RESUMO
BACKGROUND: Premenstrual syndrome (PMS) is a combination of physical, psychological and social symptoms in women of reproductive age, and premenstrual dysphoric disorder (PMDD) is a severe type of the syndrome, previously known as late luteal phase dysphoric disorder (LLPDD). Both syndromes cause symptoms during the two weeks leading up to menstruation (the luteal phase). Selective serotonin reuptake inhibitors (SSRIs) are increasingly used as a treatment for PMS and PMDD, either administered in the luteal phase or continuously. We undertook a systematic review to assess the evidence of the positive effects and the harms of SSRIs in the management of PMS and PMDD. OBJECTIVES: To evaluate the benefits and harms of SSRIs in treating women diagnosed with PMS and PMDD. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Specialised Register of Controlled Trials, CENTRAL, MEDLINE, Embase and PsycINFO for randomised controlled trials (RCTs) in November 2023. We checked reference lists of relevant studies, searched trial registers and contacted experts in the field for any additional trials. This is an update of a review last published in 2013. SELECTION CRITERIA: We considered studies in which women with a prospective diagnosis of PMS, PMDD or LLPDD were randomised to receive SSRIs or placebo. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We pooled data using a random-effects model. We calculated standardised mean differences (SMDs) with 95% confidence intervals (CIs) for premenstrual symptom scores, using 'post-treatment' scores for continuous data. We calculated odds ratios (ORs) with 95% CIs for dichotomous outcomes. We stratified analyses by type of administration (luteal phase or continuous). We calculated absolute risks and the number of women who would need to be taking SSRIs in order to cause one additional adverse event (i.e. the number needed to treat for an additional harmful outcome (NNTH)). We rated the overall certainty of the evidence for the main findings using GRADE. MAIN RESULTS: We included 34 RCTs in the review. The studies compared SSRIs (i.e. fluoxetine, paroxetine, sertraline, escitalopram and citalopram) to placebo. SSRIs probably reduce overall self-rated premenstrual symptoms in women with PMS and PMDD (SMD -0.57, 95% CI -0.72 to -0.42; I2 = 51%; 12 studies, 1742 participants; moderate-certainty evidence). SSRI treatment was probably more effective when administered continuously than when administered only in the luteal phase (P = 0.03 for subgroup difference; luteal phase group: SMD -0.39, 95% CI -0.58 to -0.21; 6 studies, 687 participants; moderate-certainty evidence; continuous group: SMD -0.69, 95% CI -0.88 to -0.51; 7 studies, 1055 participants; moderate-certainty evidence). The adverse effects associated with SSRIs were nausea (OR 3.30, 95% CI 2.58 to 4.21; I2 = 0%; 18 studies, 3664 women), insomnia (OR 1.99, 95% CI 1.51 to 2.63; I2 = 0%; 18 studies, 3722 women), sexual dysfunction or decreased libido (OR 2.32, 95% CI 1.57 to 3.42; I2 = 0%; 14 studies, 2781 women), fatigue or sedation (OR 1.52, 95% CI 1.05 to 2.20; I2 = 0%; 10 studies, 1230 women), dizziness or vertigo (OR 1.96, 95% CI 1.36 to 2.83; I2 = 0%; 13 studies, 2633 women), tremor (OR 5.38, 95% CI 2.20 to 13.16; I2 = 0%; 4 studies, 1352 women), somnolence and decreased concentration (OR 3.26, 95% CI 2.01 to 5.30; I2 = 0%; 8 studies, 2050 women), sweating (OR 2.17, 95% CI 1.36 to 3.47; I2 = 0%; 10 studies, 2304 women), dry mouth (OR 2.70, 95% CI 1.75 to 4.17; I2 = 0%; 11 studies, 1753 women), asthenia or decreased energy (OR 3.28, 95% CI 2.16 to 4.98; I2 = 0%; 7 studies, 1704 women), diarrhoea (OR 2.06, 95% CI 1.37 to 3.08; I2 = 0%; 12 studies, 2681 women), and constipation (OR 2.39, 95% CI 1.09 to 5.26; I2 = 0%; 7 studies, 1022 women). There was moderate-certainty evidence for all adverse effects other than somnolence/decreased concentration, which was low-certainty evidence. Overall, the certainty of the evidence was moderate. The main weakness was poor reporting of study methodology. Heterogeneity was low or absent for most outcomes, although there was moderate heterogeneity in the analysis of overall self-rated premenstrual symptoms. Based on the meta-analysis of response rate (the outcome with the most included studies), there was suspected publication bias. In total, 68% of the included studies were funded by pharmaceutical companies. This stresses the importance of interpreting the review findings with caution. AUTHORS' CONCLUSIONS: SSRIs probably reduce premenstrual symptoms in women with PMS and PMDD and are probably more effective when taken continuously compared to luteal phase administration. SSRI treatment probably increases the risk of adverse events, with the most common being nausea, asthenia and somnolence.
