High intramuscular doses of progesterone have been associated with increased body temperature, which may be alleviated with paracetamol treatment.Progesterone lacks undesirable off-target hormonal activity, in contrast to various progestins. As a result, it is not associated with androgenic, antiandrogenic, estrogenic, or glucocorticoid effects. Conversely, progesterone can still produce side effects related to its antimineralocorticoid and neurosteroid activity. Compared to the progestin medroxyprogesterone acetate, there are fewer reports of breast tenderness with progesterone. In addition, the magnitude and duration of vaginal bleeding with progesterone are reported to be lower than with medroxyprogesterone acetate. Central depression
Progesterone can produce central nervous system depression as an adverse effect, particularly with oral administration or with high doses of progesterone. These side effects may include drowsiness, sedation, sleepiness, fatigue, sluggishness, reduced vigor, dizziness, lightheadedness, confusion, and cognitive, memory, and/or motor impairment. Limited available evidence has shown minimal or no adverse influence on cognition with oral progesterone (100–600 mg), vaginal progesterone (45 mg gel), or progesterone by intramuscular injection (25–200 mg). However, high doses of oral progesterone (300–1200 mg), vaginal progesterone (100–200 mg), and intramuscular progesterone (100–200 mg) have been found to result in dose-dependent fatigue, drowsiness, and decreased vigor. Moreover, high single doses of oral progesterone (1200 mg) produced significant cognitive and memory impairment. Intravenous infusion of high doses of progesterone (e.g., 500 mg) has been found to induce deep sleep in humans.
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.