Charles Lynde MD, FRCPC1; Jerry Tan MD, FRCPC2; Gurbir Dhadwal MD, FRCPC, FAAD3; Adrian Gili MD, FRCPC4; Dimitrios Kyritsis MDCM, FRCPC, DABD5; Loukia-Maria Mitsos MD, Phd, FRCPC, DABD5; Eric Mongrain MD, FRCPC6; Danya Sereda MD, FRCPC7; Catherine Zip MD, FRCPC8; Anneke Andriessen PhD9
1Associate Professor, University of Toronto, Toronto, ON, Canada
2University of Western Ontario, Windsor, ON, Canada
3Clinical Instructor, University of British Columbia, Vancouver, BC, Canada
4Dermatologist, Calgary, AB, Canada
5Dermatologist, Montreal, QC, Canada
6Dermatologist, Quebec City, QC, Canada
7Dermatologist, West Vancouver, BC, Canada
8Clinical Associate Professor, University of Calgary, Calgary, AB, Canada
9UMC St Radboud, Nijmegen, The Netherlands
Conflicts of interest: The consensus meeting was supported by an educational grant from Aspri Canada. All authors of this article participated in the meeting.
Acne is the most common disorder encountered in dermatologic practice1, and can have a highly significant negative impact on quality of life. Our evolving understanding of the role of hormones in acne, along with a growing body of data from clinical trials, calls for a reappraisal of the role of hormonal therapy for acne.
Epidemiology and Impact
- 85% of 15 to 17-year-olds have acne1
- 45% of women aged 21-30 years2
- 26% of women aged 31-40 years2
- 12% of women aged 41-50 years2
- Acne is associated with mood symptoms.
- Suicidal ideation is two times more common with substantial acne versus little to no acne in girls, and three times in boys.3
- Degree of distress and psychologic harm caused by acne does not always correlate with clinical severity.4
Role of Androgens in Acne
- ~Age 8 or 9 years adrenal gland starts to produce large quantities of dehydroepiandrosterone (DHEA) sulfate5 ➝ increased sebum, abnormal keratinization of the follicular epithelium.1
- Produced by: adrenal glands, gonads, and sebaceous glands in the skin.6
- Sebocytes, sweat glands and dermal papilla cells convert circulating DHEA and androstenedione to more potent steroids
- DHEA ➝ testosterone ➝ dihydrotestosterone (DHT) by 5α reductase.6
- Sebum production ➝ comedone formation & provides a growth medium for P. acnes.6
- Women with excessive levels of androgens, as in polycystic ovary syndrome (PCOS) and congenital adrenal hyperplasia, are more likely to develop acne.1,2
- Most people with acne have androgen levels within normal limits. In these patients, increased sensitivity of sebaceous glands to androgens may account for the development of acne.6
- Aim is to reduce androgen action on cutaneous pilosebaceous units in women with elevated and normal androgen levels.7
- First-line option in women with hyperandrogenism.8
- Among women with normal androgen levels, hormonal therapy is usually reserved for those who are not trying to conceive and cannot be effectively managed with topical therapy
- May be particularly effective in adult women with inflammatory acne that involves the lower face and neck.7
- Can also be considered in women whose acne appears linked to their menstrual cycle (e.g., premenstrual flares).7,8
Role of Spironolactone in Acne Treatment
- Despite lack of high grade evidence for efficacy, spironolactone is a frequently recommended option in the management of acne in women.
- Competitive androgen receptor blocker.7
- May also inhibit 5-alpha-reductase and increase steroid hormone binding globulin.7
- 50 to 200 mg taken with meals ➝ decrease sebum excretion by 30 to 50%.9
- Can be used as monotherapy in adult women with cyclic or late onset acne or in combination with other topical and oral agents.10
- Has been prescribed in doses of up to 200 mg/day, but clinical improvement may occur with doses as low as 25 mg/day, and most physicians do not recommend above 100mg/day.11
- Therapy may be started with a lower dose with subsequent upward titration.10
- Although a 2009 Cochrane review found insufficient evidence to establish the efficacy of spironolactone12, several low quality studies have reported a clinically significant benefit, with reductions in lesions from 50 to 100%.9
- Data for truncal acne as well as facial acne.10
- Spironolactone and Diane-35 have both shown similar efficacy in improving acne in women with PCOS.13
Side Effects of Spironolactone
- Generally, well tolerated and the side effects are dose-related with lesser frequency at doses ≤100 mg/day.12,14
- Side effects include: menstrual irregularities, breast tenderness, minor gastrointestinal symptoms, orthostatic hypotension, headaches, dizziness, and fatigue.
