast tenderness, menstrual abnormalities, headache, and weight gain. Spironolactone must always be given with an oral contraceptive, because if pregnancy occurs the drug would cause feminization of a male fetus.

Cyproterone acetate is a potent antiandrogen that is useful for acne and hirsutism. When combined with ethinyl estradiol it forms the effective oral contraceptive Diane-35. However, no products containing cyproterone are approved for use in the United States.

Finasteride inhibits only Type II 5-alpha reductase and therefore is not effective in acne because sebaceous receptors are Type I.

Congenital Adrenal Hyperplasia and Acne
Congenital adrenal hyperplasia (CAH) comprises a group of autosomal recessive disorders of adrenal synthesis of cortisol. The relationship between CAH and treatment-resistant acne was discussed by Gerd Plewig, MD,[7] University of Munich, Germany. Ninety-five percent of these patients have a deficiency of the enzyme 21-hydroxylase. There are early-onset and late-onset types. When the onset is in infancy, symptoms are severe, including salt wasting, virilization, and failure to thrive. When onset is late, symptoms include hirsutism, menstrual irregularities, and acne. In some cases, acne may be the only sign of CAH in women or men.

Adrenocorticotropic hormone (ACTH) produced in the pituitary stimulates the adrenal gland to produce cortisol and androgens. Due to the 21-hydroxylase deficiency in CAH, the usual levels of ACTH do not result in an adequate level of adrenal cortisol production. The resultant elevations in ACTH production lead to overproduction of DHEAS and androstenedione, which are peripherally converted to testosterone and DHT in the sebaceous gland and other target tissues.

The clinician should suspect CAH if there is early-onset acne, acne is severe, acne is persistent, acne treatment fails, or hirsutism or irregular menses accompany acne. The work-up should proceed in collaboration with an endocrinologist.

Detection of CAH
The presence of CAH may be detected by measurement of 8-9 AM elevations of the cortisol precursor 17-alpha hydroxyprogesterone. This substance should be measured along with testosterone and androstenedione. If a female patient is on oral contraceptives, the values should be assessed on day 7 of the menstrual period. Unfortunately, many patients with late-onset CAH will have normal resting levels of 17-alpha hydroxyprogesterone. In these patients, abnormal responses to ACTH stimulation must be demonstrated to diagnose CAH.[5] This process consists of administration of intravenous ACTH and measurement of 17-alpha hydroxyprogesterone 60 minutes later.

CAH Management
The management of CAH-related acne involves isotretinoin or antibiotics combined with glucocorticoids, which are a necessity. Usually, prednisone is started at 20-40 mg per day if the condition is severe, or 4 mg per day if mild. Maintaining control differs in men and women. For women, an oral contraceptive with antiandrogen activity is employed. Diane-35 is the oral contraceptive of choice in Europe, though it is unavailable in the United States. For men, low-dose corticosteroids are used. Treatment adequacy is assessed by the clinical result. In Dr. Plewig's experience with more than 50 patients, more than 90% respond favorably to these treatments. Frequently, steroid suppression therapy can be stopped within 6 months to 1 year without recurrence.

Antibiotic Treatment and P acnes Resistance
In the United Kingdom, 2.5-3 million prescriptions for antiacne antibiotics are filled each year, pointed out William J. Cunliffe, MD,[8] University of Leeds, Leeds, United Kingdom. Therefore, the consideration of antibiotic resistance is of great importance. However, resistance matters only if the antibacterial action of the drug is the most important effect of the medication. Most antiacne antibiotics have important anti-inflammatory effects independent of their antibiotic action.

There are several reasons for treatment failures when antibiotics are used in acne. These include inadequate treatment duration, poor compliance, very high sebum rate, bacterial folliculitis (gram negative, S aureus), and P acnes resistance.

P acnes resistance has greatly increased over the past decade.[9] When skin carriage of resistant P acnes was assessed in the United Kingdom (1999-2000) at least 50% showed resistance to at least 1 of the commonly employed antibiotics tested. Fifty percent showed resistance to erythromycin, 40% to clindamycin, and 20% to tetracycline. Furthermore, in the United States in 1997, 30% of cultured carried strains were resistant to tetracycline in the laboratory.

Follicular drug concentrations and true clinical resistance are hard to assess, but it has been estimated that up to 40% of acne patients have some form of clinically relevant P acnes resistance. New patients are unlikely to harbor resistant strains, but patients with a long history of antibiotic use, particularly if their compliance and response have been poor, show significant resistance. Up to 50% of siblings and close contacts of these patients share resistant P acnes strains.[10] Besides the face, the nares is a common site of resistant bacterial carriage. In fact, we dermatologists usually carry large numbers of resistant P acnes on our own faces.

When antibiotic therapy is begun, resistance is uncommon. However, after 16 weeks of treatment, resistance is fairly high. Resistance develops by mutation, and it appears that mutants are as viable as sensitive strains. When the antibiotic is stopped, the mutants are usually not replaced by sensitive bacteria.

Tips to Avoid Resistant P acnes
The following clinical tips may help avoid the development of antibiotic-resistant strains of P acnes:

* Avoid extended antibiotic use.

* Stop antibiotics when control is achieved, maintaining control with other agents.

* Use antibiotics only in combination with benzoyl peroxide or a retinoid.

* Consider adding zinc acetate to the regimen.

* Do not hesitate to use isotretinoin when indicated.

