Random-start ovarian stimulation in an oocyte donation programme: a large, single-centre, experience.

RESEARCH QUESTION: Do live birth rates differ between recipients matched with donors using conventional ovarian stimulation compared with those using random-start protocols? DESIGN: Retrospective analysis of 891 ovarian stimulations in egg donors (January-December 2018) and clinical outcomes in matched recipients (n = 935). Donors commenced ovarian stimulation on day 1-3 of the menstrual cycle (n = 223) or in the mid/late-follicular (n = 388) or luteal phase (n = 280) under a conventional antagonist protocol. Live birth rate of matched recipients was the main outcome. RESULTS: Duration of stimulation and total gonadotrophin dose were comparable between conventional versus random-start groups. The number of collected eggs were similar (17.6 ± 8.8 versus 17.2 ± 8.5, P = 0.6, respectively). Sub-group analysis showed that stimulation length (10.2 ± 1.8 versus 9.8 ± 1.7 versus 10.4 ± 1.7, P < 0.001) and gonadotrophin consumption (2041.5 ± 645.3 versus 2003.2 ± 647.3 versus 2158.2 ± 685.7 IU, P = 0.01) differed significantly between the conventional, mid/late follicular and luteal phase groups, respectively. In matched recipients receiving fresh oocytes and undergoing fresh embryo transfer, the biochemical pregnancy (63.8% and 63.3%; P = 0.9), clinical pregnancy (54.6% and 56.1%; P = 0.8) and live birth rates (47.7% and 46.6%; P = 0.7) per embryo-transfer were similar between conventional versus random groups. Similar results were obtained in recipients receiving vitrified eggs. Euploidy rate was also comparable. CONCLUSIONS: No notable variations were found in clinical outcomes using oocytes obtained from random-start protocols and those proceeding from conventional ovarian stimulation in oocyte donation treatments. Luteal-phase stimulation seems to require longer stimulation and higher FSH consumption. Random-start stimulation strategy does not impair the potential of the oocyte yield or clinical outcomes in oocyte donation cycles.

What do TSECs provide in the menopausal hormone therapy?

Tissue-selective estrogen complex (TSEC) is projected as a progestogen-free option for the treatment of estrogen deficiency symptoms in postmenopausal, non-hysterectomized women. TSEC combines the benefits of estrogen with a selective estrogen receptor modulator (SERM), in this case bazedoxifene acetate (BZA), which has an antagonistic effect on the endometrium, thus avoiding the use of progestins. The authorized TSEC combination (conjugated estrogens [CE] 0.45 mg/BZA 20 mg) for the alleviation of vasomotor symptoms has been demonstrated in randomized clinical trials compared with placebo or menopausal hormone therapy (MHT). In addition, TSEC has shown improvements in quality of life and vaginal atrophy. In respect to MHT using progestins, the benefits of TSEC are found mainly in the bleeding pattern, amenorrhea rate, and reduction in mammary repercussion (i.e., breast tenderness and radiological density). The objective of this guide will be to analyze the efficacy and safety of TSEC consisting of CE/BZA in postmenopausal women.

Pharmacological interactions and menopausal hormone therapy: a review.

IMPORTANCE AND OBJECTIVE: Menopausal hormone therapy (HT) is widely used, and there are several statements of international scientific societies to guide prescribers; however, a summary of existing literature about possible drug interactions with HT does not exist, although many midlife women take medications for other conditions. Therefore, our objective was to create a document that presents and synthesizes the most relevant interactions. The impact of the interaction itself and the number of candidates for HT who are likely to use other treatments are considered based on the best available evidence. METHODS: A systematic review was performed to determine the best evidence of interaction effects on relevant outcomes of interest for decision making. A working framework was developed to formulate explicit and reasoned recommendations according to four predefined categories for coadministration: (1) can be used without expected risks, (2) acceptable use (no evidence of negative interaction), (3) alternative treatment should be considered, and (4) nonuse without express justification. The project protocol was registered in the Open Science Framework platform (doi: 10.17605/OSF.IO/J6WBC ) and in PROSPERO (registration number CRD42020166658). RESULTS: Studies targeting our objective are scarce, but 23 pharmacological groups were assigned to one of the predefined categories of recommendation for concomitant use of HT. Vaginal HT was assigned to category 1 for 21 of the analyzed pharmacological groups. For oral and transdermal HT (estrogen-only or combined) and tibolone, there were 12 pharmacological groups assigned to category 1, 12 to category 2, 5 to category 3, and 4 to category 4. Results are shown in crossed-tables that are useful for counseling and prescription. DISCUSSION AND CONCLUSIONS: Available evidence of HT interactions with other drugs is scarce and mainly indirect. It comes from biological plausibility, knowledge of extensive concomitant use without reported incidents, and/or extrapolation from hormonal contraception, but there are pharmacological groups in all categories showing that information is useful. These eligibility criteria summarize it and can help in the decision process of HT coadministration with other drugs. Decisions should be taken based on these recommendations but also individualized risk/benefit evaluation, according to underlying pathology, patient's clinical requirements, and the existence or nonexistence of alternatives.

