Plasma Estrogen Levels Research Articles

P-789: Novel method of ovulation induction for the patients of so-called poor responders

It is well known that there are some patients who cannot response properly by the exogenous administration of gonadotropin preparations. In addition, it is reported that plasma estrogen levels can modify the activities of gonadotropin receptors. Present study was performed to elucidate whether exogenous administration of estrogen preparation with Gn-RH agonist was effective to improve the response of gonadotropin administration in the patients of gonadotropin resistance syndrome. Open clinical trial under enough informed consents. Thirty-three patients who have resistance to gonadotropin therapy were subjected (35.4+/-3.2 years old). All of them had experiences of previous treatment of hMG (up to 600iu/day), and could not respond to the treatment (plasma estradiol levels, before: 15.3+/-5.1, after: 39.6+/-15.9 pg/ml). They were diagnosed as hyper-gonadotropic hypo-gonadismic state. Then, exogenous estrogen (conjugated equine estrogen: 1.25 - 2.5mg/day, or trans-dermal Estraderm M: 2-3 sheets/2days) was administered for 2 weeks with Gn-RH agonist (leuprorelin 1.88mg s.c.). After that, hMG preparation (Humegon 150iu/day) was administered to the subjects with estrogen preparations in gradual increasing method up to 600iu/day, and the follicular growths were observed by the transvaginal ultrasonic scanner. Then, 10000iu of hCG injection was performed when the matured follicles (diameter over 18mm) were observed, and the proper luteal support (administration of progesterone vaginal tablets, 60mg/day, for 2 weeks) was also done. Plasma FSH (before estrogen + Gn-RH agonist administration: 43.1+/-10.5, after: 7.3+/-3.1mIU/ml) and LH (before: 24.6+/-8.8, after: 5.8+/-2.6mIU/ml) decreased significantly by estrogen and Gn-RH agonist administration (p<0.001). Plasma estradiol levels increased up to 247.3+/-42.5 pg/ml after exogenous estrogen administration (p<0.001, compared to the levels before treatment). Twenty-seven cases out of 33 (total 102 cycles) could get mature follicles (over 18mm, 4.0+/-1.1 /case). Total dose of hMG preparation was 2375.6+/-239.0iu/case, and plasma estradiol level before hCG injection was 2220.5+/-472.2pg/ml. Twelve cases could get pregnancies (ten singletons and two twin) during this study. No severe side effect, such as ovarian hyper stimulation syndrome, was observed. It was suggested that gonadotropin receptors might be activated by the administration of exogenous estrogens, and the controlled ovarian stimulation using hMG with Gn-RH agonist after exogenous estrogen priming was effective for the treatment of the intractable ovulatory disturbances.

Estrus cycle: influence on cardiac function following trauma-hemorrhage

Since cardiac function is depressed in males but not in proestrus (PE) females following trauma-hemorrhage (T-H), we examined whether different estrus cycles influence cardiac function in female rats under those conditions. We hypothesized that females in the PE cycle only will have normal cardiac function following T-H and resuscitation. Sham operation or T-H was performed in five groups of rats (250-275 g) including PE, estrus (E), metestrus (ME), diestrus (DE), and ovariectomized (OVX) females (n = 6-7 per group). Cardiac function was determined 2 h after T-H, following which cardiomyocytes were isolated and nuclei extracted. Cardiomyocyte IL-6 and NF-kappaB expressions were measured using Western blotting. Moreover, plasma IL-6, estradiol, and progesterone levels were measured using ELISA or EIA kits. Results (1-way ANOVA) indicated that following T-H, 1) cardiac function was depressed in DE, E, ME, and OVX groups but maintained in the PE group; 2) the PE group had the highest plasma estrogen level; 3) plasma IL-6 levels increased significantly in DE, E, ME, and OVX groups, but the increase was attenuated in the PE group; 4) cardiomyocyte IL-6 protein level increased significantly in DE, E, ME and OVX groups after TH, but the increase was attenuated in the PE group; and 5) cardiomyocyte NF-kappaB expression increased significantly but was attenuated in the PE group. These data collectively suggest that the estrus cycle plays an important role in cardiac function following TH. The salutary effect seen in PE following TH is likely due to a decrease in NF-kappaB-dependent cardiac IL-6 pathway.

