Effects of subdermal implants of estradiol and testosterone on the endometrium of postmenopausal women.

A retrospective review of the medical records of 258 postmenopausal patients using estradiol and testosterone implants as combined hormone therapy was carried out to evaluate the effects of testosterone on the endometrium after two years of continuous use. Endometrial thickness was measured by ultrasonography. Histology was performed on samples of thickened endometria obtained during hysteroscopy with biopsy. In the 44 patients in whom endometrial thickening was >5 mm at the end of the second year of implant use, the most frequent finding at hysteroscopy was polypoid lesion in 61.3% of cases, followed by normal uterine cavity in 31.8% of cases and submucous myoma in 6.8%. Histology of the endometrial samples confirmed endometrial polyp in 38.6% of cases, a histologically normal endometrium in 31.8% of cases, simple endometrial hyperplasia in 20.4% of cases, and myoma and atrophic endometrium in 4.5%. It is possible that testosterone may exert its antiproliferative effects on the endometrium but not on polyps in an action similar to that exerted by combined estrogen/progestin therapies. A greater incidence of simple, low-grade endometrial hyperplasia was found in our study compared with studies using continuous estrogen/progestin regimens. The use of progestins as the ideal endometrial protection should therefore be reconsidered.     

An open-label study of subdermal implants of estradiol-only versus subdermal implants of estradiol plus nomegestrol acetate: effects on symptom control,lipid profile and tolerability

Objective.?To compare the effects of continuous 17-β estradiol-only silastic implants with those of continuous 17-β estradiol plus continuous nomegestrol acetate silastic implants on symptom control, lipid profile and tolerability in postmenopausal women.

Methods.?This was an open-label, parallel-group study. Women with and without uterus and no contraindications to hormone therapy (HT) in this study, we consider as HT the replacement of Estrogens-only and Estrogens + Progestogens Therapy, were enrolled. Each subject was assigned to receive four 17-β estradiol-only silastic implants (women without uterus), or four 17-β estradiol plus one nomegestrol acetate silastic implant (women with intact uterus), for 1 year.

Results.?A total of 40 subjects were enrolled and received, the silastic implants of which 40 (100.0%) subjects completed the study (n = 20, estradiol only; n = 20, estradiol plus nomegestrol acetate). The incidence of postmenopausal symptoms decreased significantly. No significant decreases in total cholesterol (1.3%), low-density lipoprotein cholesterol (1.1%), triglycerides (1.2%) and fasting glucose ((1.3%) serum levels were observed in both groups, whereas high-density lipoprotein (HDL) cholesterol increased significantly (2.8%), during the study in both groups. The incidences of adverse events were similar in both treatment groups.

Conclusions.?Women treated with 17-β estradiol-only silastic implants or 17-β estradiol plus nomegestrol acetate silastic implants showed significant improvement of postmenopausal symptoms, including urogenital and sexual health symptoms and a significant increase in HDL cholesterol and no significant differences in other lipid profiles and tolerability.     

Effects of raloxifene hydrochloride on the endometrium of postmenopausal women

OBJECTIVE: We evaluated subtle endometrial morphologic changes in postmenopausal women assigned to placebo, raloxifene hydrochloride 200 or 600 mg/day, or conjugated estrogens (Premarin 0.625 mg/day) according to a new estrogenicity scoring system. Raloxifene, a new selective estrogen receptor modulator, was not expected to stimulate the endometrium. STUDY DESIGN: Baseline and end point endometrial biopsies were performed during this double-blind, placebo-controlled 8-week study. A scoring system that was based on standard glandular and stromal morphologic criteria was used to quantitate estrogen-induced effects. Baseline, end point, and baseline–to–end point changes were analyzed for treatment differences. RESULTS: Treatment groups were similar at baseline with most women showing no estrogenic effects. At end point, statistically significant moderate and marked estrogenic effects were noted in 77% of estrogen-treated women versus 15% of placebo-treated women versus 0% of raloxifene-treated women. CONCLUSIONS: As expected, estrogen treatment stimulated postmenopausal endometrium. In contrast, raloxifene did not induce histopathologic evidence of endometrial stimulation in healthy postmenopausal women.(Am J Obstet Gynecol 1997;177:64)     

