Efficacy and acceptability of intranasal 17 β-oestradiol for menopausal symptoms: randomised dose-response study

Studd, John; Pornel, Bruno; Marton, I; Bringer, J.; Varin, Claire; Tsouderos, Y; Christiansen, Claus

doi:10.1016/s0140-6736(98)06196-0

Cited by 87 publications

(21 citation statements)

References 18 publications

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“…It displays completely different pharmacokinetics of plasma estradiol levels (Devissaguet et al 1999), leading to a transient exposure to high estradiol levels and introducing the new concept of pulsed estrogen therapy. In clinical trials, pulsed estrogen therapy has demonstrated a clinical efficacy similar to reference compounds on climacteric symptoms (Studd et al 1999, Lopes et al 2000 and bone (Garnero et al 1999) and has been shown to be safe on some estradiol target organs (Mattsson et al 2000), especially the endometrium (Gompel et al 2000).…”

Section: Discussionmentioning

confidence: 99%

“…The nasal route offers many advantages when compared with the oral route since it circumvents major estradiol intestinal and hepatic first pass effects (Hussain 1998) and their adverse repercussions (Lievertz 1987); moreover, the nasal mucosa has been proven to be a good absorption site for estradiol and several other steroid hormones. Comparative clinical and pharmacokinetic studies performed with reference products and conducted in postmenopausal women have demonstrated that nasal administration of Aerodiol at a dose of 300 µg estradiol resulted in the same efficacy on climacteric symptoms as oral estradiol at a dose of 2 mg (Studd et al 1999) and transdermal as estradiol at a dose of 50 µg/day (Lopes et al 2000); at these doses nasal, oral and transdermal formulations have close 24-h hormonal impregnation (Devissaguet et al 1999). …”

Section: Introductionmentioning

confidence: 99%

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Comparative activity of pulsed or continuous estradiol exposure on gene expression and proliferation of normal and tumoral human breast cells

Cavaillès

Gompel²,

Portois³

et al. 2002

Journal of Molecular Endocrinology

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Intranasal administration of hormone replacement therapy presents an original plasma kinetic profile with transient estrogen levels giving rise to the concept of pulsed therapy. To further understand the molecular effects of this new therapy, we have compared the effects of pulsed and continuous estradiol treatments on two critical aspects of estradiol action: gene expression and cell proliferation. Cells were stimulated with estradiol as 1-h pulsed or 24-h continuous treatments at concentrations such that the 24-h exposure (concentration×time) was identical in both conditions. In MCF7 cells, the transcriptional activity of estrogen receptors (ER) on a transiently transfected responsive estrogen response element-luciferase reporter construct was shown to be drastically (∼10-fold) and similarly stimulated after both treatments. Moreover, the increased mRNA expression of three representative estradiol-sensitive genes (pS2, cathepsin D, progesterone receptor), evaluated by Northern blot, was identical after 1-h pulse with 7 nM estradiol or continuous treatment with 0·29 nM estradiol with the same kinetic profile over 48 h. Proliferation was quantified by a histomorphometric method on primary cultures of human normal breast cells from reduction mammoplasties and using a fluorescence DNA assay in six human breast cancer cell lines which were ER positive or negative. After a 7-day treatment period, estradiol had no effect on the proliferation of the three ER negative cell lines (BT20, MDA MB231, SK BR3) but significantly stimulated the proliferation of the normal cells and of the three tumoral hormone-sensitive cell lines (MCF7, T47D, ZR 75-1); both hormone treatments producing the same increases in cell growth. In conclusion, we have shown that the genomic or proliferative effects of estradiol were identical with pulsed or continuous treatments, thus indicating that estrogenic effects are not strictly related to concentrations but rather to total hormone exposure.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparative activity of pulsed or continuous estradiol exposure on gene expression and proliferation of normal and tumoral human breast cells

Cavaillès

Gompel²,

Portois³

et al. 2002

Journal of Molecular Endocrinology

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“…After the 3-month, double blind, placebo-controlled trial, 112 of these women regardless of the treatment allocation during the first 3 months were further treated with intranasal E 2 (300 g/day), i.e. the dose that has been found to be optimal to reduce menopausal symptoms, as assessed by Kupperman index and incidence of hot flushes (23). During this second phase of the study, nonhysterectomized women received various cyclic progestative treatments, including MPA (5 mg/day), dydrogesterone (20 mg/day), chlormadinone acetate (10 mg/day), and promegestone (0.5 mg/day).…”

