Oral 17beta-estradiol Research Articles

MON-198 Feminizing Regimen Requirements in Transgender Females Following Orchiectomy

Introduction: Transgender females (TF) may undergo orchiectomy as part of their treatment. However, there is no clear recommendation in hormonal transition between pre- and post-orchiectomy (1, 2). Methods: All TF with orchiectomy in the transgender registry at Boston Medical Center (BMC) were reviewed. Feminizing regimens prior to and after orchiectomy were evaluated. The type, form and dose of hormones along with serum estradiol, testosterone, FSH and LH were assessed. Results: 124 TF consented to be included in the transgender registry at BMC. 23 of 124 (18%) TF had orchiectomy. 10/23 TF had the hormonal regimen available pre-orchiectomy and 6 months or more post-orchiectomy. All 10 TF used oral 17-beta estradiol. 6 TF were prescribed less estradiol relative to their pre-orchiectomy regimen, 3 were prescribed the same estradiol dose and 1 was prescribed a higher estradiol dose. An average of adjusted post-orchiectomy estradiol doses was 78% (range 50%-150%) of pre-orchiectomy dose. Among 10 TF with an available hormone regimen pre-and post-orchiectomy, 5 (50%) had serum estradiol at goal (100-200 pg/mL) and FSH in a pre-menopausal cis-female range. Among these 5 TF, the average of the adjusted post-orchiectomy estradiol dose was 96% (range 50%-150%) of the pre-orchiectomy dose. Estradiol doses up to 6 months or more following orchiectomy were available in 17 TF. 15 used oral 17-beta estradiol (average dose of 3.1mg/day with the range of 1-8 mg), 1 used oral conjugated estradiol and 1 used 17-beta estradiol gel. 7/17 had estradiol level at goal (100-200 pg/mL) and FSH in the pre-menopausal female range. All 7 TF used oral 17-beta estradiol. An average of post-orchiectomy estradiol doses was 2.85 mg/day (range 1-5 mg). Conclusion: Most TF who underwent orchiectomy had a lower estradiol dose (approximately 75% of the pre-orchiectomy regimen). However, to achieve the estradiol level at goal and maintain FSH in the the pre-menopausal female range, trans women required estradiol doses closer to the pre-orchiectomy regimen. The dose range of oral 17-beta estradiol in post-orchiectomy TF is 1-5 mg, similar to recommendations for TF who have not undergone orchiectomy (2-6 mg) (1).

MON-195 Trans-transgender Female: Gender Identity Reversal Following Irreversible Gender Affirming Surgeries

Background: Comprehensive transgender care involves a multidisciplinary team of primary care providers, mental health providers (MHPs), endocrinologists and surgeons. Management of gender dysphoria (GD) includes hormonal and surgical treatment, with the latter being irreversible. Mental health evaluation to confirm GD is an essential step in transgender medical care, especially in children and adolescents. Clinical case: A 29-year-old biological female lived as a transgender male for 10 years after realizing male gender identity during puberty. She began to live as a male at age 16 and was diagnosed with GD by an adolescent MHP. She started transmasculine hormonal therapy at age 17, had a mastectomy at age 18, and hysterectomy-oophorectomy at age 20. At age 25, she was hospitalized for schizophrenia. Around that time, she developed dysphoria about being a transgender male. She later reversed her gender identity and gender expression back to female. She was evaluated by a new MHP, who diagnosed GD with no confounding mental health disorders, and she was started feminizing hormonal therapy with oral 17-beta estradiol. Serum estradiol level has been maintained between 100-200 pg/ml on estradiol 4mg/day. Despite use of feminizing hormones for 3 years, no significant breast development has been observed. She reports regret about her hysterectomy-oophorectomy, but no regrets about her chest surgery as it was essential to her male gender expression at the time of transition. This patient met all of the Endocrine Society criteria for genital gender-affirming surgery. The guideline recommends at least 1 year of consistent hormonal treatment and control of coexisting mental health concerns prior to genital gender-affirming surgery (1). The World Professional Association for Transgender Health (WPATH) Standards of Care recommends two separate referrals by qualified MHPs prior to genital gender-affirming surgery (2). Although this requirement might be challenging in clinical practice, meticulous mental health evaluation should be completed in transgender individuals who consider irreversible gender-affirming surgeries. In this case, the patient had no documented mental health disorder until after transitioning, making this evaluation more challenging, but on repeat mental health evaluation had GD, leading her to ultimately detransition. Conclusion: This case emphasizes the importance of mental health evaluations in transgender care. Although not universally required for initiation of transgender hormone therapy, evaluations by two separate MHPs who are experienced in transgender care are needed prior to irreversible gender-affirming surgeries to ensure GD and decrease the likelihood of detransitioning.