No Association between Progesterone Receptor Gene +331G/A Polymorphism and Endometrial Cancer

The major hypothesis proposed to explain endometrial cancer risk is the unopposed estrogen hypothesis which states that elevated levels of plasma estrogens not counterbalanced by high levels of plasma progesterone increase risk of endometrial cancer ([1][1]-[3][2]). The action of progesterone on

Omental and subcutaneous adipose tissue steroid levels in obese men

We examined plasma and fat tissue sex steroid levels in a sample of 28 men aged 24.8–62.2 years (average BMI value of 46.3 ± 12.7 kg/m 2). Abdominal adipose tissue biopsies were obtained during general or obesity surgery. Omental and subcutaneous adipose tissue steroid levels were measured by gas chromatography and chemical ionization mass spectrometry after appropriate extraction procedures. BMI and waist circumference were negatively correlated with plasma testosterone ( r = −0.49 and −0.50, respectively, p < 0.01) and dihydrotestosterone ( r = −0.58 and −0.56, respectively, p < 0.01), and positively associated with estrone levels ( r = 0.64 and 0.62, respectively, p < 0.001). Regional differences in adipose tissue steroid levels were observed for dihydrotestosterone ( p < 0.005), androstenedione ( p < 0.0001) and dehydroepiandrosterone levels ( p < 0.05), which were all significantly more concentrated in omental versus subcutaneous fat. Positive significant associations were found between circulating level of a steroid and its concentration in omental and subcutaneous adipose tissue, for estrone ( r = 0.72 and 0.57, respectively, p < 0.01), testosterone ( r = 0.66 and 0.58, respectively, p < 0.01) and dihydrotestosterone ( r = 0.58 and 0.45, respectively, p < 0.05). Positive correlations were observed between plasma dehydroepiandrosterone-sulfate and omental ( r = 0.56, p < 0.01) as well as subcutaneous adipose tissue dehydroepiandrosterone level ( r = 0.38, p = 0.05). Positive significant associations were found between omental adipocyte responsiveness to positive lipolytic stimuli (isoproterenol, dibutyryl cyclic AMP and forskolin) and plasma or omental fat tissue androgen levels. In conclusion, although plasma androgen or estrogen levels are strong correlates of adipose tissue steroid content both in the omental and subcutaneous fat depots, regional differences may be observed. Androgen concentration differences in omental versus subcutaneous adipose tissue suggest a depot-specific impact of these hormones on adipocyte function and metabolism.

Future Directions in the Treatment of Hormone-Sensitive Advanced Breast Cancer: The RAD001 (Everolimus)-Letrozole Clinical Program

Therapeutics that interfere with estrogen receptor function (antiestrogens, eg, tamoxifen; aromatase inhibitors, eg, letrozole) have contributed to a dramatic reduction in breast cancer mortality; however, not all estrogen-receptor-positive breast cancers respond. The mammalian target-of-rapamycin (mTOR) is emerging as an important target molecule in the treatment of breast cancer. Furthermore, activation of growth-factor signaling pathways that involve mTOR may contribute to both the failure of endocrine therapy as well as the development of resistance. RAD001 (everolimus) is a potent, orally bioavailable inhibitor of the mTOR pathway. Preclinical data show that RAD001 effectively inhibits the proliferation and growth of a number of cancer cell lines in vitro and a range of tumor types in experimental animal models of cancer. Moreover, RAD001 exhibits an antiangiogenic activity, which may also contribute to its anticancer activity. The aromatase inhibitor letrozole is a potent endocrine therapy for breast cancer that acts to inhibit the aromatization of androgens, thereby reducing plasma and tumor estrogen levels. Combining RAD001 with letrozole is a rational approach to the treatment of advanced breast cancer, offering the potential for inhibition of tumor cell growth/proliferation and angiogenesis while at the same time potentially preventing the development of letrozole resistance. Preclinical data, derived from aromatase-expressing, estrogen-receptor-positive breast tumor models, suggest a synergistic interaction between RAD001 and letrozole that results in more profound effects on proliferation and the induction of tumor cell death. Importantly, early clinical data show no pharmacokinetic interaction or increase in toxicity with combined treatment, as compared with treatment with RAD001 alone, and there is evidence of antitumor activity. Enrollment into phase II studies is presently underway.

