FormalPara Key Points

Acne is a common and distressing adverse effect of gender-affirming testosterone therapy faced by transgender and non-binary patients.

Dermatologists should address acne and its specific multidisciplinary considerations in the context of testosterone therapy in an inclusive environment.

Recent iPLEDGE changes may reduce barriers to isotretinoin treatment for severe acne for transgender patients.

1 Introduction

Acne vulgaris is a common skin condition affecting 9.4% of the global population [1], representing the second highest cause of disability from skin diseases globally [2]. Acne has multifactorial etiologies that include hormones, inflammation, stress, and medications [3, 4]. Hormonal acne is caused in part by sebum overproduction due to endogenous androgens such as dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androstenedione, testosterone, and dihydrotestosterone [3]. Estrogen, on the other hand, reduces sebum production [3]. Hormonal acne tends to cluster in areas that exhibit higher dihydrotestosterone selectivity, such as the lower face, chin, and jawline [3, 5]. Hormonal acne can be more pronounced in patients receiving exogenous androgens, affecting the chest, upper arms, and back [6]. Exogenous testosterone therapy is indicated for cisgender men for hypogonadism, cisgender women for hypoactive sexual desire disorder, and transgender persons as part of gender-affirming masculinizing hormone therapy [3, 7,8,9,10]. The aim of this article was to review the epidemiology and impact of acne, overall approach to acne care and terminologies, and management for mild to severe acne and specific considerations for isotretinoin.

1.1 Terminology and Definitions

Transgender persons are persons whose gender identity or expression diverges from their sex assigned at birth [11]. The adjective ‘trans’ is also commonly used to refer to transgender among transgender community members. Gender identity is defined as the internal sense of being a man, a woman, or some other gender. For example, a transgender man is a person whose sex assigned at birth was female and identifies as a man. Since gender identity expands beyond binary constructs of male and female, the term ‘transmasculine persons’ is used inclusively to refer to transgender persons who were assigned female at birth who do not identify as women, such as transgender men and gender non-binary persons. Many transgender persons seek gender-affirming therapies aimed to alleviate gender dysphoria and to improve mental and overall well-being [12]. These treatments may include gender-affirming hormone therapy, surgical procedures, social transitions in gender expression, and/or psychotherapy. This paper focuses on understanding and treating acne that develops in transmasculine patients who receive gender-affirming testosterone therapy (often known as ‘T’) to achieve masculinization as congruent with their gender identity.

2 Epidemiology and the Impact of Acne in Transgender Persons

Transmasculine persons who receive testosterone tend to develop hormonal acne in similar locations to other forms of androgen-dependent acne, affecting the lower third of the face, chest, upper arms, and back [5, 6]. Epidemiologic studies of acne in transmasculine persons have mostly relied on limited data from single-center retrospective cohort or self-reported survey studies. In a large, single-center, retrospective cohort of 988 transmasculine patients in Boston, the prevalence of acne increased from 6.3% before testosterone therapy to 31.1% after initiating testosterone for an average of 3.4 years [13]. Younger age at the time of testosterone initiation was associated with a higher incidence of acne diagnosis [13]. In a small cohort study of 20 transmasculine patients in New York, facial and truncal acne diagnoses increased over 4 months of treatment from 35 to 82% and from 15 to 88%, respectively [14]. Acne severity increased over the first 6 months of testosterone therapy, but started to decrease by 12 months [14]. As to the timing of onset for testosterone-induced acne, most patients developed acne within 2 years of testosterone treatment [15]. Serum testosterone has been inconsistently linked with acne development. In a single-center study of 55 transgender men, serum testosterone above the study median (> 630 ng/mL) was associated with higher odds of acne diagnosis after 2 years [15]. On the other hand, in a study of 138 transmasculine patients in Okayama, Japan, no acne of ‘troublesome degrees’ was noted after testosterone treatment for 6 months; however, acne severity was not well defined in this study [16].