Improvement of the lipid profile in post menopausal women who use estradiol and testosterone implants

The authors aimed to investigate the effect of sildenafil citrate (Sc) on expressions of β₃ integrin and vascular endothelial growth factor (VEGF), which is taking part in endometrium receptivity in implantation window period in controlled ovarian hyperstimulation (COH) performed rats. In this study, Wistar albino female rats were used and were divided into four groups as control, COH, Sc, and COH + Sc groups. They were sacrificed on the third, fourth, and fifth day of pregnancy, uteruses were resected, and uteri sections were stained with immunohistochemical method and evaluated. β₃ integrin immunoreactivity was most intensely observed in the endometrial glandular epithelium (GE) and stromal cells in the Sc group on the third day, whereas immunoreactivity was most intensely detected in the luminal epithelium (LE), GE, and stromal cells in the Sc group on the fourth day. VEGF immunoreactivity was most intensely observed in the endometrial LE in the Sc group on the third day, in the Sc and COH + Sc groups on the fourth day, and in the COH + Sc group on the fifth day. Our results indicated that Sc plays a role in both implantation and decidualization by affecting β₃ integrin and VEGF expressions in implantation window period in rats.     

Effects of vaginally administered high estradiol doses on hormonal pharmacokinetics and hemostasis in postmenopausal women

OBJECTIVE: To study the effect of high doses of estradiol released from vaginal rings on the pharmacokinetics of hormones, and the long-term effect on hormones and hemostasis in postmenopausal women. DESIGN: A pilot, nonrandomized study. SETTING: Healthy volunteers in an academic research environment. PATIENTS: Postmenopausal women.Eight women were treated with 17 beta-estradiol from three vaginal rings, releasing 7.5 micro g per ring for a total of 22.5 micro g over 24 hours. The rings were changed every morning for 14 days. MAIN OUTCOME MEASURE(S): Hemostatic changes were recorded. RESULT(S): Estradiol was rapidly absorbed, and statistically significant increases in the levels were found after 15 minutes; C(max) was obtained after 1 hour and a steady state after 24 hours. No statistically significant changes were found in the levels of coagulation factors V, von Willebrand factor, and activated factor VII; nor were any changes observed for activated protein C resistance, coagulation inhibitors protein C, protein S, or plasminogen activator inhibitor-1. No indication of increased thrombin formation was demonstrated by analyses of prothrombin fragment 1+2, fibrin D-dimer, and soluble fibrin. CONCLUSION(S)No statistically significant changes in hemostasis were observed from the vaginal administration of estradiol using a dose equivalent to transdermal administration with a release rate of 100 micro g per 24 hours.     

Secretory endometrium associated with breakthrough bleeding in estrogen-treated postmenopausal women.

Paradoxical secretory changes are described in benign endometria curetted for breakthrough bleeding in postmenopausal women on cyclic low dosage Premarin therapy. This purely histologic study, though favoring progesterone mediation, provides no definitive answer to the problem of pathogenesis. Future correlative morphologic and endocrine investigations are clearly indicated.     

Effects of protracted administration of estriol on the lower genito urinary tract in postmenopausal women

Summary We investigated 80 postmenopausal women, 48 of whom (60%) agreed to undergo long-term treatment with estriol suppositories. All had symptoms of vaginal atrophy and urinary incontinence. Endometrial samples were taken after 8–10 years of therapy. Estriol had induced slight proliferative changes in the endometrium in 7 of 48 patients studied by endometrial sampling. 75% of the women reported significant subjective improvement of stress incontinence. Estriol supplementation did not produce any significant change in urethral pressure, functional length, or cystometric parameters. However, a significant increase in pressure transmission ratio to the proximal urethra was noted after vaginal medication with estriol. Replacement therapy in post-menopausal women must take into account the patients perception of risks and benefits. The risk of estriol treatment is insignificant.     

