Sandy S. Chuan, MD and R. Jeffrey Chang, MD

Department of Reproductive Medicine, Division of Reproductive Endocrinology, University of California, San Diego, CA, USA

ABSTRACT
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive aged women. It is typically characterized by hyperandrogenism, chronic anovulation, and polycystic ovaries. Women with PCOS often experience dermatologic manifestations of hyperandrogenism, including hirsutism, acne vulgaris, and androgenic alopecia. This article will review the treatments for acne due to androgen excess in PCOS women.

Key Words:
acne vulgaris, hyperandrogenism, polycystic ovary syndrome, PCOS

Pathophysiology and Prevalence

Polycystic ovary syndrome (PCOS) is typically characterized by excessive ovarian androgen production, failure of
ovulation, and slightly enlarged ovaries with numerous peripheral small follicles that appear as cysts. Individuals with this phenotype comprise 5-10% of reproductive aged women.1-3 The disorder is commonly accompanied by insulin resistance and infertility. Clinical manifestations include irregular menstrual bleeding due to anovulation and dermatologic sequelae of hyperandrogenemia, including hirsutism, acne vulgaris, and androgenic alopecia. The prevalence of acne in women with PCOS has been estimated to be 10-34%.4-7 However, in post-pubertal and adolescent PCOS women it is unclear whether acne arises secondary to androgen excess or occurs as a result of normal puberty. During puberty, acne is common and attributable to the surge of adrenal androgens with adrenarche. In adolescent girls, moderate to severe acne has been reported to be greater
than 50%.1

Acne is the most common skin disorder, affecting approximately 40-50 million people in the United States.8 This condition results from the formation of comedones, due to sebum accumulation, along with desquamated follicular epithelial cells, which allows colonization by the bacterium, Propionibacterium acnes (P. acnes).9 Androgens may worsen acne formation by increasing sebum production within the pilosebaceous unit. Many PCOS women with acne exhibit facial lesions and up to 50% of individuals demonstrate lesions on the neck, chest, and upper back.10

Past studies have shown that androgen levels are elevated in women with acne, although the severity of acne has not been positively correlated with any particular hormone, with the exception of the adrenal androgen, dehydroepiandrosterone sulfate (DHEA-S).11-13 Notably, several studies have demon-strated an inverse relationship with sex-hormone binding globulin (SHBG).11,14

About 50% of normal women with acne do not have clinical or biochemical evidence of hyperandrogenism.15 Conversely, in many PCOS women hirsutism is not associated with acne. These discrepancies may be due to variable local androgen bioactivity. It has been postulated that androgen levels within the skin are more important mediators of acne than circulating levels.13,16

In the hair follicle, androgen bioactivity is regulated, in part, by 5-α-reductase, which acts to convert free testosterone to the more potent dihydrotestosterone (DHT). This enzyme has two isoforms: type 1 is found in the sebaceous glands and pubic skin and type 2 is located primarily in the hair follicle, genital skin, and adult scalp. The relative activities of these isoenzymes within the hair follicle could account for the variable clinical presentation seen in hyperandrogenic women when the degree of hirsutism is not compatible with the severity of the acne.10 In addition, 5-α-reductase expression is also stimulated by excess androgen, insulin, and insulin-like growth factor, which likely contributes to increased local androgen bioactivity, resulting in the hirsutism and acne seen in PCOS women.10,17

Treatment

For women with PCOS in whom hirsutism is a major concern, treatment is focused on reducing androgen production, decreasing the fraction of circulating free testosterone, and limiting androgen bioactivity at the hair follicle. In those PCOS women with acne vulgaris, clinical benefit may be derived from any of these therapeutic modalities (Figure 1).

Ovarian Suppression

The most common form of ovarian suppression is treatment
with combined oral contraceptive pills (OCPs). These
drugs suppress gonadotropin secretion and ovarian steroid
synthesis, leading to decreased androgen production. The
estrogen component has been shown to stimulate SHBG
production by the liver, thereby decreasing the bioavailability
of serum testosterone.10,18 The progestin component of OCPs
may lower local androgen effect by inhibiting 5-α-reductase
activity in the hair follicle or competitive inhibition for the
androgen receptor.19,20 The anti-androgenic effects of the
progestin, cyproterone acetate, have been well documented,
whereas the benefit of drospirenone is less clear.21,22
Drospirenone is related to the anti-androgen, spironolactone,
although whether the dose contained in OCPs is sufficient
to block androgen action clinically has not been established.
It is likely that clinical improvement of hirsutism associated
with OCPs containing drospirenone may be attributed to
overall ovarian suppression. Formulations containing more
androgenic progestins, such as levonorgestrel and norgestrel,
may be less effective.