Assuntos
Transtorno Disfórico Pré-Menstrual , Síndrome Pré-Menstrual , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores Seletivos de Recaptação de Serotonina , Humanos , Feminino , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Síndrome Pré-Menstrual/tratamento farmacológico , Transtorno Disfórico Pré-Menstrual/tratamento farmacológico , Adulto , Viés , Fase Luteal/efeitos dos fármacos , Sertralina/uso terapêutico , Sertralina/efeitos adversosRESUMO
INTRODUCTION: This study compares rectal administration with vaginal administration of progesterone as luteal phase support in hormone replacement therapy frozen embryo transfer (HRT-FET) cycles. The reason for comparing the two routes of administration is that rectal administration has been suggested to be more patient friendly. METHODS AND ANALYSIS: This study is a randomised controlled trial comparing the ongoing pregnancy rate (OPR) at week 12 in HRT-FET cycles after rectal administered progesterone as the only administered progesterone compared with a vaginal luteal phase support regimen. All patients are enrolled from a Danish public fertility clinic and randomised to one of two groups, with 305 patients receiving embryo transfer assigned to each group. Endometrial preparation includes 6 mg oestradiol daily. The intervention group receives rectally administered progesterone (400 mg/12 hours) and the control group receives vaginally administered progesterone (400 mg/12 hours). If P4 is <35 nmol/L on blastocyst transfer day an additional rectal luteal phase rescue regimen is started (control group). Thawing and transferring of a single autologous vitrified blastocyst is scheduled on the sixth day of progesterone administration in both groups. The power calculation is based on a non-inferiority analysis with an expected OPR in both groups of 44% and the upper limit of a one-sided 95% CI will exclude a difference in favour of the control group of more than 10.0%. An interim analysis will be conducted once half of the study population has been enrolled. ETHICS AND DISSEMINATION: The trial was approved on 21 November 2023 by the Danish National Ethical Committee and the Danish Medicines Agency and is authorised by the Clinical Trials Information System (EUCT number 2023-504616-15-02). All patients will provide informed consent before being enrolled in the study. The results will be published in an international journal. TRIAL REGISTRATION NUMBER: EUCT number: 2023-504616-15-02.
Assuntos
Administração Retal , Criopreservação , Transferência Embrionária , Terapia de Reposição Hormonal , Fase Luteal , Taxa de Gravidez , Progesterona , Adulto , Feminino , Humanos , Gravidez , Administração Intravaginal , Criopreservação/métodos , Dinamarca , Transferência Embrionária/métodos , Estudos de Equivalência como Asunto , Terapia de Reposição Hormonal/métodos , Fase Luteal/efeitos dos fármacos , Progesterona/administração & dosagem , Progestinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Background: The serum P concentrations are suggested to have an impact on pregnancy outcome. However there is no consensus about the optimal progesterone cut-off during the luteal phase. Few studies evaluated the effectiveness of a "rescue protocol" for low serum P concentrations and most of these studies used vaginal progesterone administration. There is paucity of data on the effectiveness of rescue protocol using intramuscular progesterone (IM-P) in frozen-thawed embryo transfer (FET). Methods: This study is a retrospective cohort study included 637 single or double blastocyst FETs with artificially prepared endometrium receiving 100 mg IM progesterone (P) after incremental estrogen treatment. Serum P concentrations were evaluated using blood samples obtained 117-119 hours after the first IM-P administration and 21 ± 2 hours after the last IM-P administration. Patients with serum P concentrations <20.6 ng/ml on the ET day were administrated 400 mg vaginal progesterone for rescue. Results: Demographic and cycle characteristics were similar between patients receiving rescue vaginal P (embryo transfer (ET)-day P concentration < 20.6 ng/ml) and patients who did not need rescue vaginal P (ET-day P concentration ≥ 20.6 ng/ml). Clinical pregnancy, miscarriage, and live birth rates were similar between two groups: 52.9%(45/85) vs 59.6%(326/552), p=0.287; 11.1%(5/45) vs 14.1%(46/326), p=0.583; and 47.1%(40/85) vs 50.7%(280/552), p=0.526, respectively. Logistic regression analysis revealed that the female age (p = 0.008, OR=0.942, 95% CI = 0.902-0.984) and embryo quality (ref: good quality for moderate: p=0.02, OR=0.469, 95% CI =0.269-0.760; for poor: p=0.013, OR= 0.269, 95% CI = 0.092-0.757) were independent variables for live birth. Following rescue protocol implementation, ET-day P concentration was not a significant predictor of live birth. Conclusions: Rescue vaginal P administration for low ET day serum P concentrations following IM-P yields comparable live birth rates.
Assuntos
Coeficiente de Natalidade , Criopreservação , Transferência Embrionária , Nascido Vivo , Fase Luteal , Progesterona , Humanos , Feminino , Transferência Embrionária/métodos , Progesterona/administração & dosagem , Progesterona/sangue , Estudos Retrospectivos , Gravidez , Adulto , Fase Luteal/efeitos dos fármacos , Injeções Intramusculares , Nascido Vivo/epidemiologia , Criopreservação/métodos , Taxa de Gravidez , Fertilização in vitro/métodos , Administração Intravaginal , Resultado da GravidezRESUMO
