Methyl palmitate reversed estradiol benzoate-induced endometrial hyperplasia in female rats.

Early detection and treatment of endometrial hyperplasia (EH) is mandatory for endometrial cancer prevention. Several bioactive agents of plant origin have been shown to elicit their chemotherapeutic effect against tumors and cancer via induction of mitochondrial permeability transition(mPT) pore opening. This research was therefore aimed at evaluating the potential chemopreventive effect of methyl palmitate (MP), on estradiol benzoate(EB)-induced EH, looking at the mitochondrial-mediated pathway and other possible mechanisms of action. Mitochondria were isolated using differential centrifugation. The mPT pore, mitochondrial ATPase (mATPase) activity, lipid peroxidation and cytochrome c release were determined by standard methods using spectrophotometer. Uterine interleukin 1b, MDA levels and SOD, GSH activities, were determined using commercially available kits. The uterine histological and immunohistochemical assessment of estrogen receptor (ERα), IL-1b and caspas-3 were carried out. The fibroblast cell count density was determined using histomorphometry. At all the concentrations of MP used, there was no significant induction of mPT pore opening, neither any enhancement of mATPase activity nor release of cytochrome c when compared to the control. Similar pattern of results were recorded for the in vivo study. However, there was marked increase in the uterine MDA and interleukin 1b levels, with concurrent decrease in SOD and GSH activities, in the EB-treated group, which was significantly reversed by MP co-administration. Endometrial Hyperplasia observed in the EB-treated group was ameliorated by MP co-administration. The immunoexpression of ERα and IL-1b in the EB-treated group was reversed by MP co-administration. This study suggests anti-inflammatory, antioxidant and anti-proliferative potential of MP against EB-induced EH.

Prophylactic Risk-reducing Hysterectomies and Bilateral Salpingo-oophorectomies in Patients With Lynch Syndrome: A Clinicopathologic Study of 29 Cases and Review of the Literature.

Lynch syndrome (LS) is associated with an increased risk for colorectal, endometrial, and ovarian carcinomas in women. Risk-reducing hysterectomy and bilateral salpingo-oophorectomy (RRHSO) has been shown to be a cost-effective form of management and prevention of gynecological malignancies in patients with LS. Studies of incidental gynecologic malignancies identified in RRHSO are limited. In addition, recommendations on optimal handling of this type of specimen have ranged from submitting for microscopic examination the entire endometrium, fallopian tubes and ovaries to submitting only routine representative sections of these organs. In this study, we present the clinicopathologic findings of 29 cases of LS patients that underwent risk-reducing gynecologic surgery at our institution over a period of 13 yr. Clinical-pathologic information was obtained from the patients' charts and pathology reports. Significant pathologic abnormalities were identified in 17% (5/29) of cases, all showing endometrial hyperplasia. Four of them with atypical and 1 without atypical. All of our cases with endometrial pathology had significant findings on preoperative endometrial sampling. To further study the recommendation of in toto submission of the endometrium, ovaries and fallopian tubes and the utility of preoperative endometrial sampling, we undertook a literature review of all the reported cases of incidental pathologic findings identified in RRHSO. The findings of our cohort and the literature reviewed support in toto submission of endometrium, and adnexal structures in the absence of gross lesions. In addition, our findings show a definite benefit for preoperative endometrial sampling as part of the workup for LS patients undergoing RRHSO.

Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen.