Testosterone-induced acne can be severe and persistent in transmasculine persons. For example, 28% of transmasculine persons have reported a history of moderate to severe acne and 14% reported current moderate-to-severe acne in a survey of 346 transmasculine persons across Kaiser Permanente health systems [17]. Moreover, 66% of transmasculine persons diagnosed with moderate-to-severe acne associated their acne with testosterone therapy [17]. Regarding long-term acne, after an average of 10 years of testosterone treatment, 63% of patients still had mild acne while 6% had moderate acne in a small survey of 50 transgender men in Belgium [14]. Nonetheless, transmasculine persons were significantly less likely to see dermatologists than transfeminine persons [17], suggesting access barriers to dermatologist care for transmasculine patients with acne.

Chest binders are sometimes used by transmasculine patients to achieve a more masculine contour and to reduce gender dysphoria. However, excessive skin occlusion, physical compression, and overheating may increase the risks of acne, skin swelling, itching, skin infection, and scarring over the chest and back [18]. A large community-engaged online survey of 1800 transmasculine persons found that acne developed in 33.3 and 48.6% of patients after chest binding for 1 year and 10 years, respectively [18].

In contrast, for transfeminine patients, who were assigned male at birth, feminizing hormone therapy commonly includes estrogen and/or anti-androgens such as spironolactone [7]. Corollary to the use of estrogen-containing contraceptives and spironolactone for the treatment of moderate-to-severe acne in cisgender women, these treatments often improve acne for transfeminine persons [4, 7]. In a large survey of 350 transfeminine persons, transfeminine persons rarely reported current moderate-to-severe acne [17].

Acne negatively impacts mental health and quality of life in transgender persons receiving testosterone. Transgender and gender non-binary persons are more likely to have mental health comorbidities, such as anxiety or depression [19]. While gender-affirming hormone therapy has been shown to improve quality of life and reduce anxiety and depression symptoms [20], it should not be assumed that their adverse cutaneous effects, such as acne, are transient or innocuous. Subjective severity of acne has correlated directly with symptoms of anxiety and depression [21]. Visible acne lesions or acne scars can be stigmatizing, especially for patients who struggle with body image disorders. For transmasculine patients, acne and acne scars resulting from gender-affirming testosterone therapy might trigger self-image insecurity and body dysmorphia [22]. Notably, some transmasculine adolescents have viewed acne as a concrete sign for physical transition, which required more aggressive treatment, but also acknowledged that topical acne care may trigger dysphoria for some patients due to associated feminine connotations [23]. Recent data showed that transmasculine individuals diagnosed with moderate-to-severe acne were more likely to report clinically significant depression and anxiety symptoms compared with transmasculine persons without moderate-to-severe acne [24]. Notably, 71 and 39% of transmasculine persons with moderate-to-severe acne reported clinically significant depression and anxiety, respectively [24]. Dermatologists, primary care and hormone providers, and mental health providers should be aware of the epidemiology of acne and its associated negative mental health and psychosocial impact to provide timely and comprehensive acne care for transmasculine patients receiving testosterone therapy.

3 Clinical Guidance and Overall Approach to Care

Before acne assessment and treatment planning can even begin, it is critical to engender a welcoming clinical environment that prepares for a successful visit. Many transgender patients have had negative healthcare experiences—being misgendered, denied care, or frank harassment within healthcare settings [25]. Transgender men are more likely than transgender women to avoid health care due to anticipated discrimination [25]. Lack of providers knowledgeable in transgender health care, inadequate insurance coverage, socioeconomic barriers, and healthcare system barriers impose additional obstacles for transgender persons in accessing healthcare [26]. Having inclusive intake forms that do not assume cisgender identity or heteronormativity, having gender-neutral or all-gender restrooms available or allowing patients to use the restroom of their choice, posting welcoming signs or non-discrimination policies are all part of important efforts to create an inclusive environment that cultivates therapeutic relationships [11].