Despite the proven superiority of various luteal phase support protocols (LPS) over placebo in view of improved pregnancy rates in fresh cycles of IVF (in vitro fertilization) and ICSI (intracytoplasmic sperm injection) cycles, there is ongoing controversy over specific LPS protocol selection, dosage, and duration. The aim of the present study was to identify the optimal LPS under six core aspects of ART success, clinical pregnancy, live birth as primary outcomes and biochemical pregnancy, miscarriage, multiple pregnancy, ovarian hyperstimulation syndrome (OHSS) events as secondary outcomes. Twelve databases, namely Embase (OVID), MEDLINE (R) (OVID), GlobalHealth (Archive), GlobalHealth, Health and Psychosocial Instruments, Maternity & Infant Care Database (MIDIRS), APA PsycTests, ClinicalTrials.gov, HMIC Health Management Information Consortium, CENTRAL, Web of Science, Scopus and two prospective registers, MedRxiv, Research Square were searched from inception to Aug.1st, 2023, (PROSPERO Registration: CRD42022358986). Only Randomised Controlled Trials (RCTs) were included. Bayesian network meta-analysis (NMA) model was employed for outcome analysis, presenting fixed effects, odds ratios (ORs) with 95% credibility intervals (CrIs). Vaginal Progesterone (VP) was considered the reference LPS given its' clinical relevance. Seventy-six RCTs, comparing 22 interventions, and including 26,536 participants were included in the present NMA. Overall CiNeMa risk of bias was deemed moderate, and network inconsistency per outcome was deemed low (Multiple pregnancy χ2: 0.11, OHSS χ2: 0.26), moderate (Clinical Pregnancy: χ2: 7.02, Live birth χ2: 10.95, Biochemical pregnancy: χ2: 6.60, Miscarriage: χ2: 11.305). Combinatorial regimens, with subcutaneous GnRH-a (SCGnRH-a) on a vaginal progesterone base and oral oestrogen (OE) appeared to overall improve clinical pregnancy events; VP + OE + SCGnRH-a [OR 1.57 (95% CrI 1.11 to 2.22)], VP + SCGnRH-a [OR 1.28 (95% CrI 1.05 to 1.55)] as well as live pregnancy events, VP + OE + SCGnRH-a [OR 8.81 (95% CrI 2.35 to 39.1)], VP + SCGnRH-a [OR 1.76 (95% CrI 1.45 to 2.15)]. Equally, the progesterone free LPS, intramuscular human chorionic gonadotrophin, [OR 9.67 (95% CrI 2.34, 73.2)] was also found to increase live birth events, however was also associated with an increased probability of ovarian hyperstimulation, [OR 1.64 (95% CrI 0.75, 3.71)]. The combination of intramuscular and vaginal progesterone was associated with higher multiple pregnancy events, [OR 7.09 (95% CrI 2.49, 31.)]. Of all LPS protocols, VP + SC GnRH-a was found to significantly reduce miscarriage events, OR 0.54 (95% CrI 0.37 to 0.80). Subgroup analysis according to ovarian stimulation (OS) protocol revealed that the optimal LPS across both long and short OS, taking into account increase in live birth and reduction in miscarriage as well as OHSS events, was VP + SCGnRH-a, with an OR 2.89 [95% CrI 1.08, 2.96] and OR 2.84 [95% CrI 1.35, 6.26] respectively. Overall, NMA data suggest that combinatorial treatments, with the addition of SCGnRH-a on a VP base result in improved clinical pregnancy and live birth events in both GnRH-agonist and antagonist ovarian stimulation protocols.
Assuntos
Fertilização in vitro , Fase Luteal , Metanálise em Rede , Taxa de Gravidez , Injeções de Esperma Intracitoplásmicas , Humanos , Feminino , Injeções de Esperma Intracitoplásmicas/métodos , Gravidez , Fertilização in vitro/métodos , Fase Luteal/efeitos dos fármacos , Progesterona/administração & dosagem , Nascido Vivo , Teorema de Bayes , Indução da Ovulação/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Síndrome de Hiperestimulação Ovariana , Aborto EspontâneoRESUMO
BACKGROUND: The gonadotropin hormone-releasing hormone agonists (GnRH-a) have been widely used for controlled ovarian stimulation in assisted reproductive technology (ART). The early-follicular long-acting GnRH-a long protocol (EFL) and the luteal phase short-acting GnRH-a long protocol (LPS) are commonly used GnRH agonist protocols. We conducted a retrospective analysis to assess and compare the rates of congenital abnormalities and safety profiles in offspring born from the EFL and LPS protocols. METHODS: We conducted a retrospective cohort study to analyze and compare neonatal data from patients who using EFL or LPS protocols at our center between January 1, 2014, and June 30, 2017. The study ultimately included 1810 neonates from 1401 cycles using the EFL protocol and 2700 neonates from 2129 cycles using the LPS protocol.The main outcome measures are gestational age at delivery, birth weight, and congenital anomaly rate.To assess the influence of various factors on congenital abnormalities, a random-effects logistic regression model was employed. RESULTS: The EFL and LPS protocols led to similar congenital anomaly rates (1.64% vs. 2.35%, P = 0.149). No significant differences were found between the two groups regarding birth weight and its categories, newborn gender and congenital anomaly rate. The results of the multivariate logistic regression model indicated no association between congenital anomaly and BMI, duration of infertility, treatment protocol, fertilization method, or embryo transfer stage. Compared with singleton pregnancies, the probability of congenital defects in multiple pregnancies was 2.64 times higher (OR: 2.64, 95% CI: 1.72-4.05, P < 0.0001). Newborns with congenital defects were born with a lower gestational age compared with full-term pregnancies. CONCLUSION: In conclusion, the EFL protocol is considered a safe option for ensuring offspring safety, comparable with the LPS protocol; however, multiple pregnancies represent an independent risk factor for congenital abnormalities. This approach can be widely adopted; however, prioritizing single embryo transfers is strongly recommended to minimize the potential risks associated with multiple pregnancies in offspring.