BACKGROUND: Adjuvant tamoxifen reduces the risk of breast cancer recurrence in women with oestrogen receptor-positive breast cancer. Tamoxifen also increases the risk of postmenopausal bleeding, endometrial polyps, hyperplasia, and endometrial cancer. The levonorgestrel-releasing intrauterine system (LNG-IUS) causes profound endometrial suppression. This systematic review considered the evidence that the LNG-IUS prevents the development of endometrial pathology in women taking tamoxifen as adjuvant endocrine therapy for breast cancer. OBJECTIVES: To determine the effectiveness and safety of the levonorgestrel intrauterine system (LNG-IUS) in pre- and postmenopausal women taking adjuvant tamoxifen following breast cancer for the outcomes of endometrial and uterine pathology including abnormal vaginal bleeding or spotting, and secondary breast cancer events. SEARCH METHODS: We searched the following databases on 29 June 2020; The Cochrane Gynaecology and Fertility Group specialised register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO and Cumulative Index to Nursing and Allied Health Literature. We searched the Cochrane Breast Cancer Group specialised register on 4 March 2020. We also searched two trials registers, checked references for relevant trials and contacted study authors and experts in the field to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of women with breast cancer on adjuvant tamoxifen that compared the effectiveness of the LNG-IUS with endometrial surveillance versus endometrial surveillance alone on the incidence of endometrial pathology. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary outcome measure was endometrial pathology (including polyps, endometrial hyperplasia, or endometrial cancer), diagnosed at hysteroscopy or endometrial biopsy. Secondary outcome measures included fibroids, abnormal vaginal bleeding or spotting, breast cancer recurrence, and breast cancer-related deaths. We rated the overall certainty of evidence using GRADE methods. MAIN RESULTS: We included four RCTs (543 women analysed) in this review. We judged the certainty of the evidence to be moderate for all of the outcomes, due to imprecision (i.e. limited sample sizes and low event rates). In the included studies, the active treatment arm was the 20 µg/day LNG-IUS plus endometrial surveillance; the control arm was endometrial surveillance alone. In tamoxifen users, the LNG-IUS probably reduces the incidence of endometrial polyps compared to the control group over both a 12-month period (Peto odds ratio (OR) 0.22, 95% confidence interval (CI) 0.08 to 0.64, I² = 0%; 2 RCTs, n = 212; moderate-certainty evidence) and over a long-term follow-up period (24 to 60 months) (Peto OR 0.22, 95% CI 0.13 to 0.39; I² = 0%; 4 RCTs, n = 417; moderate-certainty evidence). For long-term follow-up, this suggests that if the incidence of endometrial polyps following endometrial surveillance alone is assumed to be 23.5%, the incidence following LNG-IUS with endometrial surveillance would be between 3.8% and 10.7%.  The LNG-IUS probably slightly reduces the incidence of endometrial hyperplasia compared with controls over a long-term follow-up period (24 to 60 months) (Peto OR 0.13, 95% CI 0.03 to 0.67; I² = 0%; 4 RCTs, n = 417; moderate-certainty evidence). This suggests that if the chance of endometrial hyperplasia following endometrial surveillance alone is assumed to be 2.8%, the chance following LNG-IUS with endometrial surveillance would be between 0.1% and 1.9%. However, it should be noted that there were only six cases of endometrial hyperplasia. There was insufficient evidence to reach a conclusion regarding the incidence of endometrial cancer in tamoxifen users, as no studies reported cases of endometrial cancer. At 12 months of follow-up, the LNG-IUS probably increases abnormal vaginal bleeding or spotting compared to the control group (Peto OR 7.26, 95% CI 3.37 to 15.66; I² = 0%; 3 RCTs, n = 376; moderate-certainty evidence). This suggests that if the chance of abnormal vaginal bleeding or spotting following endometrial surveillance alone is assumed to be 1.7%, the chance following LNG-IUS with endometrial surveillance would be between 5.6% and 21.5%. By 24 months of follow-up, abnormal vaginal bleeding or spotting occurs less frequently than at 12 months of follow-up, but is still more common in the LNG-IUS group than the control group (Peto OR 2.72, 95% CI 1.04 to 7.10; I² = 0%; 2 RCTs, n = 233; moderate-certainty evidence). This suggests that if the chance of abnormal vaginal bleeding or spotting following endometrial surveillance alone is assumed to be 4.2%, the chance following LNG-IUS with endometrial surveillance would be between 4.4% and 23.9%. By 60 months of follow-up, there were no cases of abnormal vaginal bleeding or spotting in either group. The numbers of events for the following outcomes were low: fibroids (n = 13), breast cancer recurrence (n = 18), and breast cancer-related deaths (n = 16). As a result, there is probably little or no difference in these outcomes between the LNG-IUS treatment group and the control group.  AUTHORS' CONCLUSIONS: The LNG-IUS probably slightly reduces the incidence of benign endometrial polyps and endometrial hyperplasia in women with breast cancer taking tamoxifen. At 12 and 24 months of follow-up, the LNG-IUS probably increases abnormal vaginal bleeding or spotting among women in the treatment group compared to those in the control. Data were lacking on whether the LNG-IUS prevents endometrial cancer in these women. There is no clear evidence from the available RCTs that the LNG-IUS affects the risk of breast cancer recurrence or breast cancer-related deaths. Larger studies are necessary to assess the effects of the LNG-IUS on the incidence of endometrial cancer, and to determine whether the LNG-IUS might have an impact on the risk of secondary breast cancer events.

Menopausal hormone therapy: a better and safer future.