O.05b Low molecular weight heparin actions on human endometrial angiogenesis

s / Thrombosis Research 127 (2011) S123–S150 S125 O.04b Effect of the dose of oral treatment with 17beta-estradiol associated with dydrogesterone on thrombin generation in healthy postmenopausal women: a randomized double-blind placebo-controlled study G. Gerotziafas *, V. Galea, A. Rousseau, D. Torchin, K.F. Zannad, K. Lacut, J. Demolis, T. Simon, I. Elalamy. ER2UPMC, Faculte de Medecine Pierre et Marie Curie, Universite Paris 6, Hopital Tenon, APHP, Paris, Clinical research Unit, Department of Clinical Pharmacology, APHP, Saint-Antoine hospital, Paris 6 University, Paris, Department of Gynaecology, APHP, Saint-Antoine hospital, Paris, Clinical Investigation Center, CHU, Nancy, Clinical Investigation Center, CHU, Brest, Clinical Investigation Center, Department of Clinical Pharmacology, AP-HP Saint-Antoine hospital, Paris 6 University, Paris, France Introduction: Increased risk of venous thrombosis during oral hormone therapy in postmenopausal women is related to estrogen-induced hypercoagulable state. Lower estrogen dose is recommended, but the effect of hormone dose optimisation on haemostasis has not been studied. Aim of the study: To evaluate the influence of two different doses of daily oral 17beta-estradiol therapy compared with placebo, on thrombin generation (TG) in healthy postmenopausal women. Materials-Methods: Seventy two menopausal women were randomized to receive daily 1mg (n =24) or 2mg (n =26) of 17beta-estradiol associated with 10mg dydrogesterone or placebo (n =22). TG was monitored before and 2 months after treatment using the Calibrated Automated Thrombogram® (Stago, France). Results: At baseline parameters of TG were not statistically different in the three study groups. Two months after randomisation, lag time and time to reach the peak of thrombin were decreased while the mean rate index and the peak of thrombin were significantly increased in the two groups of hormone-treated women as compared to placebo group. Endogenous thrombin potential remained unchanged. No difference was observed in TG parameters between women receiving lower and higher dose of 17betaestradiol. Conclusions: Oral hormone therapy with 2mg of 17beta-estradiol for two months induced acceleration and increase of TG. Lowering the dose by 1mg did not attenuate this effect. On the contrary endogenous thrombin potential was not influenced in any dose. The clinical significance of the profile of TG of postmenopausal women being on hormone therapy remains to be explored. Table 1: Parameters of thrombin generation 2 months after randomisation (Treatment with two different doses of 17beta-estradiol associated with dydrogesterone or placebo) placebo 17beta-estradiol

O.04b Effect of the dose of oral treatment with 17beta-estradiol associated with dydrogesterone on thrombin generation in healthy postmenopausal women: a randomized double-blind placebo-controlled study

s / Thrombosis Research 127 (2011) S123–S150 S125 O.04b Effect of the dose of oral treatment with 17beta-estradiol associated with dydrogesterone on thrombin generation in healthy postmenopausal women: a randomized double-blind placebo-controlled study G. Gerotziafas *, V. Galea, A. Rousseau, D. Torchin, K.F. Zannad, K. Lacut, J. Demolis, T. Simon, I. Elalamy. ER2UPMC, Faculte de Medecine Pierre et Marie Curie, Universite Paris 6, Hopital Tenon, APHP, Paris, Clinical research Unit, Department of Clinical Pharmacology, APHP, Saint-Antoine hospital, Paris 6 University, Paris, Department of Gynaecology, APHP, Saint-Antoine hospital, Paris, Clinical Investigation Center, CHU, Nancy, Clinical Investigation Center, CHU, Brest, Clinical Investigation Center, Department of Clinical Pharmacology, AP-HP Saint-Antoine hospital, Paris 6 University, Paris, France Introduction: Increased risk of venous thrombosis during oral hormone therapy in postmenopausal women is related to estrogen-induced hypercoagulable state. Lower estrogen dose is recommended, but the effect of hormone dose optimisation on haemostasis has not been studied. Aim of the study: To evaluate the influence of two different doses of daily oral 17beta-estradiol therapy compared with placebo, on thrombin generation (TG) in healthy postmenopausal women. Materials-Methods: Seventy two menopausal women were randomized to receive daily 1mg (n =24) or 2mg (n =26) of 17beta-estradiol associated with 10mg dydrogesterone or placebo (n =22). TG was monitored before and 2 months after treatment using the Calibrated Automated Thrombogram® (Stago, France). Results: At baseline parameters of TG were not statistically different in the three study groups. Two months after randomisation, lag time and time to reach the peak of thrombin were decreased while the mean rate index and the peak of thrombin were significantly increased in the two groups of hormone-treated women as compared to placebo group. Endogenous thrombin potential remained unchanged. No difference was observed in TG parameters between women receiving lower and higher dose of 17betaestradiol. Conclusions: Oral hormone therapy with 2mg of 17beta-estradiol for two months induced acceleration and increase of TG. Lowering the dose by 1mg did not attenuate this effect. On the contrary endogenous thrombin potential was not influenced in any dose. The clinical significance of the profile of TG of postmenopausal women being on hormone therapy remains to be explored. Table 1: Parameters of thrombin generation 2 months after randomisation (Treatment with two different doses of 17beta-estradiol associated with dydrogesterone or placebo) placebo 17beta-estradiol

