Jennifer Lipson, MD, FRCPC
Division of Dermatology, University of Ottawa, Ottawa, ON, Canada

Conflict of interest: Dr. Lipson has been a speaker, or advisory board member for, or received a grant, or an honorarium from AbbVie, Amgen, Bausch Health, Beiersdorf, Boehringer Ingelheim, Bristol Myers Squibb, L’Oréal, Galderma, Janssen, Leo, Lilly, Novartis, Pfizer, Sanofi, Sun Pharma and UCB.
Funding sources: None.

Abstract: Acne is a common inflammatory condition of the skin worldwide. The skin is an endocrine organ and hormones are a key pathogenic factor in all types of acne with a particularly important role in adult female acne pathogenesis and management. In females, we have the unique opportunity to manipulate hormones systemically to successfully manage acne and, more recently with the approval of clascoterone 1% cream, we can target the hormones topically in both genders. The intent of this paper is to provide physicians with an up-to-date clinically relevant review of the role of hormones in acne, the impact of currently available contraceptives and therapies available to target hormones in acne.

Keywords: adult female acne, etiopathogenesis, hormones, oral contraceptives, prevalence, systemic therapy, topical therapy

Introduction

Acne is an incredibly common condition affecting almost 10% of the global population and recognized as the 8th most common condition worldwide.1 There is a misconception among the public that acne is only a disease of adolescence. Acne is prevalent through adulthood, especially in women. The results from the ALL PROJECT research initiative presented at the European Academy of Dermatology and Venereology (EADV) Congress in October 2023 reported the prevalence of acne in 50,552 patients aged 16 years and older (69.5% older than 34 years of age) from 20 countries across 5 continents. This study found the frequency of acne in this broad population to be 18.99%, 16.3% in men and 21.95% in woman.2 The prevalence of adult female acne (AFA) has been shown to peak in the 20s (50.9%) and decreases with each decade to 15.3% in patients aged 50 years and older.3 In keeping with adolescent acne, acne in adult woman has sequelae of scarring and dyspigmentation, as well as mental health impacts. A 2014 survey of American women with AFA elucidated that the majority feel less confident, more self-conscious, frustrated and embarrassed when they see or think about their acne. The isolating nature of this condition was also identified in this survey; the majority of women reported feeling like ‘no one understands what it’s like to have adult female acne’.4

Acne Pathophysiology

Management of acne focuses on targeting the four main pathogenic factors: sebum, Cutibacterium acnes (C. acnes), inflammation and abnormal follicular keratinization. The relationship between these factors is complex. Acne begins with adrenarche, when sex hormone production begins. Sebocytes have androgen receptors and are exquisitely androgen responsive. Sebocytes begin to produce increased sebum upon androgen stimulation and sebum production rates have been shown to correlate with acne severity.5,6 The sebum in patients with acne has altered composition contributing to development of acne.6,7 Androgens also directly stimulate sebocytes to produce inflammatory cytokines in the skin, another important pathophysiologic factor in acne.6,8 Studies have shown that in the sebocytes of patients with acne there are increased number and/or activity of enzymes converting weak androgens to potent androgens, such as 5-alpha reductase, which converts testosterone to dihydrotestosterone (DHT). Patients with acne may also have increased numbers of androgen receptors and/or polymorphisms of androgen receptors making them more sensitive.6 Other hormones can stimulate the sebaceous gland, but to a lesser extent, such as insulin-like growth factor-1 (IGF-1), growth hormone and pro-opiomelanocortin. Within the pilosebaceous unit, the sebum rich environment creates a microenvironment ideal for C. acnes proliferation and activity.5 Loss of diversity of C. acnes with increased proportion of acnegenic phylotypes, such as phylotype IA1, stimulate inflammation and the break down of triglycerides in sebum to free fatty acids. Pro-inflammatory free fatty acids from the sebum and C. acnes biofilm stimulate keratinocytes and result in hyperkeratinization and comedogenesis.5,6

The Skin is an Endocrine Organ

AFA is notoriously challenging to treat with standard acne therapies that do not address the hormones. It frequently does not respond to monotherapy with topicals and is recurrent after courses of antibiotics and isotretinoin.9 Women experience acne lesions on the lower face and jawline often flaring prior to menses. As lesions resolve, post-acne dyspigmentation, erythema and even scarring are common. AFA responds well to systemic anti-androgen treatment. This is possibly a contributing factor to the common misconception that women with AFA have abnormal hormone levels and the condition being referred to as ‘hormonal acne’. Hormones play an integral role in all acne. While it is known that women with polycystic ovarian syndrome (PCOS) and several other hormonal conditions have greater incidence of acne, the majority of women with AFA have normal systemic hormone levels.6 The skin is an endocrine organ and, as reviewed in the pathophysiology, the increased androgen and androgen effect implicated in acne is at the level of the skin. Women with adult female acne do not require assessment of systemic hormone levels unless there are other signs or symptoms indicating hormonal abnormalities.10