Lack of effect of isoflavonoids on the vagina and endometrium in postmenopausal women

OBJECTIVE: To determine the effects of soy-derived isoflavones on vaginal epithelium and the endometrium. DESIGN: Double-blind, randomized, placebo-controlled crossover trial. SETTING: Outpatient clinic of a university hospital. PATIENT(S): Sixty-four postmenopausal women with a history of breast cancer. INTERVENTION(S): The women took (in a randomized order) 114 mg of isolated isoflavonoids or placebo in tablets daily for 3 months; the treatment regimens were crossed over after a 2-month washout period. The subjects were studied before and on the last day of each treatment period. MAIN OUTCOME MEASURE(S): Vaginal dryness, maturation index (MI) of vaginal epithelium, endometrial thickness, histology, and expression of estrogen (E) and progesterone (P) receptors and the proliferation marker Ki-67 in the endometrium. RESULT(S): Isolated isoflavones did not relieve vaginal dryness. Maturation index values remained unchanged during the isoflavone regimen, but decreased during the placebo regimen. No changes were found in any of the variables measured in the endometrium. CONCLUSION(S): Daily administration of 114 mg of isolated isoflavones for 3 months had no effect on the subjective perception of vaginal dryness or on objective findings in the vagina or endometrium. This implies safety with regard to the endometrium.     

Effect of estrogen and testosterone replacement therapy on cognitive fatigue

Both estrogen and testosterone insufficiency has been associated with reduced psychological well-being including fatigue. However, hormonal replacement studies on fatigue are rare. Therefore, we wanted to study the effect of testosterone and estrogen replacement therapy on cognitive fatigue and the relation between sex hormone levels and cognitive fatigue in oophorectomized women. Fifty women with surgically induced menopause (mean age: 54.0?±?2.9 years) were randomly assigned to treatment with estradiol valerate in combination with testosterone undecanoate or placebo for 24 weeks in a double-blind cross-over study. Neuropsychological tests and questionnaires were used to assess cognitive fatigue and psychological well-being. Cognitive fatigue was significantly associated to poor self-rated health and higher body mass index but not to general psychological well-being or sex hormone levels. Treatment with testosterone + estrogen had no significant effect on cognitive fatigue but the results indicated a curvilinear relation for hormonal levels. The estrogen/testosterone ratio was more related to functions rather than high or low hormone levels per se. We found that cognitive fatigue is frequent in oophorectomized women and negatively associated to self-perceived health and positively associated to BMI. A well-balanced ratio between estrogen and testosterone levels may be important for cognitive fatigue.     

Effects of initiation day of clomiphene citrate on the endometrium of women with regular menstrual cycles

OBJECTIVE: To investigate the effects of initiation time of clomiphene citrate (CC) on the endometrium of women with regular menstrual cycles. DESIGN: Randomized, double-blind, cross-over study. SETTING: Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. PATIENT(S): Thirty-three healthy female volunteers with regular menstrual cycles. INTERVENTION(S): The volunteers were randomized to receive either 100 mg of CC on days 1-5 and placebo on days 5-9 (study group) or placebo on days 1-5 and CC on days 5-9 (control group). After a wash-out period of 1 month of CC treatment, the medication was switched in each group. Ultrasonography was performed daily after day 10 of the cycle to detect ovulation. Ultrasonography for endometrial appearance and thickness, endometrial sampling, and blood samples obtained for determination of E(2) and P levels were performed 7 days after ovulation in both groups. MAIN OUTCOME MEASURE(S): Morphometric analysis, histologic dating, and ultrasonographic appearance and thickness of the endometrium. RESULT(S): Morphometric parameters, histologic dating, and ultrasonographic appearance and thickness of the endometrium were similar in both groups. CONCLUSION(S): Starting CC on either day 1 or day 5 of the menstrual cycle did not have any differential effects on the endometrium of women with regular menstrual cycles, particularly regarding the morphometric analysis, histologic dating, or ultrasonographic appearance.     