Familiarity with common and gender-inclusive terminology can facilitate discussion, but it is important for providers and staff members to use patient-centered language, including using the patient’s name and pronouns, as well as their terms for sexual orientation, gender identity, sexual behavior, or anatomy [11, 27, 28]. Some patients may use a name that differs from the name listed in medical records or legal documents [29]. Pronouns should not be assumed based on a person’s gender expression. Ideally, demographic information such as name, pronouns, sexual orientation, and gender identity should be routinely collected upon intake and documented in the medical records prior to the patients’ visit to facilitate care. Routine collection of sexual orientation and gender identity is highly acceptable to patients and has been advocated in outpatient dermatology care [30, 31]. If not already available on the intake form, asking about and documenting name and pronouns as well as taking an inclusive history will be important [32]. When the provider introduces themselves, they may consider offering the names and pronouns they use or employ non-verbal cues (such as pronoun pins) to signal a gender-inclusive care environment.

While taking history, using gender-inclusive language for all patients can help facilitate open and non-judgmental discussion about relevant history, particularly those related to sex and gender [33]. That way, providers would be more considerate and play an essential role in promoting sexual awareness and inclusivity. Examples of some questions that may come up in an encounter in a gender-neutral manner are listed in Table 1 [33]. When conducting a physical examination, providers should explicitly ask for patient permission and focus on body parts relevant to the chief complaint [34]. Truncal examinations may be unexpected by some patients, especially for those who wear chest binders [18].

Table 1 Example language for history taking for acne encounters with transmasculine patients
Full size table

Accordingly, both the provider and the patient should discuss the reasoning behind the skin examination, discuss mutual expectations for current and future encounters, and empower the patient to take the lead in showing the provider what is comfortable and relevant for their acne care [32].

4 Anatomic Inventory, Sexual History Taking, and Reproductive Potential Assessment

Many acne treatments have teratogenic potential and warrant a comprehensive sexual health and contraception discussion before prescription [35]. When conducting an organ inventory, it is important to check in with the patient to ensure that they are comfortable with the words used. Providers should refrain from using the words ‘breast’ and ‘vagina’ or ‘penis’ and instead use ‘chest’, and ‘genitalia’, respectively, to avoid triggering gender dysphoria in patients who are not comfortable with the aforementioned words [33]. As gender identity is distinct from sexual orientation or behavior, transgender patients’ sexual orientation and sexual behaviors should not be assumed [8]. Of note, transmasculine patients with retained functional uterus and ovaries have become pregnant, whether during and after testosterone therapy [36]. Transmasculine persons assigned female at birth who have a functional uterus and ovary should be considered as being of reproductive potential and would still need to consider contraceptive needs, even if they currently receive testosterone therapy and are currently amenorrheic [37]. On the other hand, transmasculine patients who have undergone hysterectomy and/or bilateral oophorectomy would not have reproductive potential [33]. An adapted flow chart to determine the productive potential and contraceptive needs for transgender patients initiating potentially teratogenic acne treatment (e.g., isotretinoin) is shown in Fig. 1.

Fig. 1
figure 1

Contraceptive needs assessment when prescribing teratogenic acne treatments for transgender patients. *Abstinence: any sexual contact with male (sperm-producing partner)

Full size image

5 Treatment Plan

There is no current evidence-based guideline on the best practices for treating hormonal acne in the context of testosterone therapy. Current treatment regimens for hormonal acne have been extrapolated from acne treatment guidelines designed for cisgender persons not receiving testosterone [7]. Acne treatment planning depends on multiple factors such as the predominant acne lesion type, physician- and patient-assessed severity, presence of post-inflammatory erythema, dyspigmentation or scarring, and psychological distress. Potential triggers such as the use of comedogenic skin or hair care products and medications should be assessed. The investigator global assessment is one of several commonly used physician assessments to grade acne severity and guide treatment selection. In brief, mild acne consists of some comedones and no more than a few papules/pustules; moderate acne has some papules/pustules and no more than one nodule; and severe acne encompasses having more than one nodule [38]. In the following sections, we discuss specific considerations of mild acne requiring only topical treatments, moderate acne requiring oral antibiotics or other treatments, and severe acne requiring isotretinoin.

