Sequentially combined estradiol valerate plus levonorgestrel therapy decreases 18:1 trans-fatty acid content of plasma lipids in healthy postmenopausal women.

Trans-fatty acids (TFA) have been classified as atherogenic dietary constituents but the effect of hormone replacement therapy (HRT) on their concentrations is not known. We used a washout protocol to study the effect of long-term estrogen and combined estrogen-progestin HRT on plasma elaidate (18:1t), which is the trans isomer of oleate and the major TFA in the diet. The study group comprised 15 women receiving estradiol valerate HRT and 15 women receiving combined HRT with estradiol valerate and levonorgestrel. The concentrations of elaidate in plasma phospholipids, cholesteryl esters and triglycerides were determined by gas chromatography. At baseline, the total plasma elaidate concentration was lower in the combined HRT group than in the estradiol valerate HRT group (p < 0.01). In the combined HRT group, the concentration of elaidate increased significantly after withdrawal of HRT (p < 0.001) and decreased again to the baseline level after restart of therapy (p < 0.001). These changes were due to decreases in the concentrations of phospholipids and triglycerides; in phospholipids there was also a proportional decrease of elaidate. There were no changes in elaidate in women receiving estradiol valerate alone. Our results suggest that long-term combined HRT treatment decreases plasma TFA, which is not achieved by estrogen alone.     

Serum and tissue hormone levels of vaginally and orally administered estradiol

Objective: Our purpose was to determine serum and endometrial estradiol levels when micronized estradiol is administered vaginally and orally. Study Design: Five subjects were given oral estradiol (2 mg twice daily), during an artificial luteal phase, and another group of 5 subjects were given the same dose of estradiol by the vaginal route. Endometrial biopsies and blood samples were obtained on day 21 of the cycle, 2 hours after the last dose was administered. Tissue and blood samples were assayed for estradiol. Results: Serum estradiol levels were significantly higher with vaginally administered estradiol than with orally administered estradiol (2344 ± 398 vs 279 ± 76 pg/mL, P < .005). Endometrial estradiol concentrations were also significantly higher with vaginally administered estradiol than with the oral preparation (918 ± 412 vs 13 ± 2 pg/mg protein, P < .05). Conclusions: Vaginal administration of estradiol is more effective in increasing serum and endometrial levels of estradiol than the oral route and may represent the optimal route of administration for recipients of egg donation. If the vaginal route of estradiol administration is considered for menopausal replacement therapy, much lower doses of the standard oral quantities should be used. Furthermore, if the uterus is present, a progestin must be used to compensate for the high tissue levels of estradiol. (Am J Obstet Gynecol 1999;180:1480-3.)     

Oral 17beta-estradiol and sequential progesterone in menopause: effects on insulin-like growth factors and their binding proteins.