Comparison of the Effects of Hormone Therapy Regimens, Oral and Vaginal Estradiol, Estradiol + Drospirenone and Tibolone, on Sexual Function in Healthy Postmenopausal Women

Sexual dysfunction is more prevalent in postmenopausal women. To prospectively evaluate and compare the effects of hormone therapy (HT) regimens, oral and vaginal estradiol, estradiol + drospirenone and tibolone, on sexual function in healthy postmenopausal women. The study included 169 consecutive healthy postmenopausal women, and the women were divided into two groups: 111 women received HT, and 58 women received no treatment and served as a control group. As an HT, 23 women with surgically induced menopause received oral 17-beta estradiol. The rest of the women with natural menopause were prospectively randomized: 22 received oral 17-beta estradiol + drospirenone daily, 42 received oral tibolone, and 24 received vaginal 17-beta estradiol. Sexual function was evaluated with a detailed 19-item questionnaire, the female sexual function index, including sexual desire, arousal, lubrication, orgasm, satisfaction, and pain. The differences in sexual function were compared before and 6 months after the treatment in all women. Total sexual function score increased from 19.81 +/- 7.15 to 22.9 +/- 6.44 in the HT group and decreased from 21.6 +/- 8.69 to 17.6 +/- 5.7 in the control group, revealing a significant difference from baseline to post-treatment between the two groups (P = 0.000). The highest improvement in total score and arousal was achieved with the oral 17-beta estradiol (P = 0.000 and P = 0.000, respectively). The highest improvement in lubrication was achieved with the oral and vaginal 17-beta estradiol groups (P = 0.000). The highest improvement in orgasm was achieved with the tibolone group (P = 0.000). The highest improvement in pain was achieved with the oral and vaginal 17-beta estradiol groups (P = 0.000). HT provided significant improvement in sexual function compared to women receiving no treatment, and therefore, HT regimens should be suggested for improvement in sexual functioning of postmenopausal women.

Perimenopausal Depression

Perimenopausal Depression

Postmenopausal oral estrogen therapy affects hemostatic factors, but does not account for reduction in the progression of subclinical atherosclerosis.

Hemostatic factors influenced by postmenopausal hormone therapy may contribute to atherosclerosis. The Estrogen in the Prevention of Atherosclerosis Trial (EPAT), a 2-year, randomized, double-blind, placebo-controlled trial, demonstrated reduced subclinical atherosclerosis progression measured by change in common carotid artery intima-media thickness (CIMT) with unopposed oral 17beta-estradiol. To assess the effect of postmenopausal hormone therapy on the levels of several hemostatic factors, and the relationship between these factors and the progression of subclinical atherosclerosis. We measured tissue plasminogen activator (t-PA) antigen, factor (F) VII, D-dimer and albumin longitudinally, and plasminogen activator inhibitor type 1 (PAI-1) and fibrinogen at trial-end, in 186 postmenopausal women. Estradiol vs. placebo was associated with greater FVII and lower t-PA, albumin, PAI-1 and fibrinogen (all P < or = 0.001), with no estradiol effect on D-dimer (P = 0.42). Only mean on-trial t-PA was positively associated with the absolute level of CIMT on-trial (r = 0.29, P < 0.0001), but this was attenuated with age and body mass index adjustment. No longitudinally measured hemostatic factor was associated with CIMT progression. However, higher CIMT during the trial was significantly related to increases in t-PA. These results confirm previous findings regarding estrogen's effect on hemostatic factors and show that albumin is negatively associated with estrogen therapy. These hemostatic factors did not account for the reduction of CIMT progression with 17beta-estradiol seen in EPAT. Atherosclerosis itself may affect levels of hemostatic factors (reverse causality), with subsequent involvement in atherosclerosis-associated thrombosis.

A dose‐response study of hormone replacement in young hypogonadal women: effects on intima media thickness and metabolism

