Management of sexuality, intimacy, and menopause symptoms in patients with ovarian cancer.

Issues of sexuality, intimacy, and early menopause significantly impact the quality of life of patients following the diagnosis and treatment of ovarian cancer. These are undertreated problems. Successful treatment requires the provider's awareness of the problem, ability to identify it, and willingness to treat it. Unfortunately many providers do not address these issues in the pretreatment or perioperative period. Furthermore, patients do not often alert their providers to their symptoms. While systemic hormone therapy may improve many of the issues, they are not appropriate for all patients given their action on estrogen receptors. However, other nonhormonal treatments exist including selective serotonin reuptake inhibitors, antiepileptics, natural remedies, and pelvic floor physical therapy. In addition psychological care and the involvement of the partner can be helpful in managing the sexual health concerns of these patients. At the time of diagnosis or at initial consultation, women should be informed of the potential physiologic, hormonal, and psychosocial effects of ovarian cancer on sexuality and that there is a multimodal approach to dealing with symptoms.

Update on management of genitourinary syndrome of menopause: A practical guide.

The term genitourinary syndrome of menopause (GSM) emerged following a consensus conference held in May 2013. GSM is a more descriptive term than vulvovaginal atrophy (VVA) and does not imply pathology. However there are concerns that GSM is all encompassing and includes not only symptoms resulting from estrogen deficiency, but also those arising from the effects of ageing and other processes on the bladder and pelvic floor. Focusing on symptoms related to estrogen deficiency, the update provides a practical guide for health and allied health professionals on the impact of GSM on women and their partners, assessment, management and areas for future research. As GSM is a chronic condition, long term therapy is required. Hormonal, nonhormonal, laser and alternative and complementary therapies are described.

Efficacy and safety investigation of Kuntai capsule for the add-back therapy of gonadotropin releasing hormone agonist administration to endometriosis patients: a randomized, double-blind, blank- and tibolone-controlled study.

BACKGROUND: As a Chinese Traditional Medicine product, Kuntai capsule could improve the peri-menopausal symptoms in postmenopausal women. But it is still not clear whether Kuntai capsule has a good effect on alleviating peri-menopausal symptoms induced by gonadotropin releasing hormone agonist (GnRH-a) treatment. The purpose of this study was to investigate the clinical effectiveness and safety of Kuntai capsule, on peri-menopausal symptoms in endometriosis (EMS) patients, with postoperative GnRH-a treatment. METHODS: Ninety EMS ovarian cyst women with postoperative GnRH-a administration were enrolled in the study, and were randomly divided into Kuntai group, Tibolone group, or blank Control group. The therapeutic strategy in Kuntai group was 4 Kuntai capsules tid,po for 12 weeks after the first GnRH-a injection, while Tibolone 2.5 mg qd, po for 12 weeks in Tibolone group. There was no drug addition in Control group. Climacteric complaints were evaluated by Kupperman menopausal index (KMI) and hot flash/sweating score. Liver and renal functions, lipid profile, serum sex hormone levels and endometrial thickness were measured, and the frequency of adverse events in Kuntai and Tibolone groups was recorded. RESULTS: (1) Before GnRH-a therapy, the baseline parameter results were comparable in the three groups (P > 0.05). (2) After GnRH-a therapy, KMI and hot flash/sweating scores in all the three groups increased significantly (P < 0.05). At the 4 th week after GnRH-a therapy, KMI and hot flash/sweating score results were as follows: Control group > Kuntai group > Tibolone group (P < 0.05); at the 8 th and 12 th week after GnRH-a therapy, KMI and hot flash/sweating score in Control group were significantly higher than the other two groups (P < 0.05), and no significant difference was identified between Kuntai and Tibolone group (P > 0.05). (3) No statistical change took place in the liver and renal functions and lipid profile in all the three groups after the treatment (P > 0.05). (4) The posttherapeutic serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2) level and endometrial thickness decreased significantly in all the three groups (P < 0.05). After therapy, serum E2 level in Tibolone group was obviously higher than the other two groups (P < 0.05), while FSH and LH levels were obviously lower (P < 0.05). (5) The incidence of vaginal bleeding, breast distending pain in Tibolne group was obviously higher than Kuntai group (P < 0. 05). CONCLUSIONS: Kuntai capsule is effective on the peri-menopausal symptoms induced by postoperative GnRH-a administration to EMS patients, although its clinical effect might be a few weeks later than Tibolone. Kuntai capsule might be a little safer than Tibolone tablet.

