Analysis of the Endometrial Transcriptome at the Time of Implantation in Women Receiving a Single Post-Ovulatory Dose of Levonorgestrel or Mifepristone.

BACKGROUND: Levonorgestrel (LNG) is a progesterone receptor agonist used in both regular and emergency hormonal contraception; however, its effects on the endometrium as a contraceptive remain widely unknown and under public debate. OBJECTIVE: To analyze the effects of LNG or mifepristone (MFP), a progesterone receptor antagonist and also known as RU-486, administered at the time of follicle rupture (FR) on endometrial transcriptome during the receptive period of the menstrual cycle. METHODS: Ten volunteers ovulatory women were studied during two menstrual cycles, a control cycle and a consecutively treated cycle; in this last case, women were randomly allocated to two groups of 5 women each, receiving one dose of LNG (1.5 mg) or MFP (50 mg) the day of the FR by ultrasound. Endometrial biopsies were taken 6 days after drug administration and prepared for microarray analysis. RESULTS: Genomic functional analysis in the LNG-treated group showed as activated the bio-functions embryo implantation and decidualization, while these bio-functions in the T-MFP group were predicted as inhibited. CONCLUSIONS: The administration of LNG as a hormonal emergency contraceptive resulted in an endometrial gene expression profile associated with receptivity. These results agree on the concept that LNG does not affect endometrial receptivity and/or embryo implantation when used as an emergency contraceptive.

II. THE RESEARCH ETHICS INVOLVING VULNERABLE GROUPS.

Vulnerability in research occurs when the participant is incapable of protecting his or her interests and therefore, has an increased probability of being intentionally or unintentionally harmed. This manuscript aims to discuss the conditions that make a group vulnerable and the tools and requirements that can be used to reduce the ethical breaches when including them in research protocols. The vulnerability can be due either to an inability to understand and give informed consent or to unequal power relationships that hinder basic rights. Excluding subjects from research for the only reason of belonging to a vulnerable group is unethical and will bias the results of the investigation. To consider a subject or group as vulnerable depends on the context, and the investigator should evaluate each case individually.

I. THE ROLE OF RESEARCH ETHICS COMMITTEES IN OBSERVATIONAL STUDIES: EPIDEMIOLOGICAL REGISTRIES, CASE REPORTS, INTERVIEWS, AND RETROSPECTIVE STUDIES.

It is often unclear to the clinical investigator whether observational studies should be submitted to a research ethics committee (REC), mostly because, in general, no active or additional interventions are performed. Moreover, obtaining an informed consent under these circumstances may be challenging, either because these are very large epidemiological registries, or the subject may no longer be alive, is too ill to consent, or is impossible to contact after being discharged. Although observational studies do not involve interventions, they entail ethical concerns, including threats such as breaches in confidentiality and autonomy, and respect for basic rights of the research subjects according to the good clinical practices. In this context, in addition to their main function as evaluators from an ethical, methodological, and regulatory point of view, the RECs serve as mediators between the research subjects, looking after their basic rights, and the investigator or institution, safeguarding them from both legal and unethical perils that the investigation could engage, by ensuring that all procedures are performed following the international standards of care for research. The aim of this manuscript is to provide information on each type of study and its risks, along with actions to prevent such risks, and the function of RECs in each type of study.

Digital Joint Reconstruction with Osteotendinous Joint Allograft: Experimental Study in Rats.

BACKGROUND: Fresh or frozen nonvascularized osteotendinous joint allografts (OTJA) have not been used previously, clinically or experimentally, for metacarpophalangeal joint reconstruction. Therefore, we evaluated the viability of OTJA for metatarsophalangeal joint (MTJ) reconstruction in rats. METHODS: In the experimental group of 12 Lewis rats, we reconstructed the MTJ of the third digit of the hindlimb with a fresh, nonvascularized OTJA obtained from the same digit from 12 donor rats. In the control group of 6 Lewis rats, an autologous composite osteotendinous graft of the MTJ of the same digit was obtained and repositioned in situ as an auto-transplant. Weight, pain, edema, dehiscence, and wound infection were evaluated every 24 hours for 30 days postoperatively. At the end of 30 days, we evaluated digit position, flexion and extension, passive mobility, radiological bone healing, and histological grades of rejection. RESULTS: We found no statistically different changes in weight, edema, pain, digit position, or radiological bone healing in either group. No wound dehiscence or infection was seen in any of the rats. Ten degrees of flexion and extension mobility were lost in the control group; the experimental group lost up to 30 degrees (P = 0.009). Histologically, 9 of the experimental group rats (9/12, 75%) showed rejection reactions compared with none of the controls (0%) (P = 0.009). CONCLUSIONS: Fresh nonvascularized OTJA caused an immune reaction without exposure of the graft, but with bone resorption. However, the rats maintained digital form and alignment with decreased passive flexion and extension of 10-30 degrees.

