Systematic review and meta-analysis of the effects of progestins on depression in post-menopausal women: An evaluation of randomized clinical studies that used validated questionnaires

Objective

Hormone therapy (HT) can relieve symptoms of menopause and treat chronic diseases. Its effectiveness in treating psychological symptoms is still debated. Several progestins can be used in HT, but their effects on mood, in particular depressive symptoms, is still unclear. This systematic review evaluates the evidence from randomized clinical trials with postmenopausal women on the effect of adjunctive progestins on symptoms of depression assessed by validated questionnaires. The primary aim was to evaluate scores on the Center for Epidemiologic Studies Depression Scale (CESD). The secondary aim was to assess scores on the Beck Depression Inventory (BDI), the Hamilton Depression Rating Scale (HAMD), and the Zung Self-Rating Depression Scale (SDS).

Methods

A systematic review and meta-analysis were conducted to identify the most reliable evidence of the effects of progestin on depression to inform decision-making. A PICO- and PRISMA-based framework was established to formulate explicit and reasoned recommendations. The pre-/post-treatment effect was evaluated using standardized mean change (SMC).

Results

We selected and analyzed 16 randomized clinical trials qualitatively and 12 studies quantitatively out of 9320 items identified. Most of the studies used medroxyprogesterone acetate as progestin. The results indicate that depressive symptoms do not increase with the addition of a progestin to estrogen HT. Depressive symptoms improved over time in the progestins-estrogen HT group, independent of progestin type (SMC CES-D −0.08 CI.95–0.10/−0.06, BDI −0.19 CI.95–0.32/−0.06, HAM-D −1.13 CI.95–1.47/−0.78, and SDS −0.11 CI.95–0.82/0.60). Yet similar effects were observed with estrogens alone and did not significantly differ from control groups on placebo. In one study, the addition of fluoxetine greatly increased the reduction of depressive symptoms observed with estrogen-progestin HT.

Conclusions

In summary, in randomized clinical trials using validated questionnaires adjunctive progestin with estrogens did not increase depressive symptoms of postmenopausal women. Overall, depressive symptoms decreased with estrogen-progestin HT but also with estrogen alone. The decrease was not so pronounced to differ from controls on placebo. HT does not hamper the clinical efficacy of fluoxetine. The scarcity of randomized studies makes it difficult to determine the exact effect on depressive symptoms of different types of progestins.

Project protocol registered in PROSPERO, registration number CRD42023454099.