5.1 Mild Acne Treatments

5.1.1 Topical Retinoids

Topical retinoids, such as adapalene, tretinoin, tazarotene, and trifarotene, are indicated for the treatment of both mild to moderate comedonal and inflammatory acne. Trifarotene is the only topical retinoid that is approved for the treatment of truncal acne [39], which may be more prominent in patients with testosterone-induced acne. While all topical retinoids have potential risks for teratogenicity, known teratogenic effects of tazarotene should be emphasized and the importance of contraception should be discussed in transmasculine patients (Table 2) [40]. Patient education on topical retinoid use and prevention and treatment of expected mild skin irritation is paramount to ensure treatment adherence. Patients should be advised to apply topical retinoid every other day for the first 2–4 weeks, apply gentle skin cleansing and avoid over-cleansing, and apply a non-comedogenic moisturizer. In case irritation persists, patients can use the short contact method in which topical retinoid is applied for 30–60 min then washed off for the first several weeks [41]. Most patients will be able to tolerate topical retinoids using these methods for long-term acne treatment.

Table 2 Specific considerations on acne prescriptions for transmasculine patients
Full size table

5.1.2 Topical Benzoyl Peroxide and Topical Antibiotics

Topical benzoyl peroxide and topical antibiotics, such as clindamycin and erythromycin, are often used for the treatment of mild to moderate acne. To reduce the risk of resistance, it is recommended to limit the use of topical antibiotics to 12 weeks and they should not be used as monotherapy [42]. Combining topical antibiotics with topical benzoyl peroxide is critical to reduce the risk of resistance and enhance effectiveness [38].

5.1.3 Topical Antiandrogen

Topical antiandrogen, such as clascoterone, is a topical androgen receptor inhibitor approved for acne in both males and females [43]. It inhibits sebum production and reduces inflammation in acne lesions [43]. Clascoterone reduces inflammatory and non-inflammatory facial acne with minimal adverse effects or safety concerns [44]. While clinical trials for clascoterone, like most acne clinical trials [45], did not specifically include any transgender participants or document hormone therapy use of its participants, the use of topical antiandrogens in transmasculine patients has been proposed as a targeted treatment for reducing the unwanted testosterone action in the skin [46]. Future research should examine the safety of topical androgens, including the potential systemic effects of clascoterone on serum testosterone level, as well as their acceptability by transmasculine patients and hormone providers.

5.2 Moderate to Severe Acne Treatments and Contraceptive Considerations

5.2.1 Oral Antibiotics

Oral antibiotics are indicated for moderate-to-severe acne or acne affecting a large body surface area [47, 48]. Oral doxycycline and minocycline are usually used as the first-line option, while oral erythromycin, azithromycin, amoxicillin, and trimethoprim-sulfamethoxazole can serve as possible alternatives [49]. For transmasculine patients with reproductive potential, possible teratogenicity due to oral antibiotics should be discussed (Table 2) [50]. A current acne practice guideline from the American Academy of Dermatology recommends limiting oral antibiotics as an induction therapy for no more than 3 months [51]. Therefore, maintenance topical therapy should be prescribed concurrently to enable oral antibiotic tapering after 3 months. Isotretinoin eligibility should also be re-considered if longer-term oral antibiotics are required.

5.2.2 Spironolactone

Spironolactone, a mineralocorticoid receptor antagonist, has a moderate affinity for androgen receptors and is effective in treating acne in cisgender women [52, 53]. Potential teratogenicity should be discussed in all patients of reproductive potential [54]. Many transfeminine patients receiving spironolactone often notice improvement in their acne and may help patients with their transition goals via its feminizing effects [55]. However, for transmasculine patients receiving testosterone, spironolactone may not be acceptable since it systemically blocks the masculinizing effects of testosterone and may cause adverse effects such as irregular bleeding, breast tenderness, and gynecomastia [56].