- Potassium-sparing diuretic thus hyperkalemia is a potentially serious adverse effect. But most likely to occur at high doses and in patients with renal insufficiency or severe heart failure.15
- Educate about avoiding foods that are high in dietary potassium (ex. low-sodium processed foods and coconut water). However, testing for potassium in young and healthy women taking spironolactone for acne is unnecessary.15
- Concern over induction of estrogen-dependent malignancies raised over the years.
- No definitive evidence linking human breast or other estrogen-dependent tumors to the use of spironolactone exists.10,16
- Unclear whether there is increased risk for women with a personal or family history of breast or other estrogen-dependent malignancies.16
- Co-administration of spironolactone with an oral contraceptive is advised because of serious fetal effect (feminization of the male fetus), along with the menstrual irregularities that may occur during treatment.17
Role of Oral Contraceptives in Treatment of Acne
Oral Contraceptives (OGs)
- Reduce acne lesions by increasing estrogen levels and decreasing free testosterone and androgen levels.7
- Estrogens in OCs inhibits androgen production by the ovaries and possibly the sebaceous glands.11
- Progestins in OCs may have androgenic properties (which are counteracted by the anti-androgenic properties of the estrogen component) or anti-androgenic properties.17
- OCs indicated for acne are effective across the spectrum of disease severity.18
- In Canada, 4 OCs (Alesse/Alysena, Diane 35/Cleo 35, Yaz/Yasmine and Tri-cyclen) are indicated for the treatment of acne. These agents all contain estrogen, and progestins with either minimal androgenicity or with anti-androgenic potential.18
- OCs18,19 may play a role:
- Mild acne – adjunct to topical therapy for female patients desiring contraception.
- Moderate acne – form of systemic therapy.
- Severe acne – primary form of therapy or form of contraception in women treated with systemic isotretinoin.
- Clinical trials have consistently supported the efficacy of OCs for acne.
- Cochrane review of 31 trials of combined oral contraceptives (COCs) for acne with a total of 12,579 participants.
- 9 placebo-controlled trials with suitable data for analysis, COCs reduced acne severity and lesion counts in all trials vs. placebo.20
- Some differences20 in the comparative effectiveness of COCs containing varying progestin types and dosages were observed, but they were not pronounced and data for each comparison were limited:
- OCs that contained cyproterone acetate (examples – Diane 35/ Cleo 35) improved acne to a greater degree than levonorgestrel (example – Alesse/Alysena), although this apparent advantage was based on limited data.20
- Levonorgestrel (example Alesse/Alysena) showed a slight improvement over desogestrel (example Marvelon) in acne outcomes, but results were not consistent.20
- A drospirenone (example Yaz/Yasmine) COC appeared to be more effective than norgestimate (example Tri-cyclen) or nomegestrol acetate plus 17β-estradiol, but less effective than cyproterone acetate (examples Diane 35/Cleo 35).
- Oral contraceptive versus other treatments
- Review of 32 randomized controlled trials of OCs and antibiotics
- Antibiotics superior after 3 months of treatment,
- OCs and antibiotics had equivalent efficacy at 6 months.21
- At 6-month oral antibiotics and OCs reduced acne lesions by an average of 52.8% and 55% respectively.21
- If considering long-term therapy (over 6 months) it may be more reasonable use OC rather than antibiotics due to emergence of antibiotic resistance.
- Review of 32 randomized controlled trials of OCs and antibiotics
Side Effects of Oral Contraceptives
- Main adverse events to consider when selecting hormonal treatments: cardiovascular disease, stroke, breast cancer, pulmonary emboli, deep vein thrombosis, arterial thrombosis and abnormal vaginal bleeding.21
- Decreased risk of ovarian cancer after five years of use, but there has been concern about the possible association between oral contraceptive use and the risk of breast cancer.22 The net effect of COC use may well be positive (i.e., slight increase in life expectancy).23
- A safety review of drospirenone-containing oral contraceptives (example Yaz/Yasmin) in 2011 determined they may be associated with a 1.5-to-3 per 10 000 patients per year risk of blood clots versus 1 per 10 000 patients per year in Levonorgestrel containing pills (example Alesse).24
- Similar review of cyproterone acetate/ethinyl estradiol-containing OCs (Diane 35/Cleo 35) was completed in 2014. The review, concluded that the risk of blood clots from these COCs in people without additional risk factors (e.g., obesity, smoking, decreased mobility) is very low and that these agents have a favourable benefit/risk profile when used as prescribed.25
Case-based Treatment Approaches
- A case-based approach may facilitate a treatment selection process that reflects real-world scenarios and patient-specific challenges.
- A panel of 8 dermatologists was convened for a meeting on May 2, 2015 in Toronto, to discuss, refine and select patient profiles compatible with hormonal therapy for acne. Draft cases were developed by the group prior to the meeting.