OBJECTIVE: We evaluated the acute effects of low-dose oral estradiol and sequential progesterone on the insulin-like growth factor (IGF)/growth hormone (GH) axis, IGF-binding proteins (IGFBPs) 1 and 3, and plasma levels of sex hormone-binding globulin (SHBG) in postmenopausal subjects. STUDY DESIGN: Thirty healthy normal-weight women (mean age: 54.2 +/- 5.7 years) spontaneously postmenopausal for at least 6 months were enrolled. None had used hormone replacement therapy (HRT). Appropriate investigations excluded renal, glucose, lipid and coagulation abnormalities. Breast X-ray and endometrial ultrasound examinations excluded organic pathologies. They received oral cyclical HRT for 1 year, based on the administration of oral estradiol (1 mg/day) for 28 consecutive days plus progesterone (200 mg/day) from day 15 to day 28; out of the whole group, 15 subjects received progesterone orally (group A), while in 15 progesterone was administered transvaginally (group B). On the day before treatment (T0), on day 14 (T14) and on day 28 (T28) of the first cycle, plasma levels of estradiol, progesterone, SHBG, GH, IGF-I and -II, IGFBP-1 and -3, insulin and C-peptide were assayed in all patients. The same parameters were evaluated at T14 and T28 during the 12th month of treatment. RESULTS: At T14, we observed significant increases in the levels of estradiol (from 20 +/- 16 to 115 +/- 71 pg/ml, p < 0.001), SHBG (from 132 +/- 42 to 182 +/- 55 nmol/l, p < 0.001) and IGFBP-1 (from 92 +/- 57 to 127 +/- 87 ng/ml, p < 0.004), while the level of IGF-I decreased (from 197 +/- 138 to 129 +/- 85 ng/ml, p < 0.003). At T28, progesterone levels were significantly higher in the women receiving it orally than transvaginally (8.4 +/- 6.1 vs. 3.7 +/- 3.2 ng/ml, p < 0.025). However, while oral progesterone did not affect the estrogen-induced variations, transvaginal progesterone abrogated the increase in the levels of IGFBP-1. The levels of IGF-II, IGFBP-3, GH, glucose, C-peptide and insulin did not change at any time. At 1 year, the values maintained the same trends. The estrogen-induced variations of SHBG were correlated directly with those of estradiol (r = 0.48) and inversely with those of IGF-I (r = -0.424). CONCLUSIONS: Low-dose oral estradiol reduces plasma levels of IGF-I and increases IGFBP-1 and SHBG concentrations, while GH is unchanged. These effects, significant and immediate, lead us to hypothesize a direct action of estradiol on hepatocytes.     

Failure of the combination of sequential oral and transdermal estradiol plus norethisterone acetate to affect plasma homocysteine levels

Objective: A high level of plasma homocysteine may be deleterious to vascular health. We therefore compared the effect of combinations of sequential oral and transdermal estradiol plus norethisterone acetate on plasma homocysteine.

Design: Prospective, randomized study.

Setting: Outpatient department of obstetrics and gynecology in a university hospital.

Patient(s): Forty-two healthy, nonsmoking postmenopausal women starting hormone replacement therapy (HRT) to control climacteric symptoms.

Intervention(s): In a randomized order, the women started using either oral HRT (2 mg of estradiol on days 1–12, 2 mg of estradiol plus 1 mg of norethisterone acetate (NETA) on days 13–22, and 1mg of estradiol on days 23–28; N = 21) or transdermal HRT (50 μg/d of estradiol on days 1–28 and 250 μg/d of norethisterone acetate on days 15–28, N = 21) for 1 year.

Main Outcome Measure(s): Fasting plasma levels of homocysteine were measured before the treatment and during the combined estradiol-plus-NETA phases of the sixth and 12th treatment cycles.

Result(s): Basal homocysteine levels in the oral group (8.2 ± 3.1 μmol/L, mean plusmn;SD) and transdermal group (8.7 plusmn; 1.8 μmol/L, mean plusmn;SD) were not affected by the estradiol-plus-NETA combination.

Conclusion(s): Neither an oral nor a transdermal combination of sequential estradiol and NETA causes significant changes in plasma homocysteine in Finnish postmenopausal women with normal baseline homocysteine levels.     

The effect of estradiol valerate and allylestrenol on endometrial transformation in hypergonadotropic hypogonadic women

The effect of estradiol valerate and allylestrenol on the endometrial transformation of five hypergonadotropic hypogonadic women was evaluated. Estradiol valerate was administered throughout the whole induced cycle (28 days), while allylestrenol was added during the second half of the cycle. Endometrial biopsies were performed during allylestrenol treatment and were evaluated histologically. Samples of endometrium were also subjected to one-dimensional SDS electrophoresis. Of ten biopsies performed, only one was interpreted to be in-phase, while the others were dated proliferative (4 biopsies) or showed abortive or out-of-phase secretory transformation. The highest mean serum progesterone level, detected under allylestrenol treatment, was 1.5 ng/ml. Protein electrophoresis demonstrated relative sequential changes in the protein patterns of the 115 kDa and 150 kDa protein bands. It is concluded that allylestrenol, although having gestagen properties, may not be efficient for the induction of an adequate secretory transformation of human endometrium in the absence of ovaries.     