Placental-site trophoblastic tumor with bone metastasis: A diagnostic and therapeutic challenge.

Placental-site trophoblastic tumor (PSTT) is a rare pathological entity included in the spectrum of gestational trophoblastic neoplasia (GTN). It is a neoplasia with metastatic potential that, once metastasized, has poor prognosis because the tumor tends to be less sensitive to chemotherapy. We present a rare case of gestational trophoblastic neoplasia, in which hysterectomy for persistent gestational trophoblastic disease after hydatidiform mole, revealed a primary PSTT in the uterus. Subsequently, a slight persistent elevation of the beta fraction of human chorionic gonadotropin hormone (B-hCG) during follow-up revealed the presence of bone metastases. This location is not usual from this tumor, being even more rare the case of PSTT with isolated bone metastases. Metastasic foci were only identified with PET-CT since the usual diagnostic resources were not able to do it. Finally, it is also remarkable in our case that the treatment required the confluence of chemotherapy together with immunotherapy to achieve a favorable response.

Eligibility criteria for Menopausal Hormone Therapy (MHT): a position statement from a consortium of scientific societies for the use of MHT in women with medical conditions. MHT Eligibility Criteria Group.

This project aims to develop eligibility criteria for menopausal hormone therapy (MHT). The tool should be similar to those already established for contraception A consortium of scientific societies coordinated by the Spanish Menopause Society met to formulate recommendations for the use of MHT by women with medical conditions based on the best available evidence. The project was developed in two phases. As a first step, we conducted 14 systematic reviews and 32 metanalyses on the safety of MHT (in nine areas: age, time of menopause onset, treatment duration, women with thrombotic risk, women with a personal history of cardiovascular disease, women with metabolic syndrome, women with gastrointestinal diseases, survivors of breast cancer or of other cancers, and women who smoke) and on the most relevant pharmacological interactions with MHT. These systematic reviews and metanalyses helped inform a structured process in which a panel of experts defined the eligibility criteria according to a specific framework, which facilitated the discussion and development process. To unify the proposal, the following eligibility criteria have been defined in accordance with the WHO international nomenclature for the different alternatives for MHT (category 1, no restriction on the use of MHT; category 2, the benefits outweigh the risks; category 3, the risks generally outweigh the benefits; category 4, MHT should not be used). Quality was classified as high, moderate, low or very low, based on several factors (including risk of bias, inaccuracy, inconsistency, lack of directionality and publication bias). When no direct evidence was identified, but plausibility, clinical experience or indirect evidence were available, "Expert opinion" was categorized. For the first time, a set of eligibility criteria, based on clinical evidence and developed according to the most rigorous methodological tools, has been defined. This will provide health professionals with a powerful decision-making tool that can be used to manage menopausal symptoms.

Treatment of endometriosis with transvaginal ultrasound-guided drainage and recombinant interleukin-2 left in the cysts: a third clinical trial.

