Plasma Concentrations of Progesterone are Higher in the Uterine Artery than in the Radial Artery After Vaginal Administration of Micronized Progesterone in an Oil-Based Solution to Postmenopausal Women

Cicinelli, Ettore; Cignarelli, Mauro; Sabatelli, S; Romano, Francesco; Schönauer, Luca Maria; Padovano, Rossella; Einer‐Jensen, N.

doi:10.1016/s0015-0282(97)00545-1

Cited by 73 publications

(44 citation statements)

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“…We studied a vaginal preparation of progesterone, at a dose of 400 mg twice daily, and it is possible that the results with this regimen are not generalizable to patients receiving other doses and preparations. However, we chose this route to deliver a greater proportion of the drug to the biologically relevant site (i.e., the uterus), 13,14 and the dose used (400 mg twice daily) represents a dose at the top end of the therapeutic window. 15 Some researchers have suggested that intramuscular preparations of progesterone may provide greater therapeutic benefit than vaginal preparations; however, data are lacking to support this contention, and previous trials of alternative progesterone preparations (including intramuscular progesterone) have shown varying results.…”

Section: Discussionmentioning

confidence: 99%

A Randomized Trial of Progesterone in Women with Recurrent Miscarriages

et al. 2015

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BACKGROUNDProgesterone is essential for the maintenance of pregnancy. However, whether progesterone supplementation in the first trimester of pregnancy would increase the rate of live births among women with a history of unexplained recurrent miscarriages is uncertain. METHODSWe conducted a multicenter, double-blind, placebo-controlled, randomized trial to investigate whether treatment with progesterone would increase the rates of live births and newborn survival among women with unexplained recurrent miscarriage. We randomly assigned women with recurrent miscarriages to receive twicedaily vaginal suppositories containing either 400 mg of micronized progesterone or matched placebo from a time soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) through 12 weeks of gestation. The primary outcome was live birth after 24 weeks of gestation. RESULTSA total of 1568 women were assessed for eligibility, and 836 of these women who conceived naturally within 1 year and remained willing to participate in the trial were randomly assigned to receive either progesterone (404 women) or placebo (432 women). The follow-up rate for the primary outcome was 98.8% (826 of 836 women). In an intention-to-treat analysis, the rate of live births was 65.8% (262 of 398 women) in the progesterone group and 63.3% (271 of 428 women) in the placebo group (relative rate, 1.04; 95% confidence interval [CI], 0.94 to 1.15; rate difference, 2.5 percentage points; 95% CI, −4.0 to 9.0). There were no significant between-group differences in the rate of adverse events. CONCLUSIONSProgesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with a history of unexplained recurrent miscarriages.

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Section: Discussionmentioning

confidence: 99%

A Randomized Trial of Progesterone in Women with Recurrent Miscarriages

et al. 2015

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“…After vaginal administration of progesterone, the endometrial levels of the hormone were markedly higher than those expected based on the reached systemic levels 8) . Similarly, vaginal administration of micronized E2 results in preferential absorption of E2 into the endometrium, consistent with a "uterine first pass" effect 10) .…”

Section: Introductionmentioning

confidence: 67%

“…that, after transvaginal administration, steroids may distribute preferentially to the uterus thanks to the existence of local distribution mechanisms mostly based on counter-current transfer from veins to arteries 8,9) . After vaginal administration of progesterone, the endometrial levels of the hormone were markedly higher than those expected based on the reached systemic levels 8) .…”

Section: Introductionmentioning

confidence: 99%

Ophthalmic Artery Vasodilation after Intranasal Estradiol Use in Postmenopausal Women

Ciccone

Cicinelli

Alessio

et al. 2012

JAT

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Aim:The study aim was to evaluate the acute hemodynamic effects of intranasal 17-beta-estradiol on ophthalmic arterial circulation in postmenopausal women. Methods: Twenty-one healthy women in natural menopause for at least 6 months (mean age: 53.2± 2.9 years) were investigated. Each patient received 300 μg intranasal 17-beta-estradiol. We evaluated the heart rate, systolic and diastolic blood pressure, ophthalmic artery velocity at systolic and diastolic peak and its flow curve integral (FCI) before and 30, 60 and 180 minutes after the administration of the drug. Results: At all time points, the ophthalmic artery FCI showed statistically significant variations (p＜ 0.001) of velocity (cm/sec) compared to T0 (speed recorded at baseline before drug administration). Moreover, systolic blood pressure, diastolic blood pressure and heart rate did not significantly differ each other after drug administration. Conclusions: Administration of a single dose of intranasal 17-beta-estradiol to healthy postmenopausal women increases ophthalmic artery perfusion.

