Article

[Cross-over comparison of the pharmacokinetics of estradiol during hormone replacement therapy with estradiol valerate or micronized estradiol].

Authors:
  • Kinderwunschpraxis am Goetheplatz, Frankfurt
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Abstract

The aim of this randomized cross-over study was the comparison between a sequential 28-day hormone replacement therapy (HRT) using micronized estradiol and a cyclic 21-day HRT using estradiol valerate with regard to the pharmacokinetics of estradiol. - Fifty postmenopausal women were randomly assigned to be treated either with Trisequens(R) for 28 days or with Sisare(R) for 21 days. After a wash-out cycle, the women were treated for one cycle with the other preparation in a cross-over fashion. The pharmacokinetic profile of the serum concentrations of estradiol was measured on day 1, 21 and 28 each immediately before and 1, 2, 4, 6, 8, and 10 hours after intake of a tablet, and the AUC (area under the curve) was calculated. - The serum concentrations of estradiol increased from a mean of 10 pg/ml up to 40 pg/ml (Trisequens(R)) and 30 pg/ml (Sisare(R)) on day 1, and to 80 pg/ml (Trisequens(R)) and 60 pg/ml (Sisare(R)) on day 21, and declined to 40 pg/ml (Trisequens(R)) and 10 pg/ml (Sisare(R)) on day 28. The AUC as calculated from both treatment cycles, was significantly higher on day 1, 21, and 28 during treatment with Trisequens(R) than with Sisare(R). This difference was, however, not signifcant on day 1 and 21 of the first treatment cycle. - During treatment with 2 mg micronized estradiol the serum concentrations are significantly higher than with 2 mg estradiol valerate. On day 28 of treatment with Sisare(R), the estradiol levels decline to baseline values, while using Trisequens(R) they remain in the range of those measured on day 1.

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... Historically, the use of E2 replacement in menopause was initiated by women who continued to take contraceptive pills to maintain and counterbalance declining E2 to avoid hot flushes, sleeping disorders, and particularly mood disturbances [10]. Although oral delivery of E2 is conducted for several decades in contraception, menopause or other gynecological application, the time to achieve steady state is reported in a rather anecdotal manner [11,12] and it is very surprising that the steady state development of oral immediate delivery has never been theoretically investigated, despite the immense and long-term use of this oral delivery system. A theoretical investigation is still missing, although it is known from many clinical trials that first day application or application after 2 weeks produces significantly different E2 plasma profiles [11,12]. ...
... Although oral delivery of E2 is conducted for several decades in contraception, menopause or other gynecological application, the time to achieve steady state is reported in a rather anecdotal manner [11,12] and it is very surprising that the steady state development of oral immediate delivery has never been theoretically investigated, despite the immense and long-term use of this oral delivery system. A theoretical investigation is still missing, although it is known from many clinical trials that first day application or application after 2 weeks produces significantly different E2 plasma profiles [11,12]. We therefore decided to investigate the steady state condition for immediate oral delivery. ...
... We therefore decided to investigate the steady state condition for immediate oral delivery. In contrast to our previous steady state investigation with a matrix patch for Table 1 Key characteristics of participating menopausal women [3,4,12]. ...
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. 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. 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. 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.
... After oral administration, sustained blood levels of >40 pg/mL estradiol have been reported to be achieved within 2 h of oral intake [ Supplementary Figure]. [17] Similar to other studies, fever and cough remain the most common presentation in our study as well and diabetes and hypertension are the most common comorbidities. ...
... Pharmacodynamics (own work) and pharmacokinetics of estradiol [17] (source credit: https://commons.wikimedia. org/wiki/File:Estradiol_levels_after_a_single_dose_and_with_continuous_administration_of_oral_estradiol_or_oral_ estradiol_valerate_in_women. ...
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... Antiandrogenic properties of combined contraception are related to both components of the pill: oestrogen and progestin. Oestrogen stimulates sex hormone binding globulin (SHBG) liver synthesis that in turn reduces the amount of biologically active androgens, induces oestrogen receptor expression, and decreases gonadotrophin secretion that inhibits LH-related testosterone production by theca cells in the ovaries [15]. Progestins block 5α-reductase activity, and decrease testosterone receptor expression and gonadotrophin (FSH, LH) synthesis [11]. ...
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