Tissue selectivity of ospemifene: pharmacologic profile and clinical implications.
The multifactorial consequences of menopausal estrogen deficiency affect numerous tissues throughout the body. Supplemental hormonal therapies carry the burden of a risk/benefit ratio that must be highly individualized. Selective estrogen receptor modulators (SERMs) are estrogen receptor (ER) agonist/antagonists designed to induce benefits comparable with estrogen while minimizing adverse effects. Here, we review the estrogen agonist/antagonist profile of ospemifene, a novel triphenylethylene derivative recently approved to treat dyspareunia, a symptom of vulvar and vaginal atrophy (VVA) due to menopause, both preclinically and clinically. Ospemifene binds ERα and ERβ with approximately equal affinities. In preclinical models, ospemifene increased vaginal and uterine epithelial thickness and mucification to the same extent as estrogen. Ospemifene did not induce endometrial hyperplasia in animal models; there also was no stimulatory effect on endometrial cells. In rat and human mammary cells in vitro, ospemifene evokes a dose-dependent inhibition on estrogen-induced cell responses and cell proliferation, supporting an antiestrogenic effect in breast. In contrast, ospemifene has an estrogenic effect on bone, as seen by improved bone mineral density, strength, mass, and histomorphometry in preclinical models, consistent with improvements in markers of bone resorption and formation in postmenopausal women. Based on the preclinical evidence, ospemifene has beneficial estrogen-like effects on the vaginal epithelium, preliminary evidence to support a neutral endometrial profile, antiproliferative effects in breast, and estrogenic effects in bone. Taken together, especially regarding estrogen-like effects on the vaginal epithelium, ospemifene presents a profile of tissue-specific effects that appear novel among available SERMs and well-suited for the treatment of VVA.
Hormos Medical Ltd, Turku, Finland. Electronic address: lauri.kangas@forendo.com.
Lauri
L
Kangas
Mikko
M
Unkila
D000818:Animals; D001862:Bone Resorption / Q000517:prevention & control; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D015914:Estrogen Replacement Therapy; D005260:Female; D006801:Humans; D042361:Mammary Glands, Human / Q000187:drug effects / Q000473:pathology; D009928:Organ Specificity; D020845:Selective Estrogen Receptor Modulators / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D013629:Tamoxifen / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D014621:Vagina / Q000187:drug effects / Q000473:pathology
D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; C119141:Ospemifene
AE; BMD; BrdU; DMBA; Dyspareunia; ED(50); ER; MI; MIN-O; Maturation Index; OVX; Ospemifene; SERM; Selective estrogen receptor modulator; VTE; VVA; Vulvar and vaginal atrophy; adverse event; bone mineral density; bromodeoxyuridine; dimethylbenzanthracene; estrogen receptor; half-maximal effective dose; mammary intraepithelial neoplasia outgrowth; ovariectomized; selective estrogen receptor modulator; venous thromboembolism; vulvar and vaginal atrophy