Transdermal Estradiol Therapy Research Articles

FRI412 A Case of 46,XX Gonadal Dysgenesis With Mayer-Rokitansky-Küster-Hauser Syndrome And Primary Hypothyroidism

Abstract Disclosure: S. Al Allawi: None. R. Osman: None. Introduction: The association between Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome and gonadal dysgenesis is rarely reported in the literature. Coexistence of hypothyroidism with this condition is scarce and clinical correlation remains unclear. We describe a case of this rare clinical entity in conjunction with primary hypothyroidism. Clinical case: A 27-year-old Female with a medical history of primary hypothyroidism was referred to our clinic for evaluation of primary amenorrhea. She was born with a female phenotype. Growth was appropriate, but puberty was delayed with self-reported late pubarche at age 19. She never had a menstrual cycle, and had received hormonal replacement therapy (HRT) for a few months but failed to trigger menarche. However due to financial constraints, treatment was not continued. She was diagnosed with hypothyroidism since birth, for which she is currently maintained on levothyroxine 225 mcg daily. On physical exam, blood pressure was 126/72 mmHg, pulse rate 83 BPM, height 5’9”, BMI 34 kg/m2. No facial dysmorphisms or skeletal deformity were apparent. She had normal pubic and axillary hair distribution, breast budding consistent with Tanner Stage II. Genital examination revealed normal external genitalia and a blind vaginal pouch. Hormonal workup revealed hypergonadotrophic hypogonadism with estradiol < 0.5 pg/mL and post-menopausal range follicle-stimulating hormone (FSH) 36.7 mIU/mL. Thyroid stimulating hormone (TSH) 2.19 uIU/ml (nl 0.45-4.5 uIU/mL) and anti-TPO antibodies 10 IU/mL (nl 0-34 IU/mL). Prior thyroid ultrasound reported a small thyroid gland. Fluorescence in situ hybridization (FISH) analysis revealed 46XX karyotype. Abdominal and pelvic ultrasound showed normal kidneys with a non-visualized uterus and ovaries. Pelvic MRI confirmed the absence of both and showed a blind end vaginal pouch, leading to the conclusion of the coexistence of gonadal dysgenesis with MRKH. She was then placed on transdermal estradioltherapy. Conclusion: The association between gonadal dysgenesis (the most common cause of primary amenorrhea) and MRKH syndrome (the second most common cause) is infrequent. HRT remains the only therapeutic option. It aims to trigger the development of secondary sexual characteristics and prevent osteoporosis by allowing appropriate bone mineral accrual. Unfortunately, infertility remains the most significant consequential issue; hence the availability of good caring and psychological counseling should not be underestimated. The co-existence of likely non-immune primary hypothyroidism is even less frequent. To our knowledge, our case is the second reported case of this trilogy. Given the paucity of data, the association of this condition with primary hypothyroidism cannot be well established and can be coincidental. More studies are needed to determine if this condition has a higher prevalence of hypothyroidism. Presentation: Friday, June 16, 2023

THU445 Complicated Course And Management After Denosumab Discontinuation: A Case Report

