Pharmacokinetics and systemic endocrine effects of the phyto‐oestrogen 8‐prenylnaringenin after single oral doses to postmenopausal women

M, Rad; Hümpel, M.; Schaefer, Olaf; Schoemaker, Rik C.; Schleuning, WD; Af, Cohen; Burggraaf, Jacobus

doi:10.1111/j.1365-2125.2006.02656.x

Cited by 89 publications

(100 citation statements)

References 29 publications

(33 reference statements)

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“…It could be demonstrated that daily intake over 12 weeks of a hop extract, standardized on 250 mg 8-PN, exerted favorable effects on vasomotor symptoms and other menopausal discomforts (Heyerick et al 2006). Consistent with these findings, Rad et al (2006) reported that a single dose of 750 mg 8-PN reduced LH serum levels in postmenopausal women. Interestingly, it appeared from these experiments that 8-PN was well tolerated by these women.…”

Section: Introductionsupporting

confidence: 78%

Effects of long-term treatment with 8-prenylnaringenin and oral estradiol on the GH–IGF-1 axis and lipid metabolism in rats

Böttner¹,

Christoffel²,

Wuttke³

2008

Journal of Endocrinology

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After the heart and estrogen/progestin replacement study and the women's health initiative study, the prospect of hormone replacement therapy (HRT) on cardiovascular diseases (CVD) has changed dramatically. These findings led to various attempts to search for alternatives for classical HRT, e.g. phytoestrogens.The flavanone 8-prenylnaringenin (8-PN) was identified as a phytoestrogen with strong estrogen receptor-a activity. As the pituitary and the liver are targets for estrogen action, we assessed the effect of ovariectomy (OVX) and long-term treatment (3 months) with 17-b estradiol benzoate (E 2 B) and 8-PN on pituitary and liver functions in adult OVX rats. Tested doses were 6 . 8 and 68 . 4 mg/kg body weight (BW) of 8-PN and 0 . 17 and 0 . 7 mg/kg BWof E 2 B. Our results demonstrate that 8-PN and E 2 B decreased BW and increased uterus weight. The high doses of E 2 B and 8-PN increased serum GH and decreased serum IGF-1 levels. E 2 B dose dependently decreased cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) concentrations in OVX rats. The high dose of 8-PN showed an estrogenic activity regarding cholesterol and LDL regulation but had no effect on HDL concentrations. By contrast, the low dose of 8-PN augmented HDL levels compared with intact rats. Triglyceride levels were raised in response to the high E 2 B dose but unaffected by 8-PN treatment. Taken together, 8-PN displays an anti-atherosclerotic profile that appears to be even more beneficial than the one displayed by E 2 B, and thus might demonstrate a remarkable potential for the prevention of CVD associated with estrogen deficiency.

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Section: Introductionsupporting

confidence: 78%

Effects of long-term treatment with 8-prenylnaringenin and oral estradiol on the GH–IGF-1 axis and lipid metabolism in rats

Böttner¹,

Christoffel²,

Wuttke³

2008

Journal of Endocrinology

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“…6-DMAN, although possessing a different substituent, fits nicely Page 13 of 29 A c c e p t e d M a n u s c r i p t within this range. Some authors suggest that 8-PN may have beneficial effects in postmenopausal women and may become an alternative to classical HRT treatment regimes (Rad et al, 2006). Our data indicate that 6-DMAN with its lack of uterine stimulation might match the criteria for HRT much better than the pure E2 agonist 8-PN, because it lacks the proliferational effect on the endometrial cells which may increase the risk of formation of endometrial carcinoma.…”

Section: Discussionmentioning

confidence: 68%

Time dependency of uterine effects of naringenin type phytoestrogens in vivo

Zierau

Kretzschmar

Möller

et al. 2008

Molecular and Cellular Endocrinology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Page 1 of 29A c c e p t e d M a n u s c r i p t

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“…Recently, 8-PN was tested in animals [26,27] and in a human phase I clinical trial [28]. While H. lupulus extracts have also been tested in two phase I clinical trials in menopausal women [29], extracts have not been rigorously tested in vivo following the identification of 8-PN as the compound primarily responsible for estrogenic activity.…”