Young hypogonadal women appear to have an increased risk of cardiovascular disease. We studied the influence of increasing doses of hormone replacement therapy (HRT) on markers of metabolism and vascular physiology. Nine-month sequential dose-ranging study. A total of 25 young hypogonadal women (Turner Syndrome, n = 14; 46,XX gonadal dysgenesis, n = 9), hypogonadotrophic hypogonadism (n = 2), mean age 31.9 years (range 18.5-42.2). All subjects sequentially received oral 17beta-oestradiol 1,2 and 4 mg daily in a cyclical formulation for 12 weeks each. Metabolic markers and vascular physiology measurements to assess intima media thickness (IMT); arterial stiffness: pulse wave velocity (PWV) and augmentation index (AIx); endothelial function: flow-mediated dilatation (FMD). Results Increasing doses of oestrogen resulted in a reduction in IMT (0.63 +/- 0.06 vs. 0.58 +/- 0.06 vs. 0.56 +/- 0.06 mm at 1 mg, 2 mg and 4 mg 17beta-oestradiol, respectively, P = 0.001). were similar in women with Turner Syndrome and normal karyotype. High-density lipoprotein (HDL) cholesterol concentrations increased (1.9 +/- 0.4 vs. 2.0 +/- 0.5 vs. 2.2 +/- 0.4 mmol/l, P = 0.001) and plasma glucose (4.8 +/- 0.4 vs. 4.7 +/- 0.3 vs. 4.6 +/- 0.6 mmol/l, P = 0.038) decreased slightly with the increasing dose of HRT. There was no correlation between the changes in IMT and HDL. Increasing HRT dose had no significant impact on blood pressure, weight, other lipid parameters, insulin, C-reactive protein, interleukin-6 and fibrinogen concentrations or FMD, PWV and AIx. Increasing doses of HRT result in a reduction in carotid IMT in young hypogonadal women, along with increased serum HDL and decreased plasma glucose. This study raises the possibility that exogenous oestrogen may be cardioprotective in young women, but this observation needs to be balanced against a prothrombotic effect which is predominant in postmenopausal women.

Effects of low‐dose continuous combined hormone replacement therapy on glucose homeostasis and markers of cardiovascular risk in women with type 2 diabetes

Low-dose hormone replacement therapy (HRT) has attracted interest for the treatment of postmenopausal symptoms in diabetes because of concerns about increased risk of coronary heart disease (CHD) and stroke with conventional HRT containing conjugated equine oestrogens (CEEs) and medroxyprogesterone acetate (MPA). We assessed the effects on glucose homeostasis and cardiovascular risk factors of continuous oral 17beta oestradiol (1 mg) and norethisterone (0.5 mg) in postmenopausal women with type 2 diabetes. Double-blind, randomized placebo-controlled trial. Hyperinsulinaemic isoglycaemic clamp and cardiovascular risk factors were assessed before and after 3 months of treatment. Twenty-eight women completed the study. HRT decreased fasting glucose compared with placebo [-9.4% with HRT vs.+2.3% for placebo, 95% confidence interval (CI) -23.2 to -0.3] and total cholesterol (-13.7 vs.+1.0%, 95% CI -22.4 to -3.1%) No significant effect was seen on metabolic clearance rate of glucose, glycated haemoglobin (HbA1c), triglycerides, high density lipoprotein (HDL)-cholesterol or C-reactive protein (CRP). In women with type 2 diabetes, low-dose HRT decreased fasting glucose and total cholesterol without detectable adverse effects on glucose clearance, triglycerides and CRP as reported with conventional HRT.

Differential Effects of Chronic Treatment with Estrogen Receptor Ligands on Regulation of Nitric Oxide Synthase in Porcine Aortic Endothelial Cells

In cultured endothelial cells, estrogen increases expression and activity of endothelial nitric oxide synthase (eNOS). This study was designed to determine whether estrogenic treatments increase eNOS similarly in vivo. Aortic endothelial cells were collected from adult ovariectomized pigs which were untreated (8wk-OVX) or treated with oral 17beta-estradiol (E2, 2 mg/day), conjugated equine estrogen (CEE, 0.625 mg/day), or raloxifene (60 mg/day) for 4 weeks. Plasma NOx, estrogen receptors (ERalpha and ERbeta), eNOS, eNOS regulatory proteins, and eNOS mRNA in endothelial cells were determined by Griess reaction, Western blot, and real-time polymerase chain reaction, respectively. Ovariectomy decreased, whereas all treatments restored plasma NO(x) to pre-OVX levels. On the contrary, eNOS protein and mRNA increased with ovariectomy; E2 and CEE but not raloxifene reduced mRNA; eNOS protein was reduced by CEE and raloxifene treatments. Tyrosine phosphorylation of eNOS and expression of calmodulin increased, but Hsp90 decreased with all treatments and only raloxifene treatment increased caveolin-1 compared with OVX. Expression of ERalpha/ERbeta increased with ovariectomy and was reversed by treatments such that raloxifene>CEE>E2. Three clinically relevant estrogen treatments restore plasma NO after ovariectomy, but do not affect eNOS mRNA, posttranslational regulation of eNOS or expression of estrogen receptors in the same way.