Efficacy of a standardized isopropanolic black cohosh (Actaea racemosa) extract in treatment of uterine fibroids in comparison with tibolone among patients with menopausal symptoms.

Both therapies demonstrated efficacy in relieving menopausal symptoms; however, isopropanolic black cohosh (Remifemin) seems to be a more appropriate choice in alleviating menopausal symptoms in women with uterine fibroid. Isopropanolic black cohosh seems to be a valid treatment option in patients with uterine fibroids, as it provides adequate relief from menopausal symptoms and avoids increase in uterine fibroid size, which is usually a cause of concern for the patient.

Efficacy and safety of remifemin on peri-menopausal symptoms induced by post-operative GnRH-a therapy for endometriosis: a randomized study versus tibolone.

BACKGROUND: The aim of this study was to investigate clinical efficacy and safety of Remifemin on peri-menopausal symptoms in endometriosis patients with a post-operative GnRH-a therapy. MATERIAL AND METHODS: We treated 116 women who had endometriosis with either Remifemin (n=56) 20 mg bid po or Tibolone (n=60) 2.5 mg qd po for 12 weeks after GnRH-a injection. The efficacy was evaluated by Kupperman menopausal index (KMI), and hot flash/sweating scores. The safety parameters such as liver and renal functions, lipid profile, endometrial thickness, and serum sex hormone level, as well as the incidence of adverse events were recorded. RESULTS: (1) After GnRH-a therapy, KMI and hot flash/sweating scores in both groups increased significantly (P<0.05) but we found no significant difference for KMI (2.87±1.40 for Remifemin and 2.70±1.26 for Tibolone) and hot flash/sweating scores (0.94±1.72 for Remifemin and 1.06±1.78 for Tibolone) between the 2 groups (P>0.05). (2) No statistical change was observed in liver or renal functions and lipid profile in both groups before and after the treatment (P>0.05). The post-therapeutic serum FSH, LH, and E2 level and endometrial thickness decreased remarkably in both groups (P<0.05). E2 level in the Remifemin group was obviously lower than that in the Tibolone group (P<0.05), and FSH and LH levels were strongly higher (P<0.05). No significant difference in thickness were found in either group (P>0.05). The Remifemin group had far fewer adverse events than the Tibolone group (P<0. 05). CONCLUSIONS: Compared with Tibolone, Remifemin had a similar clinical efficacy and was safer for the peri-menopausal symptoms induced by GnRH-a in endometriosis patients.

Neuroprotective effects of tibolone against oxidative stress induced by ozone exposure.

INTRODUCTION: Oxidative stress increases brain lipid peroxidation, memory and motor deficits and progressive neurodegeneration. Tibolone, a treatment for menopausal symptoms, decreases lipid peroxidation levels and improves memory and learning. AIM: To study the effect of chronic administration of tibolone on lipid peroxidation, memory and motor deficits in ozone induced oxidative stress. MATERIALS AND METHODS: 100 male Wistar adult rats were randomly divided into 10 experimental groups: control (C) was exposed to an airstream for 60 days; C + tibolone, airstream exposure plus 1 mg/kg of tibolone for 60 days; groups 3-6 were exposed to ozone for 7, 15, 30, and 60 days, and groups 7-10 received 1 mg/kg of tibolone treatment by oral gavage for 7, 15, 30 and 60 days and were then exposed to ozone. We determined the effect of tibolone on memory and motor activity. Hippocampus was processed to determine the content of 4-hydroxynonenal and nitrotyrosine by Western blot. Four animals were perfused and processed for analysis of neuronal death. RESULTS: In the hippocampus, administration of 1 mg/kg of tibolone for 30 days prevented increased levels of lipid peroxidation and protein oxidation, whereas after 60 days prevented neuronal death in the CA3 region caused by exposure to ozone. Therefore, tibolone prevents cognitive deficits in short- and long-term memory on the passive avoidance task and prevents a decrease in exploratory behavior and an increase in freezing behavior. CONCLUSION: Our results indicate a possible neuroprotective role of tibolone as a useful treatment to prevent oxidative stress neurodegeneration.

