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PubMed2002

Progesterone blocks the estradiol-stimulated luteinizing hormone surge by disrupting activation in response to a stimulatory estradiol signal in the ewe.

The preovulatory surges of GnRH and LH are activated by increased concentrations of circulating estradiol, but ovulation is blocked when progesterone concentrations are elevated. Although it is has been shown that this action of progesterone is due to a central inhibition of the GnRH surge, the mechanisms that underlie the blockade of the GnRH surge are poorly understood. In this study we investigated whether progesterone can block the estradiol-dependent activation stage of the GnRH surge induction process, and thus prevent expression of the LH surge. The results demonstrated that exposure to progesterone for half or the full duration of the activation stage can prevent the stimulation of LH surges by estradiol (experiment 1), whereas exposure to progesterone midway though a period of estradiol exposure, which in itself is sufficient to activate the surge, did not block the LH surge (experiment 2). These results suggest that progesterone 1) disrupts activation of the surge induction system in response to a stimulatory estradiol signal and 2) does not compromise the ability of animals to respond to a stimulatory estradiol signal applied immediately after progesterone exposure. Because the disruptive effects of activated progesterone in response to estradiol are rapid but transient, it may be that progesterone directly interferes with the activation of estradiol-responsive neural systems to block the GnRH/LH surge.

Animals↗
PubMedDate not supplied

Effect of estradiol versus estradiol and testosterone on brain-activation patterns in postmenopausal women.

OBJECTIVE: To determine the effect of estradiol and testosterone on brain-activation patterns in surgically postmenopausal women viewing erotic video clips using functional magnetic resonance imaging. DESIGN: Six women, who had undergone a bilateral oophorectomy and hysterectomy for benign disease, viewed erotic and neutral videos during functional magnetic resonance imaging while not on hormone therapy, while on estradiol therapy, and while on estradiol and testosterone therapy. Five similarly aged premenopausal women viewed the same videos. Areas of brain activation between the functional magnetic resonance imaging scans of both groups of women were compared with determine whether agonadal serum levels of sex hormones and administration of estradiol and testosterone impacted brain patterns of sexual arousal. RESULTS: When compared with premenopausal women, untreated postmenopausal women had significantly decreased areas of brain activation during both erotic and neutral stimulations. Administration of estradiol increased global brain-activation patterns during both visual stimulations, with erotic video viewing causing a limited increase in limbic system activation. Combined estradiol and testosterone therapy was associated with a greater activation of the central nervous system, with more limbic system activated during the erotic video. Brain-activation patterns of the postmenopausal women were similar to the premenopausal group only during the estradiol and testosterone treatment phase. CONCLUSIONS: Agonadal serum hormone levels result in globally decreased brain-activation patterns in postmenopausal women while viewing neutral and erotic videos. Administration of both estradiol and testosterone increase global brain activation, and both sex steroids are independently associated with enhanced limbic system response during erotic visual stimulation.

Adult↗
PubMed1985

The clearance and metabolism of estradiol and estradiol-17-esters in the rat.

The C-17 fatty acid esters of estradiol are naturally occurring estrogens which have been shown to circulate in blood. They are long-acting estrogens, analogous to the synthetic alkyl and aryl esters of estrogens which have been used pharmacologically for decades. To determine the mechanisms involved in the prolonged stimulation evoked by these nonpolar estrogens, several C-17 alkyl esters were synthesized and labeled with 3H at C-17 alpha, and their metabolism and clearance were studied and compared to those of estradiol in rats. The conversion of the C-17-3H to 3H2O was used as a marker of metabolism. While the clearance of the long chain esters from blood is somewhat slower than that of estradiol (t 1/2 = approximately 16 vs. 2 min, respectively), the rates of metabolism are dramatically different. For example, the t 1/2 of metabolism for two representative esters, estradiol-17-stearate and arachidonate, are 580 and 365 min, respectively, while the t 1/2 of metabolism for estradiol is about as fast as its clearance from blood (approximately 2 min). When the effect of chain length was studied, it was found that for the smaller esters, there was an inverse relationship between the size of the acyl group and the clearance from blood, i.e. the longer carboxylic acids were cleared more slowly. However, when the acyl group was lengthened from C12 to C14, the rate of clearance increased and was even faster with C18. Nevertheless, with all of the esters tested, the rate of metabolism steadily decreased as the chain length increased. These results are interpreted as indicating that the control point or rate-limiting step in the metabolism of the estradiol esters is the esterase that hydrolyzes the ester to estradiol. Thus, the prolonged estrogenic action of the C-17-alkyl esters is due to the slow release of estradiol from this hydrophobic reservoir.