Assuntos
Hormônio Liberador de Gonadotropina , Indução da Ovulação , Humanos , Estudos Retrospectivos , Feminino , Gravidez , Hormônio Liberador de Gonadotropina/agonistas , Indução da Ovulação/métodos , Recém-Nascido , Adulto , Anormalidades Congênitas/epidemiologia , Fase Luteal/efeitos dos fármacos , Peso ao Nascer , Idade Gestacional , MasculinoRESUMO
This study investigated the effect of hCG or GnRH on structural changes of the corpora lutea (CL) and the regulation of the expression of steroidogenic enzymes involved in P4 secretion in post-ovulatory (po-CL) and accessory CL (acc-CL). Sixty-four ewes were assigned to three groups receiving: 300 IU of hCG (hCG) or 4⯵g Buserelin (GnRH) or 1â¯mL of saline solution (Control) on Day (d) 4 post artificial insemination (FTAI). Laparoscopic ovarian were performed on d 4, 14 and, 21 post-FTAI to determine the numbers of CL. Blood samples were collected for serum LH and P4 analysis. On d 14 post-FTAI, both CL were removed from the ovary to determine large luteal cell (LLC) number and to evaluate the expression of steroidogenic enzymes (HSD3B1, STAR, CYP11A1). Only hCG and GnRH treated ewes generated acc-CL. The LLC in both po- and acc-CL were significantly greater in the hCG group compared to GnRH and Control groups (P<0.05). Overall, hCG group showed the greatest immunodetection of HSD3B1and STAR in both po- and acc-CL (P<0.05). rnRNA expression of HSD3B1, STAR and CYP11A1 in the acc-CL tended to be greater in hCG group than in GnRH group (P<0.1). The LH concentration was increased in GnRH group (P<0.05) and P4 concentration was greater in hCG group compared to the other groups (P<0.05). In conclusion, administration of hCG has a notably impact on acc-CL development and the expression of steroidogenic enzymes compared to GnRH treatment in ewes. This leads to elevated P4 concentration and improved luteal function.
Assuntos
Gonadotropina Coriônica , Corpo Lúteo , Hormônio Liberador de Gonadotropina , Fase Luteal , Progesterona , Animais , Feminino , Ovinos/fisiologia , Corpo Lúteo/efeitos dos fármacos , Corpo Lúteo/metabolismo , Progesterona/sangue , Progesterona/metabolismo , Gonadotropina Coriônica/farmacologia , Gonadotropina Coriônica/administração & dosagem , Hormônio Liberador de Gonadotropina/farmacologia , Hormônio Liberador de Gonadotropina/metabolismo , Fase Luteal/efeitos dos fármacos , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Hormônio Luteinizante/metabolismo , FosfoproteínasRESUMO
This study aimed to explore how natural menstrual cycle phases and dosage of oral hormonal contraceptives (OC) influence the diurnal rhythm of distal skin temperature (DST) under real-life conditions. Participants were 41 healthy females (23.9 ± 2.48 y), comprising 27 females taking monophasic hormonal oral contraceptives (OC users) and 14 females with menstrual cycles (non-OC users). Wrist DST was continuously recorded and averaged over two consecutive 24-hour days during (pseudo)follicular and (pseudo)luteal menstrual phases. Diurnal rhythm characteristics, i.e. acrophase and amplitude, describing timing and strength of the DST rhythm, respectively, were calculated using cosinor analysis. Results show that non-OC users experienced earlier diurnal DST maximum (acrophase, p = 0.019) and larger amplitude (p = 0.016) during the luteal phase than during the follicular phase. This was observed in most (71.4%) but not all individuals. The OC users showed no differences in acrophase or amplitude between pseudoluteal and pseudofollicular phases. OC users taking a higher dosage of progestin displayed a larger amplitude for DST rhythm during the pseudoluteal phase (p = 0.009), while estrogen dosage had no effect. In conclusion, monophasic OC cause changes in diurnal DST rhythm, similar to those observed in the luteal phase of females with menstrual cycles, suggesting that synthetic progestins act in a similar manner on skin thermoregulation as progesterone does.
Assuntos
Ritmo Circadiano , Ciclo Menstrual , Temperatura Cutânea , Humanos , Feminino , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/fisiologia , Adulto , Temperatura Cutânea/efeitos dos fármacos , Adulto Jovem , Ciclo Menstrual/efeitos dos fármacos , Anticoncepcionais Orais Hormonais/farmacologia , Anticoncepcionais Orais Hormonais/administração & dosagem , Fase Luteal/efeitos dos fármacos , Fase Luteal/fisiologia , Regulação da Temperatura Corporal/efeitos dos fármacosRESUMO
OBJECTIVE: To study whether midluteal serum estradiol (E2) levels are associated with the live birth rate in hormone replacement therapy frozen embryo transfer (HRT-FET) cycles in patients with optimal midluteal serum progesterone (P4) levels. DESIGN: Observational prospective cohort study. SETTING: Public fertility clinic. PATIENTS: A total of 412 women had an HRT-FET cycle single blastocyst transfer from January 2020 to November 2022. INTERVENTION: The HRT-FET cycle priming regimen included oral E2 (6mg/24 h) administered in the evening, followed by vaginal P4 (400mg/12 h). Serum E2 and P4 levels were measured using a standardized method, 2-4 hours after the latest P4 administration and 9-14 hours after E4 administration on the day of blastocyst transfer, day 6 of P4 administration. Patients with serum P4 levels (<11 ng/mL [35 nmol/L]) on the day of transfer received additional rectal P4 (400mg/12 h). No additional E2 dose was administered. MAIN OUTCOME MEASURES: The primary outcome was the live birth rate (LBR) in relation to E2 levels at blastocyst transfer day. RESULTS: The optimal serum E2 levels correlating with ongoing pregnancy were ≥292 pg/mL and <409 pg/mL (≥1,070 pmol/L and <1,500 pmol/L). The LBR was 59% (60/102) when E2 levels were within this range, whereas a significantly lower LBR of 39% (101/260) was seen in patients when E2 levels were <292 pg/mL (<1,070 pmol/L) and of 28% (14/50) when E2 levels were ≥409 pg/mL (≥1,500 pg/mL). In a logistic regression analysis, adjusting for serum P4 level ≥11 ng/mL or <11 ng/mL (≥35 nmol or <35 nmol/L) on the day of transfer, body mass index, age at oocyte retrieval, day 5 or 6 vitrified blastocysts, and blastocyst score, the adjusted risk difference of live birth was -0.21 (-0.32; -0.10) when the E2 level was <292 pg/mL (<1,070 pmol/L) and -0.31 (-0.45; -0.18) when the E2 level was ≥409 pg/mL (≥1,500 pmol/L) compared with E2 levels ≥292 pg/mL and <409 pg/mL (≥1,070 and <1,500 pmol/L). Importantly, only 25% of patents had optimal levels. CONCLUSION: The study shows a significant association between serum E2 levels and reproductive outcomes in an HRT-FET cohort in which optimal serum P4 levels were secured. Midluteal serum E2 levels are associated with the LBR in HRT-FET cycles, and E2 levels should neither be too high nor too low. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT No.: 2019-001539-29.