Maternal Obesity: Lifelong Metabolic Outcomes for Offspring from Poor Developmental Trajectories During the Perinatal Period.

The prevalence of obesity in women of reproductive age is increasing in developed and developing countries around the world. Human and animal studies indicate that maternal obesity adversely impacts both maternal health and offspring phenotype, predisposing them to chronic diseases later in life including obesity, dyslipidemia, type 2 diabetes mellitus, and hypertension. Several mechanisms act together to produce these adverse health effects including programming of hypothalamic appetite-regulating centers, increasing maternal, fetal and offspring glucocorticoid production, changes in maternal metabolism and increasing maternal oxidative stress. Effective interventions during human pregnancy are needed to prevent both maternal and offspring metabolic dysfunction due to maternal obesity. This review addresses the relationship between maternal obesity and its negative impact on offspring development and presents some maternal intervention studies that propose strategies to prevent adverse offspring metabolic outcomes.

Regulation of calcitriol biosynthesis and activity: focus on gestational vitamin D deficiency and adverse pregnancy outcomes.

Vitamin D has garnered a great deal of attention in recent years due to a global prevalence of vitamin D deficiency associated with an increased risk of a variety of human diseases. Specifically, hypovitaminosis D in pregnant women is highly common and has important implications for the mother and lifelong health of the child, since it has been linked to maternal and child infections, small-for-gestational age, preterm delivery, preeclampsia, gestational diabetes, as well as imprinting on the infant for life chronic diseases. Therefore, factors that regulate vitamin D metabolism are of main importance, especially during pregnancy. The hormonal form and most active metabolite of vitamin D is calcitriol. This hormone mediates its biological effects through a specific nuclear receptor, which is found in many tissues including the placenta. Calcitriol synthesis and degradation depend on the expression and activity of CYP27B1 and CYP24A1 cytochromes, respectively, for which regulation is tissue specific. Among the factors that modify these cytochromes expression and/or activity are calcitriol itself, parathyroid hormone, fibroblast growth factor 23, cytokines, calcium and phosphate. This review provides a current overview on the regulation of vitamin D metabolism, focusing on vitamin D deficiency during gestation and its impact on pregnancy outcomes.

Analysis of the endometrial transcriptome at the time of implantation in women receiving a single post-ovulatory dose of levonorgestrel or mifepristone

Abstract Background: Levonorgestrel (LNG) is a progesterone receptor agonist used in both regular and emergency hormonal contraception; however, its effects on the endometrium as a contraceptive remain widely unknown and under public debate. Objective: To analyze the effects of LNG or mifepristone (MFP), a progesterone receptor antagonist and also known as RU-486, administered at the time of follicle rupture (FR) on endometrial transcriptome during the receptive period of the menstrual cycle. Methods: Ten volunteers ovulatory women were studied during two menstrual cycles, a control cycle and a consecutively treated cycle; in this last case, women were randomly allocated to two groups of 5 women each, receiving one dose of LNG (1.5 mg) or MFP (50 mg) the day of the FR by ultrasound. Endometrial biopsies were taken 6 days after drug administration and prepared for microarray analysis. Results: Genomic functional analysis in the LNG-treated group showed as activated the bio-functions embryo implantation and decidualization, while these bio-functions in the T-MFP group were predicted as inhibited. Conclusions: The administration of LNG as a hormonal emergency contraceptive resulted in an endometrial gene expression profile associated with receptivity. These results agree on the concept that LNG does not affect endometrial receptivity and/or embryo implantation when used as an emergency contraceptive.

