A 2018 systematic review of progesterone and breast cancer concluded that short-term use (<5 years) of an estrogen plus progesterone is not associated with a significant increase in risk of breast cancer but that long-term use (>5 years) is associated with greater risk. The conclusions for progesterone were the same in a 2019 meta-analysis of the worldwide epidemiological evidence by the Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC).Most data on breast density changes and breast cancer risk are with oral progesterone. Data on breast safety with vaginal progesterone are scarce. The Early versus Late Intervention Trial with Estradiol (ELITE) was a randomized controlled trial of about 650 postmenopausal women who used estradiol and 45 mg/day cyclic vaginal progesterone. Incidence of breast cancer was reported as an adverse effect. The absolute incidences were 10 cases in the estradiol plus vaginal progesterone group and 8 cases in the control group. However, the study was not adequately powered for quantifying breast cancer risk. Blood clots
Whereas the combination of estrogen and a progestin is associated with increased risk of venous thromboembolism (VTE) relative to estrogen alone, there is no difference in risk of VTE with the combination of estrogen and oral progesterone relative to estrogen alone. Hence, in contrast to progestins, oral progesterone added to estrogen does not appear to increase coagulation or VTE risk. The reason for the differences between progesterone and progestins in terms of VTE risk are unclear.
However, they may be due to very low progesterone levels and relatively weak progestogenic effects produced by oral progesterone. In contrast to oral progesterone, non-oral progesterone—which can achieve much higher progesterone levels—has not been assessed in terms of VTE risk. Overdose
Progesterone is likely to be relatively safe in overdose. Levels of progesterone during pregnancy are up to 100-fold higher than during normal menstrual cycling, although levels increase gradually over the course of pregnancy. Oral dosages of progesterone of as high as 3,600 mg/day have been assessed in clinical trials, with the main side effect being sedation. There is a case report of progesterone misuse with an oral dosage of 6,400 mg per day. Administration of as much as 500 mg progesterone by intravenous infusion in humans was uneventful in terms of toxicity, but did induce deep sleep, though the individuals were still able to be awakened with sufficient stimulation. Interactions
There are several notable drug interactions with progesterone. Certain selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, and sertraline may increase the GABAA receptor-related central depressant effects of progesterone by enhancing its conversion into 5α-dihydroprogesterone and allopregnanolone via activation of 3α-HSD. Progesterone potentiates the sedative effects of benzodiazepines and alcohol. Notably, there is a case report of progesterone abuse alone with very high doses.