Assuntos
Criopreservação , Transferência Embrionária , Estradiol , Terapia de Reposição Hormonal , Nascido Vivo , Humanos , Feminino , Estradiol/sangue , Adulto , Gravidez , Nascido Vivo/epidemiologia , Transferência Embrionária/métodos , Estudos Prospectivos , Terapia de Reposição Hormonal/métodos , Progesterona/sangue , Taxa de Gravidez , Coeficiente de Natalidade , Estudos de Coortes , Fase Luteal/efeitos dos fármacos , Fase Luteal/sangueRESUMO
RESEARCH QUESTION: Does splitting the human chorionic gonadotrophin (HCG) support in IVF cycles triggered by a gonadotrophin-releasing hormone agonist result in a better progesterone profile? DESIGN: Randomized controlled three-arm study, performed at the Fertility Clinic, Odense University Hospital, Denmark. Patients with 12-25 follicles ≥12 mm were randomized into three groups: Group 1 - ovulation triggered with 6500 IU HCG; Group 2 - ovulation triggered with 0.5 mg GnRH agonist, followed by 1500 IU HCG on the day of oocyte retrieval (OCR); and Group 3 - ovulation triggered with 0.5 mg GnRH agonist, followed by 1000 IU HCG on the day of OCR and 500 IU HCG on OCRâ¯+â¯5. All groups received 180 mg vaginal progesterone. Progesterone concentrations were analysed in eight blood samples from each patient. RESULTS: Sixty-nine patients completed the study. Baseline and laboratory data were comparable. Progesterone concentration peaked on OCRâ¯+â¯4 in Groups 1 and 2, and peaked on OCRâ¯+â¯6 in Group 3. On OCRâ¯+â¯6, the progesterone concentration in Group 2 was significantly lower compared with Groups 1 and 3 (Pâ¯=â¯0.003 and P < 0.001, respectively). On OCRâ¯+â¯8, the progesterone concentration in Group 3 was significantly higher compared with the other groups (both P<0.001). Progesterone concentrations were significantly higher in Group 3 from OCRâ¯+â¯6 until OCRâ¯+â¯14 compared with the other groups (all P ≤ 0.003). Four patients developed ovarian hyperstimulation syndrome in Group 3. CONCLUSION: Sequential HCG support after a GnRH agonist trigger provides a better progesterone concentration in the luteal phase.
Assuntos
Gonadotropina Coriônica , Transferência Embrionária , Fertilização in vitro , Hormônio Liberador de Gonadotropina , Indução da Ovulação , Progesterona , Humanos , Feminino , Gonadotropina Coriônica/administração & dosagem , Hormônio Liberador de Gonadotropina/agonistas , Adulto , Transferência Embrionária/métodos , Progesterona/sangue , Gravidez , Indução da Ovulação/métodos , Fertilização in vitro/métodos , Taxa de Gravidez , Recuperação de Oócitos , Fase Luteal/efeitos dos fármacosRESUMO
RESEARCH QUESTION: Is there a difference between the proportion of patients with serum progesterone <8.8 ng/ml on the day of embryo transfer when micronized vaginal progesterone (MVP) for luteal phase support (LPS) is given as pessaries versus capsules? DESIGN: This retrospective, matched-cohort, single-centre study compared pessaries (Cyclogest) versus capsules (Utrogestan, Progeffik) for LPS in hormone replacement treatment-embryo transfer (HRT-ET) cycles. Patients under 50 years old with a triple-layer endometrial thickness of ≥6.5 mm underwent transfer of one or two blastocysts. Serum progesterone concentrations were measured on the day of transfer; patients with concentrations <8.8 ng/ml received a single 'rescue' dose of additional progesterone by subcutaneous injection. RESULTS: In total 2665 HRT-ET cycles were analysed; 663 (24.9%) used pessaries for LPS and 2002 (75.1%) used capsules. Mean serum progesterone concentrations with standard deviations on the day of embryo transfer were significantly higher in the group using MVP pessaries compared with those using capsules (14.5 ± 5.1 versus 13.0 ± 4.8 ng/ml; P = 0.000). The percentage of participants with suboptimal serum progesterone concentrations on the day of embryo transfer (<8.8 ng/ml) was significantly lower in the pessary group than the capsule group (10.3%, 95% confidence interval [CI] 7.9-12.6% versus 17.9%, 95% CI 16.2-19.6%; adjusted odds ratio 0.426, 95% CI 0.290-0.625; P = 0.000). No differences in pregnancy outcome were observed between the groups. CONCLUSIONS: Using MVP pessaries rather than capsules for LPS resulted in significantly fewer patients having suboptimal serum progesterone concentrations on the day of embryo transfer. Consequently, almost 50% fewer patients in the pessary group needed rescue treatment.