Sexualidad en el contexto de los procesos de vida de mujeres y varones con endocrinopatías: una aproximación cualitativa / Sexuality in the life processes context of women and men with endocrinopathies: A qualitative approach

Resumen Antecedentes las enfermedades del sistema endocrino pueden afectar la sexualidad por sus efectos hormonales, las comorbilidades asociadas y su impacto psicosocial, tema poco estudiado desde las perspectivas de personas con estas enfermedades. Objetivos: se realizó un estudio cualitativo dirigido a comprender las experiencias sexuales de mujeres y varones con enfermedades endocrinas que producen cambios en la apariencia física. Método: se estructuró un diseño de estudio analítico-interpretativo. Participaron 68 personas entre 20 y 45 años de edad, atendidos en el Instituto Nacional de Endocrinología, La Habana, Cuba. Los instrumentos de recolección de la información utilizados fueron una planilla de datos generales, una guía de entrevista en profundidad y dos pruebas psicológicas proyectivas. Los aspectos éticos fueron considerados. Resultados: de las entrevistas en profundidad, emergieron 4 temas: 1) la expresión multidimensional de la enfermedad, 2) enfermedad y áreas de vida, 3) ejercicio de la sexualidad con la enfermedad, y 4) estrategias de afrontamiento en el área sexual; vinculados con los significados expresados sobre la salud, el cuerpo, el género y la sexualidad. Conclusiones: las/los participantes contextualizaron sus experiencias sexuales en el impacto biopsicosocial de la enfermedad. La reproducción o cuestionamiento de los significados expresados influyó en la calidad de sus experiencias sexuales. El estudio mostró que esta constituye un área de vulnerabilidad para la salud integral de las/los participantes.

Abstract Background endocrine disorders may affect sexuality due to hormonal changes, associated comorbidities and psychosocial impact. This topic remains poorly researched from the perspective of people with these conditions. Objectives: a qualitative research was conducted to understand the sexual experiences of women and men living with endocrine disorders that change their physical appearance. Methods: an analytical-interpretive study was carried out with a sample of 68 participants aged between 20 and 45, and treated at the National Institute of Endocrinology, Havana, Cuba. Data collection instruments were a personal information sheet, an in-depth interview guide and two projective psychological tests. Ethical aspects were considered. Results: in-depth interviews gave rise to four topics: 1) multidimensional expression of the disease, 2) the disease and life areas, 3) sexuality with the disease, and 4) coping strategies in the sexual area. These topics were linked to the meanings of health, body, gender and sexuality. Conclusions: the participants contextualized their sexual experiences within the biopsychosocial impact of the endocrine disorder, as well as the reproduction or questioning of the meanings that influenced the quality of their sexual experiences. The study showed that sexuality is a vulnerable area for the participants' comprehensive health.

Fetal programming of sexual development and reproductive function.

The recent growth of interest in developmental programming of physiological systems has generally focused on the cardiovascular system (especially hypertension) and predisposition to metabolic dysfunction (mainly obesity and diabetes). However, it is now clear that the full range of altered offspring phenotypes includes impaired reproductive function. In rats, sheep and nonhuman primates, reproductive capacity is altered by challenges experienced during critical periods of development. This review will examine available experimental evidence across commonly studied experimental species for developmental programming of female and male reproductive function throughout an individual's life-course. It is necessary to consider events that occur during fetal development, early neonatal life and prior to and during puberty, during active reproductive life and aging as reproductive performance declines.

II. The research ethics involving vulnerable groups

Abstract Vulnerability in research occurs when the participant is incapable of protecting his or her interests and therefore, has an increased probability of being intentionally or unintentionally harmed. This manuscript aims to discuss the conditions that make a group vulnerable and the tools and requirements that can be used to reduce the ethical breaches when including them in research protocols. The vulnerability can be due either to an inability to understand and give informed consent or to unequal power relationships that hinder basic rights. Excluding subjects from research for the only reason of belonging to a vulnerable group is unethical and will bias the results of the investigation. To consider a subject or group as vulnerable depends on the context, and the investigator should evaluate each case individually.