TITLE: Efecto neuroprotector de la tibolona contra el estres oxidativo inducido por la exposicion a ozono.Introduccion. El estres oxidativo aumenta la lipoperoxidacion, produce deficits de memoria y de actividad motora asi como una neurodegeneracion progresiva en el sistema nervioso central. La tibolona es un tratamiento para los sintomas de la menopausia que disminuye los niveles de peroxidacion de lipidos y mejora la memoria y el aprendizaje. Objetivo. Estudiar el efecto de la tibolona sobre la peroxidacion de lipidos, los deficits de memoria y motor en el modelo de estres oxidativo inducido por la exposicion cronica al ozono. Materiales y metodos. Se dividieron aleatoriamente 100 ratas adultas Wistar en 10 grupos: control (C), que recibio aire durante 60 dias; (C + tibolona), aire mas 1 mg/kg de tibolona durante 60 dias; los grupos 3-6, ozono durante 7, 15, 30, y 60 dias; y los grupos 7-10, 1 mg/kg de tibolona durante 7, 15, 30 y 60 dias previo a la exposicion al ozono. Se realizaron pruebas de memoria y motoras y se determino el contenido del 4-hidroxinonenal y de la nitrotirosina por Western blot, asi como la muerte neuronal en el hipocampo. Resultados. La administracion de tibolona disminuyo el contenido de lipidos peroxidados, la oxidacion de proteinas y la muerte neuronal en el hipocampo; mejoro la memoria y previno las alteraciones motoras en los animales expuestos a ozono. Conclusion. Nuestros resultados indican un posible papel neuroprotector de la tibolona como un tratamiento util para prevenir la neurodegeneracion inducida por el estres oxidativo.

Berberine and monacolin effects on the cardiovascular risk profile of women with oestroprogestin-induced hypercholesterolemia.

INTRODUCTION: One of the most frequent side effect of oral contraceptives use is a stable alteration of the lipid profile. This could be even more relevant in women affected by polycystic ovary syndrome (PCOS). AIM: Considering the importance of a balanced lipid profile in cardiovascular prevention and that the exposure to the drugs could be many years long, our aim was to investigate the possible beneficial effect of a largely tested low-dosed combined lipid-lowering nutraceutical on dyslipidemias induced by oestroprogestins prescribed to young women for different indications. METHODS: We prospectively enrolled 84 patients in primary cardiovascular disease prevention, with low estimated cardiovascular disease risk (<5 % according to the ESC/EAS guidelines), and LDL-C increased above normal value (LDL-C >130 mg/dL) after the use of at least two different oral oestroprogestins treatments. Forty-four women were prescribed oral oestroprogestins for PCOS, while 40 for pure contraception. The tested nutraceutical contained berberine 500 mg/tab and monacolins 3 mg/tab was prescribed to all enrolled patients, associated the previously prescribed standard lipid-lowering diet. RESULTS: After 3 months of nutraceutical treatment, we observed a significant improvement in BMI (-1.5 ± 0.8 %, p < 0.001), FPG (-6.9 ± 5.8 %, p < 0.001), HOMA index (-3.5 ± 5.6 %, p < 0.001), TC (-20.1 ± 6.6 %, p < 0.001), LDL-C (-25.3 ± 8.9 %, p < 0.001), HDL-C (+14.1 ± 2.2 %, p < 0.001), TG (-29.9 ± 25.2 %, p < 0.001) and hsCRP (-2.5 ± 2.4 %, p = 0.019). Similar results have been obtained even repeating the analysis by subgroups, beyond hsCRP that significantly improved in PCOS patients compared to both the baseline and the non-PCOS group. CONCLUSION: It appears that the tested combined lipid-lowering nutraceutical is able to equally improve lipid metabolism in oral contraceptive induced hypercholesterolemia in women affected or not by PCOS.

