Is estrogen-only therapy safer than combined?

Whether estrogen-only or combined estrogen-progesterone therapy is more appropriate depends on an individual's health profile — most notably, whether the uterus is present. A prescriber should evaluate each patient's complete medical history before recommending either approach.

Why estrogen-only therapy may carry a different risk profile

When a woman has had a hysterectomy, estrogen can be used without a progestogen. According to the WHI long-term follow-up data, estrogen-only therapy in women without a uterus was associated with a lower incidence of breast cancer compared with combined estrogen-progestogen therapy over the same follow-up period. According to current NAMS guidelines, transdermal estrogen delivery (patch or gel) is associated with a lower risk of venous thromboembolism than oral estrogen, regardless of whether a progestogen is added. Per the Endocrine Society, the addition of a progestogen introduces a distinct set of hormonal effects that may include mood changes, breast tenderness, and fluid retention — effects not present with estrogen alone.

Why progesterone is required if the uterus is present

Per published clinical guidelines, unopposed estrogen stimulates the endometrial lining and, over time, increases the risk of endometrial hyperplasia and uterine cancer. Adding a progestogen — whether a standard formulation or, when individualized dosing is clinically indicated, a compounded preparation — protects the endometrium and makes estrogen therapy appropriate for women who retain their uterus. Compounded medications are not FDA-approved. They have not been reviewed by the FDA for safety, effectiveness, or quality. FDA-approved medications should be considered first when commercially available options meet patient needs.

Factors that inform the choice between regimens

• Uterus absent: Per FDA-approved prescribing information, estrogen monotherapy is the indicated regimen and does not require endometrial protection.
• Uterus present: According to ACOG, combined therapy is required to protect the uterine lining; estrogen alone is not appropriate in this setting.
• Venous clot or stroke history: According to the WHI long-term follow-up data, transdermal estrogen carries a lower thrombotic risk than oral formulations and may be preferable when clotting risk is elevated.
• Personal or family history of breast cancer: Per current NAMS guidelines, the breast cancer risk profile differs between estrogen-only and combined regimens, and this distinction should be factored into a shared clinical decision with a prescriber.

The bottom line

According to current NAMS guidelines, estrogen-only therapy is the appropriate regimen when the uterus has been removed, while combined therapy is required when the uterus is present in order to protect the endometrium. The relative risk profiles of the two regimens differ across outcomes including breast cancer, cardiovascular events, and tolerability, and the clinical significance of these differences varies by age, timing of therapy initiation, and individual health history. Whether HRT is appropriate depends on individual health factors. A prescriber should determine the best approach based on a patient's complete medical history.