Animals↗
PubMed1975

Estradiol receptor content in rat granulosa cells during follicular development: modification by estradiol and gonadotropins.

To examine the relationships between gonadotropic hormones, ovarian follicular development, and estradiol receptor content in rat granulosa cells, follicular growth was stimulated in intact immature rats and hypophysectomized immature rats. In intact rats, both PMSG and oFSH given for 2 days stimulated follicular growth and endogenous estrogen production but caused estradiol receptor content in granulosa cells to decrease markedly. In hypophysectomized rats estradiol (2 mg/day X 4) was capable of increasing the content of its own receptor, stimulated preantral follicular development, and potentiated the responses of granulosa cells to highly purified hFSH. Thus, subsequent treatment with hFSH stimulated antral formation and maintained high levels of estradiol receptor content in granulosa cells. LH, on the other hand, caused a rapid decline in the content of estradiol receptor in nuclei of granulosa cells. In hypophysectomized rats primed with estradiol alone, a high dose of oLH caused follicles to undergo atresia. In hypophysectomized rats primed with hFSH in addition to estradiol, oLH stimulated luteinization. Thus, induction of atresia or luteinization by oLH in these rats appears to be associated (cause or effect?) with a loss of estradiol receptor in granulosa cells. Whether follicles of estrogen-treated, hypophysectomized rats luteinize or undergo atresia in response to LH appears to be determined by their stage of differentiation and the nature of the prior stimulation by FSH.

Aging↗
PubMed2003

Abnormal levels of serum dehydroepiandrosterone, estrone, and estradiol in men with rheumatoid arthritis: high correlation between serum estradiol and current degree of inflammation.

OBJECTIVE: Men with rheumatoid arthritis (RA) have a higher than normal frequency of low testosterone levels, but not much is known about other sex hormones. We investigated serum levels of estradiol, estrone, and the adrenal androgen dehydroepiandrosterone (DHEAS) in men with RA and evaluated the association of various disease variables with these sex hormones. METHODS: Inflammatory activity, measured as disease activity score including 28 joints (Disease Activity Score 28), and degree of disability, measured with the Health Assessment Questionnaire, were estimated in 101 men with RA. Presence of erosions, rheumatoid factor (RF), smoking habits, and body mass index were recorded. DHEAS (not measured in patients taking glucocorticoids), estradiol, and estrone were measured in patients and in healthy controls. RESULTS: DHEAS and estrone concentrations were lower and estradiol was higher in patients compared with healthy controls. DHEAS differed between RF positive and RF negative patients. Estrone did not correlate with any disease variable, whereas estradiol correlated strongly and positively with all measured indices of inflammation. CONCLUSION: Men with RA had aberrations in all sex hormones analyzed, although only estradiol consistently correlated with inflammation. The high levels of estradiol may have positive implications for bone health. The low levels of estrone and DHEAS may depend on a shift in the adrenal steroidogenesis towards the glucocorticoid pathway, whereas increased conversion of estrone to estradiol seemed to be the cause of the high estradiol levels.

Adult↗
PubMed1988

Estradiol enhances binding to cultured human keratinocytes of antibodies specific for SS-A/Ro and SS-B/La. Another possible mechanism for estradiol influence of lupus erythematosus.