The benefits of lower androgen production by OCPs include
improvement of acne vulgaris.23 A recent Cochrane review
showed that OCPs reduced acne lesion count, severity grades, and self-assessed acne.21 It is unclear how OCPs compare to alternative acne treatments, such as topical and antibiotic therapies.

Anti-Androgens

Spironolactone

Spironolactone is an aldosterone antagonist with antiandrogenic
properties. It has been commonly used to treat hirsutism.24 The mechanism of action includes competition
for the androgen receptor, suppression of cytochrome P450, and inhibition of steroidogenesis, as well as reduction in 5-α-reductase activity.24-27

Spironolactone also decreases sebum production and
improves acne. The therapeutic dose for acne therapy is
50-100 mg per day. The dose of spironolactone used for
treating hirsutism is significantly higher, ranging from
100-300 mg daily. Thus, its use for hirsutism would likely
prove effective for acne as well. Spironolactone may be
used in combination with OCPs in women who have limited
response to OCPs alone.9 It is important for women to remain
on birth control while on spironolactone to avoid feminization
of a male fetus in an unplanned pregnancy. Patients should be
off the medication for 3 months before conception.

Side-effects of this medication at recommended doses for
hirsutism and acne are minimal. Occasionally, polydipsia,
polyuria, nausea, headaches, fatigue, and gastritis may occur.
In addition, some normal ovulatory women may experience
menstrual irregularity. Despite its mild diuretic effect,
spironolactone has the potential to induce hyperkalemia.
For the healthy PCOS patient this remains a theoretical risk.
However, patients should be counseled regarding foods
containing high potassium content.

Flutamide

Flutamide is a non-steroidal androgen receptor antagonist
indicated for the treatment of prostate cancer and has been
found to be effective for treating hirsutism.28-31

Flutamide may be used for the treatment of mild to moderate
acne. It should be used at low doses; 62.5 mg or 125 mg
per day have been shown to be effective. The combination of
OCPs and flutamide is likely more efficacious than flutamide
alone.32 In hirsute women with acne who were treated with
OCPs, the addition of flutamide was significantly more
effective than spironolactone.33

The potential for hepatotoxicity limits its use. However, no
cases of fatal hepatotoxicity have been reported with doses
less than 500 mg per day.30 There have been reports of mild,
transient liver impairment at doses ranging from 375-500 mg
per day.34,35 Women should remain on OCPs for birth control
purposes as feminization of a male fetus can occur while on
this medication. Patients should be off the medication for
3 months before conception.

Finasteride

As a 5-α-reductase inhibitor, finasteride is commonly used
in the treatment of prostatic disorders and has been used to
treat hirsutism. Its effectiveness for hirsutism is comparable
to that of spironolactone.36 In hyperandrogenic women, the
efficacy of this drug for acne has not been well evaluated. In
one study, finasteride was shown to decrease acne, but to a
lesser degree than flutamide and cyproterone acetate.37 The
reduced effect of finasteride on acne may be explained by
lower inhibition of 5-α-reductase type 1 activity, which is
prominent in the sebaceous gland, as compared with that of
5-α-reductase type 2 expressed primarily in the hair shaft.38

Insulin Sensitizing Agents

Insulin sensitizing agents, such as metformin and
thiazolidinediones, have been employed in women with
PCOS to decrease androgen production by lowering
hyperinsulinemia. The efficacy of this approach to treat
hirsutism has been inconsistent, as some, but not all studies
have shown benefit. In these investigations, little attention
has been given to improvement of acne. In a study of patients
with minimal acne, improvement of acne was reported after
12 months of therapy with metformin 1500 mg daily.39 At
present, these agents are not recommended as acne therapy
for women with PCOS.