Assuntos
Transferência Embrionária , Fase Luteal , Progesterona , Humanos , Feminino , Progesterona/sangue , Progesterona/administração & dosagem , Estudos Retrospectivos , Fase Luteal/efeitos dos fármacos , Adulto , Gravidez , Administração Intravaginal , Transferência Embrionária/métodos , Pessários , Taxa de Gravidez , CápsulasRESUMO
PURPOSE: To evaluate the role of serum progesterone (P4) on the day of embryo transfer (ET) when dydrogesterone (DYD) and micronized vaginal progesterone (MVP) are combined as luteal phase support (LPS) in a hormone replacement therapy (HRT) frozen ET (FET) cycles. METHODS: Retrospective study, including single euploid HRT FET cycles with DYD and MVP as LPS and P4 measurement on ET day. Initially, patients with P4 levels < 10 ng/ml increased MVP to 400 mg/day; this "rescue" was abandoned later. RESULTS: 560 cycles of 507 couples were included. In 275 women, serum P4 level was < 10 ng/ml on the ET day. Among those with low P4 levels, MVP dose remained unchanged in 65 women (11.6%) and was increased in 210 women (37.5%). Women with P4 levels ≥ 10 ng/ml continued LPS without modification. Overall pregnancy rates in these groups were 61.5% (40/65), 54.8% (115/210), and 48.4% (138/285), respectively (p = n.s.). Association of serum P4 levels with ongoing pregnancy rates was analyzed in women without any additional MVP regardless of serum P4 levels (n = 350); multivariable analysis (adjusted for age, BMI, embryo quality (EQ)) did not show a significant association of serum P4 levels with OPR (OR 0.96, 95% CI 0.90-1.02; p = 0.185). Using inverse probability treatment weights, regression analysis in the weighted sample showed no significant association between P4 treatment groups and OP. Compared to fair EQ, the transfer of good EQ increased (OR 1.61, 95% CI 1.22-2.15; p = 0.001) and the transfer of a poor EQ decreased the odds of OP (OR 0.73, 95% CI 0.55-0.97; p = 0.029). CONCLUSION: In HRT FET cycle, using LPS with 300 mg/day MVP and 30 mg/day DYD, it appears that serum P4 measurement and increase of MVP in patients with P4 < 10 ng/ml are not necessary.
Assuntos
Didrogesterona , Transferência Embrionária , Terapia de Reposição Hormonal , Taxa de Gravidez , Progesterona , Humanos , Feminino , Didrogesterona/administração & dosagem , Progesterona/sangue , Transferência Embrionária/métodos , Adulto , Gravidez , Terapia de Reposição Hormonal/métodos , Estudos Retrospectivos , Administração Intravaginal , Fertilização in vitro/métodos , Fase Luteal/efeitos dos fármacosRESUMO
OBJECTIVE: To analyze the impact on live birth rates (LBRs) of the individualized luteal phase support (termed iLPS) in patients with low serum progesterone (P) levels compared with patients without iLPS. DESIGN: Retrospective cohort study, December 1, 2018, to May 30, 2019. SETTING: Private medical center. PATIENT(S): A total of 2,275 patients checked for serum P on the day of blastocyst transfer were analyzed. During the study period, 1,299 patients showed serum P levels of ≥9.2 ng/mL, whereas 550 showed serum P levels of <9.2 ng/mL and received iLPS. Additionally, a historical group of 426 patients with serum P levels of <9.2 ng/mL but no iLPS were used for comparison. Eligible patients were aged ≤50 years with adequate endometrium morphology after receiving estrogens. Luteal phase support was provided with micronized vaginal P (MVP) to all women. Patients with personalized initiation of exogenous P according to the endometrial receptivity assay test, polyps, fibroids distorting the cavity, or hydrosalpinx were not included in the analysis. INTERVENTION(S): As routine practice since December 2018, patients with low serum P levels received an iLPS with a daily injection of 25 mg of subcutaneous P from the day of embryo transfer (ET) in addition to standard LPS (400 mg of MVP twice a day). MAIN OUTCOME MEASURE(S): Live birth rate. RESULT(S): The LBR was 44.9% in the iLPS cases vs. 45.0% in patients with normal serum P levels (crude odds ratio [OR], 1.0; 95% confidence interval [CI], 0.82-1.22). By regression analysis, low serum P levels did not affect the LBR after adjusting for possible confounders (age, oocyte origin, fresh vs. frozen, day of ET, embryo quality, number of embryos transferred) (adjusted OR, 0.99; 95% CI, 0.79-1.25). Similarly, no differences were observed in other pregnancy outcomes between groups. The LBR was significantly higher in the group of patients who received additional subcutaneous P (iLPS) compared with the historical group with low serum P levels and no iLPS (44.9% vs. 37.3%; OR, 1.37; 95% CI, 1.06-1.78). In the overall population, patients showing P levels of <9.2 ng/mL on the day of ET were slightly younger and had higher body mass index and lower estradiol and P levels during the proliferative phase compared with patients with P levels of ≥9.2 ng/mL. No differences were observed with regard to the time in between the last dose of MVP and the serum P determination. After a multivariable logistic regression analysis, only body mass index and estradiol levels in the proliferative phase reminded statistically significant. Significant differences in the LBR were observed between patients with serum P levels of <9.2 ng/mL without iLPS and patients with serum P levels of ≥9.2 ng/mL when using either own or donated oocytes. CONCLUSION(S): Individualized LPS for patients with low serum P levels produces LBRs similar to those of patients with adequate serum P levels.