BACKGROUND: To analyze the therapeutic results of recombinant interleukin-2 (rIL-2) left in the cysts after transvaginal ultrasound (US)-guided drainage of endometriomas as an alternative to surgery. METHODS: Prospective and randomized clinical trial. A total of 25 consecutive patients were included. Two transvaginal US-guided punctures were performed, and 3 million IU of rIL-2 were left in the aspirated cysts once (group I) or both (group II) times according to randomization. MAIN OUTCOME MEASURES: Clinical results, prevented surgeries, and recurrences. RESULTS: Results were moderate or good in only 16% of subjects at 3 months and in 33% of subjects at 6 months after treatment in group I; these numbers were 66 and 33%, respectively, in group II. Differences were not statistically significant. However, the evolution of symptoms, endometriomas, and CA-125 revealed the low efficacy of rIL-2 left intracyst as well as a poor control of the clinical manifestations. After 1 year, 20% (group I) and 73% (group II) of patients had to be operated; after 2 years, these numbers were 55 and 82%, respectively. CONCLUSIONS: Treatment of endometriomas with transvaginal US-guided drainage and rIL-2 left in the cysts, without using endometrial suppressive therapy with GnRH analogues as done in previous studies, has low efficacy. Recurrences are even more frequent after the use of two rIL-2 doses.

The effect of intraperitoneal interleukin-2 on surgically induced endometriosis in rats.

OBJECTIVE: To evaluate the effect of interleukin-2 (IL-2) on an experimental model of endometriosis. STUDY DESIGN: Double blind and randomized experimental prospective placebo-controlled study. Experimental endometriosis was induced in 66 three-month-old female Wistar rats, by auto-transplanting fragments of endometrium to the peritoneum. After four weeks, the size of each implant was measured in millimeters by laparotomy (L2), and animals were randomly distributed for intraperitoneal administration of human-IL-2, rat-IL-2 or placebo. Four weeks later, the implants were measured (L3) and a second dose was given. After four weeks, endometriosis size was evaluated again (L4). RESULTS: We found a reduction of experimental endometriosis at L3 that was only significant in IL-2 treated groups: 20.1% and 30.3% with human-IL-2 and rat-IL-2, respectively (p<0.001 with respect to L2 size), versus a non-significant reduction of 9.0% found in placebo group, but the differences were not statistically significant between groups. The decrease after a second dose (L4) was: 49.8%, 41.8% and 11.4% with human-IL-2, rat-IL-2 and placebo, respectively (p<0.001 in IL-2 groups versus L2 and L3, and p<0.05 in both groups versus placebo at L4). CONCLUSION: Intraperitoneal administration of IL-2 reduces experimental endometriosis, and this effect is similar using rat-IL-2 or human IL-2 (non specie-specific effect).

Intraperitoneal recombinant interleukin-2 activates leukocytes in rat endometriosis.

The aim of this double-blinded study was to determine changes in leukocyte populations in blood, peritoneal lavage fluid, eutopic and ectopic endometrium after treatment with recombinant rat interleukin-2 (IL-2) using an in vivo experimental model of rat endometriosis. The in vivo model involved transplanting four square fragments of autologous endometrium onto the inner surface of the abdominal wall in 20 Wistar rats. The control group was constituted by 20 sham-operated rats. Both groups were randomly treated (1-month interval treatment) with 2 intraperitoneal doses of glucose solution (5%) that did or did not contain recombinant IL-2, and animals were sacrificed 4 weeks after the last dose of treatment. Blood and peritoneal lavage were obtained during the initial and final laparotomy, whereas eutopic and ectopic endometrium were collected at the end of the experiment. Endometriotic implants were measured in each laparotomy to determine any change in size. Leukocyte populations were analyzed by flow cytometry and immunofluorescence microscopy. Cytometric results were similar in blood and peritoneal lavage. CD25+ and natural killer (NK) cell levels in peripheral blood were lower in rats with endometriosis treated with IL-2, whereas NK cells increased in lavage compared to placebo group. The percentage of macrophages and dendritic cells in blood were higher in all rats treated with IL-2, as well as peritoneal dendritic cells. Implant size of these rats decreased significantly, showing a greater number of activated lymphocytes, macrophages, NK and dendritic cells inside them. In conclusion, recombinant IL-2 induced recruitment of activated leukocytes into endometriotic-like foci, and this was related to a reduction of the implant size, suggesting potential effectiveness of IL-2 as an immunomodulatory agent in this pathology.

[General recommendations over perimenopausal transition therapy]. / Recomendaciones generales para el tratamiento en la transición perimenopáusica.