Abstract Disclosure: I. Arora: None. L. Ceglia: None. Background: Discontinuation of denosumab (DMAb) can lead to rapid bone loss and sometimes multiple vertebral fractures (VFx). Here we present such a case and related challenges in management. Case: A 56-year-old perimenopausal female presented for management of osteoporosis (OP) complicated by multiple VFx following a missed dose of DMAb in 8/2020. Past bone health history was notable for treatment with alendronate for approximately 11 years as a premenopausal woman. During a drug “holiday” in 2015, she was found to have a decline in bone mineral density (BMD). She was advised to start treatment with DMAb in 8/2016. She was adherent to DMAb injections for 4 years but missed a dose in 8/2020 due to the COVID-19 pandemic. In 1/2021, she developed back pain with no trauma and was diagnosed with VFx of T7, T10 and T12. She underwent vertebroplasty of all 3 vertebrae by 2/2021. DMAb was resumed in 2/2021 and 8/2021. Labs were only notable for hypercalciuria for which hydrochlorothiazide (HCTZ) was initiated. In 11/2021 she presented with new symptomatic VFx of T5, T9 and T11. In 12/2021 (3 weeks post 3 new VFx), serum fasting C-telopeptide (CTX) was 79 pg/mL. Teriparatide or abaloparatide were avoided due to hypercalciuria and potential BMD losses with this transition. Thus in 1/2022, she started romosozumab (ROMO) in an attempt to prevent new VFx. CTX was initially 78 pg/mL and rose rapidly over 3 months to 325 pg/mL with new back pain in 4/2022. No new VFx were detected; however, ROMO was discontinued due to the rise in CTX level. In 5/2022, she received a dose of zoledronic acid (ZOL). It suppressed CTX from 325 to 131 pg/mL by 6/2022. She received another 2 doses of ZOL in 8/2022 and 11/2022 due to rebound rises in CTX. Of note, as she reported ongoing menopausal complaints, transdermal low-dose estradiol therapy was started in 11/2022. She has not had a new VFx in more than 1 year. Hypercalciuria persisted throughout 2022 requiring rising doses of (HCTZ). DXA in 12/2022 was stable vs. 12/2021 without evidence of significant BMD loss. Discussion: This case not only highlights the known risk for multiple VFx in a patient discontinuing long-term DMAb treatment (4 years), but also the risks for such VFx complications in women of younger age during menopausal transition and a history of vertebroplasty. In addition, this report does not support transitioning from long-term DMAb to ROMO in order to prevent a rapid increase in the bone resorption marker, CTX. Rather, treatment with ZOL every 12 weeks based on frequent CTX monitoring successfully maintained BMD stable following long-term DMAb discontinuation. Presentation: Thursday, June 15, 2023

Effects of estradiol on biological age measured using the glycan age index.

Glycan age is a recently developed biomarker based on glycans attached to immunoglobulin G (IgG). In large population cohorts, glycan age associates well with lifestyle and disease-risk biomarkers, while some studies suggested that glycan changes precede development of several age-associated diseases. In this study we evaluated effects of estrogen on the glycan age. Gonadal hormones were suppressed in 36 healthy young women by gonadotropin releasing hormone agonist therapy for 6 months. In 15 of them estradiol was supplemented, while 21 received placebo resulting in very low estrogen levels during intervention. IgG was isolated from plasma samples before intervention, after 6 months of intervention and after subsequent 4-month recovery. Deprivation of gonadal hormones resulted in median increase of glycan age for 9.1 years (IQR 6.8 – 11.5 years, p = 3.73×10-8), which was completely prevented by transdermal estradiol therapy (change in glycan age = -0.23 years, IQR (-2.20 – 2.98). After the recovery period glycan age returned to baseline values in both groups. These results suggest that IgG glycans and consequently also the glycan age are under strong influence of gonadal hormones and that estradiol therapy can prevent the increase of glycan age that occurs in the perimenopausal period.

Global Coagulation Assays in Transgender Women on Oral and Transdermal Estradiol Therapy.

The thrombotic effects of estradiol therapy in transgender women are unclear. Global coagulation assays (GCA) may be better measures of hemostatic function compared with standard coagulation tests. To assess the GCA profiles of transgender women in comparison to cisgender controls and to compare how GCA differ between routes of estradiol therapy in transgender women. Cross-sectional case-control study. General community. Transgender women, cisgender male and cisgender female controls. Citrated blood samples were analyzed for (i) whole blood thromboelastography (TEG®5000), (ii) platelet-poor plasma thrombin generation (calibrated automated thrombogram); and (iii) platelet-poor plasma fibrin generation (overall hemostatic potential assay). Mean difference (95% confidence intervals) between groups are presented. Twenty-six transgender women (16 oral estradiol, 10 transdermal estradiol) were compared with 98 cisgender women and 55 cisgender men. There were no differences in serum estradiol concentration (P = 0.929) and duration of therapy (P = 0.496) between formulations. Transgender women demonstrated hypercoagulable parameters on both thromboelastography (maximum amplitude + 6.94 mm (3.55, 10.33); P < 0.001) and thrombin generation (endogenous thrombin potential + 192.62 nM.min (38.33, 326.91); P = 0.009; peak thrombin + 38.10 nM (2.27, 73.94); P = 0.034) but had increased overall fibrinolytic potential (+4.89% (0.52, 9.25); P = 0.024) compared with cisgender men. No significant changes were observed relative to cisgender women. Route of estradiol delivery or duration of use did not influence the GCA parameters. Transgender women on estradiol therapy demonstrated hypercoagulable GCA parameters compared with cisgender men with a shift towards cisgender female parameters. Route of estradiol delivery did not influence the GCA parameters.