Assuntos
Transferência Embrionária/métodos , Fármacos para a Fertilidade Feminina/uso terapêutico , Nascido Vivo/epidemiologia , Fase Luteal/efeitos dos fármacos , Progesterona/sangue , Adulto , Coeficiente de Natalidade , Estudos de Coortes , Endométrio/fisiologia , Feminino , Humanos , Pessoa de Meia-Idade , Indução da Ovulação/métodos , Medicina de Precisão , Gravidez , Taxa de Gravidez , Estudos RetrospectivosRESUMO
BACKGROUND: To investigate whether the endometrial thickness change ratio from the progesterone administration day to the blastocyst transfer day is associated with pregnancy outcomes in a single frozen-thawed euploid blastocyst transfer cycle. METHODS: All patients used natural cycles with luteal support for endometrial preparation and selected a single euploid blastocyst for transfer after a biopsy for preimplantation genetic testing. The endometrial thickness was measured by transvaginal ultrasound on the progesterone administration day and the transfer day, the change in endometrial thickness was measured, and the endometrial thickness change ratio was calculated. According to the change rate of endometrial thickness, the patients were divided into three groups: the endometrial thickness compaction group, endometrial thickness non-change group and endometrial thickness expansion group. Among them, the endometrial thickness non-change and expansion groups were combined into the endometrial thickness noncompaction group. RESULTS: Ultrasound images of the endometrium in 219 frozen-thawed euploid blastocyst transfer cycles were evaluated. The clinical pregnancy rate increased with the increase in endometrial thickness change ratio, while the miscarriage rate and live birth rate were comparable among the groups. The multiple logistic regression results showed that in the fully adjusted model a higher endometrial thickness change ratio (per 10%) was associated with a higher clinical pregnancy rate (adjusted odds ratio [aOR] 1.29; 95% confidence interval [CI], 1.01-1.64; P = .040). Similarly, when the patients were divided into three groups according to the change rate of endometrial thickness, the endometrial thickness noncompaction group had a significant positive effect on the clinical pregnancy rate compared with the endometrial thickness compaction group after adjusting for all covariates. CONCLUSIONS: In frozen-thawed euploid blastocyst transfer cycles in which the endometrium was prepared by natural cycles with luteal support, the clinical pregnancy rate was higher in cycles without endometrial compaction after progesterone administration.
Assuntos
Transferência Embrionária/métodos , Endométrio/patologia , Taxa de Gravidez , Progesterona/uso terapêutico , Técnicas de Reprodução Assistida , Adulto , Blastocisto , China/epidemiologia , Estudos de Coortes , Criopreservação , Implantação do Embrião/efeitos dos fármacos , Endométrio/efeitos dos fármacos , Feminino , Fertilização in vitro/métodos , Fertilização in vitro/estatística & dados numéricos , Terapia de Reposição Hormonal , Humanos , Fase Luteal/efeitos dos fármacos , Fase Luteal/metabolismo , Tamanho do Órgão/fisiologia , Gravidez , Resultado da Gravidez/epidemiologia , Progesterona/administração & dosagem , Técnicas de Reprodução Assistida/estatística & dados numéricos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Progestogens are frequently administered during early pregnancy to patients undergoing assisted reproductive techniques (ART) to overcome progesterone deficits following ART procedures. Orally administered dydrogesterone (DG) shows equal efficacy to other progestogens with a higher level of patient compliance. However, potential harmful effects of DG on critical pregnancy processes and on the health of the progeny are not yet completely ruled out. We treated pregnant mice with DG in the mode, duration, and doses comparable to ART patients. Subsequently, we studied DG effects on embryo implantation, placental and fetal growth, fetal-maternal circulation, fetal survival, and the uterine immune status. After birth of in utero DG-exposed progeny, we assessed their sex ratios, weight gain, and reproductive performance. Early-pregnancy DG administration did not interfere with placental and fetal development, fetal-maternal circulation, or fetal survival, and provoked only minor changes in the uterine immune compartment. DG-exposed offspring grew normally, were fertile, and showed no reproductive abnormalities with the exception of an altered spermiogram in male progeny. Notably, DG shifted the sex ratio in favor of female progeny. Even though our data may be reassuring for the use of DG in ART patients, the detrimental effects on spermatogenesis in mice warrants further investigations and may be a reason for caution for routine DG supplementation in early pregnancy.
Assuntos
Didrogesterona/administração & dosagem , Fase Luteal/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Animais , Suplementos Nutricionais , Implantação do Embrião/efeitos dos fármacos , Feminino , Fertilização in vitro/métodos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Parto/efeitos dos fármacos , Placenta/efeitos dos fármacos , Gravidez , Taxa de Gravidez , Progesterona/administração & dosagem , Progestinas/administração & dosagem , Técnicas de Reprodução AssistidaRESUMO
Objective: To investigate the factors that influence luteal phase short-acting gonadotropin-releasing hormone agonist (GnRH-a) long protocol and GnRH-antagonist (GnRH-ant) protocol on pregnancy outcome and quantify the influence. About the statistical analysis, it is not correct for the number of gravidities. Methods: Infertile patients (n = 4,631) with fresh in-vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) and embryo transfer were divided into GnRH-a long protocol (n =3,104) and GnRH-ant (n =1,527) protocol groups and subgroups G1 (EMT ≤7mm), G2 (7 mm
Assuntos
