Pulsed estrogen exposure selectively modulates tissue response: a hypothesis.
All postmenopausal hormone replacement therapies (HTs) aim to provide a steady mid-follicular serum concentration of estrogen, with the exception of pulsed estrogen therapy, which concentrates hormone exposure in the few hours following administration. This alteration in the kinetics of estradiol exposure does not change the beneficial effect of HT on climacteric symptoms or bone loss, but does reduce the stimulation of the breast and uterus leading to less mastalgia and bleeding. The following hypothesis provides a plausible pharmacological explanation as to how estradiol kinetics can selectively modify tissue response. Pulsed estradiol exposure influences the relative abundance of estrogen receptors (ERs) alpha and beta, via a tissue-dependent non-genomic signaling pathway, resulting in selective upregulation and activation of ERbeta in breast and endometrium, but not in bone. In addition, pulsed estrogen exposure also increases local concentration of 2-methoxyestradiol, a specific estradiol metabolite with proven anti-tumor properties.
Kenemans
P
P
Department of Obstetrics and Gynaecology, VU University Medical Center, Amsterdam, The Netherlands.
Genazzani
A R
AR
Palacios
S
S
Schneider
H P G
HP
D000077584:2-Methoxyestradiol; D000281:Administration, Intranasal; D000818:Animals; D001940:Breast / Q000737:chemistry / Q000187:drug effects; D004717:Endometrium / Q000737:chemistry / Q000187:drug effects; D004958:Estradiol / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D015914:Estrogen Replacement Therapy / Q000379:methods*; D005260:Female; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D010507:Periodicity; D017698:Postmenopause; D011960:Receptors, Estrogen / Q000032:analysis; D015398:Signal Transduction
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011960:Receptors, Estrogen; D004958:Estradiol; D000077584:2-Methoxyestradiol