Major advances in menopause hormone therapy (MHT) hold promise in the future of better and safer care for women at and after the menopause. The principal advances are: (1) the critical window or 'window of opportunity' in the 10 years or so after the menopause, during which the benefits of MHT in healthy women exceed any risks; (2) use of transdermal instead of oral administration of estrogen to reduce the risk of venous thromboembolism; (c) investigation of the use of oral micronized progesterone (MP) and vaginal MP to prevent endometrial hyperplasia and carcinoma without any increased risk of breast cancer and venous thromboembolism in postmenopausal women receiving estrogens; vaginal MP prevents endometrial proliferation in the short term but the long-term effects in MHT remain to be established; (4) investigation into the use of intrauterine levonorgestrel-releasing devices (LNG-IUDs), which are an attractive form of MHT in perimenopausal women, providing contraception and reducing uterine bleeding, although the risk of breast cancer with LNG-IUDs requires clarification. Women in the future can look forward to a symptom-free menopause and to safer and more beneficial MHT.

Non-clinical studies of progesterone.

Progesterone is a steroid hormone that is essential for the regulation of reproductive function. Progesterone has been approved for several indications including the treatment of anovulatory menstrual cycles, assisted reproductive technology, contraception during lactation and, when combined with estrogen, for the prevention of endometrial hyperplasia in postmenopausal hormonal therapy. In addition to its role in reproduction, progesterone regulates a number of biologically distinct processes in other tissues, particularly in the nervous system. This physiological hormone is poorly absorbed when administered in a crystalline form and is not active when given orally, unless in micronized form, or from different non-oral delivery systems that allow a more constant delivery rate. A limited number of preclinical studies have been conducted to document the toxicity, carcinogenicity and overall animal safety of progesterone delivered from different formulations, and these rather old studies showed no safety concern. More recently, it has been shown in animal experiments that progesterone, its metabolite allopregnanolone and structurally related progestins have positive effects on neuroregeneration and repair of brain damage, as well as myelin repair. These recent preclinical findings have the potential to accelerate therapeutic translation for multiple unmet neurological needs.

Lean Body Weight and Metformin Are Insufficient to Prevent Endometrial Hyperplasia in Mice Harboring Inactivating Mutations in PTEN.

OBJECTIVES: Obesity is a major risk factor for endometrial cancer. We evaluated whether obesity exacerbates progression of endometrial hyperplasia (EH) using the PRCre/+ PTENflox/+ mouse model and examined if the type 2 diabetes drug, metformin, could prevent EH. METHODS: Twenty obese (PRCre/+ PTENflox/+) mice were maintained on a high-fat diet, while 20 lean mice ate a matching low-fat diet. Ten mice from each group received metformin (1,000 mg/day) in drinking water. Mice were euthanized at 26 weeks. Uterine tissue was scored for degree of EH. Immunohistochemical staining for Ki67 was used to evaluate cellular proliferation. Markers of PI3K/AKT/mTOR activity were evaluated by immunohistochemistry using activation-specific antibodies. Serum adiponectin was quantified by ELISA. RESULTS: Obesity had no effect on the extent of EH in (PRCre/+ PTENflox/+) mice. While metformin significantly altered circulating adiponectin levels in obese and lean animals, it had no effect on EH. There were no differences in endometrial proliferation as measured by Ki67 staining. Neither obesity nor metformin altered PI3K/AKT/mTOR activity in these animals. CONCLUSIONS: Weight and metformin did not affect the severity of EH resulting from PTEN inactivation. Alternative mouse models of early endometrial cancer are required for preclinical cancer prevention studies.

Effects of sulpiride and ethylene glycol monomethyl ether on endometrial carcinogenicity in Donryu rats.

Sulpiride and ethylene glycol monomethyl ether (EGME) are known ovarian toxicants that stimulate prolactin (PRL) secretion, resulting in hypertrophy of the corpora lutea and increased progesterone (P4) production. The purpose of the present study was to investigate how the PRL stimulatory agents affected uterine carcinogenesis and to clarify the effects of PRL on endometrial adenocarcinoma progression in rats. Ten-week-old female Donryu rats were treated once with N-ethyl-N'-nitro-N-nitrosoguanidine (20 mg kg(-1) ), followed by treatment with sulpiride (200 ppm) or EGME (1250 ppm) from 11 weeks of age to 12 months of age. Sulpiride treatment inhibited the incidence of uterine adenocarcinoma and precancerous lesions of atypical endometrial hyperplasia, whereas EGME had no effect on uterine carcinogenesis. Sulpiride markedly prevented the onset of persistent estrus throughout the study period, and EGME delayed and inhibited the onset of persistent estrus. Moreover, sulpiride-treated animals showed high PRL and P4 serum levels without changes in the levels of estradiol-17ß, low uterine weights and histological luteal cell hypertrophy. EGME did not affect serum PRL and P4 levels. These results suggest that the prolonged low estradiol-17ß to P4 ratio accompanied by persistent estrous cycle abnormalities secondary to the luteal stimulatory effects of PRL may explain the inhibitory effects of sulpiride on uterine carcinogenesis in rats. Copyright © 2015 John Wiley & Sons, Ltd.

Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen.

BACKGROUND: Adjuvant tamoxifen reduces the risk of breast cancer recurrence in women with oestrogen receptor-positive breast cancer. Tamoxifen also increases the risk of postmenopausal bleeding, endometrial polyps, hyperplasia, and endometrial cancer. The levonorgestrel-releasing intrauterine system (LNG-IUS) causes profound endometrial suppression. This systematic review considered the evidence that the LNG-IUS prevents the development of endometrial pathology in women taking tamoxifen as adjuvant endocrine therapy for breast cancer. OBJECTIVES: To determine the effectiveness and safety of levonorgestrel intrauterine system (LNG-IUS) in pre- and postmenopausal women taking adjuvant tamoxifen following breast cancer for the outcomes of endometrial and uterine pathology including abnormal vaginal bleeding or spotting, and secondary breast cancer events. SEARCH METHODS: We searched the following databases: Cochrane Menstrual Disorders and Subfertility Group Specialised Register (MDSG), Cochrane Breast Cancer Group Specialised Register (CBCG), Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Abstracts of Reviews of Effects (DARE), The Cochrane Library, clinicaltrials.gov, The World Health Organisation International Trials Registry, ProQuest Dissertations & Theses, MEDLINE, EMBASE, CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO, Web of Science, OpenGrey, LILACS, PubMed, and Google. The final search was performed in October 2015. SELECTION CRITERIA: Randomised controlled trials of women with breast cancer on adjuvant tamoxifen that compared endometrial surveillance alone (control condition) versus the LNG-IUS with endometrial surveillance (experimental condition) on the incidence of endometrial pathology. DATA COLLECTION AND ANALYSIS: Study selection, risk of bias assessment and data extraction were performed independently by two review authors. The primary outcome measure was endometrial pathology (including polyps, endometrial hyperplasia, or endometrial cancer) diagnosed at hysteroscopy or endometrial biopsy. Secondary outcome measures included fibroids, abnormal vaginal bleeding or spotting, breast cancer recurrence, and breast cancer-related deaths. The overall quality of evidence was rated using GRADE methods. MAIN RESULTS: Four randomised controlled trials involving 543 women were identified and are included in this review. In the included studies, the active treatment arm was the 20 µg/day levonorgestrel-releasing intrauterine system (LNG-IUS) plus endometrial surveillance; the control arm was endometrial surveillance alone. In tamoxifen users, the LNG-IUS led to a reduction in the incidence of endometrial polyps over both a 12-month period (Peto OR 0.22, 95% CI 0.08 to 0.64, 2 studies, n = 212, I² = 0%) and over a long-term follow-up period (24 to 60 months) (Peto OR 0.22, 95% CI 0.13 to 0.39, 4 studies, n = 417, I² = 0%, moderate quality evidence). Also the LNG-IUS led to a reduction in the incidence of endometrial hyperplasia over a long-term follow-up period (24 to 60 months) (Peto OR 0.13, 95% CI 0.03 to 0.67, four studies, n = 417, I² = 0%, moderate quality evidence). However, it should be noted that the number of events of endometrial hyperplasia was low (n = 6). None of the trials were sufficiently powered to detect whether LNG-IUS leads to significant changes in the incidence of endometrial cancer in tamoxifen users. At 12 months of follow-up abnormal vaginal bleeding or spotting was more common in the LNG-IUS treatment group (Peto OR 7.26, 95% CI 3.37 to 15.66, 3 studies, n = 376, I² = 0%, moderate quality evidence). By 24 months of follow-up, abnormal vaginal bleeding or spotting occurred less frequently compared to 12 months of follow-up in the LNG-IUS treatment group but was still more common than the control group (Peto OR 2.72, 95% CI 1.04 to 7.10, 2 studies, n = 233, I² = 0%, moderate quality evidence). By 60 months of follow-up, no cases of abnormal vaginal bleeding or spotting were reported in either group. The numbers of events for the following outcomes were low: fibroids (n = 13), breast cancer recurrence (n = 18), and breast cancer-related deaths (n = 16). There was no evidence of a difference between the LNG-IUS treatment group and controls for these outcomes. The quality of the evidence was judged as moderate, due to limited sample sizes and low event rates for the outcome comparisons. AUTHORS' CONCLUSIONS: The LNG-IUS reduces the incidence of benign endometrial polyps and endometrial hyperplasia in women with breast cancer taking tamoxifen. At 12 and 24 months of follow-up, the LNG-IUS increased abnormal vaginal bleeding or spotting among women in the treatment group compared to those in the control. There is no clear evidence from the available randomised controlled trials that the LNG-IUS prevents endometrial cancer in these women. There is no clear evidence from the available randomised controlled trials that the LNG-IUS affects the risk of breast cancer recurrence or breast cancer-related deaths. Larger studies are necessary to assess the effects of the LNG-IUS on the incidence of endometrial cancer, and to determine whether the LNG-IUS might have an impact on the risk of secondary breast cancer events.