Acute and long-term estradiol kinetics in smoking postmenopausal women

ABSTRACT Aim We aimed to study 2-h estrogen kinetics in smoking versus non-smoking postmenopausal women receiving estrogen therapy. Moreover, we wished to study estrogen concentrations over 2 years in smokers using ten or fewer cigarettes daily versus non-smokers in postmenopausal women on estrogen treatment. Method We used post-hoc analyses from two randomized trials. In study I, we included 150 women from three groups receiving therapies containing 1 or 2 mg 17β-estradiol, where trough and 2-h blood samples was collected in cycles 1, 7 and 13. In study II, we included 94 completing women who had received either placebo or a regimen containing 1 mg 17β-estradiol. Results In study I, 35% were smokers. At 2 h post tablet intake, serum estrone and estradiol concentrations were significantly lower in smokers as compared to non-smokers, i.e. mean serum estrone was 212 pg/ml (95% confidence interval (CI) 177-247 pg/ml) in smokers as opposed to 318 pg/ml (95% CI 278-359 pg/ml) in non-smokers on 1 mg estradiol (p = 0.0002). In study II, 19% were smokers. In the estrogen group, smoking lead to significantly lower levels of both serum estrone and serum estradiol at all post-randomization time points. No differences between smokers and non-smokers were seen on placebo. Conclusion We conclude that smoking reduces serum estrogens at both trough and after 2 h in postmenopausal women on estrogen treatment. The effect of smoking on estrogen concentrations is fully expressed in women smoking ten or less cigarettes daily. These findings indicate that the influence of smoking upon the metabolism of estrogen therapy is constant and without dose-response for standard smoking intensities.     

Transvaginal absorption of estrogens through irradiated mucosa

Serum concentrations of unconjugated estrone (E1) and 17 beta-estradiol (E2) have been measured in eight patients before and after 1.25 mg of conjugated estrogens administered intravaginally. The measurements were repeated using 2 mg of micronized estradiol administered intravaginally 1 week later to six of the women and 7 months later in one. All the patients had completed a full course of irradiation for pelvic malignancy at least 8 months prior to the study. Baseline, 1/2, 1-, 2-, 4-, 8-, and 24-hr samples were analyzed. After conjugated estrogens mean serum E2 increased 4.5-fold to peak at 163 pg/ml at 2 hr while serum E1 increased 3.2-fold to peak at 222 pg/ml at 2 hr. After micronized E2 mean serum E2 increased 89.3-fold to peak at 1250 pg/ml at 1 hr while E1 increased 3.1-fold to peak at 416 pg/ml at 2 hr. These data indicate that rapid absorption of E1 and E2 occurs through irradiated vaginal mucosa.     

Pharmacokinetics of percutaneous estradiol: a crossover study using a gel and a transdermal system in comparison with oral micronized estradiol

The pharmacokinetics of three transdermal estradiol (E2) replacement regimens were studied following establishment of steady-state dynamics. Oestrogel 3.0 mg, Oestrogel 1.5 mg, and Estraderm transdermal delivery system 4 mg (0.05 mg/day) were administered for 14 days each to 15 postmenopausal volunteers, with a 14-day washout period between each regimen. The percutaneous E2 pharmacokinetics were compared with an oral micronized E2 preparation. Venous samples were obtained at 0, 1, 2, 4, 8, 12, and 24 hours on 3 sequential days 11 days after initial application of the Oestrogel and the transdermal delivery system, and at the same times after oral E2 ingestion. All three percutaneous regimens provided nearly constant serum E2 and estrone (E1) levels throughout their use. The mean serum E2 levels were 102.9 +/- 39.9, 68.1 +/- 27.4, and 41.1 +/- 13.5 pg/mL for Oestrogel 3.0 mg, Oestrogel 1.5 mg, and Estraderm, respectively. Oral E2 resulted in a mean serum E2 level of 114.0 +/- 65.2 pg/mL with marked peak and nadir values. The E1/E2 ratio was comparable with all three percutaneous regimens (1.08-1.33) and was significantly lower than that found with oral Estrace (5.05).     