Oral, more than transdermal, oestrogen therapy lowers asymmetric dimethylarginine in healthy postmenopausal women: a randomized, placebo‐controlled study

To compare the effects of oral and transdermal hormone therapy (HT) on asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, in postmenopausal women. In a multicentre, placebo-controlled, double-blind study, 152 hysterectomized healthy women were randomized to receive daily transdermal 17beta-oestradiol (tE2, n = 33), or oral micronized 17beta-oestradiol either unopposed (oE2, n = 37), or continuous combined with gestodene (oE2 + G, n = 33), or placebo (n = 49) for 13, 28-day treatment cycles. Plasma concentrations of ADMA, arginine and symmetric dimethylarginine (SDMA) were measured at baseline and in treatment cycles 4 and 13 with a high-performance liquid chromatography method. After 13 cycles all active treatment groups showed a significant reduction in ADMA compared with placebo: tE2, -4.0% (95% CI: -7.5 to -0.6%); oE2, -7.7% (95% CI: -10.9 to -4.4%) and oE2 + G, -7.5% (95% CI: -10.8 to -4.3%). ancova showed a significantly larger reduction in the oral groups compared with the transdermal group (tE2 vs. oE2 and tE2 vs. oE2 + G, both P < 0.01). Oral, but not transdermal treatment, significantly reduced arginine compared with placebo. All active treatments reduced SDMA; however, this was only statistically significant in the oE2 group. Reduction of ADMA was more pronounced after oral than after tE2 administration. Adding gestodene to oral 17beta-oestradiol did not alter the reduction of ADMA. The clinical implications of these findings remain uncertain; however, the decrease of ADMA by 17beta-oestradiol could be a key phenomenon in the modulation of nitric oxide synthesis by postmenopausal HT.

A Prospective Randomized Trial Evaluating Endometrial Preparation for Implantation of Frozen/Thawed Embryos Using an Artificial Cycle Versus a Stimulated Cycle

A Prospective Randomized Trial Evaluating Endometrial Preparation for Implantation of Frozen/Thawed Embryos Using an Artificial Cycle Versus a Stimulated Cycle

Effects of Estrogen Replacement Therapies on Mouse Platelet Funcion.

Clinical trials of hormone replacement therapy (HRT) have demonstrated an increase in stroke and myocardial infarction despite the beneficial changes in LDL and HDL cholesterols, and it has been suggested that HRT may adversely affect thrombosis and/or inflammation. Platelets participate in both of these processes and play a central role in thrombosis formation in high shear arterial vasculature. The effects of HRT on platelet function have been controversially reported, probably due to different hormone regimes used (e.g. different estrogenic compounds, different dosages and routes of administration). We used a murine model of menopause to test the hypothesis that HRT alters platelet reactivity. Bilaterally ovariectomized female littermates were treated with various estrogen regimes or matching placebo for 21 days. Three estrogen replacement therapy (ERT) regimes were studied: 1) oral conjugated equine estrogen (CEE) vs. placebo (n=5 pairs), 2) oral 17-beta estradiol (E2) vs. placebo (n=4 pairs), and 3) subcutaneously implanted E2 (SQ E2) vs. placebo (n=8 pairs). Washed platelets were used to focus on intrinsic platelet reactivity in the absence of plasma coagulation factors. Platelet reactivity was assessed by flow cytometric quantification of agonist-induced fibrinogen binding. Oral CEE, but not oral E2 enhanced the platelet response to collagen-related-peptide (CRP) (P<0.001 and P=0.87 for oral CEE and oral E2, respectively). This enhancement of platelet function was agonist specific since neither oral CEE (P=0.862) nor oral E2 (P=0.917) affected the platelet response to thrombin. We also tested whether the route of hormone administration affected platelet function. SQ E2 induced a condition different from that of oral E2: the platelet response to thrombin was enhanced (P=0.028), but only to low (<10 mU/ml), not high concentrations of thrombin. In contrast to oral E2, SQ E2 caused a reduction in CRP-induced platelet fibrinogen binding (P=0.030). Platelet surface expression of GPVI was reduced in response to SQ E2 (P<0.001), and the level of GPVI correlated with CRP-induced platelet fibrinogen binding (P<0.0001). In conclusion: 1) the effects of different estrogen replacement therapies on platelet function differ significantly, perhaps explaining some of the conflicts in the literature, 2) the effects of ERT on platelet function are dependent upon the ERT preparations and routes, 3) the effects of ERT on platelet function are agonist and agonist dose-dependent, and 4) SQ E2 induces lower platelet GPVI expression, most likely explaining the reduced response to CRP. A potential practical consequence of our findings is that oral E2 may be less prothrombotic than either oral CEE or transdermal E2.

Spotlight on Estradiol and Norgestimate as Hormone Replacement Therapy in Postmenopausal Women*