Section: Subjects and Methods Subjectsmentioning

confidence: 99%

“…As a consequence, daily intranasal administration results in a pulse-like estrogen profile, rather than the relatively sustained serum levels attained with both oral and transdermal administration (22). However, no study to date has ascertained whether a sustained profile is a requirement of efficacy, and it has recently been shown that intranasal E 2 increases serum estradiol exposure to levels similar to those achieved with oral E 2 (1-2 mg) and with an efficacy similar to that of oral estrogens in reducing menopausal symptoms (23).…”

mentioning

confidence: 99%

Effects of Intranasal 17β-Estradiol on Bone Turnover and Serum Insulin-Like Growth Factor I in Postmenopausal Women

Garnero

Tsouderos

Marton

et al. 1999

The Journal of Clinical Endocrinology &Amp; Metabolism

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Estrogen therapy, using either oral or transdermal routes, decreases bone turnover and prevents postmenopausal bone loss. It has been suggested that oral and transdermal 17␤-estradiol (E 2 ) may have different effects on serum insulin-like growth factor I (IGF-I), a potent bone-forming growth factor. In this study we investigated the effects of a new route of administration, the intranasal E 2 spray (S21400), on bone turnover and circulating IGF-I and IGF-binding protein-3 (IGFBP-3). Four hundred and twenty early postmenopausal women (Ͻ5 yr since menopause; mean age, 52 yr) were enrolled in a 3-month, double blind, placebo-controlled study of four doses of intranasal E 2 (100, 200, 300, and 400 g/day), two doses of oral E 2 valerate (1 or 2 mg/day), and placebo. One hundred and twelve women were further treated for 12 months with intranasal E 2 (300 g/day, i.e. the dose that has been shown to be adequate for the majority of postmenopausal women). Markers of bone resorption (urinary type I collagen C telopeptides) and formation [serum osteocalcin, serum type I collagen N-terminal extension propeptide (PINP), and serum bone alkaline phosphatase (BAP)] were measured at baseline, 1 month, 3 months, and 15 months. Serum IGF-I and IGFBP-3 were measured at baseline, 1 month, and 3 months. Urinary type I collagen C telopeptides decreased significantly in all active treatment groups as soon as 1 month (P Ͻ 0.001 vs. placebo) and continued to decrease at 3 months with a dose effect for intranasal E 2 . Serum osteocalcin and PINP did not change at 1 month for oral E 2 (1 and 2 mg), but decreased significantly at 3 months. In contrast, formation markers increased significantly at 1 month for the two highest doses of intranasal E 2 (P Ͻ 0.01 vs. placebo for osteocalcin and BAP) and did not decrease at 3 months. Oral E 2 induced a marked decrease in circulating IGF-I as early as 1 month, which was amplified at 3 months (Ϫ29% and Ϫ32% for 1 and 2 mg, respectively), whereas no significant change from placebo was observed for intranasal E 2 during the 3-month period. Changes in circulating IGF-I correlated significantly (P Ͻ 0.01) with changes in osteocalcin, PINP, and BAP at 3 months. Oral and intranasal E 2 did not induce any significant change from placebo in serum IGFBP-3 at both 1 and 3 months. After 1 yr of treatment with intranasal E 2 (300 g/day), both resorption and formation markers decreased, reaching the levels in premenopausal women, regardless of the type of treatment during the first 3 months.We conclude that E 2 administered by this new nasal route normalizes bone turnover to premenopausal levels. The delayed decrease in bone formation observed with intranasal E 2 compared to oral E 2 may be related to different effects on serum IGF-I levels. (J Clin Endocrinol Metab 84: 2390 -2397, 1999) E STROGEN supplementation, given mainly as conjugated equine extracts or 17␤-estradiol (E 2 ), has been shown to decrease bone turnover, prevent postmenopausal bone loss, and significantly reduce fracture risk in both ea...

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“…Clinical studies have demonstrated that pulsed therapy provides the same efficacy on climacteric symptoms as classical oral and transdermal therapy, when dosages are equivalent in terms of 24-h estrogen exposure [4]. Furthermore, the frequency of mastalgia and uterine bleeding has been found to be significantly lower with pulsed treatment compared with conventional estrogen administration [5,6].…”

Section: Introductionmentioning

confidence: 99%

Differing transcriptional responses to pulsed or continuous estradiol exposure in human umbilical vein endothelial cells

Li¹,

Wang²,

Johnson³

et al. 2008

The Journal of Steroid Biochemistry and Molecular Biology

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Efficacy and acceptability of intranasal 17 β-oestradiol for menopausal symptoms: randomised dose-response study

Cited by 87 publications

References 18 publications

Comparative activity of pulsed or continuous estradiol exposure on gene expression and proliferation of normal and tumoral human breast cells

Comparative activity of pulsed or continuous estradiol exposure on gene expression and proliferation of normal and tumoral human breast cells

Effects of Intranasal 17β-Estradiol on Bone Turnover and Serum Insulin-Like Growth Factor I in Postmenopausal Women

Differing transcriptional responses to pulsed or continuous estradiol exposure in human umbilical vein endothelial cells

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