The levonorgestrel-releasing intrauterine system for endometrial protection during estrogen replacement therapy: a clinical review.

Estrogen replacement therapy (ERT) is a well-established method of managing climacteric symptoms in women approaching the menopause, but it is associated with a significant risk of endometrial hyperplasia if unopposed by concomitant progestogen administration. The levonorgestrel-releasing intrauterine system (LNG-IUS) offers a highly effective method of minimizing this risk and has additional benefits beyond endometrial protection. The LNG-IUS provides excellent contraception, which may still be necessary in perimenopausal women, and is suitable for women with underlying conditions that may preclude their use of estrogen-containing contraceptive methods. It can effectively manage bleeding problems through the transition from perimenopause into menopause, with many women developing amenorrhea. The LNG-IUS is well tolerated with a favorable safety profile, which generally mirrors that of women of reproductive age using it for contraception only. Moreover, the LNG-IUS plus ERT combination does not appear to be associated with clinically relevant effects on plasma lipids or other markers of cardiovascular risk. Women using the LNG-IUS plus ERT also experience improvements in quality of life, and adherence and continuation rates are high. This review will summarize the clinical evidence for the use of the LNG-IUS plus ERT in peri- and postmenopausal women and present the key attributes of this combined therapy.

Effects of genistein in combination with conjugated estrogens on endometrial hyperplasia and metabolic dysfunction in ovariectomized mice.

Tissue-selective estrogen complex (TSEC), which combines a selective estrogen receptor modulator (SERM) with one or more estrogens, is a novel approach to menopausal therapy. It has been demonstrated that the phytoestrogen genistein (GEN) exhibits mixed estrogen receptor agonist and antagonist activity, suggesting that GEN may have potential for use as a natural SERM. We evaluated, for the first time, the effects of GEN, conjugated estrogens (CE), and their pairing effects as a TSEC treatment on estrogen-induced endometrial hyperplasia and metabolic dysfunction in ovariectomized (OVX) mice fed a high-fat diet. CE replacement prevented fat accumulation in the adipose tissue and liver, improved glucose homeostasis, and induced endometrial hyperplasia in OVX mice. GEN at 100 mg/kg showed CE mimetic effects in preventing ovariectomy-induced metabolic dysfunctions without endometrial stimulation. Combination treatments with CE and GEN prevented metabolic dysfunctions more strongly than CE alone, but at both low and high doses, GEN did not reverse CE-induced endometrial hyperplasia. In addition, we found that in a TSEC regimen, a typical SERM raloxifene maintains the metabolic benefits of CE while simultaneously protecting the endometrium in OVX mice. These findings indicate that GEN acts as an estrogen agonist in metabolic regulation, but has no SERM function in the uteri of OVX mice.

[Levonorgestrel-releasing intrauterine system Mirena® (Bayer) for the prevention and treatment of endometrial adenocarcinoma and the incidence of other malignancies in women]. / Wplyw systemu wewnatrzmacicznego uwalniajacego lewonorgestrel Mirena® (Bayer) na prewencje i leczenie raka gruczlowego blony sluzowej macicy oraz na inne nowotwory zlosliwe u kobiet.

The use of hormone-releasing intrauterine devices has been on the increase for the last three decades. To date, evidence of their long-term efficiency is available. The aim of the present paper was to briefly review beneficial prophylactic effects of the levonorgestrel-releasing intrauterine system on the incidence of a variety of malignancies in women. Such an influence is of a particular importance in the light of the currently observed increased prevalence of endometrial and cervical adenocarcinomas. Low-dose releasing intrauterine systems are also available, but the hard evidence-based medical data have been derived primarily for Mirena® (Bayer) device, which topically releases from 20 to 14 pg of levonorgestrel daily. Consequently the risk of developing endometrial carcinoma in Mirena® users is lowered by as much as 50% compared with the general population risk To a lesser extent, the intrauterine system decreases the risk for cervical adenocarcinoma and squamous cell carcinoma, as well as ovarian, pancreas, and lung carcinomas. In one population-based study Mirena® increased the risk for breast carcinoma by approximately 20%, whereas a number of other studies failed to demonstrate such a hazard. In the recent decades of the increased predominance of insulin resistance and obesity and an occurrence of hormone-dependent carcinomas at earlier age, a broad application of levonorgestrel-releasing intrauterine systems may become a particularly important component of primary prevention of malignancies in women. Both obese and overweight patients seem perfect candidates for such a hormonal intervention.