Effect of transdermal estradiol therapy on bone mineral density of amenorrheic female athletes.

The effects of transdermal estradiol treatment (HT) in amenorrheic athletes (AA) with low body weight (BW) and low bone mineral density (BMD) are unknown. To investigate whether HT increases BMD in AA with low BW and to compare the results with levels in AA who have recovered spontaneous menstruation (SM). Female athletes (n=151) were recruited at the Japan Institute of Sports Sciences and the University of Tokyo. All participants were divided into four groups: an AA group (untreated group) (n=36), a HT group (n=55), a SM group (n=21), and an eumenorrheic athletes (EA) group (n=39). Height, body weight, blood tests, and dual-energy X-ray absorptiometry were measured at baseline and after 12months. The HT group was treated daily for 12months with transdermal estrogen therapy. In addition, participants received oral progestin for 7days once every 3months. After 12months, BMD in the AA group was significantly lower than at baseline; however, BMD in the other three groups was significantly higher than at baseline. The ratio of the change in BMD values before and after 12months was -1.6±3.2% for the AA group, 5.3±8.7% for the HT group, 11.1±8.9% for the SM group, and 2.3±5.7% for the EA group. The rate of change in BMD values in the SM group was greater than that in the HT group. HT increased BMD in AAwith low BW, and the increase in those with SM was greater than that in those treated with HT.

Low-dose estradiol and endothelial and inflammatory biomarkers in menopausal overweight/obese women

Objective: We aimed to investigate the effects of low-dose transdermal estrogen on endothelial and inflammatory biomarkers in menopausal overweight/obese women.Methods: We recruited 44 menopausal women (47–55 years; body mass index 27.5–34.9 kg/m2) and divided them into estradiol (1 mg/day; n = 22) or placebo groups (n = 22). They were double-blinded, followed and treated for 3 months. At baseline and post-intervention, inflammatory biomarkers (hs-CRP, IL-1β, IL-6, MCP-1 and TNF-α) and of vascular injury (activated circulating endothelial cells, CEC-a) and repair (endothelial progenitor cells, EPC) were quantified. Resting CECs (CEC-r) were also assessed. Microvascular reactivity and vasomotion were analyzed by laser-Doppler flowmetry.Results: Volunteers (51.8 ± 2.3 years; mean body mass index 31.5 ± 2.5 kg/m2) had been menopausal for 3 (range 2–5) years. After treatment, no changes were observed in the placebo group, while levels of CEC-r and EPC increased in the estradiol group. In this group, no changes in inflammatory biomarkers were observed but it required a lower cumulative dose of acetylcholine to achieve peak velocity during endothelial-dependent vasodilatation and there was increased endothelial-independent vasodilatation.Conclusions: The short-term use of low-dose transdermal estradiol therapy in overweight/obese menopausal women increased markers of vascular repair and improved microvascular reactivity without changing the inflammatory biomarkers.Clinical trial registration: NCT01295892 at www.clinicaltrials.gov.

Effect of medroxyprogesterone on depressive symptoms in depressed and nondepressed perimenopausal and postmenopausal women after discontinuation of transdermal estradiol therapy

Concern about adverse effects of progestins on mood has influenced the use of medroxyprogesterone (MPA) and other progestins. In this brief report, we examined whether the administration of MPA leads to depressive symptoms in two groups of perimenopausal and postmenopausal women randomly assigned to treatment with estrogen: one currently experiencing clinical depression and another without depression. Open-label MPA 10 mg/day was administered for 14 days for endometrial protection after completion of double-blinded treatment with 17β-estradiol 0.1 mg/day for 8 to 12 weeks in 40- to 60-year-old perimenopausal and postmenopausal women enrolled in two separate randomized placebo-controlled trials for treatment of cognitive problems ("nondepressed group") or clinical depression ("depressed group"). Nonparametric tests were used to compare changes in depressive symptoms on the Beck Depression Inventory (BDI) within each group and between groups during MPA therapy. Of the 24 nondepressed (median BDI at baseline, 5.5; interquartile range [IQR], 2.5-8.5) and 14 depressed (median BDI at baseline, 17; IQR, 15-21) women treated with MPA, the BDI scores did not change during MPA treatment in either group (median change, 0; IQR, -2 to 0.5 and median, 0; IQR, -0.5 to 1.5, P = 0.28 and P = 0.50, respectively). Changes in BDI scores during treatment with MPA did not differ between groups (P = 0.25). Among women receiving MPA for 2 weeks after discontinuation of estradiol, depressive symptoms did not emerge on MPA. These findings were consistent for both depressed and nondepressed women, suggesting that, even among women who are currently experiencing depression, brief treatment with MPA is unlikely to disrupt mood.

