The objective of this study was to evaluate the psychological side effects of a transvaginal natural progesterone gel in hormone replacement therapy (HRT). This 3-month preliminary study was part of a multicenter study previously performed in our center. We enrolled 49 women (ages 18-45 years) with hypothalamic amenorrhea (HA) (n = 40) and premature ovarian failure (POF) (n = 9). Estrogenized patients applied vaginal progesterone gel (4% or 8%) every other day for six doses per month. The Hopkins Symptom Checklist (HSCL), a psychometric profile test, was administered at baseline, day 13 of cycle 2, day 24 of cycle 2, and day 24 of cycle 3. Application of the progesterone gel caused no significant change in HSCL total scores or individual symptom scores for somatization, obsession-compulsion, interpersonal sensitivity, depression, and anxiety. Natural vaginal progesterone gel can be an effective alternative to oral progesterone for women on HRT.