Section: Introductionmentioning

confidence: 99%

“…Conjugates of 8-PN were also reported in urine of men after consuming beer or beer spiked with 8-PN [25], but the radioimmunoassay used in this study did not allow for the identification of specific conjugates. However, little information is available concerning the formation of metabolites of 8-PN in vivo.Recently, 8-PN was tested in animals [26,27] and in a human phase I clinical trial [28]. While H. lupulus extracts have also been tested in two phase I clinical trials in menopausal women [29], extracts have not been rigorously tested in vivo following the identification of 8-PN as the compound primarily responsible for estrogenic activity.…”

mentioning

confidence: 99%

In vivo estrogenic comparisons of Trifolium pratense (red clover) Humulus lupulus (hops), and the pure compounds isoxanthohumol and 8-prenylnaringenin

Overk

Guo

Chadwick

et al. 2008

Chemico-Biological Interactions

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The lack of a safe and reliable alternative to hormone therapy (HT) for treating menopausal symptoms underscores the need for alternative therapies. OBJECTIVE: The purpose of this study was to assess the in vivo estrogenic effects of the botanical dietary supplements Trifolium pratense (red clover) and Humulus lupulus (hops), and two compounds obtained from H. lupulus, isoxanthohumol and 8-prenylnaringenin (8-PN) using the ovariectomized uterotrophic adult rat model. A H. lupulus extract and a 30% isoflavone extract of T. pratense were tested at three escalating doses as was one dose of isoxanthohumol for 21 days. 8-Prenylnaringenin, the major estrogen in H. lupulus, was also tested at three relevant escalating doses. In order to determine the in vivo metabolism of 8-PN, the major Phase I and Phase II metabolites were also identified. The primary outcome measure, uterus weight gain, indicated that H. lupulus and T. pratense did not have an estrogenic effect on the uterus, and none of the secondary outcome measures were positive. In contrast, there was a clear dose response when 8-PN was evaluated where the middle and high doses of 8-PN were active. 8-Prenylnaringenin in rat plasma, liver, and mammary gland was measured and the major Phase I and Phase II 8-PN metabolites were detected. Our findings suggest that while both the H. lupulus and T. pratense extracts do not have an effect on the rat uterus, 8-PN at equivalent doses to those previously used in humans did have an effect, and may therefore have a deleterious effect in women. IntroductionSymptoms associated with menopause such as insomnia, loss of libido, vaginal atrophy, depression, and hot flashes can greatly affect the quality of life for women. Many women have used hormone therapy (HT) to alleviate menopausal symptoms; however, with the publication The strobiles of Humulus lupulus L. (Cannabaceae) (hops) are primarily used to flavor beer, and have been studied since 1953 for a potential estrogenic mechanism of action [13][14][15]. In the past, the flavonoids 8-PN and 6-PN, and the chalcone, isoxanthohumol (IX), have been isolated and reported to be estrogenic in vitro and/or in vivo [16,17]. The most potent estrogen in H. lupulus is 8-PN, which is in actuality an artifact formed through isomerization of the precursor chalcone, desmethylxanthohumol [18,19]. 8-Prenylnaringenin has been shown in a variety of in vitro assays to be estrogenic in the nanomolar range [16,17,20,21]. It can also be formed from precursors such as IX, and xanthohumol (XH), through metabolism [22].In previous metabolic studies, it has been shown that human liver microsomes convert 8-PN to 12 metabolites [22]. Among them, are the most abundant monooxygenated metabolites (Figure 1). The estrogenicities of the 8-PN alcohols have been previously determined [23] and were found to be ∼10 fold less estrogenic than 8-PN. Phase II metabolites of 8-PN, including glucuronides and sulfate conjugates, have been identified in incubations with human Caco-2 cells and human hepatocytes [2...

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Pharmacokinetics and systemic endocrine effects of the phyto‐oestrogen 8‐prenylnaringenin after single oral doses to postmenopausal women

Cited by 89 publications

References 29 publications

Effects of long-term treatment with 8-prenylnaringenin and oral estradiol on the GH–IGF-1 axis and lipid metabolism in rats

Effects of long-term treatment with 8-prenylnaringenin and oral estradiol on the GH–IGF-1 axis and lipid metabolism in rats

Time dependency of uterine effects of naringenin type phytoestrogens in vivo

In vivo estrogenic comparisons of Trifolium pratense (red clover) Humulus lupulus (hops), and the pure compounds isoxanthohumol and 8-prenylnaringenin

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