Natural cycle cryo-thaw transfer may improve pregnancy outcome

Objective: To compare natural vs. hormone replacement treatment (HRT) for cryo-thaw embryo transfer cycles in patients with frozen embryos from previous ART. Design and Settings: Retrospective chart review of 164 patients (242 cycles) who underwent natural or HRT cryo-thaw embryo transfer between January 2002 and April 2005. Main Outcome Measures: Pregnancy rates per transfer in natural and HRT cryo-thaw cycles. Results: The pregnancy rate per transfer was higher with natural cycles (36.76% vs. 22.99%, P = 0.0298). There was no statistical difference in mean age, endometrial thickness, and average embryo quality in successful cycles. Mean endometrial thickness prior to transfer was greater in natural cycles (9.95 vs. 8.89 mm, P < 0.001). Mean serum estradiol levels were higher in the HRT group prior to transfer (526.1 vs. 103.8 pg/ml, P < 0.001), and were found to be lower in women who achieved pregnancy (337.1 vs. 433.3 pg/ml, P = 0.0136). Conclusion: Hormone replacement in preparation for cryo-thaw transfer of embryos was found to be associated with decreased pregnancy rates in comparison to natural cycle cryo-thaw transfer. Greater endometrial thickness was achieved with lower serum estradiol levels in patients undergoing natural cycles, suggesting that higher estradiol levels during HRT cycle may interfere with the window of implantation. Financial disclosure: none of the above authors had any financial interests with commercial companies.     

Endometrial response to a cyclic regimen of percutaneous 17beta-estradiol and low-dose vaginal micronized progesterone in women with mild-to-moderate hypertension.

Endometrial response to natural estradiol and low-dose vaginal progesterone replacement therapy was evaluated in 20 postmenopausal women with chronic, mild-to-moderate hypertension. A cyclic hormone replacement therapy (HRT) regimen was used (21/28 days) with percutaneous estradiol (1.5 mg/day) and vaginal micronized progesterone (100 mg/day). Menopausal symptoms decreased and estradiol concentrations increased substantially and remained in the physiological range throughout treatment. Serum gonadotropin concentrations decreased significantly (p < 0.001, Friedman's ANOVA). Bone mineral density increased by 2.1% (p = 0.029) only at the lumbar spine. Endometrial thickness remained unchanged. Breakthrough bleeding or spotting occurred in 18% of cycles in the first 3 months of HRT, 30% in months 4-9 and 22% in months 10-12. Withdrawal bleeding occurred in 40% of cycles in the first 3 months and decreased to 25% in months 10-12. At month 12, there were 11 women with amenorrhea due to endometrial atrophy. Nine women had active endometria (proliferative or secretory) and thus reported vaginal bleeding. No severe bleeding, hyperplasia, or carcinoma was found. Vaginal bleeding was tolerated, and no subject withdrew from the study. Results suggest that this regimen confers endometrial protection and is well tolerated, and can therefore safely be used for at least 1 year by postmenopausal women with hypertension and menopausal symptoms.     