BACKGROUND: Medical attention during perimenopause requires different therapeutic strategies. OBJECTIVE: To define strategies for the attention of perimenopause women that can favor a healthy aging. METHODS: Review of influencing factors and lifestyle modifications that can be introduced in perimenopause to prevent pathologies. RESULTS: Diet composition and weight control influence cardiovascular and bone risks. It is difficult to get permanent changes in diet habits and there is a lack of conclusive evidence over the results of these recommendations, however there begin to arise better works that shows cardiovascular and osseous benefits of physical activity and specific exercise schedules. Due to them higher risk, it is necessary to suppress toxic habits. Several studies suggest phytotherapeutic supplements consumption benefit, however there is a lack of well-designed clinical essays to justify them recommendation. CONCLUSIONS: Correct nutritional state, appropriate diet, weight control, a common exercise practice, and suppression of toxic habits are applicable measures during perimenopause transition that could influence woman's health level for them lifespan. Individualized identification of diseases risk can justify the recommendations.

Multilocus analysis of estrogen-related genes in Spanish postmenopausal women suggests an interactive role of ESR1, ESR2 and NRIP1 genes in the pathogenesis of osteoporosis.

Osteoporosis is a common disease with multiple environmental and genetic risk factors involved. Using a marker-by-marker approach, the role of different estrogen-related genes has been analyzed in different populations, but most of these studies ignore the complex multigenic nature of human osteoporosis. Looking for markers related to osteoporosis, we have analyzed five single nucleotide polymorphisms located in genes related to the estrogen pathway, Follicle Stimulating Hormone Receptor (FSHR) gene, the CYP19 aromatase (CYP19A1) gene, the Estrogen Receptor alpha (ESR1) gene, the Estrogen Receptor beta (ESR2) gene and the Nuclear Receptor Interacting Protein 1 (NRIP1) gene in 265 unrelated postmenopausal women. We have obtained nominal P values for the NRIP1 Gly75Gly and ESR2 *39A>G markers (P=0.013 and P=0.02 respectively), but no gene seems to be associated after multiple test corrections. Reanalysis of this study using 437 postmenopausal women confirmed our results and only detect marginal effects for ESR2 marker (P=0.045). By contrast, multilocus analysis predicted epistatic interactions between ESR1, ESR2 and NRIP1 loci and its involvement in postmenopausal osteoporosis (P=0.003). We detected two digenic genotypes involving ESR2-NRIP1 and ESR2-ESR1 genes strongly associated with osteoporosis (P=0.007). Replication of multilocus studies using 437 patients confirmed the detected interactions (P<0.01). We proposed a non-additive non-multiplicative oligogenic model including ESR2 AG genotype modulated by NRIP1 A+ or ESR1 TT genotypes involved in osteoporosis. Our results reaffirm the polygenic nature and the genetic complexity of osteoporosis trait adding a new candidate gene (NRIP1) for association studies of bone-related traits.

Use of intraperitoneal interferon alpha-2b therapy after conservative surgery for endometriosis and postoperative medical treatment with depot gonadotropin-releasing hormone analog: a randomized clinical trial.

OBJECTIVE: To evaluate the possible therapeutic effects of interferon alpha-2b left in the peritoneum after surgery, followed by or not followed by treatment with GnRH analogs. DESIGN: A prospective, randomized clinical trial. SETTING: University hospital. PATIENT(S): Fifty-two infertile patients with moderate or severe endometriosis. INTERVENTION(S): Laparotomic conservative surgery and either interferon alpha-2b or saline alone left in the pouch of Douglas followed by administration of either GnRH analogs depot or oral indomethacin with transvaginal echography and analysis of CA-125, immunoglobulins, and lymphocyte populations. MAIN OUTCOME MEASURE(S): Recurrence of endometriosis was considered clinically, echographically, and laparoscopically. RESULT(S): Recurrence of endometriosis in four cases without interferon (15.4%) versus 11 patients (42.3%) with interferon alpha-2b. Life table analysis showed significant differences between the groups with and without interferon 21 months after conservative surgery. There were no differences in the recurrence between the groups with or without GnRH analogs. Likewise, there were no significant changes in immunoglobulins and lymphocyte populations among patients with and without recurrence of endometriosis. The patients that received GnRH analogs depot showed a decrease in the number of CD16 and an increase of CD11b cells after treatment. CONCLUSION(S): The use of interferon alpha-2b within the peritoneal cavity after conservative surgery may be inappropriate because it increased later recurrence of endometriosis. The postoperative treatment with GnRH analogs did not significantly reduce the recurrence rate. Immunoglobulins and lymphocyte populations did not change in relation to the recurrence of endometriosis.