I. The role of research ethics committees in observational studies: epidemiological registries, case reports, interviews, and retrospective studies

Abstract It is often unclear to the clinical investigator whether observational studies should be submitted to a research ethics committee (REC), mostly because, in general, no active or additional interventions are performed. Moreover, obtaining an informed consent under these circumstances may be challenging, either because these are very large epidemiological registries, or the subject may no longer be alive, is too ill to consent, or is impossible to contact after being discharged. Although observational studies do not involve interventions, they entail ethical concerns, including threats such as breaches in confidentiality and autonomy, and respect for basic rights of the research subjects according to the good clinical practices. In this context, in addition to their main function as evaluators from an ethical, methodological, and regulatory point of view, the RECs serve as mediators between the research subjects, looking after their basic rights, and the investigator or institution, safeguarding them from both legal and unethical perils that the investigation could engage, by ensuring that all procedures are performed following the international standards of care for research. The aim of this manuscript is to provide information on each type of study and its risks, along with actions to prevent such risks, and the function of RECs in each type of study.

Efficacy of estrogen plus progestin on menopausal symptoms in women with systemic lupus erythematosus: a randomized, double-blind, controlled trial.

OBJECTIVE: To define the effects of continuous sequential estrogen plus progestin therapy on menopausal symptoms in women with systemic lupus erythematosus (SLE). METHODS: We performed a randomized, double-blind, 24-month clinical trial involving 106 women with SLE who were in the menopausal transition or early or late postmenopause. Patients received continuous sequential estrogen plus progestin (n = 52) or placebo (n = 54). Menopausal symptoms were assessed using the Greene Climacteric Scale at 0, 1, 2, 3, 6, 9, 12, 15, 18, 21, and 24 months. A new factor analysis of the scale reduced 21 items to 5 factors. The primary outcome was improvement of menopausal symptoms throughout the followup period. Results were analyzed by the intent-to-treat principle. RESULTS: At baseline, demographic and disease characteristics were similar in both groups. Fifteen of 21 menopausal symptoms had a prevalence of ≥50%, with a similar distribution between groups. Vasomotor factor scores decreased over time in both groups (P = 0.002), but in the estrogen plus progestin group the reduction was more pronounced than in the placebo group (1.5-2.0 versus 0.35-0.8 points on a scale of 0-6; P = 0.03). Maximum effects were observed among the most symptomatic women. Psychological, subjective-somatic, and organic-somatic factors scores also improved along time (P < 0.001), but the treatment and placebo arms improved to a similar degree. Thromboses occurred in 3 patients receiving estrogen plus progestin and in 1 patient receiving placebo. CONCLUSION: Menopausal symptoms are highly prevalent in peri- and postmenopausal lupus patients. Estrogen plus progestin improved vasomotor symptoms at a clinically significant level, but not other menopausal symptoms. Given the thrombotic risks of menopausal hormone therapy, this should be used only in women with significant vasomotor symptoms.

Menopause hormonal therapy in women with systemic lupus erythematosus.

OBJECTIVE: To evaluate the effects of menopause hormonal therapy on disease activity in women with systemic lupus erythematosus (SLE). METHODS: We conducted a double-blind, randomized clinical trial involving 106 women with SLE who were in the menopausal transition or in early or late postmenopause. Patients received a continuous-sequential estrogen-progestogen regimen (n = 52) or placebo (n = 54). Disease activity was assessed at baseline and at 1, 2, 3, 6, 9, 12, 15, 18, 21, and 24 months, according to the SLE Disease Activity Index (SLEDAI). The primary outcome measure was global disease activity, estimated by measuring the area under the SLEDAI curve. Secondary outcome measures included maximum SLEDAI score, change in SLEDAI score, incidence of lupus flares, median time to flare, medication use, and adverse events. Results were studied using intent-to-treat analysis. RESULTS: At baseline, demographic and disease characteristics were similar in both groups. Mean +/- SD SLEDAI scores were 3.5 +/- 3.3 and 3.1 +/- 3.4 in the menopause hormonal therapy and placebo groups, respectively (P = 0.57). Disease activity remained mild and stable in both groups throughout the trial. There were no significant differences between the groups in global or maximum disease activity, incidence or probability of flares, or medication use. Median time to flare was 3 months in both groups. Thromboses occurred in 3 patients who received menopause hormonal therapy and in 1 patient who received placebo. One patient in each group died during the trial due to sepsis. CONCLUSION: Menopause hormonal therapy did not alter disease activity during 2 years of treatment. However, an apparently increased risk of thrombosis seems to be a real threat in women with SLE who receive menopausal hormone therapy.