Effects of tibolone on plasma levels of nitric oxide in postmenopausal women

OBJECTIVE: To determine the effects of tibolone on nitric oxide (NO) plasma levels in postmenopausal women.DESIGN: Randomized, double-blind, placebo-controlled, cross-over trial.SETTING: Healthy volunteers in an academic research environment.PATIENT(S): Eighteen healthy women who have been in postmenopause for 1-4 years.INTERVENTION(S): Women received either tibolone 2.5 mg/day (group A) or placebo (group B) for 1 month; then the treatment was inverted for the second month.MAIN OUTCOME MEASURE(S): Plasma concentration of NO stable oxidation products and blood pressure were evaluated at baseline, month 1, and month 2.RESULT(S): Baseline concentration of NO metabolites were similar in both groups. At month 1, mean concentration of NO metabolites increased significantly in group A alone. At the end of month 2, NO metabolite levels in group A returned to baseline, whereas in group B they increased significantly.CONCLUSION(S): Tibolone induced a sustained increase in plasma levels of NO in postmenopausal women, suggesting that tibolone may exert a direct cardiovascular protective effect in postmenopausal women.     

Similar efficacy of low and standard doses of transdermal estradiol in controlling bone turnover in postmenopausal women

Objectives.?To investigate the effects of a low transdermal estradiol dose on bone metabolism and to compare it with both the standard dose and absence of treatment.

Methods.?In this study performed in a third-level academic center, 66 healthy postmenopausal women underwent hormone therapy (HT) with patches containing estradiol at standard (0.050 mg/day, HT50, 33 women) or low dosage (0.025 mg/day, HT25, 33 women) and 70 women were without treatment (NT). The values (mean of three samples) of several bone biochemical parameters were compared between groups after adjusting for confounding factors. Bone mineral density (BMD) was assessed (by dual-energy X-ray absorptiometry) in the spine and hip in all cases, and a second densitometry scan was performed in 44 women.

Results.?Bone turnover markers tended to show lower values in the treated groups, but significance was restricted to total alkaline phosphatase (NT vs. HT25, p < 0.05) and cross-linked N-telopeptides of type I collagen (NTX) (NT vs. HT25, p < 10^?6; NT vs. HT50, p < 10^?5). The loss of BMD observed in NT women, as assessed by the annual percentage change, was blocked in both the HT25 and HT50 women. No significant differences were detected between both HT groups.

Conclusions.?Low and standard dosages of transdermal estradiol were equally effective in controlling bone metabolism, as assessed by turnover markers. Additionally, NTX was confirmed as the most sensitive marker for detecting changes in bone resorption.     

怎样做到正确应用绝经后激素治疗

针对绝经相关的临床问题,给予绝经后妇女以单一雌激素或与孕激素联合的治疗方法在既往的英文文献中常统称之为HRT(hormone replacement therapy),国内的中译名有激素替代治疗和激素补充治疗。自2002年7月以后,特别是随着美国WHI临床试验结果的陆续发表,不少国家或     

Vaginal rings delivering progesterone and estradiol may be a new method of hormone replacement therapy

OBJECTIVE: To determine whether a low dose of P delivered together with E(2) from a vaginal ring on a continuous schedule can prevent endometrial proliferation and yield a bleeding pattern dominated by amenorrhea. DESIGN: Longitudinal clinical study. SETTING: Three university hospitals. PATIENT(S): Fifty-five women 45 to 75 years of age, not hysterectomized, with E(2) levels of <20 pg/mL and hot-flash incidence of two or more per day in the past week. INTERVENTION(S): A vaginal ring delivering approximately 150 microg/d of 17beta-E(2) and approximately 5 mg/d or approximately 9 mg/d of P used continuously for 4 and 6 months. MAIN OUTCOME MEASURE(S): Endometrial thickness, bleeding pattern, and hot flash incidence. RESULT(S): Endometrial proliferation was prevented by both P doses. Bleeding incidence decreased. In months 4, 5, and 6, 8 of 12 women had no bleeding. Incidence of hot flashes and night sweats decreased quickly and significantly.CONCLUSION(S): A vaginal ring delivering E(2) and a low dose of P merits further study as a method for long-term hormone replacement therapy.