The focus of this review is hormone replacement therapy (HRT) with continuous administration of micronized, oral 17beta-estradiol 1 mg/day (herein referred to as continuous estradiol) plus micronized, oral norgestimate 90 microg/day administered for 3 days then withdrawn for 3 days in a 6-day repeating sequence (herein referred to as intermittent norgestimate). According to data from randomized, comparative trials of 1 year's duration, continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day relieves climacteric symptoms (vasomotor symptoms and vulvovaginal atrophy) in postmenopausal women. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day appeared as effective as estradiol 1 mg/day alone or continuous estradiol 2 mg/day plus continuous norethisterone acetate 1 mg/day in the treatment of postmenopausal women with vasomotor symptoms. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day was as effective as continuous estradiol 1 mg/day in causing the maturation of vaginal epithelial cells. In a randomized, double-blind study, bone mineral density (BMD) increased to a significantly greater extent and the rate of bone turnover was slower in postmenopausal women treated with continuous oral estradiol 1 mg/day plus intermittent norgestimate 90 microg/day than in placebo-treated patients. Two randomized, double-blind studies indicated that the addition of norgestimate 90 microg/day to continuous estradiol 1 mg/day did not attenuate the beneficial effects of estradiol on lipid parameters. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day was associated with increases in mean serum high density lipoprotein (HDL)-cholesterol levels and decreases in total cholesterol, low density lipoprotein (LDL)-cholesterol and lipoprotein (a) levels, compared with baseline. There was no statistically significant increase in triglyceride levels. In comparative trials, continuous oral estradiol 1 mg/day plus intermittent oral norgestimate 90 microg/day was well tolerated. Headache, breast pain or discomfort, abdominal pain or discomfort, uterine bleeding, dysmenorrhea, edema, nausea and depression were the most commonly reported adverse events. Continuous estradiol 1 mg/day plus intermittent oral norgestimate 90 microg/day was associated with a favorable uterine bleeding profile that improved over time. In a randomized trial, 80% of women were free from bleeding (irrespective of spotting) during month 12 of treatment. Norgestimate 90 microg/day was effective in protecting postmenopausal women against induction of endometrial hyperplasia by continuous estradiol 1 mg/day. In conclusion, data from a limited number of randomized studies indicate that HRT with continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day is effective in relieving climacteric symptoms, increasing BMD and slowing the rate of bone turnover in postmenopausal women. This HRT regimen is well tolerated and is associated with a similar incidence of adverse events to that reported in recipients of continuous estradiol 1 mg/day. The norgestimate component of the regimen provides good endometrial protection and is associated with a favorable bleeding profile. Long-term studies investigating the associated risk of breast cancer and thromboembolic events in recipients of continuous estradiol plus intermittent norgestimate are needed. In the meantime, continuous oral estradiol plus intermittent oral norgestimate can be regarded as an effective new option for HRT in postmenopausal women.

Comparison of the antiatherosclerotic effect of tibolone with that of estradiol and ethinyl estradiol in cholesterol-fed, ovariectomized rabbits

Tibolone is a synthetic steroid with tissue-specific estrogenic, progestogenic, and androgenic properties. The drug relieves climacteric symptoms and prevents osteoporosis but does not stimulate the endometrium. We have previously shown that in laboratory animals tibolone inhibits the atherogenesis induced by a high-cholesterol diet. Therefore, we compared the antiatherosclerotic effect of oral tibolone at different dose levels with that of oral 17beta-estradiol (E2) and ethinyl estradiol (EE). Atherosclerotic lesion formation (increase in vessel wall cholesterol deposition and fatty streak formation) was measured in ovariectomized rabbits after 20 weeks on an atherogenic diet (fed daily 80 g of a rabbit chow containing 0.4% cholesterol, 3.75% peanut oil, and 3.75% coconut oil) in eight groups: group 1, placebo (n = 35); group 2, control (n = 34) received normal rabbit chow; group 3, E2 group (E2 4 mg, n = 12); group 4, EE group (EE 60 microg, n = 10); and groups 5-8, tibolone (6 mg, n = 12; 2 mg, n = 13; 0.6 mg, n = 25; and 0.15 mg, n = 11, respectively). During the study, blood samples were obtained for the evaluation of plasma triglycerides, cholesterol, lipoproteins, and glutamate pyruvate transaminase. After 20 weeks, the animals were killed, and cholesterol concentration and the formation of fatty streaks in the wall of the aortic arch were evaluated. In the placebo group, the atherogenic diet induced a mean increase in total plasma cholesterol concentration from 1.1+/-0.1 mmol/L (control group) to 34.1+/-1.8 mmol/L (mean +/- SE). This resulted in an accumulation of cholesterol in the aortic arch from 48+/-4 (control group) to 608+/-44 nmol/mg protein and in the formation of fatty streaks (41.8+/-3.2% of the surface of the aortic arch was covered with fatty streaks). Tibolone had strong dose-dependent antiatherosclerotic effects. It reduced the accumulation of cholesterol in the aortic arch at doses of 6 to 0.15 mg by 99, 97, 87, and 57% and the formation of fatty streaks by 98, 97, 81, and 38%, respectively. E2 had only a marginal antiatherosclerotic effect, whereas EE showed an effect comparable to that of tibolone at doses of 2 to 0.6 mg. With EE, the accumulation of cholesterol in the vessel wall was reduced by 93% and the formation of fatty streaks by 73%. Mean plasma cholesterol concentrations were also reduced by tibolone (64, 70, 61, and 47%) and EE (57%). This reduction was mainly mediated via a reduction in beta-very-low-density lipoprotein cholesterol. Analysis, however, indicated that the observed antiatherosclerotic effects of tibolone and EE, at least partly, are due to a direct effect on the vessel wall and independent of the changes in plasma cholesterol. At equipotent antiatherosclerotic doses, EE showed a stronger uterotropic effect (measured as the increase in uterine weight) than tibolone. EE increased uterine weight from 0.57 g/kg body weight (BW) (control group) to 3.5 g/kg BW; tibolone at doses of 6, 2, 0.6, and 0.15 mg increased uterine weight to 2.5, 2.8, 2.2, and 1.3 g/kg BW, respectively. Tibolone can protect the arterial vessel wall against atherosclerotic lesions induced by a hypercholesterolemic diet. However, it has much less estrogenic effects on the uterus compared with EE at equipotent doses, indicating tissue selectivity for tibolone. The clinical implications of these findings require investigation.

