To the Editor,
Hormones play a complex role in acne pathogenesis and treatment. Androgens typically increase the size and secretion of sebaceous glands, worsening acne, while estrogen counters androgen effect by direct local opposition, inhibition of androgen production, and gene regulation (Barros & Thiboutot, 2017; Beinenfeld et al, 2019). Despite multiple guidelines on acne management, there is a paucity of high-quality data on the treatment of acne among patients receiving hormone therapy (Beinenfeld et al, 2019; Del Rosso et al, 2015; Zaenglein et al, 2016). In the United States, this potentially impacts the treatment of acne among at least 9.1 million women using oral contraceptive pills in 2015–2017 and 2.3 million cisgender and transgender men receiving testosterone replacement therapy (Daniels & Abma, 2015–2017; Centers for Drug Evaluation and Research, 2018). We sought to examine the inclusion and exclusion criteria of acne clinical trials to identify potential barriers to the enrollment of patients receiving hormone therapy.
We queried clinicaltrials.gov for interventional studies from 1/1/2009 to 5/16/2019 using the search term “acne.” All age groups and sexes were included, including those with healthy volunteers. Inclusion and exclusion criteria of acne interventions with a focus on those related to hormone therapy and contraception were analyzed.
Of 121 studies identified, 86 were included (2 duplicates, 8 not related to acne, 25 targeted acne scar appearance) (Table 1). Thirty-three studies (38%) had exclusion criteria related to hormone therapy, including recent changes in therapies such as oral contraceptives, estrogens and anti-androgenic medications within specified time ranges (ranging from 4 weeks to 1 year). Patients with hormone disorders were excluded in 4 studies (4.7%). Other exclusion criteria included current use of oral contraceptives (3.5%), androgen blockers (4.7%), and hormone-replacement therapy (2.3%). Overall, patients receiving consistent oral contraceptives, androgen blocker therapy, or hormone-replacement therapy would be excluded from 9 trials (10.5%). Contraceptive requirements were specified in 36 studies (41.9%), which were listed based on gender, sexual behavior, and/or reproductive potential.
Table 1.
Hormone and contraception related inclusion and exclusion criteria in clinical trials for acne.
| N (%) | |
|---|---|
| Total number of clinical trials examined | 86 (100) |
| Intervention(s):a | |
| Topical retinoids | 18 (20.9) |
| Topical antibiotics | 22 (25.6) |
| Other topical treatmentsb | 46 (53.5) |
| Oral antibiotic | 4 (4.7) |
| Other oral medication | 7 (8.1) |
| Dietary / lifestyle | 5 (5.8) |
| Devices | 13 (15.1) |
| Procedures | 2 (2.3) |
| Sex: | |
| All sexes | 75 (87.2) |
| Females only | 5 (5.8) |
| Males only | 6 (7.0) |
| Age range (years):c | |
| 9–11 | 3 (3.5) |
| 12–17 | 38 (44.2) |
| 18–25 | 84 (97.7) |
| 26–40 | 84 (97.7) |
| 41–50 | 59 (68.6) |
| 51+ | 37 (43.0) |
| Exclusion criteria related to hormone therapy:d | 33 (38.4) |
| Recent change in hormone therapye | 28 (32.6) |
| Current oral contraception use | 3 (3.5) |
| Current androgen blocker use | 4 (4.7) |
| Menopause or hormone-replacement therapy | 2 (2.3) |
| Any hormone disorder | 4 (4.7) |
| Specified contraceptive requirements | 36 (41.9) |
| Exclusion of pregnant or nursing patients | 66 (76.7) |
These percentages do not add up to 100% since multiple modalities may be tested within the study.
Other topical treatments benzoyl peroxide or proprietary topical formulas.
These percentages do not add up to 100% since multiple age ranges may be included within the study. The age range was counted if any part of the inclusion criteria age requirements fell in the range.
These percentages do not add up to 100% since multiple exclusion criteria may be used within the study.
Timeframe specified within eligibility criteria ranged from 4 weeks to 1 year.
Nearly half of acne clinical trials had exclusion criteria that presented potential barriers to patients receiving hormone therapy, including women receiving hormone contraception and men receiving testosterone replacement therapy. In general, women over the age of 25 with acne tend to have acne that is refractory to conventional therapies and related to androgen production regardless of whether or not they have clinical signs of hyperandrogenism (Barros & Thiboutot, 2017; Beinenfeld et al, 2019, Del Rosso et al, 2015). Men may experience increased sebum production and acne from testosterone replacement for hypogonadism or for gender-affirming hormone therapy, and hormone related exclusion criteria further contributes to the dearth of evidence on optimizing testosterone-related acne treatment for cisgender and transgender men (Yeung et al, 2019). In some cases the practice of excluding patients on hormone therapy may be reasonable; clinical trials typically restrict patients newly placed on hormone therapy as it may worsen or improve acne, confounding research findings. However, the specific time ranges surrounding changes in hormone therapy are variable between studies and not evidence based.
Restricting enrollment of patients on hormone therapy or those with hormone-related acne could be moderated by developing clinical trials focused on the treatment of hormone-related acne. However, in our search only 3 studies targeted populations with hormone-related acne, and 1 other sought general effects of diet on hormonal markers. Our study was limited to clinical trials for acne registered on clinicaltrials.gov; we did not examine interventions for hyperandrogenism that did not pre-specify acne as an outcome.
Acne is the most common dermatologic condition in the United States, yet robust evidence guiding the optimal treatment of acne across diverse patient populations receiving hormone therapy remains scarce. Current guidelines on acne management may apply to women on stable hormone contraception without hormone-related acne. While one presumes that many acne trials included patients receiving stable hormone therapy, clearly reported data on the inclusion of those receiving hormone therapy are lacking. This may be mitigated by the disaggregation of data by hormone therapy status in future acne clinical trials to demonstrate generalizability to patients receiving stable hormone contraception. Furthermore, inclusion of diverse populations may not be practical in explanatory clinical trials. Nevertheless, it is important to further demonstrate acne treatment effectiveness across diverse patient populations receiving hormone therapy via pragmatic trials with broadened eligibility criteria or real-world prospective observational studies.
Acknowledgements:
Thank you to Dr. Suephy C. Chen for manuscript feedback. This study was in part supported by NIAMS L30 AR076081 (HY).
Footnotes
IRB Statement: Emory University IRB determined that this study does not constitute human subjects research and IRB oversight is not required.
Conflict of Interest: None.
Financial Disclosure: Dr. Yeung has received honorarium from Syneos Health.
Data Availability:
Datasets related to this article are publicly available at clinicaltrials.gov.
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Data Availability Statement
Datasets related to this article are publicly available at clinicaltrials.gov.