Effects of a sequential combination of estradiol valerate and cyproterone acetate on the functional properties of the arterial wall in menopausal women

Several studies have shown that estrogen replacement therapy protects postmenopausal women against coronary artery disease. This protective effect has been ascribed to the hormone's effect on serum lipids, as well as a direct action on the vascular wall. Concurrent administration of a progestin to protect women from the risk of endometrial hyperplasia may alter the protective effects of estrogen. The aim of this study was to assess the evolution of the endothelial function in postmenopausal women given a sequential combination of oral 2 mg estradiol valerate for 11 days, followed by 2 mg estradiol valerate associated with 1 mg cyproterone acetate for ten days (Climène). Each 21-day sequence was followed by a seven-day treatment-free interval. The women received a three-month treatment course. Thirty-one healthy postmenopausal women participated in the study (median age: 51 years; range: 45-59 years). Flow-mediated dilatation (FMD), a reflection of endothelium-dependent vasomotor function, increased from 8.47% at baseline (range: 4.57-11.02%) to 9.64% (range: 7.07-13.12%) at the end of the first treatment cycle; i.e., a 15% increase over baseline (P < 0.0001). FMD further increased after three treatment cycles to 10.59% (range: 8.09-15.22%); i.e., a 28.6% increase over baseline (P < 0.0001). FMD at the end of the first combined sequence or after the 11 days of estradiol only were similar (delta = 0.25%; range: -2.31-5.81%; not significant). In conclusion, in postmenopausal women, a three-month sequential treatment combining estradiol valerate and estradiol valerate plus cyproterone acetate (Climène) has beneficial effects on endothelial function as demonstrated by the evolution of the FMD. There was no decrease in the effect of estradiol on FMD when cyproterone acetate was added to estradiol.     

Clinical performance and endocrine profiles with contraceptive vaginal rings containing a combination of estradiol and d-norgestrel

Contraceptive vaginal rings, impregnated with d-norgestrel (77 mg) and estradiol (29-66 mg) were studied in 10 subjects aged 24-28. 5 subjects were studied for 3 cycles and 5 for 6 cycles. The rings were inserted (on Day 5) for 3 weeks and removed for 1 week to allow withdrawal bleeding. Serum samples were obtained at least 3 times/week; estradiol and d-norgestrel were assayed in each sample, and progesterone weekly. Clinical acceptance was good. Ovulation was inhibited in all treatment cycles and resumed within 1 month following completion of the trial. There was regular withdrawal bleeding, no episodes of failure of withdrawal bleeding, and only 3 days of breakthrough spotting. Serum d-norgestrel levels were relatively constant in each subject except for the 1st half of the 1st treatment cycle which had slightly higher levels. Serum estradiol levels rose rapidly following insertion of the ring to levels between 100-300 pg/ml, but then declined over the next few days to levels generally less than 50 pg/ml. After treatment, mean levels of the binding capacity of corticosteroid-binding-globulin did not become significantly elevated and serum triglycerides declined. This method has the advantage of inhibition of ovulation and good control of bleeding without the disadvantage of producing some adverse metabolic effects.     

Effect of estradiol valerate and levonorgestrel on vaginal health

OBJECTIVES: To evaluate the effect of the combined hormone replacement therapy (HRT) estradiol valerate/levonorgestrel on vaginal symptoms, vaginal health index, vaginal pH, and vaginal cytology. STUDY DESIGN: A prospective, open-label study involving 32 postmenopausal women was performed in Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. All the subjects received sequential oral estrogen-progestogen hormone replacement therapy, which contains 2 mg estradiol valerate and 0.15 mg levonorgestrel, for 6 months. The results in terms of vaginal health index, vaginal pH, and vaginal cytology before and after treatment were analyzed. RESULTS: The mean age of these postmenopausal women was 52.56 +/- 3.33 years (range: 46-60 years). The mean time since the last menstrual period was 3.41 +/- 2.95 years (range: 1-15 years). The vaginal health index, which indicates vaginal health by means of scores for vaginal moistness, vaginal fluid volume, vaginal elasticity, vaginal mucosa, and vaginal pH rose significantly in all the women. The mean vaginal pH became significantly lower. The vaginal cytology showed an estrogenic effect on the karyopyknotic index (KPI) and the maturation value (MV) after 3 and 6 months of treatment. CONCLUSION: During estradiol valerate and levonorgestrel treatment, there were demonstrable improvements in the objective signs of vaginal atrophy: atrophic vaginal epithelium became thicker and vaginal pH lower, and the morphology of the vaginal cells was better.     

