Are hormone replacement therapy (HRT) sequential patches more effective than micronised progesterone and estrogen gel for managing breakthrough bleeding?

Breakthrough Bleeding Management: Sequential Patches vs. Micronised Progesterone and Oestrogen Gel

For breakthrough bleeding, switching to a continuous combined regimen of transdermal oestrogen gel with micronised progesterone 100 mg daily is superior to sequential patches, as this approach resolves breakthrough bleeding within 3 months while providing better cardiovascular and thrombotic safety. 1

Why Continuous Combined Therapy Outperforms Sequential Regimens

The fundamental issue with sequential HRT—whether patches or gel/progesterone combinations—is that breakthrough bleeding occurs when progestogen dosing or duration is inadequate for endometrial protection 1. The most effective solution is abandoning sequential therapy altogether in favour of continuous combined HRT using transdermal 17β-oestradiol (50-100 μg daily) plus micronised progesterone 100 mg daily. 1

Key Evidence Supporting This Approach:

• Continuous combined regimens produce significantly fewer bleeding days compared to sequential regimens, particularly in the first 3 months of therapy 2
• 80.6% of women achieve complete amenorrhoea with continuous combined transdermal oestrogen plus vaginal/oral progesterone, versus only predictable withdrawal bleeding with sequential therapy 3
• Breakthrough bleeding resolves within 3 months when proper continuous therapy is implemented 1

If Sequential Therapy Must Be Maintained

If a patient strongly prefers withdrawal bleeding and insists on sequential therapy, the critical factor is optimising progestogen dose and duration—not the delivery method (patch vs. gel). 1

Sequential Optimisation Strategy:

• Increase micronised progesterone to 200 mg daily for 12-14 days per month (never less than 12 days) 4, 1
• This applies equally whether using patches or gel/progesterone combinations 4
• Higher progestogen doses prevent breakthrough bleeding when oestrogen doses are increased 2

Evidence on Sequential Regimens:

• When oestradiol valerate was increased from 1 mg to 2 mg, breakthrough bleeding increased in women taking lower-dose progestogen (2.5 mg MPA) but not in those taking higher doses (5 mg MPA) 2
• Micronised progesterone in sequential regimens produces more irregular bleeding episodes compared to synthetic progestogens like dydrogesterone or nomegestrol acetate 5
• However, micronised progesterone remains strongly preferred due to superior cardiovascular and thrombotic safety profiles 4, 6

Why Micronised Progesterone Is Non-Negotiable

Regardless of delivery method, micronised progesterone should be the progestogen of choice due to:

• Minimal cardiovascular risk compared to synthetic progestogens 4, 6
• Lowest thrombotic risk profile among all progestogens 4
• Neutral or beneficial effects on blood pressure 4
• Likely lower breast cancer risk compared to synthetic progestogens, particularly medroxyprogesterone acetate 6

The only progestogen with stronger evidence for endometrial protection is medroxyprogesterone acetate, but its adverse cardiovascular effects make it a poor choice for long-term therapy 4.

Practical Algorithm for Breakthrough Bleeding

1. First-line: Switch to continuous combined HRT with transdermal oestradiol 50-100 μg daily plus micronised progesterone 100 mg daily 1

   • Reassess at 3 months—bleeding should resolve 1

2. If patient refuses continuous therapy: Optimise sequential regimen by increasing micronised progesterone to 200 mg daily for 12-14 days per month 4, 1

   • This works equally with patches or gel 4

3. If breakthrough bleeding persists after 3-6 months: Perform endometrial assessment to exclude pathology 1, 7

Common Pitfalls to Avoid

• Insufficient progestogen duration: Sequential regimens require at least 12 days of progestogen per month for adequate endometrial protection 4, 1
• Assuming patches are inherently better: The delivery method matters less than the progestogen dose and regimen type (sequential vs. continuous) 4
• Using synthetic progestogens for convenience: The cardiovascular and thrombotic risks outweigh any bleeding pattern advantages 4, 6
• Tolerating persistent breakthrough bleeding: This often indicates inadequate endometrial protection and requires investigation 7