Long-term resveratrol treatment prevents ovariectomy-induced osteopenia in rats without hyperplastic effects on the uterus.

Resveratrol (Res), a polyphenol that is abundant in many medicinal plants and is a selective oestrogen receptor modulator, exhibits multiple biological activities. In the present study, we determined whether Res prevents oestrogen deficiency-induced osteopenia and whether Res administration decreases pathological changes in the endometrium and lumen of the uterus compared with oestradiol replacement therapy (ERT). A total of sixty 3-4-month-old female Wistar rats were randomly divided into a sham-operated group (Sham) and five ovariectomy (OVX) subgroups, i.e. OVX rats as a control group (OVX); OVX rats receiving oestradiol valerate (ERT, 0·8 mg/kg); and OVX rats receiving Res 20, 40 and 80 mg/kg. Daily oral administration was initiated at week 2 after OVX for 12 weeks. A dose-response difference was observed in the effects of Res on bone mineral density (BMD) and trabecular microarchitecture. Only at the highest dose, bone loss was almost equivalent to that observed in the ERT group. The dose-response effects of Res on the biochemical parameters (alkaline phosphatase, IL-6, TNF-α and transforming growth factor-ß1 concentrations in the serum as well as urinary Ca and P excretion) and the expressions of receptor activator of nuclear factor κB ligand (RANKL) and the RANKL:osteoprotegerin protein ratio in the femur were also observed. Furthermore, the thickening of the endometrium and the infiltration of lymphocytes were prevented in all the three Res-treated groups compared with the ERT group. In conclusion, Res treatment not only improves BMD and trabecular microarchitecture but also does not affect the uterus and Res might be a potential remedy for the treatment of postmenopausal osteoporosis.

The role of levonorgestrel-releasing intrauterine system for endometrial protection in women with breast cancer taking tamoxifen.

PURPOSE OF INVESTIGATION: To review the evidence concerning the efficacy of levonorgestrel-releasing intrauterine system (LNG-IUS) in preventing endometrial pathology in women treated with tamoxifen. MATERIALS AND METHODS: Randomized controlled trials (RCTs) of women with breast cancer on tamoxifen that compared endometrial surveillance or placebo alone vs. the LNG-IUS were reviewed. The eligible trials were identified from the following electronic databases: Cochrane CENTRAL, Medline, and EMBASE. The authors extracted data on all reported outcomes and conducted meta-analyses on the endometrial polyps, endometrial hyperplasia, proliferative endometrium, and endometrium thickness. RESULTS: According to the subgroup analysis, a significant reduction of endometrial polyps was obtained (OR = 0.22, 95% CI 0.13-0.37, p < 0.00001). The use of LNG-IUS reduced the incidence of endometrial hyperplasia (OR = 0.13, 95% CI 0.03-0.58, p = 0.007). Increased abnormal vaginal bleeding for LNG-IUS users may be an adverse aspect of LNG-IUS. CONCLUSION: This meta-analysis confirms that endometrial hyperplasia is also reduced as well as endometrial polyp formation reduced after long-term follow-up.

Factors associated with uterine endometrial hyperplasia and pyometra in wild canids: implications for fertility.

The ability to safely and effectively manage reproduction is central to the success of AZA captive-breeding programs. Although the AZA Wildlife Contraception Center routinely monitors contraceptive safety, there have been no studies that compare the effects of contraceptive use to separation of males from females, the other option for preventing reproduction. We used retrospective medical records and pathology reports submitted by AZA and related facilities for the seven AZA-managed canid species to assess rates of uterine pathology relative to female reproductive life histories. Our results showed that the prevalence of both pyometra and endometrial hyperplasia (EH) was associated not only with treatment with the two most common contraceptives (Suprelorin® and MGA implants) but also with the number of years barren (i.e., not producing a litter and not contracepted). Rates of pyometra and EH were especially high in African painted dogs and red wolves, but lowest in swift and fennec foxes. The number of years producing a litter had a low association, suggesting it could be protective against uterine pathology. A more recently developed Suprelorin® protocol using Ovaban® to prevent the initial stimulation phase, followed by implant removal when reversal is desired, may be a safer contraceptive option. These results concerning the relationship between reproductive management and uterine health have important implications for AZA-managed programs, since the unsustainability of many captive populations may be due at least in part to infertility. Managing a female's reproductive lifespan to optimize or maintain fertility will require a reconsideration of how breeding recommendations are formulated.

