We are all cognizant of the changing moods which seem to be heightened in women when compared to men. Depression is much more common in women than men, especially postpartum and in perimenopausal times. Mood swings are common around menstruation associated with Pre-menstrual Syndrome (PMS), although the extent to which they encumber women may be debated. Biologic evidence suggests that Estrogen may be a key determinant in mood disorders in women, especially the rapid withdrawal of Estrogen, which occurs at the above times.

Estrogen, derived from the Greek "Oistros, meaning mad desire" and "gennan, to produce", is the generic term for a family of hormones produced naturally in the female and synthetically by the pharmaceutical companies. Six of the top 100 best selling prescription drugs are products containing ethinyl estradiol or conjugated equine estrogens. They are marketed for contraception or hormone replacement therapy (HRT). A new preparation, Cenestin is synthetically derived from the plant sterols of Soy and Yam. It contains nine weaker estrogens and it's effectiveness has not been demonstrated beyond a 3 month study. It is marketed primarily as alternative HRT. Estrogens (Es) belong to the steroid class of hormones derived from Cholesterol and are naturally produced by the ovaries, adrenals and by peripheral fat in the breasts. Es include estradiol-E2, estrone-E1, estriol-E3 and progesterone. 17 beta Estradiol is produced by the ovary in the largest quantity and has the highest affinity for estrogen receptors in the breasts and female reproductive organs. Oral Es are first conjugated in the liver to inactive estrone and estriol, which have diminished potency, but then are excreted into the intestines where they are converted to active Es and reabsorbed into the circulation. This first pass effect stimulates the liver to improve your cholesterol and HDL lipid profile, but also produces binding proteins which carry the active hormones in the bloodstream to the receptors.

In the past decade, we have discovered much evidence to support the role of estrogen�s effect on the brain. A large number of both alpha and beta estrogen receptors are located on neurons throughout the brain and concentrated in the limbic and hippocampal areas associated with emotions. Estrogens appear to have an excitatory effect stimulating sensory perception. Clinicians and patients alike have reported that estrogens can be associated with improvement in mood and well-being in healthy menopausal women increasing their quality of life.

But now we have to look at the differences in male and female brains to examine if this will occur with Cross Sex Hormones. First the male brain is much larger than the female brain in humans. The left hemisphere is more prominent in men, with specialized areas developing earlier. In the area of speech, men activate their left frontal lobe, but women activate both right and left frontal lobes simultaneously and consequently have more activated areas, which may be correlated with faster speech patterns and enhanced memory of emotional events.

Women appear to have higher concentrations of the neurotransmitter norepinephrine and more cross-brain connections. Estradiol (E2) has been shown to inhibit norepinephrine, stimulate Serotonin and increase brain endorphins, which may contribute to mood improvement with Estrogen therapy. On the other hand, Progesterone appears to have the opposite effect causing depressive and negative moods and it is postulated that it attenuated the effects on mood, depression and memory in the WHI Prempro study, which showed no improvement in these areas. The Estrogen-only arm has not been completed. The good news is that Estrogen receptors in other parts of the body appear to respond equally in both male and female to estrogen stimulus with minor variations.

The only relevant psychological testing that has been done in the TS population consistently showed improvement from the diagnostic phase through the real-life test with hormones and finally in the 2 year followup from surgery. Mate-Kole et al. showed that their patients at each stage suffered less from depression, anxiety, obsessive behavior and hysteria. Then at 2 years, they were divided into two groups, those planning surgery in a few months and those not planning or having surgery much later. Although both groups obtained similar results in the initial evaluation, the operated transsexuals presented a clear decrease in neurotic symptoms compared to the patients waiting for SRS. Six separate studies have confirmed these findings and according to Kuiper and Cohen-Kettenis if the operation did not take place these gains disappeared.

While depression may be present in both sexes, a new class of drugs known as Selective Serotonin Reuptake Inhibitors (SSRI) has been shown to be superior to the older drugs and is designated as the first line of treatment for depression. Does anybody know someone, who is not on Prozac or one of its relatives? Only Kidding, but now they have been shown to reduce hot flashes and the vasomotor symptoms of menopause. Now that is exactly what Black Cohosh is supposed to do, so do not confuse the treatment of hot flashes with Estrogen effect.

Recently a placebo-controlled study tested the efficacy of .1 mg Estradiol patches versus Placebo in 50 Perimenopausal women with major and minor depression. Remission was achieved in 68% of the Estradiol users as compared to only 20% in the Placebo Group. This was repeated in another study using .05 mg Estradiol patches and an 80% therapeutic response was noted compared to a 22% response in the Placebo group. No further improvement could be noted after 6 weeks of Estradiol, but that is a significant incremental improvement to a steady state.  On the other hand in another study, Girdler found no effect on mood of 0.625 of Premarin in post menopausal women.  In the UK, a study in of 1600 women on HRT and SSRIs report a higher quality of life and mood elevation in the group taking both than women who took SSRIs alone.
In conclusion, this is one of the unheralded benefits of Estrogen therapy to consider when making your decision.

Best of Luck in Your New Future,

Cerise Richards, M.D.