LAUSR

Hormonal Contraception and Its Association With Depression To the Editor Skovlund and colleagues1 wrote that depression is hitherto a relatively unnoticed adverse effect of hormonal contraceptives. Depressive mood changes are important reasons for discontinuing use and also why the high progestin dose oral contraceptives tested in the 1960s were never widely used.2 The Council for the Investigation of Fertility Control London Trial begun in 1961 enrolled more than 800 women. The effects of 60 combinations of 7 progestins and 2 estrogens were examined in these previously healthy volunteers. The incidence of depressive mood changes, including loss of libido, increased from 10% to 44% of women during the first year of use as progestin doses increased and estrogen doses decreased.2 High incidences of depression matched large increases in monoamine oxidase activity in endometrial glandular epithelium during the prolonged postsecretory phases of treated cycles.2 The enzyme monoamine oxidase inactivates, or stores, monoamines, which control mood and behavior and vascular reactivity. Monoamine oxidase inhibitor drugs were found to be antidepressants in the 1950s, which is why we performed this research. Estrogens decrease, but progesterone or progestins increase monoamine oxidase activity.2 Endometrial monoamine oxidase activity increased 6-fold in the human menstrual cycle from less than 4000 cpm/mg in proliferative and early secretory phases to 10 000 to 21 000 cpm/mg in the late secretory phase.3 This increase coincides with the timing of the premenstrual syndrome. Parallel histochemical and biochemical microassay procedures have been used to confirm that a large increase in endometrial monoamine oxidase occurs in the late secretory phase of the human menstrual cycle. No such variation was observed during the rat estrous cycle. The value of biochemical microassay procedures in supplementing information obtained by histochemical methods is pointed out. Skovlund and colleagues1 found significantly increased relative risks of first use of antidepressants in users of hormonal contraceptives compared with nonusers. Relative risks were 1.2 (95% CI, 1.22-1.25) for combined oral contraceptives (or 1.7 [95% CI, 1.66-1.71] if compared with never users), 1.3 (95% CI, 1.27-1.40) for progestin-only pills (or 2.2 [95% CI, 2.182.31] if used by adolescents aged 15-19 years), 1.4 (95% CI, 1.311.42) for a levonorgestrel intrauterine system, 1.6 (95% CI, 1.551.69) for a levonorgestrel vaginal ring, 2.0 (95% CI, 1.76-2.18) for a norgestrolmin transdermal patch, 2.1 (95% CI, 2.012.24) for an implant, and 2.7 (95% CI, 2.45-2.87) for depot medroxyprogesterone acetate. This suggests that continuous use of potent progestins, especially without estrogens, causes most depression probably because of prolonged increases in monoamine oxidase activity. Estrogen doses were lowered or removed in hormonal contraceptives to reduce the risk for venous thromboembolic disease by 1969 but the incidences of depression or anxiety and weight gain have increased in young women. Suicides, crashes, or violence constituted a main cause of death in current users in 1974.4 In 2014, the UK National Health Service mental health survey found that 26% of young women aged 16 to 24 years in England had mental health problems compared with 9.1% of young men.5