- The panel developed 5 case in which hormonal therapy can be considered. The cases were selected to cover a spectrum of real-world acne presentations compatible with the use of hormonal therapy.
- Adherence to topical agents is related to duration of treatment, complexity of the treatment regimen, as well as therapy cost, patient self-image and QoL.8,35
- Demands associated with disease management can create a significant treatment burden for patients with chronic diseases. This burden combined with general life demands (e.g., job, family) comprises the overall patient workload.
- Treatment fatigue is common, with disengagement from recommended health behaviors when a person’s workload exceeds their capacity, a primary contributing factor to non-adherence.36
- When considering cost of therapy, it is important to remember both direct (e.g., prescription drug costs, physician visits, treatment in day clinics) and indirect costs (e.g., loss of time from work, loss of income, non-prescription drug costs). These costs are likely exacerbated by non-adherence to medication. In psoriasis particularly, QoL is adversely affected with people coping by avoiding social situations and covering their lesions.8
- With topical dermatologic products, studies suggest that patients prefer, and are more adherent to, certain topical vehicles based on convenience and cosmetic acceptability.37
- In appropriately selected patients, hormonal therapy provides an effective alternative to topical and oral antibiotics.29
- While relatively few OCs are approved for the use in acne, clinical trials suggest that many other OCs are also effective.30
- The benefits of hormonal therapy may extend beyond improvement of acne in some patient subgroups, such as those with PCOS or those with menstrual irregularities.
- More research into the subtypes of acne most responsive to hormonal treatment, as well as the comparative efficacy of available hormonal treatments, will help tailor treatment to different acne patient presentations.
- Mancini AJ. Adv Stud Med. 2008 Mar;8(4):100-5.
- Perkins AC, et al. J Womens Health (Larchmt). 2012 Feb;21(2):223-30.
- Halvorsen JA, et al. J Invest Dermatol. 2011 Feb;131(2):363-70.
- Collier CN, et al. J Am Acad Dermatol. 2008 Jan;58(1):56-9.
- Khunger N, Kumar C. Indian J Dermatol Venereol Leprol. 2012 May-Jun;78(3):335-41.
- Lai JJ, et al. Arch Dermatol Res. 2012 Sep;304(7):499-510.
- Rich P. Cutis. 2008 Jan;81(1 Suppl):13-8.
- Bettoli V, et al. Br J Dermatol. 2015 Jul;172 Suppl 1:37-46.
- Thiboutot D, Chen W. Dermatology. 2003;206(1):57-67.
- Kim GK, Del Rosso JQ. J Clin Aesthet Dermatol. 2012 Mar;5(3):37-50.
- George R, et al. Semin Cutan Med Surg. 2008 Sep;27(3):188-96.George R, et al.
- Brown K, et al. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD000194.
- Chung JP, et al. J Pediatr Adolesc Gynecol. 2014 Jun;27(3):166-71.
- Kraemer WJ, et al. Metabolism. 2006 Mar;55(3):282-91.
- Russell JJ. Am Fam Physician. 2000 Jan 15;61(2):357-66.
- Vaidya D, et al. Metabolism. 2008 Jun;57(6):782-90.
- Shaw JC, White LE. J Cutan Med Surg. 2002 Nov-Dec;6(6):541-5.
- Assai Y, et al. CMAJ. 2016 Feb 2;188(2):118-26. doi: 10.1503/cmaj.140665. Epub 2015 Nov 16.
- Lynde C, et al. J Cutan Med Surg. 2014 Jul-Aug;18(4):243-55.
- Arowojolu AO, et al. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD004425.
- Koo EB, et al. J Am Acad Dermatol. 2014 Sep;71(3):450-9.
- Frangos JE, et al. J Am Acad Dermatol. 2008 May;58(5):781-6.
- Brynhildsen J. Ther Adv Drug Saf. 2014 Oct;5(5):201-13.
- Government of Canada update. Yazmin and Yaz: updated information on increased
risk of blood clots. Accessed June 11, 2015 at http://www.healthycanadians.gc.ca/
- Health Canada. Summary Safety Review – DIANE 35 (cyproterone acetate and
ethinyl estradiol) – venous thromboembolism (blood clot). Accessed June 11, 2015 at
- Williams HC, et al. Lancet. 2012 Jan 28;379(9813):361-72.
- Titus S, Hodge J. Am Fam Physician. 2012 Oct 15;86(8):734-40.
- Nast A, et al. J Eur Acad Dermatol Venereol. 2012 Feb;26 Suppl 1:1-29.
- Ingram JR, et al. Clin Exp Dermatol. 2010 Jun;35(4):351-4.
- Salvaggio HL, Zaenglein AL. Int J Womens Health. 2010 Aug 9;2:69-76.