Effects of a continuous-combined regimen of low-dose hormone therapy (oestradiol and norethindrone acetate) and tibolone on the quality of life in symptomatic postmenopausal women: a double-blind, randomised study.

OBJECTIVE: This study compared the effects of a continuous-combined regimen of low-dose hormone therapy (LD-HT) versus tibolone and supplemental calcium/vitamin D3 (control) on quality of life (QoL) in symptomatic postmenopausal women. DESIGN: This study was a prospective, randomised, double-blind, comparative trial with a control group. SETTING: The study was conducted in a climacteric outpatient clinic in the University Hospital of Federal University of Juiz de Fora, Brazil. POPULATION: A total of 174 postmenopausal women under 60 years of age who attended the climacteric outpatient clinic between June 2009 and June 2011 were recruited. These women complained of moderate or intense vasomotor symptoms and exhibited no contraindications for the use of hormone therapy. INTERVENTIONS: The patients were randomised into three groups: (1) daily treatment with 2.5mg tibolone (n=64), (2) 50mg calcium carbonate+200 IU vitamin D3 (Ca/Vit D3, n=54) or (3) 1mg oestradiol+0.5mg norethindrone acetate (E2/NETA, n=56) for 12 weeks. PRIMARY OUTCOME MEASURES: The primary outcome was the evaluation of QoL using the Women's Health Questionnaire (WHQ) in all subjects at baseline and after 4, 8 and 12 weeks of treatment. RESULTS: A total of 130 women in the following groups completed the study: tibolone (n=42), Ca/Vit D3 (n=44) and E2/NETA (n=44). An improved QoL based on the WHQ was observed at T0 (80.12±14.04, 77.73±15.3, 77.45±15.4) and T12 (57.0±15.5, 55.7±16.7, 58.4±12.6) for the tibolone, E2+NETA and Ca/Vit D3 groups, respectively (p values <0.05). The three groups exhibited significantly different scores at T12 for sexual behaviour and vasomotor symptoms. The tibolone group exhibited better sexual function compared with the E2/NETA and Ca/Vit D3 groups (4.2±26, 5.6±2.8, 5.4±2.8, respectively, p values <0.05). LD-HT was superior to tibolone and Ca/Vit D3 treatment for improvements in vasomotor symptoms (3.2±1.5, 4.0±1.8, 4.3±2.0, respectively, p values <0.05). Adverse effects were few and mild. CONCLUSIONS: An improved QoL was observed in the three study groups. Tibolone primarily improved sexual function, and E2/NETA exhibited a superior response for vasomotor symptoms.

Gonadotrophin receptor hormone analogues in combination with add-back therapy: an update.

Gonadotrophin receptor hormone analogues (GnRHa) have been used in a range of sex hormone-dependent disorders. In the management of premenstrual syndrome, they can completely abolish symptoms. The success of GnRHa in the treatment of endometriosis and adjuvant therapy in the management of fibroids is proven. This efficacy does not come without a cost and the side-effects of the hypo-estrogenic state have limited their application. The use of add-back therapy to counter these effects has enabled wider application, longer durations of treatment and an increase in compliance. This review article is an update on the evidence supporting gonadotrophin receptor hormone analogues in combination with add-back therapy.

Prevention of osteoporosis: one step forward, two steps back.

For many years, hormone replacement therapy (HRT) was the mainstay for osteoporosis prevention in postmenopausal women until a large randomized clinical trial raised serious safety concerns. This resulted in a big drop in HRT use and its demotion by regulatory authorities to second-line treatment. Many clinicians now feel that HRT is not safe to use, and recommend various alternatives for the treatment of osteoporosis. But how effective are these alternative therapies, are they any safer than HRT, and how do their costs compare? This review questions the validity of the safety concerns about HRT, and highlights the safety concerns about alternative therapies. It concludes that HRT is as safe as the other treatment options, and its efficacy and low cost demand that it be restored as a first-line treatment for the prevention of postmenopausal osteoporosis. Other therapies are available for use in osteoporosis, and the bisphosphonates are particularly effective for the treatment of the established disease. However, they must be used selectively and with caution, and are best restricted to those patients who are elderly or have severe disease. New treatments are emerging, but again caution must be taken until any long-term adverse effects have been identified.