Expression of steroid hormone receptors, proliferation and apoptotic markers in primate endometrium

In humans, circulating levels of steroid hormones vary during the menstrual cycle, with oestrogen elevated in the proliferative phase and progesterone increased during the secretory phase. In humans, oestrogen levels also increased during the mid-secretory phase, but this is not observed in non-human primates. In marmosets, the New World monkeys, plasma oestrogen and progesterone levels exhibit similar profiles as those found in Old World monkeys, however, these animals do not menstruate. Proliferative and apoptotic changes occur at specific phases of the menstrual cycle, suggesting regulation by steroid hormones. It was, therefore, of interest to compare expression of steroid hormone receptors, proliferation and apoptotic markers in the uterine endometrium of marmosets and humans. Localization of oestrogen receptor-α (ER-α) was observed in glandular epithelial cells during the proliferative phase in marmosets and in human endometria. A decrease in ER-α and progesterone receptor (PR-A) was observed during the mid luteal phase in both species although a postovulatory oestradiol peak is observed in human but not in marmoset. A decrease in PR-A in the late secretory phase was seen in marmoset as well as in human endometria. The proliferation marker PCNA was enhanced in the proliferative phase in both species, but it was increased in late secretory phase only in marmosets. Apoptosis as revealed by a TUNEL assay was moderate in early stage in both species. Surprisingly, apoptosis, as well as the localization of the pro-apoptotic Bcl-2 family member, Bax, was optimal in marmosets during the mid-secretory phase when plasma progesterone levels were high. On the other hand, in the human, apoptosis was maximal by TUNEL assay in late secretory phase, but Bax protein was highest in the mid-secretory phase. Thus, Bax may be initiating apoptosis in the endometrial glands as well as in the stroma. Although the pattern of steroid receptor expression in endometria of marmosets and humans are similar, proliferation and apoptosis markers appear to be regulated by other factors along with steroid hormones.

A Case of Factitious Adrenal Insufficiency after Vascular Graft Surgery Caused by Spurious Immunometric Assays

A 70-year-old man with abdominal aortic aneurysm underwent surgical repair with Hemashield vascular graft. Postoperatively, he was found to have very low plasma cortisol levels, which failed to increase after stimulation with ACTH. A tentative diagnosis of adrenal insufficiency was made despite the lack of its clinical manifestations and a replacement therapy with hydrocortisone was started. He had also elevated plasma levels of TSH, thyroid hormones and estrogen without any clinical manifestations. Such abnormal hormone levels were spontaneously normalized three months after operation, which was later proven to be factitious by different immunometric assays (IMA). Since the vascular graft coated with bovine type I collagen has been reported to induce a transient immune response in some patients after surgery, we speculated that certain antibodies generated against heterologous collagen and/or yet-unknown components derived from the graft may have caused such factitious data; exogenous addition of bovine type I collagen and albumin to patient's serum, however, failed to affect the assay results. Whatever the cause, caution must be paid that some patients with surgical repair using heterologous materials may have such factitious hormone data by IMAs.

Acute Toxicity of Administered Bisphenol A Di Glycidyl Ether in Male Sprague Dawley Rats