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“…3,[33][34][35] Our choice of administration via the vaginal route was, therefore, rational to deliver a greater proportion of drug to the relevant site (the uterus) using the 'first uterine pass' effect. 36,37 Furthermore, studies of vaginal progesterone in the prevention of preterm birth have shown its effectiveness when given via this route. 19,21,22 Therefore, we believe that any alternative preparation or route of administration is unlikely to result in a greater effect.…”

Section: Contextual Suitabilitymentioning

confidence: 99%

PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages – a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation

Coomarasamy

Williams

Truchanowicz

et al. 2016

Health Technol Assess

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Background and objectivesProgesterone is essential to maintain a healthy pregnancy. Guidance from the Royal College of Obstetricians and Gynaecologists and a Cochrane review called for a definitive trial to test whether or not progesterone therapy in the first trimester could reduce the risk of miscarriage in women with a history of unexplained recurrent miscarriage (RM). The PROMISE trial was conducted to answer this question. A concurrent cost-effectiveness analysis was conducted.Design and settingA randomised, double-blind, placebo-controlled, international multicentre study, with economic evaluation, conducted in hospital settings across the UK (36 sites) and in the Netherlands (nine sites).Participants and interventionsWomen with unexplained RM (three or more first-trimester losses), aged between 18 and 39 years at randomisation, conceiving naturally and giving informed consent, received either micronised progesterone (Utrogestan®, Besins Healthcare) at a dose of 400 mg (two vaginal capsules of 200 mg) or placebo vaginal capsules twice daily, administered vaginally from soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) until 12 completed weeks of gestation (or earlier if the pregnancy ended before 12 weeks).Main outcome measuresLive birth beyond 24 completed weeks of gestation (primary outcome), clinical pregnancy at 6–8 weeks, ongoing pregnancy at 12 weeks, miscarriage, gestation at delivery, neonatal survival at 28 days of life, congenital abnormalities and resource use.MethodsParticipants were randomised after confirmation of pregnancy. Randomisation was performed online via a secure internet facility. Data were collected on four occasions of outcome assessment after randomisation, up to 28 days after birth.ResultsA total of 1568 participants were screened for eligibility. Of the 836 women randomised between 2010 and 2013, 404 received progesterone and 432 received placebo. The baseline data (age, body mass index, maternal ethnicity, smoking status and parity) of the participants were comparable in the two arms of the trial. The follow-up rate to primary outcome was 826 out of 836 (98.8%). The live birth rate in the progesterone group was 65.8% (262/398) and in the placebo group it was 63.3% (271/428), giving a relative risk of 1.04 (95% confidence interval 0.94 to 1.15;p = 0.45). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Economic analysis suggested a favourable incremental cost-effectiveness ratio for decision-making but wide confidence intervals indicated a high level of uncertainty in the health benefits. Additional sensitivity analysis suggested the probability that progesterone would fall within the National Institute for Health and Care Excellence’s threshold of £20,000–30,000 per quality-adjusted life-year as between 0.7145 and 0.7341.ConclusionsThere is no evidence that first-trimester progesterone therapy improves outcomes in women with a history of unexplained RM.LimitationsThis study did not explore the effect of treatment with other progesterone preparations or treatment during the luteal phase of the menstrual cycle.Future workFuture research could explore the efficacy of progesterone supplementation administered during the luteal phase of the menstrual cycle in women attempting natural conception despite a history of RM.Trial registrationCurrent Controlled Trials ISRCTN92644181; EudraCT 2009-011208-42; Research Ethics Committee 09/H1208/44.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 20, No. 41. See the NIHR Journals Library website for further project information.

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Plasma Concentrations of Progesterone are Higher in the Uterine Artery than in the Radial Artery After Vaginal Administration of Micronized Progesterone in an Oil-Based Solution to Postmenopausal Women

Cited by 73 publications

References 11 publications

A Randomized Trial of Progesterone in Women with Recurrent Miscarriages

A Randomized Trial of Progesterone in Women with Recurrent Miscarriages

Ophthalmic Artery Vasodilation after Intranasal Estradiol Use in Postmenopausal Women

PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages – a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation

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