5.2.3 Hormonal Contraceptives

Hormonal contraceptives such as combined oral contraceptive (COC) pills contain estrogens and progestins and can both treat acne and provide contraception [57]. Many transfeminine patients receiving estradiol notice acne improvement [55]. For transmasculine persons, contraception is an important part of moderate-to-severe acne treatment if the patient is eligible for oral antibiotics and/or oral isotretinoin. It is important to note that testosterone use is not a contraindication per se for any form of hormonal or non-hormonal contraception. Current guidelines recommend highly effective birth control for transmasculine persons at risk of being pregnant. Nevertheless, some transmasculine patients may avoid COCs due to concerns of potential feminizing effects, risk of spontaneous bleeding if not consistently adherent, and potential adverse effects such as nausea, weight gain, and breast tenderness [58, 59]. Progestin-only contraceptives, such as norethindrone, may be used by hormone providers to cease uterine bleeding, but may exacerbate acne due to their androgenic property and, unlike other hormonal contraceptive options, would not be considered as a primary contraceptive method if isotretinoin is ultimately required [60]. Common primary contraceptive options that may prepare transmasculine persons for isotretinoin are listed in Table 3 [33]. Of note, long-acting reversible contraception—depot medroxyprogesterone, hormonal implants, or hormonal intrauterine device—as well as monophasic (continuous) oral contraceptives may induce amenorrhea, an often-desirable effect in transmasculine patients who have not achieved amenorrhea from testosterone therapy alone [33]. Discussion with a reproductive health specialist knowledgeable in transgender health care will be important to tailor contraceptive methods to the patients’ needs.

Table 3 Primary methods of contraception appropriate for iPLEDGE in transmasculine patients
Full size table

5.3 Isotretinoin and Multidisciplinary Considerations

Oral isotretinoin is indicated for the treatment of severe recalcitrant acne, treatment-refractory moderate acne, or acne that causes significant scarring or psychosocial distress [38]. Clinical trials of isotretinoin formulations have demonstrated an 87–90% decrease in inflammatory acne lesion counts, and 69–75% either became clear or had excellent response after 20 weeks [61]. Isotretinoin has been reported to be effective in treating severe testosterone-associated acne in two case series of transmasculine adults and adolescents [62]. In our experience, isotretinoin is feasible, acceptable, and highly effective in providing remission of moderate-to-severe acne in our transmasculine patients receiving testosterone (Fig. 2).

Fig. 2
figure 2

Clinical appearance of acne in a transmasculine patient a, b before and c, d after isotretinoin treatment

Full size image

Teratogenic effects of isotretinoin exposure during pregnancy can lead to fetal death and severe birth defects [63]. In the US, registration in the US FDA iPLEDGE program is required for isotretinoin prescription. For transgender patients eligible for isotretinoin treatment, navigating the iPLEDGE program was a major barrier to treatment access. Prior to December 2021, iPLEDGE used a gender binary categorization to register patients based on their sex assigned at birth, which led to ethical dilemmas when caring for transgender patients [37]. For some patients, signing the iPLEDGE consent was psychologically traumatic, leading them to forgo acne treatment [64]. iPLEDGE required transmasculine patients assigned female at birth who had not undergone a hysterectomy, a bilateral oophorectomy, and were not postmenopausal to be registered as ‘females of reproductive potential’. The FDA announced that effective 13 December 2021, iPLEDGE will start using a gender-neutral assignment for patients, categorizing them into ‘patients who can become pregnant (PWCBP)’ and ‘patients who cannot get pregnant (PWCNBP)’ [65]. Per new iPLEDGE categories, PWCBP are defined as cisgender females (born a female with a uterus and at least one ovary) and transgender males (born female with a uterus and at least one ovary, transitioned to a man), and PWCNBP are defined as cisgender male (born a male), cisgender females and transgender males that have undergone a hysterectomy, cisgender females and transgender males that have undergone bilateral oophorectomy, cisgender females and transgender males who are postmenopausal, and transgender females (born male and transitioned to female) [66]. While these definitions still use gender binary classification that may not apply to non-binary patients, it is a first step forward from the FDA to create a more inclusive environment for iPLEDGE.

Patients who can get pregnant must receive monthly contraceptive counseling, conduct monthly pregnancy monitoring, and commit to either complete abstinence with men (sperm-producing partners) or consistent use of two forms of contraception [63]. A thorough and gender-affirming discussion of the aims and requirements of iPLEDGE is critical to develop therapeutic alliances that enable access for transgender patients who may benefit from isotretinoin treatment [37].