Objectives: Bisphenol A Di Glycidyl Ether (BADGE) is the major component in commercial liquid epoxy resins, which are manufactured by co-reacting bisphenol A with epichlorohydrin. The authors investigated the acute toxicity of BADGE. Methods: BADGE was administered by a gavage to 8 week old SPF Sprague Dawley rats in a single dose of 0 (negative control), 0.37 (Diethylstilbesterol, DES), 1000, 2000, 4000, and 8000 mg/kg/day of BADGE. Each treatment group contained 7 rats. The general status and weight of the rats were observed for 14 days. The rats were anesthetized by ether at 14 days, and the changes in morphology, organ weight, sperm count and motility, and hormone level were measured. Results: All the rats treated with BADGE had diarrhea on the 1st day. The rats administered BADGE at 1000, 2000, and 4000 mg/kg/day showed a soiled perineal region and soft stools with diarrhea until the 3rd day. The 8000 mg/kg/day BADGE rats had diarrhea for two days followed by emaciation, soiled fur, a soiled perineal region, staining around the mouth and were moribund for three to eight days. No weight gain was observed after the 1st day in the 2000, 4000, and 8000 mg/kg/day BADGE rats and after the 7th day in all the treatment groups compared with the control groups. Some treatment groups were observed to have a decrease in the weight of the heart (BADGE 1000, 2000 and 4000 mg/kg/day), liver (BADGE 1000, 2000, 4000 and 8000 mg/kg/day) and prostate (BADGE 4000 mg/kg/day) compared with control group. The weight of the liver was significantly lower in all treatment groups compared with the control group. The relative weight of the liver (BADGE 1000 and 4000 mg/kg/day) was significant lower than the control. No pathological changes were observed in the brain, liver, thyroid, heart, spleen, kidney, lung and prostate. The number of spermatid in the seminiferous tubule in the testes was lower in all treatment groups than the control. The sperm motility tended to decrease with increasing concentration but the sperm count was similar in all treatment groups. The plasma Estrogen and testosterone level were similar in the control and treatment groups. Conclusions: These results suggest that BADGE induces general, hepatic and reproductive toxicity at 1000 mg/kg/day.

The effect of dexamethasone on disruption of ovarian steroid levels and receptors in female rats

This study was conducted to investigate if the injection of a single dose of dexamethasone may cause disruption of adult female rat gonadal function in terms of plasma and ovarian level of both androgen and estrogen, ovarian morphology, and changes in localization of androgen, estrogen and glucocorticoid receptors. Adult female Long Evans rats (n=50, 250-300 g) were used. At day 0 rats received subcutaneously 1 ml of saline (n=25; control group) or dexamethasone at 0.1 mg/kg (n=25, treated group). Rats were sacrificed in groups of five on days 10, 15, 20, 25 and 30 after injection. Blood samples and one ovary were collected to analyze dexamethasone, 17beta-estradiol (E2), testosterone (T) and androstenedione (A4) concentrations by amplified EIA. The remaining ovary was removed and processed for histopathology and immunocytochemistry. Differences between individual means were analyzed by Pairwise t-test and Bonferroni post test to asses whether values presented statistical significance. Increased E2, T and A4 levels were observed both in plasma and ovary samples in treated group when comparing with control (p< 0.01) at all days post-injection even when dexamethasone was undetectable. Ovarian morphology of treated group showed features compatible with female infertility. Inmmunolocalization of androgen and estrogen receptors showed that both were negative in treated group while controls showed highest positivity (AR +++, ER ++). Glucocorticoid receptor showed higher positivity in dexamethasone treated rats (GR ++) than in controls (GR +). Obtained results showed clear evidence that a single dose of dexamethasone may disrupt gonadal function in rats, and that possibly leads to infertility.

Treatment with high-dose estrogen (diethylstilbestrol) significantly decreases plasma estrogen and androgen levels but does not influence in vivo aromatization in postmenopausal breast cancer patients

While growth factors and hormones are known to influence aromatase expression in experimental systems, little is know about potential factors influencing peripheral aromatization in postmenopausal women. The fact that peripheral aromatase activity is higher in old compared to young women and the finding of relatively high tissue estradiol (E 2) concentrations after the menopause suggests peripheral aromatization could be influenced by estrogen concentration. To test this hypothesis, we determined plasma hormone levels ( n = 9) and in vivo aromatization ( n = 3) in postmenopausal women suffering from advanced breast cancer before and during treatment (4 weeks) with diethylstilbestrol (DES) 5 mg three times daily. Plasma levels of cortisol (C), corticosteroid-binding globulin (CBG), and sex hormone binding globulin (SHBG) were significantly increased in all patients ( P < 0.05 for all). While we found no change in total body aromatization and plasma estrone (E 1) levels, estradiol (E 2) and estrone sulfate (E 1S) were suppressed by a mean of 48.8 and 68.2%, respectively ( P = 0.043 and 0.008). Surprisingly, plasma levels of androstenedione (A), testosterone (T), dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) were also suppressed by a mean in the range of 32.1 to 52.6% ( P < 0.05 for all androgens). In contrast, no change in plasma progesterone or 17α-hydroxyprogesterone was found. Thus, one possible explanation to our findings could be that DES administered in high doses reduces 17,20-lyase activity in the adrenal gland.