Managing the Hormones

Targeting the hormones in the treatment of patients with AFA is highly effective. In female patients we have the unique opportunity to manipulate the hormones systemically to manage acne. Traditionally this has been achieved with combined oral contraceptives and/or spironolactone. The combined oral contraceptives (COCs), which contain both estrogen and a progestin, have varying degrees of anti-androgenic effects. Estrogen is anti-androgenic through the increase of sex hormone globulin, which results in lower levels of circulating free testosterone.9 The progestins vary in their androgenic and anti-androgenic effect, resulting in distinct differences in efficacy of the various COCs.11,12 First generation progestins, such as norethindrone, have a marked intrinsic androgenic effect. COCs containing first generation progestin can cause or exacerbate acne and should be avoided in acne prone women or stopped in women who develop acne (Table 1).2,11 Second generation progestins have variable androgenic effect. COCs containing second generation progestins such as levonorgestrel and norgestrel are commonly prescribed and may improve acne in some patients and exacerbate in others. While there are levonorgestrel-containing COCs approved for both contraception and treatment of acne, they are not as effective at treating acne as COCs containing more anti-androgenic progestins.13 Third generation progestins, such as desogestrel, norgestimate and etonogestrel, are the least androgenic. COCs containing third generation progestin are effective for treating acne.11,14 The fourth generation synthetic progesterone analogues, drospirenone and cyproterone acetate, are anti-androgenic and highly effective in the treatment of acne.14 In Canada, there are only five COCs approved for the treatment of acne (Table 2).15-19 Based on pathophysiology of the hormones, all COCs containing third or fourth generation synthetic progesterone should work effectively to treat acne. COCs can take at least 4-6 months to show effect when treating acne.

Adult Female Acne: Managing the Hormones - image

Adult Female Acne: Managing the Hormones - image

Forms of contraception other than COCs also impact acne (Table 3). Depo-Provera® and the older progesterone-only pills Micronor® and Movisse™ contain first generation progestins, medroxyprogesterone acetate and norethindrone, respectively. These can cause or exacerbate acne. The new and highly effective progesterone-only birth control pill Slynd® is a fourth generation synthetic progesterone, drospirenone, at a dose equivalent to 25 mg of spironolactone.20 While there are no studies investigating the effect of Slynd® on acne, based on the pathophysiology of drospirenone, this contraceptive option has promise as a treatment option for acne-prone women, in particular for those who require contraception without estrogen or are breastfeeding. Hormonal intrauterine devices (IUDs) contain the second generation progestin levonorgestrel without estrogen, and may cause or exacerbate acne.21,22 The contraceptive vaginal ring and patch containing third generation progestins may reduce acne. The newer contraceptive device, Nexplanon®, contains a third generation progestin etonogestrel without estrogen. The effect of Nexplanon® implant on acne has yet to be determined. There is a promising retrospective claims-based analysis that looked at new incident acne encounters among women starting COC compared with various other forms of contraception. This showed increased risk of clinical encounters for acne with both copper and levonorgestrel IUDs and decreased risk of incident clinical encounters for acne with the etonogestrel implant.23 More data is required on this topic. Interestingly, there are hormonal treatments prescribed for menopausal symptoms which contain first generation progestin and may cause acne; this should be considered in post-menopausal women presenting with acne (Table 1).

Adult Female Acne: Managing the Hormones - image

Spironolactone, an antagonist of the androgen receptor and aldosterone, is effectively used off-label for treatment of acne in females at doses typically between 50-200 mg daily.24 Like COCs, spironolactone is very slow to show effect. Spironolactone is contraindicated in pregnancy but safe during lactation.

Another off-label therapy that has been used to target hormones in the treatment of acne is metformin. Metformin enhances peripheral tissue sensitivity to insulin, thereby reducing IGF-1. IGF-1 stimulates androgen production from the gonads and adrenals and decreases sex hormone binding globulin leading to increased free testosterone.25,26 Metformin has long been considered a treatment option for patients with PCOS associated acne, with mixed efficacy results in the literature.25 There are now studies showing promising results for treatment of acne with metformin in males and females as monotherapy (500 mg BID) or adjunct therapy (875 mg OD).25,26

Most recently, clascoterone 1% cream (Winlevi®) has entered the acne treatment landscape; this first-in-class topical anti-androgen is approved for the treatment of mild to severe acne in males and females aged 12 years and older.27 Clascoterone is believed to work by competitive inhibition of the androgen receptor resulting in decreased sebum and inflammatory cytokine production locally in treated skin.8 This will be a great addition to the repertoire of treatment options for all acne, including AFA. Clascoterone 1% cream is currently the only treatment available to target the hormonal factor in males with acne.

Conclusion

AFA is a common and devastating condition. It is frequently recurrent after standard acne treatments (topicals, antibiotics and isotretinoin) and responds very well to anti-androgen treatment. The majority of females with AFA have normal circulating hormone levels; the increased androgen level and effect is locally at the level of the skin. Understanding the androgenic effect of the various progestins in currently available hormonal treatments is helpful in managing AFA. Third and fourth generation COCs and spironolactone play important roles in treating this common condition. The drospirenone containing progesterone only birth control pill is a new option for females with acne who cannot take COC. Often simply an adjustment of contraceptive can result in acne resolution. Clascoterone cream is a topical anti-androgen with local effect in the skin and has a promising future in treatment of acne, including AFA.

References



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