Which is better for a female patient of reproductive age with hormonal acne, Lo Loestrin (ethinyl estradiol and norethindrone acetate) or Tri-estarylla (norgestimate and ethinyl estradiol)?

Combined Oral Contraceptive Selection for Hormonal Acne

For a woman of reproductive age with hormonal acne who desires contraception, prescribe a drospirenone-containing COC (ethinyl estradiol 20-30 mcg/drospirenone 3 mg) as first-line therapy; if drospirenone is contraindicated or unavailable, Tri-Estarylla (norgestimate/ethinyl estradiol) is the preferred alternative over Lo Loestrin (norethindrone acetate). 1

Evidence-Based Ranking

First-Line: Drospirenone-Containing COCs

• Drospirenone demonstrates superior anti-androgenic effects through multiple mechanisms: decreasing ovarian androgen production, increasing sex hormone-binding globulin (reducing free testosterone by 40-50%), reducing 5α-reductase activity, and blocking androgen receptor activation 1
• Drospirenone-containing COCs show significantly greater reductions in inflammatory, non-inflammatory, and total acne lesions compared to placebo, with evidence suggesting slightly superior efficacy versus other progestins in head-to-head trials 1, 2
• The American Academy of Dermatology specifically recommends drospirenone-containing COCs as the first-line option for women with moderate acne who also desire contraception 1

Second-Line: Tri-Estarylla (Norgestimate/Ethinyl Estradiol)

• Tri-Estarylla (generic for Ortho Tri-Cyclen) is FDA-approved specifically for acne treatment and represents the best alternative when drospirenone is contraindicated 1
• Norgestimate-containing COCs demonstrate significant efficacy with mean decreases in inflammatory lesion counts of 62.0% versus 38.6% for placebo (p=0.0001), and total lesion count reductions of 53.1% versus 26.8% for placebo (p=0.0001) 3
• Combined trial data shows reduced total lesion counts (MD -9.32; 95% CI -14.19 to -4.45), reduced inflammatory lesions and comedones, with 93.7% of patients rated as improved versus 65.4% on placebo 2, 3
• Norgestimate has the lowest venous thromboembolism risk among COCs as established by the European Medicine Agency, with excellent cycle control 4

Third-Line: Lo Loestrin (Norethindrone Acetate/Ethinyl Estradiol)

• Lo Loestrin is FDA-approved for acne treatment but shows less robust comparative data 1
• Norethindrone acetate COCs demonstrate better results for clinician global assessment of no acne to mild acne (OR 1.86; 95% CI 1.32 to 2.62) 2
• While effective, norethindrone acetate lacks the specific anti-androgenic advantages of drospirenone or the extensive acne-specific trial data of norgestimate 5, 2

Critical Timeline Expectations

• Counsel patients explicitly that visible improvement requires 3-6 months of continuous therapy 1
• Statistically significant improvement becomes evident by the end of cycle 3 (approximately 3 months) compared to baseline 1
• Assess maximal benefit at 6 months (end of cycle 6) 1
• Common pitfall: Patients may discontinue prematurely during the first 2-3 months when side effects (breakthrough bleeding, nausea, breast tenderness) are present but acne improvement is not yet apparent 1

Combination Therapy Strategy

• Initiate topical retinoids and/or benzoyl peroxide concurrently with the COC to provide more immediate benefit during the initial 3-month period when hormonal effects are developing 1
• Continue topical treatments for the first 2-3 months rather than waiting to see COC effects alone 1
• If inadequate response after 6 months on any COC, add spironolactone 50-100 mg daily rather than switching COCs immediately 1

Safety Considerations and Contraindications

Absolute Contraindications for All COCs

• Current or history of deep vein thrombosis or pulmonary embolism 1
• Current breast cancer or estrogen/progestin-sensitive cancers 1
• Severe liver disease, hepatic dysfunction, or liver tumors 1
• Uncontrolled hypertension 1
• Smoking if ≥35 years of age 1
• Migraine with aura at any age, or migraine without aura if ≥35 years 1
• Ischemic heart disease 1

VTE Risk in Perspective

• Baseline VTE risk in non-pregnant, non-COC users: 1-5 per 10,000 woman-years 1
• Standard COCs (norgestimate, norethindrone): 3-9 per 10,000 woman-years 1
• Drospirenone-containing COCs: approximately 10 per 10,000 woman-years 1
• For context, pregnancy VTE risk: 5-20 per 10,000 woman-years; postpartum (within 12 weeks): 40-65 per 10,000 woman-years 1

Required Pre-Treatment Evaluation

• Obtain comprehensive medical history focusing on VTE risk factors, cardiovascular disease, migraine characteristics, liver disease, and smoking status 1
• Measure blood pressure (mandatory) 1
• Perform pregnancy test 1
• For drospirenone specifically: obtain baseline potassium level and recheck at 4-6 weeks, though routine monitoring is not required in young, healthy women without kidney, liver, or adrenal disease 1

Clinical Decision Algorithm

1. Screen for absolute contraindications to COCs (listed above) 1
2. If no contraindications exist: Prescribe drospirenone 3 mg/ethinyl estradiol (20 or 30 mcg formulation) 1
3. If drospirenone contraindicated (renal dysfunction, adrenal insufficiency, or patient preference due to slightly higher VTE risk): Prescribe Tri-Estarylla (norgestimate/ethinyl estradiol triphasic) 1, 4
4. If both unavailable or contraindicated: Consider Lo Loestrin (norethindrone acetate/ethinyl estradiol) as third-line 1
5. Add topical therapy (retinoids, benzoyl peroxide, or fixed-dose combinations) at initiation 1
6. Reassess at 3 months for initial response and side effects 1
7. If inadequate response at 6 months: Add spironolactone 50-100 mg daily or switch to drospirenone-containing COC if not already prescribed 1

Important Caveats

• All COCs produce a net anti-androgenic effect when combined with estrogen, regardless of progestin type, because the estrogen component increases sex hormone-binding globulin 1, 6
• Progestin-only contraceptives should be avoided as they consistently worsen acne 1
• COCs should only be used for acne in women who also desire contraception, as this is the FDA-approved indication 5, 1
• The 2012 Cochrane meta-analysis of 31 trials with 12,579 women found that while all nine placebo-controlled COCs worked well to reduce acne, no consistent differences in acne reduction were appreciated based on formulation or dosage when comparing 17 different COCs head-to-head 5, 2