Low levels of endogenous estradiol protect bone mineral density in young postmenopausal women.

OBJECTIVE: Low levels of endogenous estrogens may play a role in the protection of bone mineral density (BMD) in healthy postmenopausal women. The aim of this study was to evaluate the effect of endogenous estradiol and testosterone on bone mass in young and older healthy postmenopausal women. METHODS: The study involved 99 postmenopausal women aged 55-75 years. The BMDs of the lumbar spine, proximal femur and total skeleton were determined. Measurements were taken of serum calcium, bone alkaline phosphatase, Crosslaps, estradiol, estrone, sex hormone binding globulin, testosterone, bioavailable testosterone and urine calcium. Estradiol was measured using a sensitive assay with a lower detection limit at 5 pg/ml. RESULTS: A multivariate analysis showed that the BMD of the lumbar spine was significantly predicted by estradiol (p < 0.05), and testosterone (p < 0.0001). Likewise, testosterone was found to be an independent predictor of the BMD of the total femur (p < 0.001) and the total skeleton (p < 0.001). The population was divided into two groups: < or = 65 (Group 1) and > 65 years (Group 2) of age and also stratified according to estradiol levels: > 10 and < or = 10 pg/ml. Significant differences in BMD were found in women in Group 1 in whom estradiol levels higher than 10 pg/ml were associated with a higher BMD of the lumbar spine (+ 14%, p < 0.01), proximal femur (+ 6%, p < 0.05) and total skeleton (+ 7%, p < 0.05) compared with women with estradiol levels below 10 pg/ml. Bone alkaline phosphatase levels (p < 0.05) and serum Crosslaps (not significant) were lower in women in Group 1 with a level of estradiol more than 10 pg/ ml. CONCLUSION: Endogenous estradiol levels higher than 10 pg/ml and testosterone protected bone mass in healthy postmenopausal women under 65 years of age. These results were not observed in the group of older women.     

Uterine and vaginal effects of unopposed ultralow-dose transdermal estradiol

OBJECTIVE: To investigate uterine effects of unopposed ultralow-dose transdermal estradiol administered to postmenopausal women for 2 years. METHODS: Postmenopausal women (n = 417), aged 60-80 years, with a uterus and with bone mineral density that was normal for age (z score >or=-2.0) were randomly assigned to receive unopposed transdermal estradiol (14 microg per day) or identical placebo patch. We evaluated effects on endometrial histology, vaginal bleeding, and vaginal epithelial cell maturation. RESULTS: At baseline, estradiol and placebo groups were similar in age (67 +/- 5 years) and in median baseline serum estradiol level (4.8 pg/mL, interquartile range 2.7, 8.0 pg/mL). In the estradiol group, median estradiol level increased to 8.6 pg/mL, (interquartile range 4.4, 13.9 pg/mL, P < .001). In the estradiol group, focal atypical endometrial hyperplasia developed in 1 woman, and adenosarcoma of the uterus developed in 1 woman. The placebo group had no endometrial hyperplasia. Endometrial proliferation occurred in 8.5% of the estradiol group and in 1.1% of the placebo group (P = .06). Incidence of vaginal bleeding was 12.4% in the estradiol group and 8.6% in the placebo group (P = .3). Vaginal epithelial cells showed greater maturation in the estradiol group than in the placebo group (P < .001) but less than typically observed with standard doses of estrogen. CONCLUSION: During 2 years of treatment with ultralow-dose unopposed estradiol, treatment and placebo groups had similar rates of endometrial hyperplasia, endometrial proliferation, and vaginal bleeding. This therapy apparently causes little or no endometrial stimulation. LEVEL OF EVIDENCE: I.     