A strong association between anti-SS-A/Ro and anti-SS-B/La antibodies and skin lesions has been well documented in subacute cutaneous lupus erythematosus and neonatal lupus erythematosis in which 70 to 80% of patients are female. In order to better understand the mechanisms of the influence of sex hormones on cutaneous lupus, we designed immunopathological in vitro experiments to evaluate the effects of estradiol and other sex steroids on the binding of SS-A/Ro- and SS-B/La-specific antibodies to cultured human keratinocytes from neonates. Cultured human keratinocytes incubated with antisera specific for SS-A/Ro or SS-B/La Ag were fixed with either acetone or paraformaldehyde and then analyzed in indirect immunofluorescent assays or by FACS analysis to detect cell surface IgG binding as an indirect measure of SS-A/Ro and SS-B/La Ag expression on the cell surface of keratinocytes. Estradiol (10(-5) to 10(-7) M) augmented binding of antiserum probes on the surface of cultured keratinocytes, with 10(-7) M estradiol showing the highest induction of cell surface binding of antisera specific for SS-A/Ro plus SS-B/La Ag (24.5% of cells were positive). In contrast, dihydrotestosterone, testosterone, and progesterone showed no augmentation. The augmentation by estradiol was partially inhibited by the antiestrogen nafoxidine. Estradiol augmented the relative incidence and absolute number of small or cuboidal cells binding antibodies specific for SS-A/Ro and SS-B/La Ag, whereas the number and incidence of larger differentiated cells binding anti-SS-A/Ro and anti-SS-B/La decreased significantly in cell cultures stimulated with estradiol. Flow cytometric analysis utilizing monospecific anti-SS-A/Ro or anti-SS-B/La sera showed that estradiol induced binding of anti-SS-A/Ro in 13.1% of cultured keratinocytes, of anti-SS-A/La in 14.4%, and of sera specific for both Ag in 21.4%. This direct association between estradiol and the augmentation of binding to the cell surface of human keratinocytes of IgG from antisera specific for SS-A/Ro and SS-B/La Ag may be a trigger factor of immunologic damage in lupus and may be important in the different sex rates observed in skin manifestation of subacute cutaneous and neonatal lupus erythematosis.

Adjuvants, Immunologic↗
PubMed1985

Conversion of estrone to estradiol and estradiol to estrone in postmenopausal women.

The conversion of estrone to estradiol and metabolism of estradiol to estrone have been measured in postmenopausal women to examine factors that influence these conversions. Transfer constants for the conversion of estrone to estradiol and estradiol to estrone were not significantly correlated with age (r = -.01 and r = .1, respectively) or subjects' percentage of ideal body weight (r = -.25 and r = -.22, respectively). There was a significant negative correlation between the transfer constants for the conversion of estradiol to estrone and plasma levels of dehydroepiandrosterone sulphate (r = -.45, P less than .05) but not plasma levels of progesterone. Transfer constants for the conversion of estrone to estradiol and metabolism of estradiol to estrone in women with breast or endometrial disease were similar to values in normal women, but metabolism of estradiol to estrone was elevated in two women with primary biliary cirrhosis.

Aged↗
PubMed1996

Pharmacokinetic data on estradiol in light of the estring concept. Estradiol and estring pharmacokinetics.

The pharmacokinetics and pharmacodynamics of estradiol in humans are briefly reviewed in this paper. The estradiol vaginal ring was designed and developed to obtain controlled local delivery of very low doses of estradiol resulting in a marginal effect on plasma concentrations of estradiol, associated with a margin of safety over a prolonged period of time. Three clinical studies in postmenopausal women with signs and symptoms while plasma levels remain virtually unchanged in the lower part of the normal postmenopausal range. No pharmacodynamic effects of estrogen could be detected, reflecting a very low systemic exposure. The estradiol exposure and the plasma concentration time course during treatment with first and second ring during first month of the intended three month treatment period are compared. The very low systemic exposure is discussed in relation to existing therapies. Ongoing pharmacokinetic work with estradiol vaginal ring is briefly described. It is concluded that the estradiol vaginal ring is a very stable alternative to existing vaginal therapies, resulting in a very low systemic exposure to estradiol, and is associated with a minimal risk of drug interaction and has a high margin of safety.