Endogenous Estrogen Levels and the Effects of Ultra-Low-Dose Transdermal Estradiol Therapy on Bone Turnover and BMD in Postmenopausal Women

In a randomized controlled trial of a 0.014 mg/d transdermal estradiol patch, serum bone turnover markers decreased to a greater degree in postmenopausal women with lower versus higher endogenous estradiol levels. This suggests that the protective effects of ultra-low-dose estrogen therapy on the postmenopausal skeletal health may depend critically on women's endogenous estrogen levels before treatment. Postmenopausal women with very low or undetectable estradiol levels have lower BMD, increased bone turnover, and increased risk of hip and vertebral fracture. We assessed whether the effects of ultra-low-dose 0.014 mg/d transdermal estradiol (Menostar; Berlex, Montvale, NJ, USA) on bone turnover and BMD are influenced by endogenous estradiol levels. We analyzed data from postmenopausal women (mean age, 66 yr) randomized to an 0.014-mg/d transdermal estradiol patch or placebo in the ultra-low-dose transdermal estrogen (ULTRA) trial. The free estradiol index (FEI), calculated as the ratio of total estradiol (by mass spectometry) to sex hormone-binding globulin (SHBG; by immunoradiometric assay) x 100, was used to estimate bioavailable estradiol at baseline. Among the 382 women who adhered to >or=80% of study medication, we examined change in serum osteocalcin and bone-specific alkaline phosphatase levels at 12 mo and total hip and lumbar spine BMD at 24 mo in each quintile of FEI. Compared with women in the highest quintile of FEI, those in the lowest quintile of FEI had a 26% greater reduction in bone-specific alkaline phosphatase and 15% greater reduction in osteocalcin in response to ultra-low estradiol treatment (p for trend across quintiles < 0.05). There was a trend toward greater improvement in total hip BMD (p = 0.06) but not spine BMD (p = 0.90) in those with lower versus higher FEI levels. The beneficial effects of ultra-low-dose 0.014-mg/d transdermal estrogen therapy on skeletal health may depend critically on women's endogenous estrogen levels before treatment.

Effects of oestradiol and oestroprogestin on erythrocyte antioxidative enzyme system activity in postmenopausal women

Data concerning the relationship between sex steroid hormones and the cellular antioxidative enzyme system are controversial. We investigated the effects of oestradiol deficiency after menopause and the influence of transdermal oestradiol therapy (ET) and hormonal (oestradiol plus medroxyprogesterone) replacement therapy (HT) on erythrocyte superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT). GSH and selenium (Se) concentrations were also estimated. Serum lipid peroxide (LPO) levels were measured as an indicator of free-radical production and lipid peroxidation. The study group consisted of 80 postmenopausal women, divided into two subgroups: 26 women with surgically induced menopause (ET1) and 54 women with physiological menopause (HT1). Forty premenopausal healthy volunteers were controls (C group). LPO was higher in postmenopausal women and decreased after both ET and HT. GSH-Px and GSH were lower in the postmenopausal groups but increased significantly after both types of therapy. Se concentrations did not differ significantly among the groups. CAT activities were similar in all groups and decreased after ET and HT. SOD activities in postmenopausal women were similar to those in the C group and did not change significantly after treatment. The administration of natural oestrogens to postmenopausal women diminishes oxidative stress and increases antioxidative cell potency.