The role of noradrenaline in the generation of the preovulatory LH surge in the ewe

Increasing plasma estrogen (E) levels during the follicular phase of the estrous cycle trigger the pre-ovulatory surge of gonadotropin-releasing hormone (GnRH)/LH. Noradrenaline (NA)-producing cells of the brain stem are involved in regulating GnRH cells and project to the preoptic area (POA) and bed nucleus of stria terminalis (BnST). Input to GnRH cells may be direct or indirect, via relay neurons in the POA/BnST. To investigate this, we ascertained whether an α 1-adrenergic antagonist would block/delay the LH surge in ovariectomised (OVX), E-treated ewes. E benzoate (EB) (50 μg) was injected (i.m.) and Doxazosin (100 nmol/h) or vehicle was infused into the third ventricle 2–26 h after EB injection. Doxazosin reduced the magnitude of the LH surge, but did not affect timing. To determine if NA is released in the POA/BnST of cyclic ewes, we immunostained dopamine-β-hydroxylase (DBH) in terminal fields. Reduced numbers of varicosities staining for DBH indicates release of NA. The number of varicosities immunostained for DBH was reduced in the dorsal and lateral BnST during the follicular phase and during the preovulatory LH surge compared to the luteal phase. These data suggest that noradrenergic mechanisms are involved in generation of the GnRH/LH surge via projections to the BnST and relay to GnRH cells. Since Doxasozin reduced the magnitude of the LH surge in the E-treated OVX ewe, and release of NA in cyclic ewes occurred during the follicular phase of the estrous cycle, we speculate that NA is a permissive factor in surge generation. Thus, increased noradrenergic activity is not a trigger mechanism for initiation of the surge.

A hypothalamic endorphinic lesion attenuates acquisition of cocaine self-administration in the rat

The present study explores the role of β-endorphin-producing neurons of the arcuate nucleus in the behavioral effects of cocaine (i.e. acquisition of cocaine self-administration). Eight-week-old female rats were treated with a single estradiol valerate injection that causes a progressive lesion that is specific to β-endorphin-producing neurons throughout the arcuate nucleus. Cocaine acquisition was suppressed following estradiol valerate pretreatment, while water reinforced behavior was similar to controls. Since estradiol valerate treated rats exhibit low estrogen plasma levels, estrogen replacement was performed but cocaine self-administration acquisition remained suppressed. In addition, analysis of β-endorphin, dopamine, and DOPAC tissue levels confirmed the specificity of the endorphinic lesion resulting from estradiol valerate treatment. The suppression of cocaine self-administration acquisition following estradiol valerate treatment provides evidence for a significant role for β-endorphin in cocaine reward.

The stress system in the human brain in depression and neurodegeneration

The stress system in the human brain in depression and neurodegeneration

Endocrine effects of aromatase inhibitors and inactivators in vivo: Review of data and method limitations

The so-called “third-generation” aromatase inhibitors/inactivators have become standard first-line endocrine therapy for postmenopausal women in the metastatic setting. In addition, these compounds, administered as monotherapy or in sequence with tamoxifen, are likely to become standard adjuvant therapy in most countries in the near future. In contrast to the SERMs, aromatase inhibitors may be assessed for their biochemical efficacy in vivo either by measuring their ability to suppress plasma and tissue estrogen levels or, alternatively, by measuring their ability to inhibit the conversion of tracer-labelled androstenedione into estrone. While contemporary methods for estrogen measurement (with the exception of estrone sulphate) lack the sensitivity to measure plasma estrogen levels during treatment with the most potent compounds, in vivo aromatase inhibition can be determined with a much better sensitivity. Thus, in a joint program conducted by the Royal Marsden Hospital, London and our team in Bergen, we were able to reveal profound differences between first- and second-generation aromatase inhibitors, causing 50–90% aromatase inhibition, and the three third-generation compounds, causing >98% inhibition of total body aromatization.