Endometrial response to a cyclic regimen of percutaneous 17β-estradiol and low-dose vaginal micronized progesterone in women with mild-to-moderate hypertension

Endometrial response to natural estradiol and low-dose vaginal progesterone replacement therapy was evaluated in 20 postmenopausal women with chronic ,mild-to-moderate hypertension. A cyclic hormone replacement therapy (HRT) regimen was used (21/28 days) with percutaneous estradiol (1.5 mg/day) and vaginal micronized progesterone (100 mg/day). Menopausal symptoms decreased and estradiol concentrations increased substantially and remained in the physiological range throughout treatment. Serum gonadotropin concentrations decreased significantly (p < 0.001 ,Friedman's ANOVA). Bone mineral density increased by 2.1% (p = 0.029) only at the lumbar spine. Endometrial thickness remained unchanged. Breakthrough bleeding or spotting occurred in 18% of cycles in the first 3 months of HRT ,30% in months 4-9 and 22% in months 10-12. Withdrawal bleeding occurred in 40% of cycles in the first 3 months and decreased to 25% in months 10-12. At month 12 ,there were 11 women with amenorrhea due to endometrial atrophy. Nine women had active endometria (proliferative or secretory) and thus reported vaginal bleeding. No severe bleeding ,hyperplasia ,or carcinoma was found. Vaginal bleeding was tolerated ,and no subject withdrew from the study. Results suggest that this regimen confers endometrial protection and is well tolerated ,and can therefore safely be used for at least 1 year by postmenopausal women with hypertension and menopausal symptoms.     

Inhibition of gonadotropin surge by a brief mid-cycle regimen of ethinyl estradiol and norethindrone: possible role in in vitro fertilization.

Various methods to prevent premature luteinizing hormone (LH) surge and improve cycle control during hyperstimulation for in vitro fertilization (IVF) are standard of care. The purpose of the present study was to determine the influence of a 5-day regimen of ethinyl estradiol (EE) and norethindrone (NET) on folliculogenesis, gonadotropin surge, and ovulation. In a prospective randomized and comparative study, ten patients were assigned to two groups. A combination of 50 micrograms of EE and 1 mg of NET was used in groups I and II from days 6 through 10, and days 8 through 12, respectively. Blood samples and transvaginal ultrasound imaging were carried out throughout a 28-day cycle. Follicular diameter, plasma levels of LH, follicle-stimulating hormone (FSH), estradiol and progesterone, and endometrial thickness were determined. No LH surge or ovulation was detected in any patient studied. Peak estradiol concentrations were not significantly different between the groups (152.04 +/- 107.1 pg/ml vs 162.1 +/- 56.1 pg/ml [mean +/- SD] for groups I and II, respectively). No differences were noted between the groups for serum concentrations of FSH (range: 2-9 mIU/ml) or LH (range: 2-10 mIU/ml) for any given cycle day. Mean follicular diameters were not different between groups I and II (20.5 +/- 8.1 mm2 vs 20.6 +/- 14.2 mm2). Ultrasound assessment of mid-cycle follicular growth revealed diameters ranging from 18.5 mm2 to 34.0 mm2. Endometrial thickness ranged from 8 to 10 mm. There was no evidence of ovulation on ultrasound examination and either persistence or gradual resolution of follicles through the luteal phase. Peak serum concentrations at mid-luteal phase were < or = 2 ng/ml. In this pilot study, the combination of EE and NET restricted to a 5-day course beginning on day 6 or 8 permitted folliculogenesis but effectively inhibited midcycle LH surge and ovulation. Such regimens may have a role in IVF cycles for prevention of premature LH surges, especially as stimulation regimens evolve toward decreased gonadotropin use for stimulation and strict FSH preparations with the potential need for less complete pituitary suppression.     