Conclusion

Acne is a ubiquitous condition that is often exacerbated by
androgen overproduction in women with PCOS. Hormonal
agents targeted at reducing hyperandrogenemia and androgen
bioactivity may effectively reduce both hirsutism and acne
simultaneously. OCPs are recommended as first-line therapy
unless otherwise indicated. Anti-androgens may be added to
improve the clinical outcome.

References

  1. Azziz R, Woods KS, Reyna R, et al. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 89(6):2745-9 (2004 Jun).
  2. Yen SS, Jaffe RB. Yen and Jaffe’s reproductive endocrinology. 6th ed. Strauss JF, Barbieri RL (eds). Philadelphia: Elsevier- Saunders, p928 (2009).
  3. Knochenhauer ES, Key TJ, Kahsar-Miller M, et al. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab 83(9):3078-82 (1998 Sep).
  4. Dramusic V, Rajan U, Chan P, et al. Adolescent polycystic ovary syndrome. Ann N Y Acad Sci 816:194-208 (1997 Jun 17).
  5. Azziz R, Marin C, Hoq L, et al. Health care-related economic burden of the polycystic ovary syndrome during the reproductive life span. J Clin Endocrinol Metab 90(8):4650-8 (2005 Aug).
  6. Chang WY, Knochenhauer ES, Bartolucci AA, et al. Phenotypic spectrum of polycystic ovary syndrome: clinical and biochemical characterization of the three major clinical subgroups. Fertil Steril 83(6):1717-23 (2005 Jun).
  7. Jones GL, Benes K, Clark TL, et al. The Polycystic Ovary Syndrome Health-Related Quality of Life Questionnaire (PCOSQ): a validation. Hum Reprod 19(2):371-7 (2004 Feb).
  8. George R, Clarke S, Thiboutot D. Hormonal therapy for acne. Semin Cutan Med Surg 27(3):188-96 (2008 Sep).
  9. Berson DS, Chalker DK, Harper JC, et al. Current concepts in the treatment of acne: report from a clinical roundtable. Cutis 72(1 Suppl):5-13 (2003 Jul).
  10. Archer JS, Chang RJ. Hirsutism and acne in polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol 18(5):737-54 (2004 Oct).
  11. Walton S, Cunliffe WJ, Keczkes K, et al. Clinical, ultrasound and hormonal markers of androgenicity in acne vulgaris. Br J Dermatol 133(2):249-53 (1995 Aug).
  12. Karrer-Voegeli S, Rey F, Reymond MJ, et al. Androgen dependence of hirsutism, acne, and alopecia in women: retrospective analysis of 228 patients investigated for hyperandrogenism. Medicine (Baltimore) 88(1):32-45 (2009 Jan).
  13. Deplewski D, Rosenfield RL. Role of hormones in pilosebaceous unit development. Endocr Rev 21(4):363-92 (2000 Aug).
  14. Borgia F, Cannavo S, Guarneri F, et al. Correlation between endocrinological parameters and acne severity in adult women. Acta Derm Venereol 84(3):201-4 (2004).
  15. Ozdemir S, Ozdemir M, Gorkemli H, et al. Specific dermatologic features of the polycystic ovary syndrome and its association with biochemical markers of the metabolic syndrome and hyperandrogenism. Acta Obstet Gynecol Scand 89(2):199-204 (2010).
  16. Cappel M, Mauger D, Thiboutot D. Correlation between serum levels of insulin-like growth factor 1, dehydroepiandrosterone sulfate, and dihydrotestosterone and acne lesion counts in adult women. Arch Dermatol 141(3):333-8 (2005 Mar).
  17. Falsetti L, Gambera A, Andrico S, et al. Acne and hirsutism in polycystic ovary syndrome: clinical, endocrine-metabolic and ultrasonographic differences. Gynecol Endocrinol 16(4):275-84 (2002 Aug).
  18. Azziz R. The evaluation and management of hirsutism. Obstet Gynecol 101(5 Pt 1):995-1007 (2003 May).
  19. Cassidenti DL, Paulson RJ, Serafini P, et al. Effects of sex steroids on skin 5 alpha-reductase activity in vitro. Obstet Gynecol 78(1):103-7 (1991 Jul).