Administration, Topical↗
PubMedDate not supplied

[Effect of ethynyl estradiol and estradiol dipropionate on the esterification of saturated and unsaturated fatty acids in the rat liver].

Effect of estradiol ethynyl and estradiol propionate on esterification of saturated and non-saturated fatty acids in liver tissue, as one of possible mechanisms in development of estrogen-induced hypertriglyceridemia, was studied using labelled precursors 3H-palmitic and 14C-linoleic acids. Both these estrogens stimulated the incorporation of exogenous fatty acids into triglycerides. After administration of estradiol dipropionate relative esterification of 14C-linoleic acid into triglycerides was increased as compared with controls. Estradiol ethynyl increased and estradiol dipropionate decreased the incorporation of exogenous fatty acids into liver phospholipids. Both estrogens activated the relative esterification of linoleic acid into phospholipids. A decrease in exogenous fatty acids esterification into fraction of cholesterol esters, caused by both these estrogens, occurred due to an increase in relative incorporation of linoleic acid into these lipids. As shown in experiments of relative esterification of saturated and non-saturated fatty acids, estradiol propionate stimulated synthesis of more non-saturated forms of triglycerides, phospholipids and cholesterol esters in rat liver tissue as compared with the estradiol ethynyl action. The data obtained and the data of literature suggest that activation of exogenous fatty acids esterification into triglycerides and alterations in relative esterification of saturated and non-saturated fatty acids into triglycerides and phospholipids of liver tissue are of importance in pathogenesis of estrogen-induced hypertriglyceridemia.

Animals↗
PubMed1982

[Enzymatic determination of urinary estrone and estradiol: correlations with plasma estradiol in the menstrual cycle in women].

Enzymatic determination of urine estrone and estradiol concentrations were done daily during a menstrual cycle in six female volunteers. The results were compared with plasma estradiol determined by radioimmunoassay in the same patients. The pattern of estrone and estradiol excretion in morning urine sample fairly reproduced plasma estradiol variations and a good correlation was observed (r = 0.78). The urine pattern of estrone and estradiol variation determined by the enzyme assay can be considered as a good index of oestrogen secretion. The preovulatory peak of estrone and estradiol was observed in urine the day before or the same day as the LH peak. Estrone and estradiol concentration in urine doubled the mean value of the concentration of the follicular phase several days before the LH peak giving a useful indication for prediction of ovulation.

Estradiol↗
PubMed1996

Effect of 17beta-estradiol-bisphosphonate conjugates, potential bone-seeking estrogen pro-drugs, on 17beta-estradiol serum kinetics and bone mass in rats.

In order to target 17beta-estradiol directly at bone we synthesized three 17beta-estradiol-bisphosphonate conjugates (E2-BPs) with different esterase-sensitive linkers between both molecular moieties. The systemic administration of these compounds should result primarily in local estrogenic effects on bone with no or negligible systemic hormonal effects. Only if a considerable margin exists between the doses required for inhibition of bone loss and those for systemic hormonal effects can such a pro-drug be considered acceptable for patients refusing systemic estrogen replacement therapy for several reasons. The conjugates were tested in vitro for their 17beta-estradiol release in rat serum and in vivo for their local and systemic effects in rats: in vitro, the conjugates expressed cleavage resistance, low cleavage (4.8%), or high cleavage (33.1%) within 48 hours of incubation. The conjugate with the low-cleavage doubled 17beta-estradiol serum half-life (3.78 hours) whereas the high-cleavage conjugate resulted in approximately four times higher serum half-life (8.36 hours) when compared with free 17beta-estradiol. In ovariectomized rats, bone loss was optimally prevented by 50 nmol/kg/day of 17beta-estradiol when administered S. C. over a period of 5 weeks, and protection against uterine atrophy was achieved at doses as low as 5 nmol/kg/day. The cleavage-resistant conjugate was ineffective in preserving bone and uterus in doses ranging from 5 to 150 nmol/kg/day. The other two E2-BPs revealed a dose-dependent inhibition of bone loss which was paralleled by the respective uterus weight with a dose range of 1.5-150 nmol/kg/day being fully effective in a range similar to 17beta-estradiol alone. The higher sensitivity of the uterus versus bone to protective estrogenic effects (1:10) was abolished by the conjugates. We conclude that E2-BPs containing esterase-sensitive linkers failed to act as bone-seeking pro-drugs expressing primarily local effects on bone without systemic effects.