Hormonal replacement therapy in ovarian cancer survivors: a survey among Greek gynecologists.

PURPOSE OF INVESTIGATION: In this survey we evaluated the prescription attitude of Greek gynecologists towards hormone replacement therapy (HRT) for ovarian cancer survivors. METHODS: An anonymous questionnaire was sent to 900 members of the Hellenic Society of Obstetrics and Gynecology presenting a hypothetical case of an ovarian cancer survivor with indications for HRT followed by a series of relevant questions. RESULTS: Two hundred and ninety-eight responses were analyzed with regards to age, gender and practice setting. HRT would be prescribed by 48% of Greek gynecologists; regarding type of regimen, 60% would prescribe tibolone, 19% estrogen alone and 21% estrogen plus progestagen. In contrast, 52% of Greek gynecologists would not prescribe HRT due to the fear of ovarian cancer relapse (83%), or the development of breast cancer (6%), or both cancers (9%); among them, 21% would alternatively prescribe CNS medications, 9% SERMs, phyto-estrogens or bisphosphonates, while the remaining 70% would not prescribe anything. CONCLUSIONS: One out of two Greek gynecologists would prescribe HRT in ovarian cancer survivors. An alternative therapy, mainly CNS medications, would be suggested by 21% of the opposers.

Summary of the recommendations on sexual dysfunctions in women.

INTRODUCTION: Women's sexual dysfunction includes reduced interest/incentives for sexual engagement, difficulties with becoming subjectively and/or genitally aroused, difficulties in triggering desire during sexual engagement, orgasm disorder, and sexual pain. AIM: To update the recommendations published in 2004, from the 2nd International Consultation on Sexual Medicine (ICSM) pertaining to the diagnosis and treatment of women's sexual dysfunctions. METHODS: A third international consultation in collaboration with the major sexual medicine associations assembled over 186 multidisciplinary experts from 33 countries into 25 committees. Twenty one experts from six countries contributed to the Recommendations on Sexual Dysfunctions in Women. MAIN OUTCOME MEASURE: Expert opinion was based on grading of evidence-based medical literature, widespread internal committee discussion, public presentation, and debate. RESULTS: A comprehensive assessment of medical, sexual, and psychosocial history is recommended for diagnosis and management. Indications for general and focused pelvic genital examination are identified. Evidence based recommendations for further revisions of definitions for sexual disorders are given. An evidence based approach to management is provided. Extensive references are provided in the full ICSM reports. CONCLUSIONS: There remains a need for more research and scientific reporting on the optimal management of women's sexual dysfunctions including multidisciplinary approaches.

[Efficacy and safety of remifemin compared to tibolone for controlling of perimenopausal symptoms].

OBJECTIVE: To investigate the efficacy and safety of remifemin (isopropanolic extract of cimicifuga racemosa) treating perimenopausal symptoms in comparison of tibolone. METHODS: One hundred and eighty postmenopausal women at range of 40 - 60 years old were enrolled in a multicenter, randomized and double blind study. They were divided into remifemin and tibolone group at ratio 1:1. The therapeutic strategy was remifemin 20 mg bid po for 12 weeks in remifemin group and tibolone 2.5 mg qd po for 12 weeks in tibolone group. To evaluate therapeutic effect, total score of Kupperman menopause index (KMI) was used as the major observed index and single item score of KMI were secondary observed index. Safety warning was determined by laboratory tests and adverse events at timepoint of before, at 4 and 12 weeks treatment. RESULTS: (1) Total score of KMI: it were 24 +/- 5 in remifemin group and 25 +/- 6 in tibolone group before treatment. At timepoint of 4 weeks treatment, it were 11 +/- 6 in remifemin group and 11 +/- 7 in tibolone group. At timepoint of 12 weeks treatment, it were 7 +/- 6 in remifemin group and 6 +/- 5 in tibolone group. Total KMI score between two groups did not show statistical difference at various timepoint (P > 0.05). (2) Single item score of KMI: when compared before, at 4 and 12 weeks treatment, did show remarkable difference (P < 0.05) either in remifemin or in tibolone group. However, those single items of KMI score did not show statistical difference between 4 and 12 weeks timepoint in each treatment group (P > 0.05). (3) Adverse effect: the incidence of adverse effect in remifemin group was significantly lower than that of tibolone group. None case with vaginal bleeding was observed in remifemin group, however, 17 cases with vaginal bleeding occurred in tibolone group (19%, 17/90). The incidence of breast swelling were 16% (14/90) in remifemin group and 36% (32/90) in tibolone group; before treatment, the thickness of endometrium were (2.6 +/- 1.1) mm in remifemin group and (2.8 +/- 1.1) mm in tibolone group; at timepoint of 12 weeks treatment, the thickness of endometrium were (2.9 +/- 1.4) mm in remifemin group and (3.4 +/- 2.0) mm in tibolone group. In comparison of thickness of endometrium before and at 12 weeks treatment, no remarkable changes was observed in remifemin group, however, endometrium displayed significantly thicker in tibolone group. CONCLUSIONS: Our study suggested that remifemin was one effective and safe agent to manage women with climacteric symptom. It has similar therapeutic effect and lower incidence of adverse effect when compared with tibolone.