Complex genital malformation: ectopic ureter ending in a supposed mesonephric duct in a woman with renal agenesis and ipsilateral blind hemivagina.

We present a clinical case of a patient with left renal agenesis and ipsilateral blind hemivagina who also had one or more atretic ectopic ureters opening into supposed mesonephric duct, which in turn opened into, or joined onto, the ipsilateral hemicervix, continuing with the blind hemivagina. The diagram of this complex genitourinary malformation would strongly support our hypothesis of the embryology of the human vagina as deriving from the Wolffian ducts and the Mullerian tubercle.

Spanish Menopause Society position statement: Use of denosumab in postmenopausal women.

Denosumab is a new drug developed for the treatment of osteoporosis. Moreover, increasing evidences link denosumab with benefits in cancer, an area of interest for those in charge of the postmenopausal health. Denosumab has shown efficacy in the control of bone loss associated with hypogonadic states created by chemotherapy in breast and other cancers. Moreover, some studies reveal efficacy in reducing the progression of metastases. A panel of experts from the Spanish Menopause Society has met to develop usage recommendations based on the best available evidence.

Effect of human interferon-alpha-2b on experimental endometriosis in rats: comparison between short and long series of treatment.

OBJECTIVE: A randomised and controlled experimental study was carried out to determine the effect of short and long series of treatment with recombinant human interferon-alpha-2b on surgically induced endometriosis in rats. STUDY DESIGN: Ninety-six Wistar adult female rats, which had undergone an autotransplant into the peritoneal cavity of four endometrial fragments measuring 4.5mm at the side, were randomly divided into three groups. One third of the animals were manipulated like the treated animals but were not given treatment and served as control (group C). Another third (group S) were treated with three doses (one every 48 h, 100,000 U per dose) of recombinant human interferon-alpha-2b (subcutaneous route), and the last third (group L) were treated with fifteen doses of interferon (100,000 U every 48 h). RESULTS: Before interferon was administered, there were no differences between groups in the average growth of experimental endometriosis per animal (17.3±6.7, 18.1±9.2, 16.4±5.6mm in groups C, S and L respectively). After the treatment, experimental endometriosis per animal was significantly smaller in the groups treated with interferon than in the control non-treated group (p<0.001), and in the group treated with 15 doses versus the group treated with 3 doses (p<0.05), (17.6±7.5, 14.0±9.5, 9.4±6.0mm in groups C, S, and L respectively). While the implants of the animals in the control group showed no change in size throughout the study (120 days) (+1.96% of variation), the mean size of the implants in the treated rats decreased, (22.7% with the short and 42.8% with the long series of treatment with interferon). Only one implant in group C (0.8%) disappeared, while this occurred in 27 cases (22.5%) in group S (p<0.001) and in 45 (37.5%) in group L (p<0.001 versus group C and p<0.05 versus group S). CONCLUSION: The long series of treatment with human interferon-alpha-2b was more effective than the short one in reducing the size of surgically induced endometriosis in the peritoneal cavity of the rat.

Is a bowel resection necessary for deep endometriosis with rectovaginal or colorectal involvement?

BACKGROUND: The purpose of this paper is to report the long-term results of surgery without bowel resection in patients suffering from deep infiltrating endometriosis with rectovaginal or colorectal involvement. METHODS: This retrospective observational study identified 42 patients suffering with deep infiltrating endometriosis who underwent surgery. Conservative surgery was performed in 23 women (only one of them with bowel resection), and 19 women underwent a hysterectomy and bilateral salpingo-oophorectomy (HBSO). In the conservative surgery group, a later HBSO was performed in eight patients as a second operation. Pregnancies, recurrences, reoperations, use of hormone replacement therapy, and outcomes during long-term follow-up were analyzed. RESULTS: The average follow-up duration was 7 ± 5.7 years in conservative surgery cases. Only one patient was treated with sigmoid bowel resection in 1997 and had complications. In this conservative surgery group, 13 patients (56%) received medical treatment after surgery, 10 patients wanted to get pregnant (of whom seven [70%] were successful), and eight patients underwent a subsequent HBSO because of recurrent symptoms and/or endometrioma. Therefore, HBSO was performed in 27 patients, of whom 14 (51.8%) used hormone replacement therapy for 5.6 ± 3.6 years. No recurrences or complications were observed in patients after HBSO with or without hormone replacement therapy. CONCLUSION: Good clinical results can be obtained by performing only conservative surgery and/or HBSO without bowel resection, an alternative that could reduce the number of colorectal resections that are performed very frequently nowadays. After HBSO, patients may use hormone replacement therapy for several years with total satisfaction and well-being.