Aromatase inhibitors: Future directions

Estrogen and its cognate estrogen receptor are key players in the etiology and progression of breast cancer. Aromatase inhibitors, suppressing tumor and plasma estrogen levels by blocking testosterone conversion to estrogen, have been proven to provide the most effective endocrine therapy for postmenopausal breast cancer patients. Aromatase inhibitors are now the first choice endocrine therapy in the metastatic setting for postmenopausal women. These endocrine agents also seem likely to soon become the standard adjuvant therapy, either alone or in sequence with tamoxifen, though their long-term toxicity and the optimum duration of therapy still remain to be defined. Advanced experimental studies and some clinical observations reveal the importance of blocking both the genomic and non-genomic activities of the estrogen receptor, as well as its crosstalk with growth factor and other cellular signaling, for greatest effectiveness of endocrine therapy. Consequently, these studies provide a mechanistic explanation for the superb performance of aromatase inhibitors, and also suggest how inhibiting selected growth factor receptors might delay or prevent the onset of resistance to aromatase inhibitors and other endocrine therapies.

Endogenous Estrogens Increase Postischemic Hyperemia in the Skin Microcirculation

Estrogens have been recognized as a major regulator of vascular tone and structure, particularly in the skin. The objective of this study was to investigate the effects of endogenous estrogens on the skin microcirculation. Skin blood flow was measured at the forearm at rest and during postischemic hyperemia using laser Doppler flowmetry in 32 healthy women (mean age 34.5 +/- 3.9 years) involved in an in-vitro fertilization program. Women were treated for 10 to 12 days with gonadotropin-releasing hormone agonist (total dose 40.3 +/- 3.3 mg) and human menopausal gonadotropin (1942 +/- 801 IE) or follicle-stimulating hormone (2544 +/- 1071 IE) according to individual estrogen levels. Plasma estrogen levels increased from 132 +/- 90 pmol/L (36 +/- 25 pg/mL) to 8471 +/- 4386 pmol/L (2308 +/- 1195 pg/mL) during treatment (P < 0.0001). Maximal hyperemic blood flow increased from 353 +/- 81% before treatment to 516 +/- 144% after hormonal stimulation (P < 0.0001), whereas basal skin flow was not altered. This study shows that endogenous estrogens enhance the postischemic hyperemic response of the skin microcirculation.

Comparison of pituitary–ovarian function in patients who have undergone successful renal transplantation and healthy women

Twenty-eight renal transplantation patients, aged 19-35 years, and 30 healthy women of reproductive age were enrolled into the study. Analyses revealed significant differences between study and control groups' midluteal serum P levels and between study and control groups' serum PRL levels. Although most renal transplantation patients have plasma estrogen and gonadotropin levels similar to those in healthy women, several problems, such as luteal phase defect, might affect transplant recipients.

Gonadal steroids vary with reproductive stage in a tropically breeding female anuran

Tropically breeding anurans that require heavy rainfall in order to reproduce are subject to favorable breeding conditions that are sporadic. Although there is an increased probability of rain during the rainy season, the probability of local rainfall is unpredictable and this may influence female anuran reproductive strategies. The female túngara frog, a neotropical frog that requires standing water to breed, maintains readiness to breed at any time via asynchronous oogenesis. Although females constantly produce and maintain oocytes during the breeding season, this study shows that they have cyclic fluctuations in gonadal hormone levels. Plasma levels of estrogen significantly change during three reproductive stages within a single reproductive cycle ( P = 0.03), as do plasma levels of progesterone and androgen ( P < 0.001 and P = 0.001, respectively). Furthermore, elevation in plasma estrogen and progesterone concentrations occurs during the same reproductive stage in which it has been reported that females display the maximum frequency of reproductive behaviors, the amplexed stage. Androgen levels, however, are elevated prior to the reproductive stage in which females display maximal reproductive behavior, that is, the unamplexed stage. Our study suggests that the pattern of gonadal hormone fluctuation in a tropically breeding female anuran is similar to the classic paradigm in which there is a temporal relationship between the appearance of reproductive hormones and reproductive behaviors.