Topical Retinoids
Topical retinoids were first used for acne by Dr. Albert Kligman in 1969. The characterization of retinoid receptors beginning in 1987 allowed chemists to begin to design retinoids to fit selective receptors.[11] Receptor binding produces a variety of notable effects on follicular keratinization which have a favorable effect on acne.

Clinically visible acne lesions consist of comedones, inflammatory papules, pustules, and nodules. Precursor lesions consist of microcomedones, in which the mid-portion of the follicle begins to expand with lipid and keratinous material, resulting in a thinning and ballooning of the follicular wall. These microcomedones may progress to fully developed comedones or inflammatory lesions. The microcomedo provides a good environment for P acnes growth. P acnes elaborates a variety of inflammatory molecules, including chemotactic factors for polymorphonuclear leukocytes and lymphocytes. Rupture of the follicle wall leads to massive inflammation as evidenced by visible papules, pustules, and nodules.

The topical retinoids and similar compounds act mainly at the level of the microcomedo. They effect changes in the environment that affect the viability and growth of P acnes and enhance the penetration of other drugs such as antibiotics. The topical retinoids do not affect sebum production, though patients sometimes subjectively feel that their faces are less oily.

Acne Preparations With Retinoid Activity
The 3 available retinoid or retinoid-like medications are tretinoin (Retin-A, Avita), tazarotene (Tazorac), and adapalene (Differin). While tretinoin binds to alpha, beta, and gamma retinoid receptors, tazarotene and adapalene selectively bind beta and gamma receptors.[12,13] Traditionally recognized to be effective in comedonal acne, all 3 agents are also useful in papulopustular acne. James J. Leyden, MD,[14] University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, noted a 45% to 55% reduction in inflammatory acne lesions after a 12-week course of tretinoin (0.025%). Tazarotene is thought to be slightly more effective and adapalene slightly less effective in clinical practice. All work best in combination with oral or topical antibiotics.

Retinoid Irritation
Unfortunately, besides being effective antiacne agents, the retinoids also have the potential for promotion of inflammation, especially in patients with atopy or rosacea. This irritancy potential is the reason topical retinoids are less frequently used in inflammatory acne. One confounding factor is that the sorbic acid in many tretinoin preparations stimulates vasodilation leading to flushing. However, true irritancy is an important factor. Dr. Leyden noted 60 patients treated with tazarotene 0.1% gel, tretinoin 0.1% gel microsphere, tretinoin 0.25 % gel, or adapalene 0.1% gel. When side-to-side facial comparisons were made, erythema was noted with all 3 preparations, but tazarotene and tretinoin 0.025% gel were more irritating than tretinoin microsphere or adapalene. However, reactions strong enough to cause patients to alter their treatment program were only slightly more common in tazarotene users. Differences in irritation among the 3 products were much more minor if atopic or rosacea patients were excluded.

A variety of factors influence retinoid tolerability. These include both patient and environmental factors. "Sensitive skin" factors include factors important in atopy and rosacea such as integrity of the stratum corneum, tendency to vascular reactivity, and ability to downregulate inflammation. Environmental factors include seasonal climate changes and moisturizer use. It appears that retinoid irritation depends more on these factors than on which retinoid is chosen. Tips to tell patients to enhance tolerability include:

* Wash only with mild soaps or cleansers.

* Minimize astringents.

* Delay application of retinoids for 20-30 minutes after cleansing.

* Avoid early use of alpha-hydroxy acids.

* Start slowly, every 2-3 days.

* Minimize application to the nasolabial and periocular areas.

* Use noncomedogenic moisturizers.

References

1. Lever L, Marks R. Current views on the etiology, pathogenesis and treatment of acne vulgaris. Drugs. 1990;39:681-692.
2. Kelly PA. Acne and related disorders. In: Sams WM Jr, Lynch PJ, eds. Principles and Practice of Dermatology. New York: Churchill Livingstone; 1996:801-818.
3. Strauss JS. Sebaceous glands. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, eds. Dermatology in General Medicine. New York: McGraw-Hill; 1995;709-726.
4. Berson D. Hormones and acne: clinical evaluation and management. Program of the 59th Annual Meeting of the American Academy of Dermatology; March 2-7, 2001; Washington, DC. Page 170.
5. Sperling LC, Heimer WL. Androgen biology as a basis for the diagnosis and treatment of androgenic disorders in women. II. J Am Acad Dermatol. 1993;28:901-916.
6. Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol. 1999;41:577-580.
7. Plewig G. Adrenogenital syndrome in difficult to manage acne patients. Program of the 59th Annual Meeting of the American Academy of Dermatology; March 2-7, 2001; Washington, DC. Page 170.
8. Cunliffe WJ. New insights into P acnes resistance. Program of the 59th Annual Meeting of the American Academy of Dermatology; March 2-7, 2001; Washington, DC. Page 170.
9. Espersen F. Resistance to antibiotics used in dermatological practice. Br J Dermatol. 1998;139(suppl 53):4-8.
10. Eady EA. Bacterial resistance in acne. Dermatology. 1998;196:59-66.
11. Petrovich M, Brand NJ, Krust A, Chambon P. A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature. 1987;330:444-450.
12. Chandraratna RAS. Rational design of receptor-selective retinoids. J Am Acad Dermatol. 1998;39:S124-128.
13. Michel S, Jomard A, Demarchez M. Pharmacology of adapalene. Br J Dermatol. 1998;139(suppl 52):3-7.
14. Leyden JJ. Topical retinoids: new insights. Program of the 59th Annual Meeting of the American Academy of Dermatology; March 2-7, 2001; Washington, DC. Page 170.


Copyright © 2001 Medscape Portals, Inc.