Spanish Menopause Society position statement: use of tibolone in postmenopausal women.

Tibolone is a drug with complex tissue-specific action that exhibits a combination of estrogenic, progestogenic, and slight androgenic activity. Its variable profile explains its clinical effects, depending on the target tissue where it is metabolized, its metabolites' affinity for and potency in hormone receptors, and probable enzymatic activity modulation.In recent reviews and clinical trials, the effectiveness of tibolone in alleviating different hot flush menopause symptoms, mainly in mood and sexuality disorders, has been noted. In Spain, tibolone is the most prescribed hormonal treatment, and one of the most common complaints among postmenopausal women is change in sexual drive. For such reason, a panel of experts from the Spanish Menopause Society met to develop usage recommendations based on the best evidence available.

Position of the Spanish Menopause Society regarding the management of menopausal symptoms in breast cancer patients.

Breast cancer is the most common female cancer in Spain. Its high prevalence, its high survival rate, and its incidence are the reasons treatment is increasingly sought for common problems by young women who have survived it. Besides the contraception and fertility issues, many breast cancer survivors develop sexual disorders and menopausal symptoms, whether as a consequence of treatment-induced menopause or side effects of treatment. For such reasons, a panel of experts from the Spanish Menopause Society has met to develop usage recommendations for the relief of vasomotor symptoms and for sexual and reproductive health in patients with breast cancer based on the best evidence available.

Lowering the age at menarche and risk of early menarche in a population of Spanish postmenopausal women during the past two decades.

AIM: The purpose of this study is to confirm in our population the decreasing secular trend in the age of menarche (AAM) observed in other European countries. Another aim is to investigate the association between early menarche and breast cancer, metabolic disorders risk or early menopause. MATERIALS AND METHODS: We conducted a nationwide population-based study of 1980 Caucasoid Spanish postmenopausal women from 2003 to 2006 to investigate the AAM, the duration of the fertile period and the relation of early menarche with breast cancer and some metabolic disorders. RESULTS: Regression analysis of AAM demonstrates a trend towards the younger AAM in our population during the past decades (P > 0.001). Parallel to this decrease we observe a significant increase in the fertility period and the height of our population (P < 0.001). In the women with AAM less than 11 years, there is an increased risk of hypercholesterolaemia, being overweight and obesity. However, early menarche does not raise the risk of adult onset diabetes, hypertension or breast cancer. CONCLUSIONS: These data indicate a decreasing secular trend of AAM in a Spanish population in the last decades. Furthermore, hypercholesterolaemia and obesity, but not breast cancer, appears to be influenced by younger AAM. Only women who have their menarche at the age of nine years or less are more likely to have an earlier menopause.

Impact of anthropometric parameters on quality of life during menopause.

OBJECTIVE: To investigate whether body mass index (BMI), abdominal obesity, and fat distribution in postmenopausal women influence quality of life. DESIGN: Cross-sectional survey. SETTING: Outpatient clinics in the hospital setting and private practices. PATIENT(S): 274 postmenopausal Spanish women, distributed by body phenotype, fat distribution (android or gynoid), and BMI. INTERVENTION(S): The Cervantes scale, a specific health-related quality of life (HRQOL) questionnaire. MAIN OUTCOME MEASURE(S): The quality of life of the obese and overweight patients was compared by age, sex, education, marriage, and municipality with matched healthy normal-weight controls. RESULT(S): Women of the pyknoid phenotype have worse general HRQOL, menopausal symptoms, and psychological and sexuality scores than athletic or lean women. Android fat distribution is also related to low global Cervantes scale scores. All scores on the Cervantes scale worsened with increasing BMI (>or=25). CONCLUSION(S): Pyknoid phenotype, android fat distribution, and a higher BMI are related to poor HRQOL.