Estradiol and norgestimate: a review of their combined use as hormone replacement therapy in postmenopausal women.

The focus of this review is hormone replacement therapy (HRT) with continuous administration of micronised, oral 17beta-estradiol 1 mg/day (herein referred to as continuous estradiol) plus micronised, oral norgestimate 90 microg/day administered for 3 days then withdrawn for 3 days in a 6-day repeating sequence (herein referred to as intermittent norgestimate). According to data from randomised, comparative trials of 1 year's duration, continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day relieves climacteric symptoms (vasomotor symptoms and vulvovaginal atrophy) in postmenopausal women. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day appeared as effective as estradiol 1 mg/day alone or continuous estradiol 2 mg/day plus continuous norethisterone acetate 1 mg/day in the treatment of postmenopausal women with vasomotor symptoms. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day was as effective as continuous estradiol 1 mg/day in causing the maturation of vaginal epithelial cells. In a randomised, double-blind study, bone mineral density (BMD) increased to a significantly greater extent and the rate of bone turnover was slower in postmenopausal women treated with continuous oral estradiol 1 mg/day plus intermittent norgestimate 90 microg/day than in placebo-treated patients. Two randomised, double-blind studies indicated that the addition of norgestimate 90 microg/day to continuous estradiol 1 mg/day did not attenuate the beneficial effects of estradiol on lipid parameters. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day was associated with increases in mean serum high density lipoprotein (HDL)-cholesterol levels and decreases in total cholesterol, low density lipoprotein (LDL)-cholesterol and lipoprotein (a) levels, compared with baseline. There was no statistically significant increase in triglyceride levels. In comparative trials, continuous oral estradiol 1 mg/day plus intermittent oral norgestimate 90 microg/day was well tolerated. Headache, breast pain or discomfort, abdominal pain or discomfort, uterine bleeding, dysmenorrhoea, oedema, nausea and depression were the most commonly reported adverse events. Continuous estradiol 1 mg/day plus intermittent oral norgestimate 90 microg/day was associated with a favourable uterine bleeding profile that improved over time. In a randomised trial, 80% of women were free from bleeding (irrespective of spotting) during month 12 of treatment. Norgestimate 90 microg/day was effective in protecting postmenopausal women against induction of endometrial hyperplasia by continuous estradiol 1 mg/day. In conclusion, data from a limited number of randomised studies indicate that HRT with continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day is effective in relieving climacteric symptoms, increasing BMD and slowing the rate of bone turnover in postmenopausal women. This HRT regimen is well tolerated and is associated with a similar incidence of adverse events to that reported in recipients of continuous estradiol 1 mg/day. The norgestimate component of the regimen provides good endometrial protection and is associated with a favourable bleeding profile. Long-term studies investigating the associated risk of breast cancer and thromboembolic events in recipients of continuous estradiol plus intermittent norgestimate are needed. In the meantime, continuous oral estradiol plus intermittent oral norgestimate can be regarded as an effective new option for HRT in postmenopausal women.

Effects of oral and transdermal 17β-estradiol with cyclical oral norethindrone acetate on insulin sensitivity, secretion, and elimination in postmenopausal women

Few studies have examined the effects of 17beta-estradiol on parameters of insulin and glucose metabolism. We studied 42 healthy, untreated postmenopausal women seeking relief from menopausal symptoms. They were randomized to receive either oral 17beta-estradiol 2 mg daily combined with sequential oral norethindrone acetate (NETA) 1 mg daily from days 12 to 22, or transdermal 17beta-estradiol 0.05 mg daily combined with sequential oral NETA 1 mg daily from days 17 to 28. Intravenous glucose tolerance tests (IVGTTs) were performed at baseline and after 46 weeks (estrogen-alone phase) and 48 weeks (combined phase) of completed therapy. Mathematical modeling analysis of plasma glucose, insulin, and C-peptide concentration profiles provided measures of insulin resistance, secretion, and elimination. Both types of therapy were associated with a decrease in fasting insulin and glucose levels. Insulin sensitivity was increased by oral estradiol during the estrogen-alone phase but was reversed by the addition of NETA. Transdermal estradiol did not affect insulin sensitivity. Hepatic insulin uptake and insulin secretion were increased with both types of treatment. The oral regimen of estradiol therapy was favorable to both insulin elimination and sensitivity. Transdermal estradiol therapy had relatively few effects on insulin metabolism.