Chinese medicinal herbs in relieving perimenopausal depression: a randomized, controlled trial.

OBJECTIVE: To explore the effects of GengNianLe (GNL, also called perimenopausal depression relieving formula), a defined formula of Chinese medicinal herbs in relieving perimenopausal depression in Chinese women. METHODS: Between September 2004 and April 2008, 47 Chinese women were randomized into a GNL group (n = 21) and a control group which received tibolone (n = 26) using a randomization chart. Depression was rated with the 24-item Hamilton Depression Scale (HAMD). The serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E(2)) were detected before and after the treatment. RESULTS: After 12 weeks of treatment, HAMD scores in both groups decreased significantly (p < 0.05) with no significant difference between the groups (p > 0.05). The levels of FSH decreased significantly and the level of E(2) increased significantly in both groups, and they changed more in the control group. No side-effect of treatment was reported in either group during treatment. CONCLUSIONS: The Chinese medicinal formula GNL showed promise in relieving perimenopausal depression and merits further study.

Recurrence rate of endometrioma after laparoscopic cystectomy: a comparative randomized trial between post-operative hormonal suppression treatment or dietary therapy vs. placebo.

OBJECTIVE(S): To assess the recurrence rate of endometrioma after laparoscopic cystectomy plus hormonal suppression treatment or plus dietary therapy compared to post-operative placebo. STUDY DESIGN: A randomized comparative trial was conducted on 259 consecutive women who underwent laparoscopic unilateral/bilateral cystectomy for endometrioma. Seven days after surgery, the patients were randomly allocated on the basis of a computer-generated randomization sequence, to one of four post-operative management arms as follows: placebo (n=65) or gonadotrophin-releasing hormone analogue (tryptorelin or leuprorelin, 3.75 mg every 28 days) (n=65) or continuous low-dose monophasic oral contraceptives (ethynilestradiol, 0.03 mg plus gestoden, 0.75 mg) (n=64) or dietary therapy (vitamins, minerals salts, lactic ferments, fish oil) (n=65) for 6 months. At 18 months' follow-up after surgery, all patients were monitored with a clinical gynecologic examination, and a transvaginal ultrasonography for possible evidence of endometrioma recurrence. RESULT(S): At 18 months' transvaginal ultrasonographic follow-up after surgery, no significant recurrence rate of endometrioma was detected in women who received a postoperative course of hormonal suppression treatment or dietary therapy when compared with placebo (placebo vs. GnRH-a P=0.316, placebo vs. estroprogestin P=0.803, placebo vs. dietary therapy P=0.544). Second-look laparoscopy was performed on a clinical basis and confirmed the ultrasonographic suspicion of recurrence of endometrioma in all cases: 10 (16.6%) in the post-operative placebo group vs. 6 (10.3%) in the post-operative GnRH-a group vs. 9 (15.0%) in the post-operative continuous estroprogestin group vs. 11 (17.8%) in the post-operative dietary therapy group. Of 36 patients with recurrent ovarian endometriosis, 8 had recurrence on the treated ovary, 20 on the contralateral ovary that appeared to be normal at the time of the first-line surgery, and 8 on both the treated and untreated ovaries. Endometrioma recurrences were associated with moderate-to-severe painful symptoms in 14/36 patients (38.8%), while the remaining 22 (61.1%) patients were asymptomatic. CONCLUSION(S): A 6-month course of hormonal suppression treatment or dietary therapy after laparoscopic cystectomy had no significant effect on the recurrence rate of ovarian endometriosis when compared with surgery plus placebo. So, treatment of endometrioma can be carried out exclusively by laparoscopic cystectomy without post-operative therapy, if a complete excision of ovarian endometriosis has been assured.

