Contraindications
Contraindications of progesterone include hypersensitivity to progesterone or progestogens, prevention of cardiovascular disease (a Black Box warning), thrombophlebitis, thromboembolic disorder, cerebral hemorrhage, impaired liver function or disease, breast cancer, reproductive organ cancers, undiagnosed vaginal bleeding, missed menstruations, miscarriage, or a history of these conditions. Progesterone should be used with caution in people with conditions that may be adversely affected by fluid retention such as epilepsy, migraine headaches, asthma, cardiac dysfunction, and renal dysfunction. It should also be used with caution in patients with anemia, diabetes mellitus, a history of depression, previous ectopic pregnancy, and unresolved abnormal Pap smear. Use of progesterone is not recommended during pregnancy and breastfeeding. However, the medication has been deemed usually safe in breastfeeding by the American Academy of Pediatrics, but should not be used during the first four months of pregnancy. Some progesterone formulations contain benzyl alcohol, and this may cause a potentially fatal "gasping syndrome" if given to premature infants. Side effects
Progesterone is well tolerated, and many clinical studies have reported no side effects. Side effects of progesterone may include abdominal cramps, back pain, breast tenderness, constipation, nausea, dizziness, edema, vaginal bleeding, hypotension, fatigue, dysphoria, depression, and irritability, among others. Central nervous system depression, such as sedation and cognitive/memory impairment, can also occur.Vaginal progesterone may be associated with vaginal irritation, itchiness, and discharge, decreased libido, painful sexual intercourse, vaginal bleeding or spotting in association with cramps, and local warmth or a "feeling of coolness" without discharge. Intramuscular injection may cause mild-to-moderate pain at the site of injection.
A 2018 systematic review reported that breast density with an estrogen plus oral progesterone was significantly increased in three studies and unchanged in two studies. Changes in breast density with progesterone appear to be less than with the compared progestins.In large short-term observational studies, estrogen alone and the combination of estrogen and oral progesterone have generally not been associated with an increased risk of breast cancer. Conversely, the combination of estrogen and almost any progestin, such as medroxyprogesterone acetate or norethisterone acetate, has been associated with an increased risk of breast cancer. The only exception among progestins is dydrogesterone, which has shown similar risk to that of oral progesterone. Breast cancer risk with estrogen and progestin therapy is duration-dependent, with the risk being significantly greater with more than 5 years of exposure relative to less than 5 years. In contrast to shorter-term studies, the longer-term observations (>5 years) of the French E3N study showed significant associations of both estrogen plus oral progesterone and estrogen plus dydrogesterone with higher breast cancer risk, similarly to estrogen plus other progestogens. Oral progesterone has very low bioavailability and has relatively weak progestogenic effects. The delayed onset of breast cancer risk with estrogen plus oral progesterone is potentially consistent with a weak proliferative effect of oral progesterone on the breasts. As such, a longer duration of exposure may be necessary for a detectable increase in breast cancer risk to occur. In any case, the risk remains lower than that with most progestins.