Unopposed Estrogen Increases Total Plasma Factor VII, but not Active Factor VII

Estrogen therapy may increase the risk of arterial thromboembolism, at least in the short term. In a randomized, double-blind and placebo-controlled study in 25 healthy postmenopausal women (52.5 +/- 2.8 years), we therefore examined the short-term effect of unopposed estrogen on the fasting and fat-load-stimulated plasma levels of total factor VII versus active factor VII. Plasma total factor VII was measured by use of a chromogenic assay; plasma active FVII by a recently developed method using truncated tissue factor. As compared to placebo, 8 weeks of oral 17beta-estradiol (2 mg daily) increased the mean fasting and postprandial plasma levels of total factor VII by 17 and 21% points, respectively (both P < 0.01 ), but did not affect the fasting and/or postprandial plasma levels of active factor VII (mean change both 0.05 ng/mL; P > 0.35). Furthermore, the change in the fasting level of total factor VII after therapy was not associated with the change in the fasting level of active factor VII (r = 0.27; P = 0.21). These findings argue against the idea that elevated levels of total factor VII underlie an increased risk of arterial thromboembolism in postmenopausal women using unopposed estrogen replacement.

Tibolone prevents atherosclerotic lesion formation in cholesterol-fed, ovariectomized rabbits.

Tibolone (Org OD14), a synthetic steroid with estrogenic and progestogenic/androgenic properties, is clinically effective for the treatment of climacteric symptoms and the prevention and treatment of osteoporosis in postmenopausal women. The effect on atherogenesis, however, is not known. In the current study, we investigated the effect of tibolone in comparison with that of estradiol and norethisterone acetate on atherogenesis in 140 ovariectomized New Zealand White rabbits that had been induced by an atherogenic diet (0.4% cholesterol, 20 weeks). Tibolone at 18, 6, or 2 mg/d orally completely prevented cholesterol accumulation and fatty streak formation in the aorta; the impairment of endothelium-dependent smooth muscle relaxation of the aorta; and complex lesion formation after endothelial denudation in the carotid artery. Tibolone also reduced the increased postovariectomy plasma lipid concentrations. Analysis of the results, however, indicated that a substantial part of the strong, beneficial effects were plasma lipid independent. Compared with subcutaneous estradiol decanoate (150 microgram once weekly) and oral 17beta-estradiol (4 mg/d), the effects of tibolone were more pronounced at equipotent uterotropic activity. Norethisterone acetate (1 mg/d) did not affect atherosclerotic lesion formation. There are no indications that the progestogenic/androgenic properties of tibolone counteracted its atheroprotective effect on the vessel wall. Therefore, tibolone has the intrinsic potential to be a compound that protects the arterial vessel wall against atherosclerotic processes.

Plasma nitrate+nitrite levels are regulated by ovarian steroids but do not correlate with trabecular bone mineral density in rats.

Nitric oxide (NO) is a mediator of bone metabolism and its production is under the control of gender hormones in several cell types or tissues. Changes in endogenous NO production, measured as plasma nitrate+nitrite levels, may therefore contribute to ovariectomy (OVX)-induced bone loss. We studied plasma nitrate+nitrite levels and trabecular bone mineral density (TBMD) 4 weeks after sham-operation or OVX in rats receiving various hormonal treatments. OVX decreased plasma nitrate+nitrite levels significantly and this was accompanied by a significant decrease in TBMD. Treatment with oral ethinyl oestradiol (EE) and subcutaneous 17beta-oestradiol dose-dependently prevented the decrease in plasma nitrate+nitrite levels after OVX, but treatment with oral 17beta-oestradiol did not. Oestrogen treatment, 17beta-oestradiol (s. c. or orally) or EE (orally), prevented the OVX-induced decrease in TBMD. Treatment of sham-operated rats with the anti-oestrogen ICI164, 384 induced a significant decrease in TBMD that corresponded to 54% of the decrease observed after OVX, but did not affect plasma nitrate+nitrite levels. Treatment of ovariectomized rats with Org 2058, a pure progestagen, did not prevent bone loss, but prevented the decrease in plasma nitrate+nitrite levels dose-dependently. Treatment with tibolone, a synthetic steroid with combined weak oestrogenic, progestagenic, and androgenic properties, or with progestagen in combination with EE completely prevented bone loss after OVX. These treatments, however, only partly prevented the OVX-induced decrease in plasma nitrate+nitrite levels. In conclusion, OVX decreased both TBMD and plasma nitrate+nitrite levels. Although plasma nitrate+nitrite levels were under the control of both oestrogen and progesterone, TBMD was affected by oestrogen only. Decreased systemic production of NO is, therefore, not involved in OVX-induced bone loss in rats.