Impact of soy supplementation on sex steroids and vascular inflammation markers in postmenopausal women using tibolone: role of equol production capability.

OBJECTIVES: Tibolone is often taken concurrently with soy. Tibolone, soy and equol-producing capacity each affect vascular health, whereas their concomitant effects are unknown. We studied the effects of soy on sex steroids and vascular inflammation markers in long-term tibolone users. METHODS: Postmenopausal women (n = 110) on tibolone were screened with a soy challenge to find 20 equol producers and 20 non-producers. All women were treated for 8 weeks in a cross-over trial with soy (52 g of soy protein containing 112 mg of isoflavones) or placebo. Serum estrone, 17beta-estradiol, testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), sex hormone binding globulin (SHBG), C-reactive protein (CRP), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and platelet-selectin (P-selectin) were assessed. RESULTS: Soy decreased (7.1%) the estrone level, significantly (12.5%) only in equol producers (from 80.2 +/- 10.8 to 70.3 +/- 7.0 pmol/l; p = 0.04). Testosterone was reduced (15.5%; from 586 +/- 62.6 to 495 +/- 50.1 pmol/l, p = 0.02) during soy treatment, and more markedly in equol producers than non-producers (22.1% vs. 10.0%). No changes appeared in SHBG, CRP or ICAM-1, but VCAM-1 increased (9.2%) and P-selectin decreased (10.3%) during soy treatment. CONCLUSIONS: Soy modified the concentrations of estrone, testosterone and some endothelial markers. Equol production enforced these effects. Soy supplementation may be clinically significant in tibolone users.

Efficacy of tibolone as "add-back therapy" in conjunction with a gonadotropin-releasing hormone analogue in the treatment of uterine fibroids.

OBJECTIVE: To assess the efficacy of tibolone add-back therapy with Goserelin treatment of uterine fibroids. DESIGN: Randomized placebo-controlled study. SETTING: Gynecology department of an inner-city teaching hospital. PATIENT(S): Seventy-five women of reproductive age with uterine fibroids. INTERVENTION(S): All women were given monthly SC implants of 3.6 mg goserelin and were randomized to take 3 months of placebo followed by 3 months of tibolone 2.5 mg daily (delayed administration), tibolone 2.5 mg daily for 6 months, or placebo for 6 months. MAIN OUTCOME MEASURE(S): Changes in bone mineral density (BMD) at the hip and spine, fibroid and uterine size, and patient symptomatology. RESULT(S): In the tibolone group, 2% loss of BMD at the spine was observed compared with 5.5% loss in the placebo group. For total hip, tibolone led to a 0.7% gain in BMD compared with a loss of 1.7% in the placebo group. Tibolone did not affect GnRH analogue-induced fibroid shrinkage. Vasomotor symptom scores in women taking tibolone were 2.2 and were significantly lower than those taking placebo or in the delayed administration groups (mean scores 2.9 and 2.7, respectively). CONCLUSION(S): Tibolone appears to be a safe and effective add-back therapy which can be given from the commencement of GnRH analogue treatment for fibroids.

Safety of tibolone in the treatment of vasomotor symptoms in breast cancer patients--design and baseline data 'LIBERATE' trial.

