Do you need progesterone (progestin) with estrogen gel (estrogen replacement therapy)?

Estrogen Gel and Progestogen Requirement

Women with an intact uterus must use progestogen with estrogen gel to prevent endometrial hyperplasia and cancer. 1

Why Progestogen is Necessary

Unopposed estrogen (estrogen without progestogen) significantly increases the risk of endometrial hyperplasia and cancer in women who have a uterus. This risk increases with duration of use:

• The FDA label for estrogen products clearly states: "There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer." 2

• The risk of endometrial hyperplasia increases dramatically with unopposed estrogen use, with relative risk reaching 9.5 for 10 years of use 1

• Studies show that endometrial hyperplasia rates increase significantly with longer duration of unopposed estrogen treatment 3

Who Needs Progestogen

The requirement for progestogen depends on uterine status:

1. Women with intact uterus: MUST use combined estrogen-progestogen therapy

   • This is mandatory to prevent endometrial hyperplasia and cancer 1
   • The FDA label explicitly states this requirement 2

2. Women without a uterus (hysterectomized): Do NOT need progestogen

   • "Estrogen-only HRT should be prescribed to hysterectomized women: indeed, there is no therapeutic advantage in prescribing progestins to this selected cohort of patients" 4

Progestogen Options and Dosing

Several progestogen options are available for endometrial protection:

1. Micronized progesterone (MP):

   • 200 mg orally daily for 12 continuous days per 28-day cycle 5
   • May have a more favorable cardiovascular and breast profile compared to synthetic progestogens 6

2. Medroxyprogesterone acetate (MPA):

   • 2.5 mg daily when used in continuous combined regimens 1
   • Effectively prevents endometrial hyperplasia but may have less favorable cardiovascular effects 4

3. Other progestogens:

   • Norethisterone acetate (NETA): Minimum 1 mg daily provides effective protection 7
   • Dydrogesterone: Listed among suggested progestogens by guidelines 4

Administration Regimens

Two main approaches for adding progestogen to estrogen gel:

1. Continuous combined regimen:

   • Estrogen and progestogen taken daily
   • More effective for endometrial protection with longer duration of treatment 3
   • May cause more irregular bleeding in the first year of therapy 3

2. Sequential (cyclic) regimen:

   • Estrogen daily, progestogen added for 12-14 days per month
   • Example: 200 mg micronized progesterone daily for 12-14 days per month 1
   • May cause more predictable withdrawal bleeding 3

Monitoring and Safety

Regular monitoring is essential:

• Initial follow-up at 3 months, then annual follow-up
• Monitor for abnormal bleeding, which may indicate endometrial pathology
• Any persistent or recurring abnormal bleeding should prompt endometrial evaluation 2

Common Pitfalls to Avoid

1. Skipping progestogen with intact uterus: This significantly increases endometrial cancer risk
2. Using long-cycle sequential therapy: Progestogen given every three months has higher hyperplasia risk than monthly regimens 3
3. Inadequate progestogen dose: Insufficient doses fail to provide endometrial protection
4. Ignoring abnormal bleeding: Any unusual bleeding patterns should prompt medical evaluation

Conclusion

The evidence is clear and consistent: women with an intact uterus using estrogen gel must use progestogen to protect the endometrium. Only women who have undergone hysterectomy can safely use estrogen gel without progestogen.