Different effects of oral conjugated estrogen and transdermal estradiol on arterial stiffness and vascular inflammatory markers in postmenopausal women

Aims We compared the effects of oral conjugated equine estrogen (CEE) therapy and transdermal estradiol therapy on pulse wave velocity (PWV) and circulating levels of vascular inflammatory markers in postmenopausal women and we also explored the interrelationship between the change in PWV and the changes in vascular inflammatory markers. Methods and results In a randomized 12-month trial, 28 postmenopausal women received a continuous oral CEE plus cyclic medroxyprogesterone acetate (MPA), 28 received a continuous transdermal estradiol patch plus cyclic MPA, and 27 did not receive either therapy. In each subject, we measured the brachial-ankle PWV (baPWV) using an automated device, the blood pressure, and the circulating levels of vascular inflammatory markers (C-reactive protein [CRP], cell adhesion molecules [CAMs], monocyte chemoattractant protein-1 [MCP-1], and matrix metalloproteinase [MMP-9]) before and 12 months after the start of the study. Oral CEE therapy did not change the baPWV but significantly increased the CRP and MMP-9 levels ( P < 0.05, each) and significantly decreased the CAMs and MCP-1 levels ( P < 0.05, each). Transdermal estradiol therapy significantly decreased the baPWV, and the CAMs and MCP-1 levels ( P < 0.05, each) but had no effect on the CRP or MMP-9 levels. No significant changes were seen in the control group. The blood pressures of the subjects remained unchanged. In the transdermal estradiol group, the change in baPWV was not significantly correlated with the changes in vascular inflammatory markers. Conclusion Transdermal estradiol, but not oral CEE therapy, may have antiatherosclerotic effects by improving arterial stiffness. The reduction in baPWV may contribute to the direct effect of estrogen, but not to the decrease in estrogen-induced vascular inflammatory markers.

Changes in vascular flow after transdermal oestradiol therapy for prostate cancer: a mechanism for cardiovascular toxicity and benefit?

To report the influence of transdermal oestradiol therapy on the vascular dynamics of men with advanced prostate cancer. Twenty patients with newly diagnosed locally advanced or metastatic prostate cancer (10 each) were treated using transdermal oestradiol patches. The vascular flow was assessed 6-monthly before and during a year of therapy using arterial and venous Doppler and duplex ultrasonography, arterial and venous photoplethysmography and opto-electronic plethysmography. Arterial flow, as measured by the mean and peak systolic velocities and photoplethysmography, significantly increased over time. Arterial compliance initially decreased but had normalized after 12 months. The venous variables were unaffected. As a result, the total limb blood flow and the capillary filtration rate were significantly increased. Transdermal oestradiol therapy causes an increase in arterial but not venous flow, and an initial decrease in arterial compliance, which adapts to the physiological range with time. It is possible that these changes may account for the increase in cardiovascular toxicity seen in the early phase of oestrogen therapy, and the cardioprotective effect that accrues thereafter.

Author reply

We applaud the authors for pursuing the interesting hypothesis that estrogens may enhance the activity of chemotherapy in prostate cancer. Unlike these authors, we did not find evidence of activation of coagulation with transdermal estradiol therapy.1 It is possible that this difference was due to differences in pharmacokinetics of the intramuscular and transdermal formulation. Other explanations should also be considered. As the authors do not report the results of their assays in control groups of patients treated with intramuscular estradiol valerate alone or chemotherapy alone, it is difficult to ascertain whether the observed changes in measures of coagulation were indeed related to estradiol or to the combination with chemotherapy. Clearly, further study is necessary to more robustly characterize the effects of parenteral estrogens on coagulation. We would caution against making the assumption that biochemical evidence of coagulation activation can be used as a surrogate for thromboembolic complications. Evidence for this assumption is lacking. For example, in a prospective observational study that involved 21,690 participants, elevated D-Dimers were associated with an increased risk of subsequent venous thrombosis in the general population, but in patients with cancer, D-Dimer levels did not predict future venous thrombosis.2 Furthermore, we caution against the use of anticoagulation therapy based on biochemical evidence of coagulation activation alone. Before such clinical approaches can be recommended, a surrogacy relation between specific changes in biochemical markers of coagulation and specific adverse clinical outcomes needs to be established in prospective clinical trials. Then, the safety and efficacy of anticoagulation therapy administered on the basis of biochemical evidence of coagulation activation must be prospectively tested. We share the authors' enthusiasm for further studies of estrogen-based prostate cancer therapy. Based on preclinical evidence that diethylstilbestrol specifically inhibits the expression of beta-tubulin Type IVa, an isotype that is thought to mediate taxane resistance3-5 and improves efficacy of docetaxel in a xenograft model6 we joined Dr. Bruce Montgomery of the University of Washington to investigate the safety and efficacy of diethylstilbestrol with docetaxel in androgen-independent prostate cancer. We also believe that the greatest promise of parenteral estrogens may lie in front-line hormonal therapy for prostate cancer. To this end, we are developing a double-blind randomized trial that will compare transdermal estradiol to conventional androgen deprivation in the initial hormonal management of prostate cancer. Lisa B. Bland M.D., M.P.H.*, Tomasz M. Beer M.D. , Mark Garzatto M.D. , * Department of Urology and Renal Transplantation, Oregon Health & Science University, Portland, Oregon, Department of Hematology & Medical Oncology and Oregon Health & Science University Cancer Institute, Oregon Health and Science University, Portland, Oregon, Urology Section, Portland VA Medical Center, and Division of Urology and Renal Transplantation, Oregon Health & Science University, Portland, Oregon.