  20. Rabe T, Kowald A, Ortmann J, et al. Inhibition of skin 5 alpha-reductase by oral contraceptive progestins in vitro. Gynecol Endocrinol 14(4):223-30 (2000 Aug).
  21. Arowojolu AO, Gallo MF, Lopez LM, et al. Combined oral contraceptive pills for treatment of acne. Cochrane Database Syst Rev (3):CD004425 (2009).
  22. Thorneycroft IH. Evolution of progestins. Focus on the novel progestin drospirenone. J Reprod Med 47(11 Suppl):975-80 (2002 Nov).
  23. Lowenstein EJ. Diagnosis and management of the dermatologic manifestations of the polycystic ovary syndrome. Dermatol Ther 19(4):210-23 (2006 Jul-Aug).
  24. Farquhar C, Lee O, Toomath R, et al. Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne. Cochrane Database Syst Rev (4):CD000194 (2003).
  25. Speroff L, Glass RH, Kase NG. Hirsutism. In: Speroff L, Glass RH, Kase NG (eds). Clinical gynecologic endocrinology and infertility. 6th ed. Baltimore: Williams and Wilkins, p523-56 (1999).
  26. Cumming DC, Yang JC, Rebar RW, et al. Treatment of hirsutism with spironolactone. JAMA 247(9):1295-8 (1982 Mar 5).
  27. Armanini D, Karbowiak I, Goi A, et al. In-vivo metabolites of spironolactone and potassium canrenoate: determination of potential anti-androgenic activity by a mouse kidney cytosol receptor assay. Clin Endocrinol (Oxf) 23(4):341-7 (1985 Oct).
  28. Cusan L, Dupont A, Belanger A, et al. Treatment of hirsutism with the pure antiandrogen flutamide. J Am Acad Dermatol 23(3 Pt 1):462-9 (1990 Sep).
  29. Moghetti P, Castello R, Negri C, et al. Flutamide in the treatment of hirsutism: long-term clinical effects, endocrine changes, and androgen receptor behavior. Fertil Steril 64(3):511-7 (1995 Sep).
  30. Muderris, II, Bayram F. Clinical efficacy of lower dose flutamide 125 mg/day in the treatment of hirsutism. J Endocrinol Invest 22(3):165-8 (1999 Mar).
  31. Simard J, Luthy I, Guay J, et al. Characteristics of interaction of the antiandrogen flutamide with the androgen receptor in various target tissues. Mol Cell Endocrinol 44(3):261-70 (1986 Mar).
  32. Thiboutot D, Chen W. Update and future of hormonal therapy in acne. Dermatology 206(1):57-67 (2003).
  33. Cusan L, Dupont A, Gomez JL, et al. Comparison of flutamide and spironolactone in the treatment of hirsutism: a randomized controlled trial. Fertil Steril 61(2):281-7 (1994 Feb).
  34. Moghetti P, Tosi F, Tosti A, et al. Comparison of spironolactone, flutamide, and finasteride efficacy in the treatment of hirsutism: a randomized, double blind, placebo-controlled trial. J Clin Endocrinol Metab 85(1):89-94 (2000 Jan).
  35. Muderris, II, Bayram F, Guven M. Treatment of hirsutism with lowest-dose flutamide (62.5 mg/day). Gynecol Endocrinol 14(1):38-41 (2000 Feb).
  36. Wong IL, Morris RS, Chang L, et al. A prospective randomized trial comparing finasteride to spironolactone in the treatment of hirsute women. J Clin Endocrinol Metab 80(1):233-8 (1995 Jan).
  37. Carmina E, Lobo RA. A comparison of the relative efficacy of antiandrogens for the treatment of acne in hyperandrogenic women. Clin Endocrinol (Oxf) 57(2):231-4 (2002 Aug).
  38. Schwartz JI, Tanaka WK, Wang DZ, et al. MK-386, an inhibitor of 5alpha-reductase type 1, reduces dihydrotestosterone concentrations in serum and sebum without affecting dihydrotestosterone concentrations in semen. J Clin Endocrinol Metab 82(5):1373-7 (1997 May).
  39. Harborne L, Fleming R, Lyall H, et al. Metformin or antiandrogen in the treatment of hirsutism in polycystic ovary syndrome. J Clin Endocrinol Metab 88(9):4116-23 (2003 Sep).