Modulation of Metoprolol Pharmacokinetics and Hemodynamics by Diphenhydramine Coadministration during Exercise Testing in Healthy Premenopausal Women

Premenopausal women may be most vulnerable to acute coronary syndromes at a point in their menstrual cycle when their plasma estrogen levels are the lowest during and immediately after menstruation. Metoprolol is a first-line drug in the management of patients with acute coronary syndrome; however, when metoprolol was marketed in 1982, women were largely excluded from clinical trials. Furthermore, the over-the-counter antihistamine diphenhydramine inhibited the metabolism of the CYP2D6 substrate metoprolol in healthy, young men with pharmacokinetic and pharmacodynamic consequences. The pharmacokinetics and pharmacodynamics of metoprolol and its interaction with diphenhydramine were investigated in a randomized, double-blind, crossover, placebo-controlled manner in healthy, premenopausal extensive (EM; n = 16) and poor metabolizer (PM; n = 4) women immediately after menstruation. During the placebo phase, EMs had between 5.2- and 8.4-fold higher total clearance (CL/F) of R- and S-metoprolol compared with PMs, whereas the latter had a 35% greater area under the effect curve (AUEC) and 60% greater EC(50) value for heart rate reduction than EMs (all P < 0.05). Diphenhydramine coadmininstration caused a 2.2- to 3.2-fold decrease in CL/F of metoprolol enantiomers with a resulting 21% increase in AUEC and 29% increase in EC(50) value for heart rate reduction in EMs (all P < 0.05). This is the first study to report an in-depth elucidation of metoprolol's pharmacokinetics and hemodynamics in premenopausal EM and PM women at a point in their menstrual cycle when vulnerability for acute coronary events may be greatest. Caution is warranted when the over-the-counter antihistamine diphenhydramine is part of a chronic therapeutic regimen.

Skin temperature rise induced by calcitonin gene-related peptide in gonadotropin-releasing hormone analogue-treated female rats and alleviation by Keishi-bukuryo-gan, a Japanese herbal medicine

The effects of Keishi-bukuryo-gan on calcitonin gene-related peptide (CGRP)-induced elevation of skin temperature were investigated in gonadotropin-releasing hormone (GnRH) analogue-treated female rats. Leupline® (1.0 mg/kg) as the GnRH analogue was subcutaneously (s.c.) injected into female rats. After Keishi-bukuryo-gan (100–1,000 mg/kg, p.o.) or 17β-estradiol (0.010 mg/kg, s.c.) was administered to GnRH analogue-treated rats for 14 days, CGRP-induced skin temperature elevation, concentration of plasma 17β-estradiol and pituitary gonadotropin (luteinizing hormone; LH, and follicle stimulating hormone; FSH) were measured. In addition, effects of 17β-estradiol and Keishi-bukuryo-gan on the proliferation of estrogen-dependent human breast cancer (MCF-7) cells were investigated under in vitro conditions. GnRH analogue significantly lowered the concentrations of plasma 17β-estradiol and pituitary gonadotropins. Tissue weights of the ovaries and uterus were also decreased by the analogue. Under the condition of estrogen deficiency, intravenous (i.v.) injection of exogenous CGRP (10 μg/kg) elevated the skin temperature of the hind paws more significantly than it did in sham-treated control rats. Estrogen supplementation inhibited this elevation of skin temperature with restoration of both the lowered plasma estrogen level and the decreased uterine weight in GnRH analogue-treated rats. On the other hand, Keishi-bukuryo-gan inhibited the elevation of skin temperature in a dose-dependent manner without restoring the plasma estrogen level and uterine weight. In addition, in an in vitro study, MCF-7 cells proliferated in a dose-dependent manner by the addition of 17β-estradiol (10 −13–10 −8M) to the medium. However, Keishi-bukuryo-gan (10 −6–10 −4 mg/ml) did not activate the MCF-7 cell proliferation. These results suggest that Keishi-bukuryo-gan, which does not exhibit estrogen activity, may be useful for the treatment of hot flashes in women who are undergoing medical ovariectomy with a GnRH analogue.