Taking an inclusive sexual history is also essential in understanding contraceptive needs, as sexual behaviors cannot be assumed from sexual orientation or gender identity alone. iPLEDGE allows ‘complete abstinence from men’ as a primary contraceptive method. In other words, transmasculine patients of reproductive potential who never engage in penis–vagina sexual intercourse with sperm-producing partners would be employing abstinence as a primary contraceptive method [37, 63]. For transgender patients with reproductive potential who have penis–vagina receptive sexual intercourse with a sperm-producing partner, consistent use of two forms of contraception will still be required.

Isotretinoin may be associated with delayed wound healing that can persist for up to 6–12 months after discontinuation [38]. Therefore, dermatologists considering isotretinoin for a transgender patient should inquire about patient plans for gender-affirming surgeries [7]. Transmasculine patients often use the terms ‘top’ surgery to refer to chest reconstruction such as mastectomy, and ‘bottom’ surgery to refer to genital reconstruction such as metoidioplasty, phalloplasty, hysterectomy, and/or oophorectomy. Delay of isotretinoin treatment should be considered to avoid delays in gender-affirming surgical plans. Nevertheless, aggressive treatment of moderate-to-severe truncal acne, such as with oral antibiotics, may be required to reduce inflammation, reduce scarring, and optimize top surgery outcomes.

Monthly pregnancy tests at certified laboratories are required for all patients of reproductive potential. During the coronavirus disease 2019 (COVID-19) outbreak, home urine pregnancy tests became acceptable for iPLEDGE pregnancy monitoring [67], which may provide better privacy, comfort, and convenience to transmasculine patients. For transmasculine patients who are not comfortable with urine pregnancy tests, a qualitative serum b-HCG may be offered [63].

Monitoring of the liver function test and lipid panel should also be conducted, especially due to the theoretically amplified risk of isotretinoin hepatotoxicity in the context of testosterone therapy [8].

Isotretinoin has been controversially associated with depression, mood alterations, anxiety, and suicidality, but causality remains poorly established [68]. Conversely, some studies suggested that isotretinoin improved depressive symptoms and enhanced quality-of-life impact from moderate-to-severe acne [69]. Notably, transgender persons face substantially higher prevalence of depression, anxiety, and suicidality compared with cisgender persons [70, 71]. In a case series of four transgender adolescents receiving isotretinoin for severe acne, two stopped treatment due to depression, anxiety, and self-harm [72]. Providers should screen and monitor for signs of depression and mental health comorbidity for transgender patients receiving isotretinoin, such as using the Patient Health Questionnaire-9 (PHQ-9) depression screening tool to monitor depression symptoms [73]. Fortunately, many transgender patients receive care from mental health providers as part of their multidisciplinary gender-affirming care. Multidisciplinary management between the dermatologist, primary care or hormone provider, gender-affirming surgeon, reproductive health specialist, and mental health provider are essential for successful treatment of severe acne using isotretinoin in transmasculine patients receiving testosterone. Given the high level of barriers to isotretinoin care, there is an ongoing call for increases in the number of isotretinoin prescribers for transgender patients [74]. As such, dermatologists have an important and under-recognized role in providing isotretinoin treatment for the effective and safe treatment of severe acne in transgender patients.

6 Conclusion

Acne is common and imposes high social and quality-of-life impacts on transgender patients receiving testosterone. Transgender patients deserve equitable acne care as for their cisgender peers. Culturally competent and comprehensive acne encounters involve inclusive history taking, routine collection of sexual orientation and gender identity data, and patient-centered physical examination. As multiple acne medications may be teratogenic, providers should conduct a thorough assessment of reproductive potential and provide counseling accordingly. While discussing the different contraception options, providers should keep in mind that testosterone therapy is neither a reliable contraception nor a contraindication to all other forms of contraception. Acne treatment regimen selection should also consider the patients’ transition goals. When isotretinoin is indicated, providers should discuss iPLEDGE requirements with the patient while building a therapeutic alliance. The clinical encounter should discuss the effects of isotretinoin in a multidisciplinary approach and plans to monitor and alleviate potential adverse effects. Dermatologists should continue to learn with their patients on how to optimize skin, mental health, and quality-of-life outcomes of gender-affirming testosterone therapy. Dermatologists have an important role in advocating for comprehensive and culturally competent healthcare that the transgender population deserve.