Many patients with a history of breast cancer (BC) will suffer from vasomotor symptoms, which can be induced or exacerbated by treatment with tamoxifen or aromatase inhibitors. The LIBERATE trial was designed as a randomized, double-blind, multicenter trial to demonstrate that tibolone 2.5mg/day (Livial) is non-inferior to placebo regarding BC recurrence in women with vasomotor symptoms surgically treated for primary BC within the last 5 years. Secondary objectives are effects on vasomotor symptoms as well as overall survival, bone mineral density and health-related quality of life. Mean age at randomization was 52.6 years, and the mean time since surgery was 2.1 years. The mean daily number of hot flushes and sweating episodes was 7.3 and 6.1, respectively. For the primary tumor, Stage IIA or higher was reported for >70% of the patients. In subjects whose receptor status was known, 78.2% of the tumors were estrogen receptors positive. At randomization, tamoxifen was given to 66.2% of all patients and aromatase inhibitors to 7%. Chemotherapy was reported by 5% at randomization. The adjuvant tamoxifen use in LIBERATE allows a comparison with the Stockholm trial (showing no risk of BC recurrence associated with hormone therapy), which was stopped prematurely subsequent to HABITS. The LIBERATE trial is the largest, ongoing, well-controlled study for treatment of vasomotor symptoms in BC patients.

Tibolone and osteoporosis.

BACKGROUND: We conducted a 5-year prospective, observational, controlled study to assess the effects of tibolone 1.25 mg/day on bone mineral density (BMD) in postmenopausal women with osteopenia or osteoporosis. METHODS: The subjects were 420 women, an average of 66.4 years old, who had been postmenopausal between 8 and 19 years when enrolled in the study. Of the 420 women enrolled, 346 agreed to take tibolone for 5 years. The 74 who refused tibolone took only calcium/vitamin D supplements and served as the control group. BMD was measured in the lumbar spine and total hip region at baseline and annually by dual-energy X-ray absorptiometry (DXA). RESULTS: At the first two follow-up visits, women taking tibolone had a significant increase in BMD at the spine (P < 0.001) and at the hip (P < 0.001) when compared to baseline values and when compared to BMD values for the control group, which decreased from baseline. In the final 3 years of the study, BMD values (spine and hip) continued to decrease in the control group and also tended to decrease in the tibolone group, but at the end of the fifth year, mean BMD in the tibolone group was still higher than BMD before the start of tibolone treatment (P < 0.05). Calculations showed that if women taking tibolone continued to lose BMD at the same rate as during the final 3 years of the study, after 11 years of tibolone treatment the average patient would have the same BMD as she had when treatment started. CONCLUSION: This 5-year observational study provides evidence that tibolone is effective in increasing BMD in postmenopausal women with osteopenia and osteoporosis during the first 2 years of treatment, but because BMD starts to decline in the third year, it is vital that postmenopausal women start treatment with tibolone as early as possible, so that bone mineral density levels are kept high as long as possible.

Effects of tibolone on the breast of postmenopausal women.

For decades, hormone therapy (HT) has been the mainstay for managing menopausal symptoms. However, the prolonged use of either single estrogen therapy (ET) or a combination therapy of estrogen and progestogen (EPT) might be associated with a slightly increased risk of breast cancer. Alternative therapies that are effective in the prevention and/or treatment of menopause, having associated morbidities but no unwanted effects, are of primary interest in clinical practice. Tibolone (Livial; NV Organon, Oss, The Netherlands) is structurally related to 19-nortestosterone derivatives and is a new postmenopausal regimen with a unique pharmacological profile, licensed for the relief of climacteric symptoms and the prevention of osteoporosis in postmenopausal women. Tibolone exhibits weak estrogenic, progestogenic, and androgenic activities, which in theory might influence the breast. The effect of tibolone on breast tissue, however, is obscure. The purpose of this study was to assess the effects of tibolone on breast safety, and the collected data include preclinical models, clinical observation, and epidemiologic study. Although in vitro studies showed conflicting results (with the majority being favorable effects) regarding the effects of tibolone on breast cells, in vivo studies showed favorable effects of tibolone on the breast in animal models. Similarly, an epidemiologic study indicated an increased risk of breast cancer when tibolone was used to manage climacteric symptoms of postmenopausal women, but accumulated data obtained from radiologic studies (mammography) showed a possible protective effect of tibolone on the breast. Taken together, we conclude that tibolone, if not superior to conventional HT, may be more acceptable to clinicians as a therapeutic drug option for use with symptomatic menopausal women. Only time will tell whether tibolone will be the preferred option.