Relationship of estradiol levels to breakthrough bleeding during continuous combined hormone replacement therapy

OBJECTIVE: To determine whether serum estradiol and dydrogesterone concentrations are associated with the occurrence of breakthrough bleeding. METHODS: In a prospective, double-blind study, 194 postmenopausal women were allocated randomly to receive one of four doses of dydrogesterone (2.5 mg, 5 mg, 10 mg, 15 mg) continuously combined with 2 mg of micronized 17beta-estradiol. All medication was taken orally for a total of 168 days. Vaginal bleeding was recorded on a daily basis. Serum estradiol (E2) and dihydrodydrogesterone (the main metabolite of dydrogesterone) trough levels were measured at day 85 and at the end of the study (day 168). Bleeding pattern analysis was done according to the reference period method. RESULTS: One hundred fifty-two of 177 women who completed the study supplied valid data on drug compliance, smoking habits, bleeding episodes, and serum hormone concentrations, which were used to assess the impact of serum E2 and dihydrodydrogesterone concentrations on the occurrence of breakthrough bleeding. Logistic regression analysis identified only the serum E2 concentration as having an independent, statistically significant effect (P = .003) on the occurrence of breakthrough bleeding; no such effect was associated with dihydrodydrogesterone levels (P = .118). The relative risk for the occurrence of breakthrough bleeding was 2.7 (95% confidence interval [CI] 1.454, 5.609) for serum E2 concentrations greater than 40 pg/mL. CONCLUSION: The occurrence of breakthrough bleeding during continuous combined hormone replacement therapy with estradiol and dydrogesterone in postmenopausal women was related to serum estradiol levels and not to dydrogesterone levels. Further studies are needed to test the hypothesis that estrogen is a major factor in the incidence of bleeding during postmenopausal hormone replacement therapy.     

Low serum progesterone the day prior to frozen embryo transfer of euploid embryos is associated with significant reduction in live birth rates

Abstract

A retrospective cohort study was performed to examine whether, in artificial endometrial preparation for frozen embryo transfer (FET) cycles, progesterone (P) levels the day prior to embryo transfer of euploid embryos have an impact on pregnancy outcomes. In a private university clinic, 244 FETs between January 2016 and June 2017 were analyzed. Endometrial preparation was achieved with estradiol valerate and vaginal micronized progesterone. Serum P and estradiol levels the day prior to embryo transfer were measured. A multivariable analysis to assess the relationship between serum P level and pregnancy outcomes was performed, adjusted for confounding variables. Mean P value was 11.3?±?5.1?ng/ml. Progesterone levels were split in quartiles: Q1: ≤ 8.06?ng/ml; Q2: 8.07–10.64?ng/ml; Q3: 10.65–13.13?ng/ml; Q4: > 13.13?ng/ml. Patients included in the lower P quartile had a significantly higher miscarriage rate and significantly lower live birth rate (LBR) compared to the higher ones. A low serum P level (≤ 10.64?ng/ml) one day before FET is associated with a lower pregnancy and LBR following FET of euploid embryos.     

The effect of estradiol valerate and dienogest combination on serum homocysteine levels in postmenopausal women: a clinical trial.

Several studies have verified that hormone replacement therapy (HRT) has protective effects on postmenopausal women's cardiovascular condition. However, highly significant recent studies have reported that women treated with HRT have more cardiovascular events than untreated women. An elevated homocysteine level is one important risk factor for cardiovascular disease (CVD). As a good indicator of CVD risk, we examined the changes in plasma homocysteine levels of postmenopausal women treated with HRT. In our study, we administered estradiol valerate (2 mg) and dionegest (2 mg) to 34 postmenopausal women recruited randomly from our menopause clinic, and measured plasma homocysteine levels of patients at baseline and after 3 and 6 months of therapy. The changes in plasma homocysteine levels of treated patients were not statistically significant (p = 0.241). Our results indicate that 6 months of estradiol valerate and dionegest therapy does not change homocysteine levels in postmenopausal women.