Comparison of steady state development and reduction of menopausal symptoms after oral or transdermal delivery of 17-β-estradiol in young healthy symptomatic menopausal women.
OBJECTIVE
There is a renewed interest in the delivery of estradiol (E2) for the reduction of menopausal symptoms in young symptomatic menopausal women. This paper compares experimentally and theoretically obtained E2 plasma values by oral and transdermal delivery and compares them with relevant menopausal symptoms.


METHODS
Two independent previously published studies were compared, which each contained 42 young symptomatic menopausal women. Experimentally obtained plasma values at days 1, 7 and 21 were compared with a theoretical model, taken from the literature, for describing plasma values for an oral immediate release formulation, consecutively for 21 days. Menopausal symptoms were determined in the steady state for oral and transdermal delivery with the Kuppermann index, previously not reported. In the case of oral delivery, estradiol was compared with estradiol valerate.


RESULTS
Previously published results for transdermal delivery of E2 showed that the matrix system establishes a steady state condition with the application of the first patch. Excellent agreement between theoretically predicted and experimentally obtained E2 plasma values for oral delivery in menopausal women was obtained. Circadian E2 plasma levels were observed continuously for transdermal delivery, were seen in oral delivery during first application and disappeared when steady state was achieved. Application of the prodrug E2-valerate delayed the maximum plasma peak from 1 pm to 4 pm, similar to the transdermal matrix patch. Investigating menopausal symptoms determined with the Kuppermann index did not reveal differences between oral or transdermal "E2 kinetic (hot flushes) relationship". This relationship was similar to symptomatic women suffering from hot flushes in untreated menopausal women or premenopausal women. Different menopausal symptoms required different E2 plasma levels: the average E2 levels higher than 23 pg/mL in plasma did abolish insomnia in 50% of postmenopausal women, with 28 pg/mL is needed to suppress 50% of dysthymia; however, rather high levels of 41 pg/mL are needed to suppress 50% of hot flushes, suggesting a rather complex mechanism beyond an E2 receptor mediated process.


CONCLUSIONS
There is a difference in the steady state between oral and transdermal E2 delivery. Steady state condition is achieved in the first application of a matrix patch, whereas with the application of a tablet the steady state is achieved in transdermal delivery within 12-14 days. Our reported calculated missed intake of a E2 tablet shows that E2 plasma levels drop for 4 days consecutively. Our conducted study has several limitations: firstly, no cross-over was conducted, but a rather cumbersome mathematical modeling; secondly, healthy women with no accompanying severe diseases were included in this study. The higher the oral dose, the higher the E2 steady state levels, but the time to achieve steady state levels is independent from the E2 dose.
Uwe D
UD
Rohr
Claus D
CD
Volko
Adolf E
AE
Schindler
D000279:Administration, Cutaneous; D000284:Administration, Oral; D002940:Circadian Rhythm; D019263:Dysthymic Disorder / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D004958:Estradiol / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D005260:Female; D019584:Hot Flashes / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D008593:Menopause / Q000187:drug effects* / Q000502:physiology / Q000523:psychology; D008875:Middle Aged; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D007319:Sleep Initiation and Maintenance Disorders / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology
D011355:Prodrugs; D004958:Estradiol