Hormonal Contraceptives and Dermatology

Natalie M. Williams; Michael Randolph; Ali Rajabi-Estarabadi; Jonette Keri; Antonella Tosti

Am J Clin Dermatol. 2021;22(1):69-80.

Hidradenitis Suppurativa

Hidradenitis suppurativa (HS) is a chronic skin condition affecting apocrine gland-bearing sites, such as the axillary, inframammary, and anogenital regions. The disease is characterized by recurrent, inflamed nodules with sterile abscesses, followed by draining sinus tracts with subsequent scarring.^[109] While the role of hormones is not clearly defined for HS, the fact that there is a female predominance, propensity for premenstrual flares, and improvement during pregnancy suggests that hormones are part of the pathogenesis.^[110] In addition, antiandrogen medications such as spironolactone, finasteride, and COCs may improve the disease in women.^[111,112]

There is limited, anecdotal evidence of HS occurring in patients taking COCs (Table 5). Stellon and Wakeling identified seven females who developed HS after starting COCs, with the time of onset after initiating the pill ranging from 1 to 24 months.^[113] The most common COC used was the combination of EE 30 μg and levonorgestrel 150 μg. Two patients achieved complete remission after discontinuation of the COC, while three patients benefited from a change to a pill with a higher estrogen–progesterone ratio. One patient who stayed on a progesterone-only pill continued to have HS flares. The last patient who experienced HS flares on the EE–levonorgestrel combination was switched to a pill containing desogestrel, a compound thought to have low androgenicity, but the patient experienced another HS flare within 1 month. As there is no stronger evidence available, a relationship between HS development and COCs seems unlikely.

Furthermore, several case–control studies have not found an association between HS and COC use. When comparing 58 cases of females with HS and 268 female controls, Jemec et al. found that both groups used COCs at similar rates (74% and 73% for estrogen-based, and 19% and 19% for progestogen-based pills, respectively).^[114] Furthermore, a separate case–control study found that the use of hormonal contraceptives was significantly less common in women with HS than controls.^[115] This not only countered the idea that COCs may cause HS but also suggested the potential use of hormonal contraceptives in its treatment.

One of the earliest reports on the utility of COCs in HS was a randomized, double-blind, crossover trial of 24 females with HS that compared the reverse sequential combination of EE and CPA with EE with norgestrel.^[116] While two patients dropped out due to disease exacerbation, the remaining patients demonstrated clinical improvement, with no difference in efficacy between the two arms. Of note, seven patients in the study achieved complete clearance of their disease. Similarly, a case series that used a reverse sequential regimen of CPA (100 mg/day for 10 days) and EE (50 mg/day for 21 days) in four patients with longstanding HS demonstrated clinical improvement after only one to two cycles of treatment;^[117] however, when CPA was decreased to 50 mg/day, three of the patients exhibited worsening of their symptoms. Other researchers have suggested that hormonal manipulation, including COCs, may be equivalent or superior to antibiotic therapy in HS patients. Kraft and Searles found that antiandrogenic hormonal manipulation, most commonly with the combination of CPA and EE, resulted in a higher response rate (55%) compared with oral antibiotic therapy (26%, p < 0.04) in female HS patients.^[118]

Overall, there is limited evidence to support or refute the effects COCs in HS, or which form would be most ideal for these patients. It is believed that COCs containing drospirenone might be preferred due to the effects being similar to spironolactone.^[119] While a Cochrane review in 2013 suggested a relationship between drospirenone-containing COCs and venous thromboembolism, various large trials since have not identified an association.^[120–123] In addition, it is important to note that the effect of COCs is reduced if the patient is also taking rifampin due to its induction of the P450 enzyme.^[124] Recently, the North American clinical management guidelines for HS were published, which recommended antiandrogen contraceptives at a grade C recommendation strength and a recommendation level of II.^[125] Ultimately, higher-quality patient-oriented data on the use of hormonal contraception in HS are needed.

