<unk> is well tolerated, and many clinical studies have reported no side effects. Side effects of<unk> 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<unk> 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. High intramuscular doses of<unk> have been associated with increased body temperature, which may be alleviated with paracetamol treatment.<unk> 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,<unk> 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<unk>  In addition, the magnitude and duration of vaginal bleeding with<unk> are reported to be lower than with medroxyprogesterone acetate. Central depression<unk> can produce central nervous system depression as an adverse effect, particularly with oral administration or with high doses of<unk>  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<unk> (100–600 mg), vaginal<unk> (45 mg gel), or<unk> by intramuscular injection (25–200 mg). However, high doses of oral<unk> (300–1200 mg), vaginal<unk> (100–200 mg), and intramuscular<unk> (100–200 mg) have been found to result in dose-dependent fatigue, drowsiness, and decreased vigor. Moreover, high single doses of oral<unk> (1200 mg) produced significant cognitive and memory impairment. Intravenous infusion of high doses of<unk> (e.g., 500 mg) has been found to induce deep sleep in humans. Some individuals are more sensitive and can experience considerable sedative and hypnotic effects at lower doses of oral<unk> (e.g., 400 mg). Sedation and cognitive and memory impairment with<unk> are attributable to its inhibitory neurosteroid metabolites. These metabolites occur to a greater extent with oral<unk>  and may be minimized by switching to a parenteral route.<unk> can also be taken before bed to avoid these side effects and to help with sleep. The neurosteroid effects of<unk> are unique to<unk> and are not shared with progestins. Breast cancer Breast cell proliferation has been found to be significantly increased by the combination of an oral estrogen plus cyclic medroxyprogesterone acetate in postmenopausal women but not by the combination of transdermal estradiol plus oral<unk>  Studies of topical estradiol and<unk> applied to the breasts for 2 weeks have been found to result in highly pharmacological local levels of estradiol and<unk>  These studies have assessed breast proliferation markers and have found increased proliferation with estradiol alone, decreased proliferation with<unk>  and no change in proliferation with estradiol and<unk> combined. In the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, the combination of estrogen and cyclic oral<unk> resulted in a higher mammographic breast density than estrogen alone (3.1% vs. 0.9%) but a non-significantly lower breast density than the combination of estrogen and cyclic or continuous medroxyprogesterone acetate (3.1% vs. 4.4–4.6%). Higher breast density is a strong known risk factor for breast cancer. Other studies have had mixed findings however. A 2018 systematic review reported that breast density with an estrogen plus oral<unk> was significantly increased in three studies and unchanged in two studies. Changes in breast density with<unk> appear to be less than with the compared progestins. In large short-term observational studies, estrogen alone and the combination of estrogen and oral<unk> 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<unk>  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<unk> and estrogen plus dydrogesterone with higher breast cancer risk, similarly to estrogen plus other progestogens. Oral<unk> has very low bioavailability and has relatively weak progestogenic effects. The delayed onset of breast cancer risk with estrogen plus oral<unk> is potentially consistent with a weak proliferative effect of oral<unk> 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. A 2018 systematic review of<unk> and breast cancer concluded that short-term use (5 years) is associated with greater risk. The conclusions for<unk> 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<unk>  Data on breast safety with vaginal<unk> 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<unk>  Incidence of breast cancer was reported as an adverse effect. The absolute incidences were 10 cases in the estradiol plus vaginal<unk> 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<unk> relative to estrogen alone. Hence, in contrast to progestins, oral<unk> added to estrogen does not appear to increase coagulation or VTE risk. The reason for the differences between<unk> and progestins in terms of VTE risk are unclear. However, they may be due to very low<unk> levels and relatively weak progestogenic effects produced by oral<unk>  In contrast to oral<unk>  non-oral<unk> which can achieve much higher<unk> levels—has not been assessed in terms of VTE risk.
Progesterone 
Estrogen 
Estrogen
Androgen
Estradiol 
Estradiol
Methyltestosterone
Progestogen