Effects of Transdermal Estradiol Therapy (100 Micrograms per Day) on Gonadotropin Levels in Young Women With 46,XX Spontaneous Premature Ovarian Failure

We previously demonstrated by histological examination that inappropriate luteinization is a major mechanism of Graafian follicle dysfunction in women with 46,XX spontaneous premature ovarian failure. Pregnancies are known to occur in women with this diagnosis, but there is little evidence available regarding the effect of estrogen therapy on gonadotropin levels in these women. Theoretically, estrogen replacement therapy might improve pregnancy rates in this condition by suppressing serum LH levels into the normal range. The purpose of this study was to determine the proportion of women with spontaneous premature ovarian failure who achieve serum LH levels in the normal range on a standardized dose of transdermal estradiol. Analysis of data collected as part of a prospective controlled study designed to evaluate bone density as the primary outcome parameter. Blood samples were drawn during the mid follicular phase (days 5-8) from healthy regularly menstruating control women (cycles between 21 and 35 days) (n=70). Women with 46,XX spontaneous premature ovarian failure (n=106) had baseline samples drawn after being off hormone therapy for 2 weeks, and again 3 months later during the estrogen-only phase of a standard replacement regimen (100 micrograms per day estradiol patch, medroxyprogesterone acetate 10 mg for 12 days each month). All women were between the ages of 18 and 42 years. We measured LH and FSH by microparticle enzyme immunoassay (Abbott Diagnostics, Abbott Park, IL) and estradiol by competitive chemiluminescence immunoassay (Diagnostic Products Corporation, Los Angeles, CA). To compare data before and after hormone therapy we used the paired t-test for continuous variables and the signed rank test for binary variables. We defined the normal limit of mid follicular phase serum LH level in our assay as 3 to14 IU/L based on the 5th and 95th centiles from 67 control samples. (We excluded 3 control samples that had predefined mid-cycle LH levels >20 IU/L.) Transdermal estradiol therapy significantly reduced mean (SEM) serum LH levels in women with spontaneous premature ovarian failure from 52.3 (2.6) IU/L while off therapy to 15.9 (1.6) IU/L while on therapy (p<0.0001). While on transdermal estradiol therapy, 58/106 (55%) of these women had serum LH levels in the normal range, as compared to 5/106 (4.7%) at baseline (p<0.0001). We defined the normal limit of mid follicular phase serum FSH level in our assay as 3 to10 IU/L based on the 5th and 95th centiles from 67 control samples. While on transdermal estradiol therapy, 29/106 (27%) patients had FSH in the normal range, as compared to 3/106 (2.8%) at baseline (p<0.0001). Only 2/106 (1.9%) of these women had FSH suppressed below normal, whereas10/106 (9.4%) had LH suppressed. On this replacement regimen, LH was significantly more likely to be in the normal range than FSH (p<0.0001). Mean (SEM) serum estradiol level on therapy was 95.6 (8.6) pg/mL compared to 40.5 pg/mL while off replacement (p<0.0001). A standard regimen of 100 microgram transdermal estradiol replacement achieved normal serum LH levels in 55% (44.8%, 64.4%) of women with 46,XX spontaneous premature ovarian failure. Theoretically this may reduce the chance of inappropriate follicle luteinization and improve ovulatory rates. Controlled studies to assess the effect of hormone replacement regimens on ovulatory rates in these women are warranted.