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Table 1. Effect of hormonal contraceptives on acne
Contraceptive	Conclusions
Combined oral contraceptive	Improves acne (strong evidence)
	COCs have an overall net antiandrogenic effect due to the combined effects of ethinylestradiol and progestin, with few therapeutic differences between the various COC options [7, 9, 11–13, 130–132]
	The US FDA has approved four COCs for the treatment of acne:
	Ethinylestradiol/drospirenone
	Ethinylestradiol/norgestimate
	Ethinylestradiol/drospirenone/levomefolate
	Ethinylestradiol/norethindrone acetate/ferrous fumarate
Vaginal ring	Improves acne (moderate evidence)
Vaginal ring	On average, vaginal ring users reported an improvement in acne, with even fewer reports of worsening acne than COCs [13, 18–20]
Skin patch	Improves acne (limited evidence)
Skin patch	Reduction in acne reported in 33% of users following patch initiation, and commonly reported in several case series [15–17]
Hormonal IUD	Causes acne (moderate evidence)
Hormonal IUD	No RCTs have directly evaluated IUDs on acne vulgaris. Several studies have noted the worsening of acne lesions and acne is one the most common causes of IUD discontinuation [13, 22–28]
Subdermal implant	Causes acne (moderate evidence)
Subdermal implant	One of the most common adverse events and reasons for discontinuation, with 3–27% of patients reporting acne in clinical trials [13, 29–33]
Depot injection	Causes acne (moderate evidence)
Depot injection	Acne has frequently been reported as a minor adverse effect among users [13, 34–40]

COCs combined oral contraceptives, RCTs randomized controlled trials, IUD intrauterine device

Table 2. Effect of hormonal contraceptives on hirsutism
Contraceptive	Conclusions
Combined oral contraceptive	Improves hirsutism (strong evidence)
Combined oral contraceptive	First-line for premenopausal women not seeking pregnancy [55]. Superior to other monotherapeutic options for hirsutism [44–51], but more effective when used in combination with antiandrogens [54]
Vaginal ring	Improves hirsutism (moderate evidence)
Vaginal ring	Preferred to oral EE/drospirenone for overweight PCOS patients with metabolic risk or moderate insulin resistance that does not require metformin [59]
Hormonal IUD	Causes hirsutism (limited evidence)
Hormonal IUD	Up to 41% of participants may experience upon IUD insertion [22]
Subdermal implant	Causes hirsutism (limited evidence)
Subdermal implant	Few reports of hirsutism as an adverse effect of levonorgestrel implants [27, 41]

EE ethinylestradiol, PCOS polycystic ovary syndrome, IUD intrauterine device

Table 3. Effect of hormonal contraceptives on hair loss
Contraceptive	Conclusions
Combined oral contraceptive	Improves AGA (moderate evidence)
	Androgenic effects of the progesterone component may trigger AGA, but the estrogen component promotes hair growth. Women with AGA taking COCs have significantly decreased hair loss and thinning [85, 86]; however, they are not as successful as with acne and hirsutism [90]
	Causes TE (limited evidence)
	TE has been associated with COC interruption in several case series [67, 76]
Hormonal IUD	Causes AGA (limited evidence)
Hormonal IUD	Estimated cumulative incidence of AGA associated with an LNG-IUD is 0.33% over 1 year [75]
Subdermal implant	Causes AGA (moderate evidence)
Subdermal implant	Reported in 1.1–11.5% of patients with progestin implants and is the third most common reason for requesting removal [70–73]

AGA androgenetic alopecia, COCs combined oral contraceptives, TE telogen effluvium, LNG-IUD levonorgestrel intrauterine device

Table 4. Effect of hormonal contraceptives on rosacea
Contraceptive	Conclusions
Combined oral contraceptive	Unclear effect on rosacea (very limited evidence)
Combined oral contraceptive	COCs, particularly earlier generations with high estrogen, are reported as exacerbating factors for rosacea, potentially secondary to estrogen potentiation of corticosteroids on skin [99–101]; however, COCs have been effective in managing the papulopustular lesions, particularly in patients with endocrine disorders [105, 106]
Hormonal IUD	Causes rosacea (very limited evidence)
Hormonal IUD	Case reports of rosacea after IUD implantation, with improvement after removal [107]
Vaginal ring	Causes rosacea (limited evidence)
Vaginal ring	Reported as an adverse effect in trials studying combined contraceptive vaginal rings [108]

COCs combined oral contraceptives, IUD intrauterine device

Table 5. Effect of hormonal contraceptives on hidradenitis suppurativa
Contraceptive	Conclusions
Combined oral contraceptive	Improves HS (moderate evidence)
Combined oral contraceptive	While there are a few reports of HS occurring in association with COCs, the majority of evidence suggests improvement in disease [113]. Female HS patients demonstrate clinical improvement to complete clearance on COCs, which may be equivalent or superior to antibiotic therapy [116–118]

HS hidradenitis suppurativa, COCs combined oral contraceptive

Table 6. Effect of hormonal contraceptives on lichen sclerosus
Contraceptive	Conclusions
Combined oral contraceptive	Causes LS (limited evidence)
Combined oral contraceptive	While a negative association between vulvar LS and COCs has been reported, the most compelling evidence demonstrated a 2.53-fold risk of early-onset LS among antiandrogenic COC users [126, 129]