Progestogens for endometrial protection in combined menopausal hormone therapy: A systematic review.

Menopausal women with an intact uterus choosing estrogens for menopausal symptom relief require a progestogen for endometrial protection. The aim of this systematic review was to evaluate the risks of endometrial hyperplasia resp. malignancy with different progestogens used in combined MHT. Overall, 84 RCTs were included. We found that 1) most studies were done with NETA, followed by MPA, MP and DYD and LNG, 2) most progestogens were only available as oral formulations, 3) the most frequently studied progestogens (oral MP, DYD, MPA, oral and transdermal NETA, transdermal LNG) were assessed in continuously as well as in sequentially combined MHT regimens, 4) FDA endometrial safety criteria were only fulfilled for some progestogen formulations, 5) most studies demonstrated endometrial protection for the progestogen dose and time period examined. However, 6) study quality varied which should be taken into account, when choosing a combined MHT, especially if off-label-use is chosen.

Endometrial, breast and liver safety of soy isoflavones plus Lactobacillus sporogenes in post-menopausal women.

OBJECTIVE: To assess the safety of a nutraceutical compound containing soy isoflavones and Lactobacillus sporogenes on endometrium, breast and liver function. SETTING: Outpatient Menopausal Clinic. STUDY DESIGN: 130 healthy postmenopausal women suffering from menopausal symptoms were randomized to receive soy isoflavones 60 mg and Lactobacillus sporogenes 1 billion spores (group E: 65 women) or calcium and vitamin D3 (group C: 65 women). Safety of the treatment was assessed at baseline and after 1 year taking into account endometrial thickness, mammographic density, serum levels of transaminases, γ-GT and bilirubin. Efficacy of the treatment was evaluated rating the score of menopausal symptoms at baseline and every 3 months. The statistical analysis was carried out with χ², Fisher exact's test and ANOVA. RESULTS: After 12 months of treatment mammographic density, endometrial thickness and hepatic function did not show significant differences between groups, while menopausal symptoms were progressively and significantly reduced in severity and frequency during treatment with soy isoflavones plus Lactobacillus sporogenes versus calcium plus vitamin D3. CONCLUSION: A 12 months treatment with a nutraceutical compound based on isoflavones and Lactobacillus sporogenes at the recommended doses is safe for endometrium, mammary glands and liver function in postmenopausal women.

Efficacy of the levonorgestrel intrauterine system (LNG-IUS) in the prevention of the atypical endometrial hyperplasia and endometrial cancer: retrospective data from selected obese menopausal symptomatic women.

The aim of this retrospective study was to evaluate the efficacy of levonorgestrel intrauterine system-releasing (LNG-IUS) insertion in preventing atypical endometrial hyperplasia (AH) and endometrial cancer (EC) in symptomatic postmenopausal overweight/obese women. A total of 34 overweight/obese postmenopausal women, presenting abnormal uterine bleeding (AUB) and endometrial hyperplasia (EH), and who were submitted to LNG-IUS insertion, were identified from registry data. Endometrial histology at LNG-IUS insertion showed simple EH in 20 cases (58.8%), complex EH in 14 cases (41.2%). At 36 months, 91% of patients showed no recurrence of AUB and a significant reduction in the mean endometrial thickness (from 8.2 ± 2.2 to 3.2 ± 1.5 mm, p < 0.05) was observed. Histologic regression of EH was observed in 27 (79.4%) and 33 (97.5%) cases at 12 and 36 months, respectively. None of the women in which EH persisted, reported cellular atypia or cancer progression at 12 and 36 months of follow-up. LNG-IUS represents an effective treatment option to manage postmenopausal obese women affected by AUB and EH. The device seems to be able to prevent the onset of AH and EC in women at high risk. Further prospective controlled studies in a well selected group of women are needed.

Microwave endometrial ablation for endometrial protection in women with breast cancer on adjuvant tamoxifen.