Absorptiometry, Photon↗
PubMed1988

Evidence for suppression of serum LH without elevation in serum estradiol or prolactin with a brain-enhanced redox delivery system for estradiol.

We developed a redox system for brain-enhanced delivery of estradiol based on an interconvertible dihydropyridine in equilibrium pyridinium salt carrier. Estradiol (E2), when combined with the lipoidal carrier, readily crosses the blood-brain barrier. The carrier, when oxidized, reduces the rate of exit of the estradiol-carrier complex from the brain. Subsequent hydrolysis of the carrier provides sustained production of estradiol in the brain. The aim of the study was to evaluate the effects of single vs. multiple injections of the estradiol-chemical delivery system (E2-CDS) on both central and peripheral estrogen-responsive tissues. Ovariectomized Sprague-Dawley rats received an intravenous injection of E2-CDS at 10, 33, 100 or 333 micrograms/kg BW or the drug vehicle, dimethyl sulfoxide (DMSO; 0.5 ml/kg) every 2 days for 7 injections (2 weeks) or a single injection only at 2 days before sacrifice. With a single injection, E2-CDS did not affect serum luteinizing hormone (LH) levels at the 10 micrograms/kg dose but caused a dose-dependent reduction in serum LH of 39-52% at the dose range of 33 to 333 micrograms/kg. By contrast, multiple injections of E2-CDS caused a 32 to 76% reduction in serum LH levels at doses ranging from 10 micrograms/kg to 333 micrograms/kg. Additionally, multiple doses of E2-CDs caused a dose-dependent reduction in body weight at the 10 and 33 micrograms/kg doses with the higher doses causing no further weight reduction. For both single and multiple dosage groups, serum E2 levels remained unchanged after doses of E2-CDS of 10 and 33 micrograms/kg, then increased to 21 pg/ml for the single dosage group and to 23 pg/ml for the multiple dosage group at the 100 micrograms/kg dose, and to 59 pg/ml for singly-injected rats and 60 pg/ml for multiply-injected rats at the 333 micrograms/kg dose. Serum prolactin concentrations were closely correlated with serum E2 levels for both the single and multiple dose groups. These data reveal that a single or multiple doses of E2-CDS can reduce serum LH levels without elevating serum E2 or prolactin concentrations, supporting the concept of brain-enhanced delivery of estradiol with an estradiol chemical delivery system.

Adrenal Glands↗
PubMed1983

17-alpha-Estradiol and 17-beta-estradiol in hippocampus.

Electrophysiological field potentials recorded from in vitro hippocampal slice preparations show responses to exogenous gonadal steroids added to the incubation medium. The peak effect of the addition of 17-beta-estradiol occurred at a 100 pmol concentration; the CA1 field potential was increased by an average of 148 percent. 17-alpha-estradiol, often used as a negative control in experiments demonstrating estrogen specificity of receptor binding sites and biological responses, had no effect on field potentials following addition of drug to the incubation medium. The addition of a 100 pmol concentration of 17-beta-estradiol to the same slices which had been pretreated with 17-alpha-estradiol, blocked the facilitatory response elicited by the 17-beta-estradiol administered alone. Since no enhancement of the field potential is observed with 17-beta-estradiol following pretreatment of 17-alpha-estradiol, this would support the hypothesis that hippocampal modulation by gonadal steroid hormones may be due to involvement of an estrogen receptor mediated phenomena.

