Previous studies have indicated that the addition of
progestins during sequential hormonal replacement
therapy (HRT) causes negative mood and physical symptoms. History of
premenstrual syndrome, type of
progestin, and dose of
progestin have thus far been shown to influence the
progestin-induced adverse mood symptoms during HRT. The aim of this study was to compare adverse mood effects of two different doses of
estradiol, in combination with a
progestin, during postmenopausal HRT. Twenty-eight perimenopausal women were included in this randomized, double-blind, crossover study comparing 2- or 3-mg continuous
estradiol, with an addition of 10 mg
medroxyprogesterone acetate on d 17-28 during each treatment cycle. The main outcome measures were mood and physical symptoms kept on a daily rating scale. Together with the
progestin, the higher dose of
estrogen caused significantly more negative mood symptoms than the lower dose. Tension, irritability, and depressed mood were all significantly augmented during the
progestin phase of cycles with 3 mg
estradiol (P < 0.001). Physical symptoms also increased during the
progestin phase of 3-mg
estradiol cycles (P < 0.001), whereas positive mood symptoms were less affected. The only positive mood that changed with
estrogen dose was friendliness, which decreased during the
progestin phase of high
estradiol cycles compared with cycles with lower
estradiol (P < 0.05). Our conclusion is that an increase of the
estrogen dose accentuates negative mood and physical symptoms during the
progestin phase of sequential hormonal
therapy.