Hormonal Treatment of Acne in Canada: Clinical Update and Case-Based Treatment Approaches

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.

Introduction

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

• Adrenarche
  • ~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
• Androgens
  • 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

Hormonal Therapy

• 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
• OCs^18,19 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.

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

Rationale

• A case-based approach may facilitate a treatment selection process that reflects real-world scenarios and patient-specific challenges.

Approach

• 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.

Case 1: 34-year-old female with facial acne that varies with menstrual cycle
	Her acne is present since adolescence, is mainly inflammatory and often located along the jawline, chin and periorally. She is otherwise healthy and has normal menses. She reports that her acne significantly interferes with her quality of life. Previous topical acne therapy caused dryness, peeling, and irritation. She failed a trial of oral antibiotics. To the best of her recollection, past use of OCs (for contraception) did not significantly improve her acne.
Discussion Negative experience with topical therapy consider systemic therapy. Her acne appears to have a hormonal component. Has used OCs in the past for contraception rather than acne, the lack of observed improvement in her acne argues against OC monotherapy as a first choice. Thus, spironolactone10-12 seems a reasonable option to consider, either alone or in combination with OCs.13
Case 2: 17-year-old female presents with sensitive skin, moderate-to-severe acne and potential sexual activity
	She first developed acne at the beginning of puberty, and it has since progressively worsened. She has tried many topical treatments, which yielded generally poor results and caused dryness and irritation on her face. A light smoker for the past 2 years, she reports that she is not yet sexually active but has a steady boyfriend. She has no signs of elevated androgen levels, but has bothersome skin oiliness. She and her parents are opposed to using antibiotics, and her mother is concerned that using OCs could promote sexual activity.
	Discussion Adolescent acne tending toward the severe end of the spectrum – had not responded to topical treatment and scarring is a concern thus systemic therapy seems appropriate in this case.19 Options include OCs18,20, spironolactone10,18, isotretinoin26 and antibiotics.19 OCs could be considered as a first-line option18,20, with the addition of isotretinoin if response is suboptimal.13
Case 3: 30-year-old sexually active female with severe truncal-predominant acne located mainly on the upper back
	She has no signs of hyperandrogenism. Certain fabrics irritate her back, and application of topical treatments on this area has proven challenging. For this reason, she finds topical products inconvenient. She has tried oral antibiotics in the past, and they only worked while she was taking the medication. She had a similar experience with isotretinoin, which she does not want to try again. She quit smoking 2 years ago after smoking for 11 years. She lives alone and is occasionally sexually active.
Discussion All systemic therapies (OCs, spironolactone, isotretinoin, antibiotics) can be considered.19,26,27 Because of the patient’s time-limited response to prior oral antibiotic therapy, this option should be kept in reserve in case the other options prove unsatisfactory.19 OCs are effective in truncal acne and provide added benefit of birth control.18 PCOS should be addressed by appropriate evaluations. BPO wash can be considered concomitantly.19
Case 4: 34-year-old female with multisite acne of variable severity and features consistent with PCOS
	She was diagnosed with type 2 diabetes a year ago and is currently taking metformin. She has Class I obesity (BMI 30.9). Upon questioning, she states that her periods have always been irregular and also has excessive facial hair that requires her to shave every few days. She also has a lot of hair on her abdomen and arms. She mentions that her mother is similarly hirsute. Her voice is lower than average, but within the normal female range. Upon testing, the patient’s follicle-stimulating-hormone (FSH) levels are normal, but her luteinizing hormone (LH) levels are elevated. Her fasting insulin levels were also high. Other lab results are normal, and pelvic ultrasound results are equivocal, with “possible” signs of polycystic ovaries. Overall, these results are consistent with PCOS.
Discussion Would benefit from OCs26, 27 or spironolactone.10 Target the hormonal abnormalities underlying acne and provide other benefits such as diminution of hirsutism and regularization of menses.16
Case 5: 32-year-old female with skin of colour and moderate-to-severe acne including some painful lesions, scarring and PIH
	She has some scarring and post-inflammatory hyperpigmentation (PIH). Previous acne therapy has resulted in dryness, peeling and irritation. She in a long-term relationship, has two children, and is not currently trying to conceive.
Discussion Would benefit from OCs26, 27 or spironolactone.10 Target the hormonal abnormalities underlying acne and provide other benefits such as diminution of hirsutism and regularization of menses.16

Adherence

• 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

Conclusion

• 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.