Article

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

Authors:
  • Kinderwunschpraxis am Goetheplatz, Frankfurt
To read the full-text of this research, you can request a copy directly from the authors.

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.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... 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]. ...
Article
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. ...
Article
Full-text available
Background: Protective role of estrogen in COVID-19 was speculated once the epidemiological studies reported increased susceptibility of estrogen-deficient population - males and postmenopausal females to severe disease category and involvement of angiotensin-converting enzyme 2 receptors and renin-angiotensin- aldosterone system in pathophysiology. Materials & methods: An open-label randomized controlled trial was planned to assess the efficacy of short-course oral estradiol in preventing the clinical progression to severe disease and reduce case-fatality rate and the hospital stay duration in estrogen-deficient postmenopausal women. The intervention group (n = 40) received 2 mg per day of estradiol valerate per orally for 7 days along with the standard care, while the control group (n = 40) received only the standard care. Results: A significant difference was observed in the rate of reverse transcriptase-polymerase chain reaction negativization in the intervention versus control group at day 5 and day 7 of admission (42.5% vs. 15%, P = 0.007; 72.5% versus 50%, P = -0.026). No significant difference was noted in the duration of hospitalization (P = 0.213). A significant decrease was noted in the mean values of inflammatory biomarkers - D-dimer, lactate dehydrogenase, and C-reactive protein on day 5 in the intervention group. Interleukin-6 also showed a declining trend on day 5 in the intervention group, while a rising trend was noted in the control arm. Only one case (2.5%) in the intervention group while seven in the control group (17.5%) progressed to the moderate category; however, the difference was not statistically significant (P = 0.057). Conclusion: Oral estradiol in postmenopausal females can be a novel and efficient option for managing nonsevere COVID-19 infection.
... 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]. ...
Article
Full-text available
Hormonal contraception in both reproductive and late reproductive age, as well as contraceptive action, is used also for other indications like dysmenorrhoea, menstrual disorders, endometriosis, acne vulgaris, and hirsutism. Acne vulgaris and hirsutism are important signs related to hyperandrogenaemia and present a serious medical problem for the patients and a challenge for medical doctors in terms of effective treatment. The application of hormonal contraception to treat acne vulgaris and hirsutism requires knowledge of the mechanism of antiandrogenic actions and the possible contraindications and complications. These data are presented in this review.
Article
Full-text available
A consistent observation in osteoporosis is bone volume reduction accompanied by increased marrow adipose tissue. No single cause linking the two phenomena has yet been identified. In a human progenitor cell clone (hOP 7) derived from bone marrow, however, we have demonstrated that rabbit serum can direct differentiation away from an osteoblast lineage to one of adipocytes. We now report on whether human serum has a similar effect. Serum was collected from 10 pre- and 10 postmenopausal women and from the 10 postmenopausal women before and following 6-week hormone replacement therapy (HRT). hOP 7 cells were cultured with the various sera, and after 7-14 days adipocytogenesis was determined by oil red O staining and lipoprotein lipase (LPL) and glycerol 3-phosphate dehydrogenase (G3PDH) expression. Incubation with 10% premenopausal serum led to labeling of 10.9% of cells (P<0.05) with oil red O, whereas application of 10% postmenopausal serum led to a much larger effect, 43.5% labeling (P<0.001 with respect to premenopausal serum). Oil red O positivity was accompanied by loss of type I collagen expression and increased LPL and G3PDH expression. HRT did not reverse the adipocytogenic effect of postmenopausal serum. In conclusion, serum from postmenopausal women contains factors that steer hOP 7 bone progenitor cells toward an adipocytic phenotype, irrespective of HRT. The study suggests a role for serum factors in the development of fatty marrow in postmenopausal osteoporosis.
Article
Inflammation, and especially mononuclear cell adhesion to endothelium, is an important physiopathological component of atherosclerosis. Since coronary heart disease in women of reproductive age and/or with estrogen replacement therapy is reduced, our aim was to determine if 17beta-estradiol had a regulatory effect on the adhesion of lymphocytes to the endothelium. We performed U-937 cells adhesion assays in TNF-alpha-stimulated HUVECs, and we also quantitated IL-8 and MCP-1 in culture supernatants, in the presence or not of 17beta-estradiol. The presence of alpha- and beta-estrogen receptors was determined by Western blot and RT-PCR, respectively, whereas the transcription of both chemokines was evaluated by RT-PCR. The results showed a 35% decrease in the adhesion of U-937 monocyte cells to TNF-alpha-stimulated HUVECs, and a 54% and 65% inhibition of TNF-alpha-induced IL-8 and MCP-1 secretion by physiological and physiologically high doses of 17beta-estradiol. The hormone did not affect the transcription of both chemokine genes. Tamoxifen reverted the inhibitory effect induced by 17beta-estradiol. In conclusion, 17beta-estradiol modifies the adhesion of leukocytes to endothelial cells by inhibiting the secretion, but not the gene transcription, of proinflammatory chemokines.
ResearchGate has not been able to resolve any references for this publication.