Animals↗
PubMed1985

Effects of estradiol and estradiol-progesterone treatment on gonadotropin secretion in castrate aging female rats.

Estradiol-17 beta and estradiol-17 beta-progesterone were administered to aging female rats immediately after castration. Estradiol (1.6 micrograms) alone suppressed the castration hypersecretion of FSH in mature animals to 70% of the castration controls, but in 360-day-old and older animals, the inhibition was less than 10%. There was a decrease in the castration hypersecretion of LH by exogenous estradiol-17 beta with increasing age, but the pattern of suppression was similar in all animals, regardless of age. When a constant dose of estradiol-17 beta of 0.4 micrograms/kg body wt. was administered to castrate rats with varying doses of progesterone, it was shown that after 270 days of age the negative feedback effect of these steroids on FSH secretion was not found. Whereas, when progesterone of varying doses was administered with a constant dose of 0.8 micrograms/kg BW of estradiol-17 beta, it was shown that after 180 days of age the positive feedback effect of these steroids on FSH was absent. After 270 days of age the augmentation of LH secretion by estradiol-17 beta and a middle dose of progesterone was not apparent even though the negative feedback on LH was effective. A defect in positive and negative feedback effects of gonadal steroids on gonadotropin secretion may be causative to age-related changes in the estrous cycle of rats.

Aging↗
PubMed1976

Affinity chromatography of the uterine estradiol receptor on estradiol-PAB-cellulose: an artefact.

Estradiol-PAB-cellulose, an easily prepared adsorbent, has been proposed to purify the uterine estradiol receptor according to the principle of biospecific affinity chromatography. It apparently removes all hormone binding sites when cytosol preparations are incubated with it. A systematic study of this adsorbent was undertaken, including the synthesis and testing of the radioactive material. Two main results were obtained: 1) Estradiol-PAB-cellulose is heavily contaminated with free ligand and releases it during the normal chromatographic conditions. 2) Estradiol spacer derivatives (hydroxyethylphenyl-diazo (2 or 4)-estradiol) have a very low affinity for the receptor (Ki = 10 muM). The conclusion is that estradiol-PAB-cellulose is unsuitable for affinity chromatography of estradiol receptor.

4-Aminobenzoic Acid↗
PubMed1996

Pharmacokinetics of a 7-day 17 beta-estradiol transdermal delivery system: effect of application site and repeated applications on serum concentrations of estradiol and estrone.

FemPatch (Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI), a new 7-day 17 beta-estradiol transdermal delivery system (TDS), has been developed for treatment of menopausal vasomotor symptoms. This two-period crossover study was conducted to determine the effects of TDS application site (buttocks versus abdomen) and early TDS replacement on estradiol and estrone concentrations, and to quantify intersubject and intrasubject pharmacokinetic variability. Eighteen healthy, postmenopausal female volunteers received a single 7-day TDS application to the abdomen and repeated TDS applications to the buttocks (regular replacement on days 7 and 14, intentional early replacement on day 17, and removal on day 21). Serial serum samples were assayed for estradiol and estrone by validated radioimmunoassay methods. The 7-day TDS delivers estradiol at a constant, near zero-order rate for the duration of application, independent of application site. Mean serum estradiol concentrations were higher after application to the buttocks than after application to the abdomen (19 and 15 pg/mL above baseline, respectively), making the buttocks the preferred site for TDS application. Mean serum concentration of estradiol was slightly higher (23 pg/mL above baseline) for the treatment week with early TDS replacement due to the transient increase in concentration over the first 24 hours after replacement. Parallel but smaller increases in concentrations of estrone were observed. Serum estradiol and estrone concentrations are reproducible within an individual from application to application (coefficient of variation, 25%). Variability between individuals was higher (coefficient of variation, 40-50%).