Comparison of Oral and Transdermal Estradiol Therapy on Insulin Resistance Parameters in Postmenopausal Women With Metabolic Syndrome

Comparison of Oral and Transdermal Estradiol Therapy on Insulin Resistance Parameters in Postmenopausal Women With Metabolic Syndrome

TRANSDERMAL ESTRADIOL THERAPY FOR PROSTATE CANCER REDUCES THROMBOPHILIC ACTIVATION AND PROTECTS AGAINST THROMBOEMBOLISM

Oral estrogens were an effective treatment for prostate cancer but were abandoned because of an increased risk of cardiovascular toxicity and particularly thromboembolism. We have recently shown that transdermal estradiol produces an effective tumor response and negligible cardiovascular toxicity. Here we report the influence of transdermal estradiol therapy on the coagulation profile of men with advanced prostate cancer. A total of 20 patients with newly diagnosed locally advanced or metastatic prostate cancer were treated using transdermal estradiol patches and the coagulation profile was assessed before and during 12 months therapy. Activation of coagulation was assessed by assaying the levels of activated factor VII (VIIa), activated factor XII (XIIa), prothrombin fragments 1 and 2 (F1 + 2), thrombin-antithrombin III (TAT III) complex and fibrinogen. Inhibition of the coagulation cascade was assayed by protein C, protein S and activated protein C resistance (APC-R). Fibrinolytic activity was determined by assaying tissue plasminogen activator (TPA) and plasminogen activation inhibitor type 1 (PAI-1). D-Dimer levels assessed both coagulation and fibrinolytic (thrombophilic) activity. Venous Duplex, color Doppler ultrasound and photoplethysmography were used to assess for thrombosis. Levels of VIIa and XIIa were unaffected by transdermal estradiol therapy. Although levels of TAT III were increased in some patients at 12 months, the increase was markedly less than that observed historically with equivalent doses of oral estrogens. Levels of the inhibitory and fibrinolytic factors including protein C, protein S, APC-R, TPA and PAI-1 remained stable. Reductions in F1+F2, fibrinogen and D-Dimer levels represented a normalization from increased levels to the physiological range. These results suggest that transdermal estradiol reduces thrombophilic activation in men with advanced prostate cancer, and protects against the risk of thrombosis.

Efficacy of tibolone and transdermal estrogen therapy on psychological symptoms in women following surgical menopause

Objective: This study investigated the efficacy of tibolone and transdermal estradiol therapy on menopausal and psychological symptoms in women following surgical menopause. Method: Seventy-five women who had undergone surgical menopause were randomized to a 6-month double-blind interventional study treatment with oral 2.5 mg/day tibolone, transdermal 3.9 mg/week estradiol or oral placebo. The patients were assessed using Kupperman's Scale, Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale (HARS) before and at the end of the 6 months of treatment. Result: Sixty-five subjects completed the study: 23 on tibolone, 21 on transdermal estradiol and 21 on placebo. At the end of the 6 months of therapy, highly significant improvements in menopausal symptoms, depression and anxiety scores were observed in both groups (tibolone and transdermal estradiol groups) as compared with baseline values ( p<0.001). However, in the placebo group, there were no significant differences on changes from baseline to the end of treatment ( p > 0.05). Conclusion: These results suggest that tibolone and transdermal estradiol therapy significantly improve menopausal and psychological symptoms in women following surgical menopause.

Transdermal estradiol therapy improves bone mineral density (BMD) of men with prostate cancer,

Transdermal estradiol therapy improves bone mineral density (BMD) of men with prostate cancer,

A Randomized Placebo-Controlled Trial of Short-Term Graded Transdermal Estradiol in Healthy Gonadotropin-Releasing Hormone Agonist-Suppressed Pre- and Postmenopausal Women: Effects on Serum Markers of Bone Turnover, Insulin-Like Growth Factor-I, and Osteoclastogenic Mediators