AIM: The purpose of the current study was to determine the effectiveness of microwave endometrial ablation (MEA) in inhibiting the proliferative response of the endometrium in women with breast cancer who are treated with tamoxifen. MATERIAL AND METHODS: In the before-after study, we treated 31 postmenopausal patients who had received adjuvant tamoxifen for 1 year or more with MEA, the endometrial changes were compared before and after MEA. RESULTS: After MEA, the thickness of the uterine lining was decreased significantly. No patient had recurrent endometrial polyps or abnormal vaginal bleeding during the follow-up period. CONCLUSION: MEA had a protective action against the uterine effects of tamoxifen for postmenopausal patients. MEA is a safe and effective minimally invasive treatment method for breast cancer patients treated with tamoxifen.

Unilateral hydroureteronephrosis after introduction of a levonorgestrel-releasing intrauterine system: a case report and literature review.

Insertion of a LNG-Intra-uterine System (LNG-IUS) has many gynecological indications. The approved indications worldwide are contraception, treatment of abnormal uterine bleeding depending on not organic disease, and endometrial protection in case of an estrogenic therapy. Instead adenomyosis, fibroids, and fertility-sparing management of endometrial hyperplasia or early endometrial cancer in patients with desire of pregnancy are off label indications. Hydroureteronephrosis is an uncommon complication during LNG-IUS insertion. There are few cases described in the literature. The first diagnostic approach for this complication is an abdominal-pelvic ultrasound scan to identify the abnormal position of the device. Diagnostic management includes computed tomography (CT) or magnetic resonance imaging (MRI), which are necessary to confirm hydroureteronephrosis and to assess the exact location of the LNG-IUS in the abdomen. A minimally invasive approach is the standard of care with the removal of the device, while the therapeutic management of the hydroureteronephrosis depends on ureteral and kidney involvement. We report the history of a dislocated LNG-IUS in the left paracervical space with subsequent ipsilateral hydroureteronephrosis. In our case we removed the device through hysteroscopy and later inserted a J-J stent. Follow-up at three months revealed the persistence of left hydroureteronephrosis, so we performed ureter reimplantation. We also performed a review of the literature to analyze common diagnostic and therapeutic pathways for this rare complication.

Hormone therapy in postmenopausal women and risk of endometrial hyperplasia.

BACKGROUND: Reduced circulating estrogen levels around the time of the menopause can induce unacceptable symptoms that affect the health and well-being of women. Hormone therapy (both unopposed estrogen and estrogen/progestogen combinations) is an effective treatment for these symptoms, but is associated with risk of harms. Guidelines recommend that hormone therapy be given at the lowest effective dose and treatment should be reviewed regularly. The aim of this review is to identify the minimum dose(s) of progestogen required to be added to estrogen so that the rate of endometrial hyperplasia is not increased compared to placebo. OBJECTIVES: The objective of this review is to assess which hormone therapy regimens provide effective protection against the development of endometrial hyperplasia or carcinoma. SEARCH METHODS: We searched the Cochrane Menstrual Disorders and Subfertility Group trials register (searched January 2012), The Cochrane Library (Issue 1, 2012), MEDLINE (1966 to January 2012), EMBASE (1980 to January 2012), Current Contents (1993 to May 2008), Biological Abstracts (1969 to 2008), Social Sciences Index (1980 to May 2008), PsycINFO (1972 to January 2012) and CINAHL (1982 to May 2008). Attempts were made to identify trials from citation lists of reviews and studies retrieved, and drug companies were contacted for unpublished data. SELECTION CRITERIA: Randomised comparisons of unopposed estrogen therapy, combined continuous estrogen-progestogen therapy, sequential estrogen-progestogen therapy with each other or placebo, administered over a minimum period of 12 months. Incidence of endometrial hyperplasia/carcinoma assessed by a biopsy at the end of treatment was a required outcome. Data on adherence to therapy, rates of additional interventions, and withdrawals owing to adverse events were also extracted. DATA COLLECTION AND ANALYSIS: In this update, 46 studies were included. Odds ratios (ORs) were calculated for dichotomous outcomes. The small numbers of studies in each comparison and the clinical heterogeneity precluded meta-analysis for many outcomes. MAIN RESULTS: Unopposed estrogen is associated with increased risk of endometrial hyperplasia at all doses, and durations of therapy between one and three years. For women with a uterus the risk of endometrial hyperplasia with hormone therapy comprising low-dose estrogen continuously combined with a minimum of 1 mg norethisterone acetate (NETA) or 1.5 mg medroxyprogesterone acetate (MPA) is not significantly different from placebo at two years (1 mg NETA: OR 0.04; 95% confidence interval (CI) 0 to 2.8; 1.5 mg MPA: no hyperplasia events). AUTHORS' CONCLUSIONS: Hormone therapy for postmenopausal women with an intact uterus should comprise both estrogen and progestogen to reduce the risk of endometrial hyperplasia.