Abdomen↗
PubMed2000

Enhanced sensitivity to steroid-negative feedback during breast-feeding: low-dose estradiol (transdermal estradiol supplementation) suppresses gonadotropins and ovarian activity assessed by inhibin B.

Breast-feeding reduces fertility, and this seems to be related, in part, to an enhancement of the sensitivity of the GnRH system to the negative feedback effects of estradiol related to suckling. Previously, we showed that short-term treatment with small doses of estradiol delivered transdermally suppress plasma gonadotropin concentrations in breast-feeding women. We have now monitored the effects on ovarian function of longer-term low-dose estradiol treatment using plasma inhibin B and inhibin A concentrations and ultrasonography. Breast-feeding women (n = 45) using barrier methods of contraception were enrolled at 6 weeks postpartum and followed up to 18 weeks PP. Nineteen women agreed to being randomized to wear either an estrogen [transdermal estradiol supplementation (TES); n = 10; Estraderm, 50 microg/24 h] or a placebo (PL; n = 9) patch for 12 weeks, whereas the remaining 26 women acted as untreated controls. TES did not significantly increase plasma estradiol concentrations. Plasma FSH levels decreased from 6.1+/-0.8 U/L to 3.3+/-0.6 U/L after 2 weeks of treatment (P < 0.01) and were lower in the TES group compared with the PL group at all times during the treatment (at least P < 0.05). Plasma LH concentrations in the TES group were lower than in the PL group after 4, 6, 8, and 10 weeks of estrogen treatment (at least P < 0.05). Throughout the study, no ovarian follicles detected by ultrasound were greater than 10 mm in diameter. Nevertheless, after 2 weeks of treatment, plasma inhibin B concentrations were significantly lower in the TES group than in the PL group (15.5+/-5.8 vs. 64.9+/-11.1 ng/L; P < 0.01) and remained significantly (P < 0.01) suppressed throughout the treatment, suggesting a suppression of the functional ovarian activity during TES. Inhibin A levels remained low in all groups (3-45 ng/L) but were suppressed further by TES treatment with no levels greater than 7 ng/L. We conclude that low-dose estradiol treatment given as TES suppresses ovarian activity as measured by inhibins B and A by reducing the secretion of LH and FSH during breast-feeding for several weeks. This supports the concept that suckling-induced suppression of the GnRH system is associated with an enhancement of the negative effects of estradiol on the hypothalamic GnRH system. Furthermore, because the contraceptive efficacy of breast-feeding is complicated by the unpredictable early return of ovarian activity in some women, TES could be the basis for the development of a novel contraceptive for breast-feeding women.

Administration, Cutaneous↗
PubMed1999

Significant differences in estradiol bioavailability from two similarly labelled estradiol matrix transdermal systems.

OBJECTIVE: To compare the bioavailabilities of estradiol delivered by two transdermal estradiol matrix systems; Alora and Evorel. STUDY DESIGN: A single-center, open-label, randomized, two-period cross-over study in 33 postmenopausal women. The subjects received two successive 84-h applications of either Alora or Evorel (each labelled to deliver 50 micrograms/day 17 beta-estradiol) in a randomized sequence. Serial serum samples, collected over the 84-h period following the application of the second patch, were analyzed for estradiol using a validated radioimmunoassay method. RESULTS: The fluctuation index produced by Evorel was significantly higher than that produced by Alora (Evorel, 135%; Alora, 76%; p < 0.0005). In addition, the estradiol baseline-corrected area under the curve for Evorel was significantly lower than that for Alora (Alora, 2871.8 pg h/ml; Evorel, 1870.6 pg h/ml; p < 0.0005). Both patches were found to be generally well tolerated. CONCLUSION: Alora delivered a higher, more consistent concentration of estradiol into the systemic circulation over the entire dosing interval than did Everol. Although the full clinical significance of these findings is currently unknown, this study demonstrates that there are significant differences in estradiol delivery from these two products, although they are labelled with the same nominal delivery rate.

Administration, Cutaneous↗