The acute effects of estradiol on procollagen type 1 formation in pre- and postmenopausal women are controversial. Twenty-three premenopausal women and 13 postmenopausal women received two consecutive im injections of 3.75 mg leuprolide acetate 3 wk apart to block endogenous ovarian steroidogenesis. Transdermal estradiol therapy commenced on the night of the second leuprolide injection in all subjects, except five pre- and two postmenopausal women who were randomized to receive placebo patches. Estradiol therapy was applied incrementally, with each dose of 0.05, 0.10, 0.15, and 0.20 mg/d administered for 4 consecutive days, to mimic the estradiol changes typifying the follicular phase of the menstrual cycle. Blood aminoterminal propeptide of type I procollagen (PINP), intact osteocalcin (OC), carboxyterminal telopeptide of type I collagen (CTx), IGF-I, and estradiol were measured before and at the end of each estradiol increment. Potential mediators such as osteoprotegerin and receptor activator of nuclear factor-kappaB ligand (RANKL) were also measured. Despite comparable increases in serum estradiol, PINP increased more in postmenopausal compared with premenopausal women (between-group P = 0.03) and occurred at a time when CTx and OC did not change. CTx and IGF-I changed minimally and inconsistently, whereas OC, RANKL, and osteoprotegerin were stable. Repeated measures linear regression disclosed a significant negative association between increases in estradiol and PINP in premenopausal women (P = 0.0006) only. This suggests that lower dose estradiol should greatly increase PINP. Analogous regressions also showed significant negative relationships between changes in estradiol and RANKL in both pre- (P = 0.04) and postmenopausal (P = 0.002) women. Changes in serum markers of bone formation (PINP or OC) did not correlate with those of IGF-I. We conclude that lower dose estradiol rapidly increases osteoblastic collagen synthesis in women at a time when collagen degradation is stable and that this response differs between pre- and postmenopausal women. The effect of estradiol on bone formation does not appear to be mediated by IGF-I. In contrast, RANKL is likely to mediate the effect of estradiol on osteoclastogenesis.

Short-term transdermal estradiol therapy, cognition and depressive symptoms in healthy older women. A randomised placebo controlled pilot cross-over study

The potential role of estrogen in protecting women from cognitive decline and reducing depressive symptoms is of great therapeutic interest. In a pilot randomised placebo controlled cross-over study, we aimed to determine the short-term effects of transdermal estradiol therapy on cognition and depressive symptoms in healthy cognitively normal post-menopausal women over 60 years of age. Nineteen cognitively normal women, without clinical depression whom had undergone a hysterectomy in the past were recruited. Women were randomised to receive either transdermal estradiol 50 microg/24 h (Femseven) or transdermal placebo for 12 weeks before crossing over to the other medication for a further 12 weeks. Cognition was assessed every 6 weeks by the cognitive drug research (CDR) computerised assessment which recorded both accuracy and speed in the following cognitive tests; simple reaction time, choice reaction time, digit vigilance, visual tracking, spatial working memory, immediate and delayed word recall and delayed face and picture recall. Depressive symptoms were measured using the brief assessment scale depression card (BASDEC) depression rating scale at baseline, 12 and 24 weeks. Participants had a mean age of 71, IQ of 115 and MMSE of 29. Simple reaction time and the BASDEC depression rating scale improved after 12 weeks of estradiol use. All other tests were unaltered by estradiol. Twelve weeks of transdermal estradiol therapy did not consistently improve the speed or accuracy of older women in various cognitive tests. However, the results do support the concept that depressive symptoms may be reduced by estradiol, and not simply due to the relief of climacteric symptoms.

TRANSDERMAL ESTRADIOL IMPROVES BONE DENSITY WHEN USED AS SINGLE AGENT THERAPY FOR PROSTATE CANCER

Current androgen deprivation therapies for men with prostate cancer cause accelerated osteoporosis and a significant risk of osteoporotic fracture. We have recently shown that transdermal estradiol is an effective alternative for such patients. Here we report the impact of transdermal estradiol therapy on the bone mineral density of men with prostate cancer. A total of 20 patients with newly diagnosed locally advanced or metastatic prostate cancer were treated with transdermal estradiol patches. Bone mineral density of the lumbar spine and the proximal femur was measured with dual-energy x-ray absorptiometry, and correlated with computerized tomography and isotope bone scan findings at 6-month intervals. In all measured regions bone mineral density increased with time. By 1 year mean bone mineral density +/- SEM had increased by 3.60% +/- 1.6% in the lumbar spine (p = 0.055), 2.19% +/- 1.03% in the femoral neck (p = 0.055), 3.76% +/- 1.35% in the Ward's region (p = 0.008) and 1.90% +/- 0.85% in the total hip (p = 0.031), respectively. Of 12 osteoporotic sites 4 had improvement based on World Health Organization grading. All other sites improved toward a better classification. Transdermal estradiol protects against bone loss in men with prostate cancer and may improve bone density in those at risk for osteoporotic fracture.