Endométrio/patologia , Fármacos para a Fertilidade Feminina/uso terapêutico , Infertilidade/tratamento farmacológico , Fase Luteal/efeitos dos fármacos , Adulto , Coeficiente de Natalidade , China/epidemiologia , Endométrio/efeitos dos fármacos , Feminino , Fármacos para a Fertilidade Feminina/farmacologia , Fertilização in vitro/métodos , Hormônio Liberador de Gonadotropina/agonistas , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Antagonistas de Hormônios/uso terapêutico , Humanos , Recém-Nascido , Infertilidade/epidemiologia , Infertilidade/patologia , Infertilidade/fisiopatologia , Fase Luteal/fisiologia , Tamanho do Órgão/fisiologia , Indução da Ovulação/métodos , Gravidez , Resultado da Gravidez/epidemiologia , Taxa de Gravidez , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Low serum progesterone on the day of frozen embryo transfer (FET) is associated with diminished pregnancy rates in artificial endometrium preparation cycles, but there is no consensus on whether strengthened luteal phase support (LPS) benefits patients with low progesterone on the FET day in artificial cycles. This single-centre, large-sample retrospective trial was designed to investigate the contribution of strengthened LPS to pregnancy outcomes for groups with low progesterone levels on the FET day in artificial endometrium preparation cycles. METHODS: Women who had undergone the first artificial endometrium preparation cycle after a freeze-all protocol in our clinic from 2016 to 2018 were classified into two groups depending on their serum progesterone levels on the FET day. Routine LPS was administered to group B (P ≥ 10.0 ng/ml on the FET day, n = 1261), and strengthened LPS (routine LPS+ im P 40 mg daily) was administered to group A (P < 10.0 ng/ml on the FET day, n = 1295). The primary endpoint was the live birth rate, and the secondary endpoints were clinical pregnancy, miscarriage and neonatal outcomes. RESULTS: The results showed that the clinical pregnancy rate was significantly lower in group A than in group B (48.4% vs 53.2%, adjusted risk ratio (aRR) 0.81, 95% confidence interval (CI) 0.68, 0.96), whereas miscarriage rates were similar between the two groups (16.0% vs 14.7%, aRR 1.09, 95% CI 0.77, 1.54). The live birth rate was slightly lower in group A than in group B (39.5% vs 43.3%, aRR 0.84, 95% CI 0.70, 1.0). Birthweights and other neonatal outcomes were similar between the two groups (P > 0.05). CONCLUSIONS: The results indicated that the serum progesterone level on the FET day was one of the risk factors predicting the chances of pregnancy in artificial endometrium preparation cycles, and strengthened LPS in patients with low progesterone on the FET day might help to provide a reasonable pregnancy outcome in artificial cycles, although further prospective evidence is needed to confirm this possibility.
Assuntos
Fármacos para a Fertilidade Feminina/uso terapêutico , Fase Luteal/efeitos dos fármacos , Ciclo Menstrual/efeitos dos fármacos , Indução da Ovulação/métodos , Progesterona/sangue , Adulto , China , Criopreservação , Transferência Embrionária/métodos , Embrião de Mamíferos , Feminino , Congelamento , Humanos , Recém-Nascido , Infertilidade/sangue , Infertilidade/terapia , Masculino , Gravidez , Taxa de Gravidez , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Background: Luteal-phase ovarian stimulation (LPOS) is an alternative in vitro fertilization (IVF) protocol. However, limited data showed the genes expression of cumulus cells (CCs) in LPOS. Therefore, this study aimed to investigate CC genes expression between LPOS and follicular-phase ovarian stimulation (FPOS) in poor ovarian responders (PORs) undergoing IVF cycles. Methods: This was a prospective non-randomized trial (ClinicalTrials.gov Identifier: NCT03238833). A total of 36 PORs who met the Bologna criteria and underwent IVF cycles were enrolled. Fifteen PORs were allocated to the LPOS group, and 21 PORs were allocated to the FPOS group. The levels of CC genes involved in inflammation (CXCL1, CXCL3, TNF, PTGES), oxidative phosphorylation (NDUFB7, NDUFA4L2, SLC25A27), apoptosis (DAPK3, BCL6B) and metabolism (PCK1, LDHC) were analyzed using real-time quantitative PCR and compared between the two groups. Results: The number of retrieved oocytes, metaphase II oocytes, fertilized oocytes, day-3 embryos and top-quality day-3 embryos, clinical pregnancy rates and live birth rates were similar between the two groups except for significantly high progesterone levels in the LPOS group. The mRNA expression levels of CXCL1 (0.51 vs 1.00, p < 0.001) and PTGES (0.30 vs 1.00, p < 0.01) were significantly lower in the LPOS group than in the FPOS group. The LPOS group had significantly lower mRNA expression of NDUFB7 (0.12 vs 1.00, p < 0.001) and NDUFA4L2 (0.33 vs 1.00, p < 0.01) than the FPOS group. DAPK3 (3.81 vs 1.00, p < 0.05) and BCL6B (2.59 vs 1.00, p < 0.01) mRNA expression was significantly higher in the LPOS group than in the FPOS group. Increased expression of PCK1 (3.13 vs. 1.00, p < 0.001) and decreased expression of LDHC (0.12 vs. 1.00, p < 0.001) were observed in the LPOS group compared to the FPOS group. Conclusions: Our data revealed different CC genes expression involving in inflammation, oxidative phosphorylation, apoptosis and metabolism between LPOS and FPOS in PORs. However, the results are non-conclusive; further large-scale randomized controlled trials are needed to validate the results.
Assuntos
Células do Cúmulo/metabolismo , Fertilização in vitro/métodos , Fase Luteal/fisiologia , Indução da Ovulação/métodos , Adulto , Células do Cúmulo/efeitos dos fármacos , Feminino , Fertilização in vitro/estatística & dados numéricos , Hormônio Foliculoestimulante/administração & dosagem , Fase Folicular/efeitos dos fármacos , Fase Folicular/fisiologia , Perfilação da Expressão Gênica , Humanos , Infertilidade/terapia , Nascido Vivo , Fase Luteal/efeitos dos fármacos , Hormônio Luteinizante/administração & dosagem , Recuperação de Oócitos/estatística & dados numéricos , Indução da Ovulação/estatística & dados numéricos , Projetos Piloto , Gravidez , Taxa de Gravidez , Estudos Prospectivos , RNA Mensageiro/metabolismo , Proteínas Recombinantes/administração & dosagem , Resultado do TratamentoRESUMO
Neurones in the arcuate nucleus co-expressing kisspeptin, neurokinin B (NKB) and dynorphin (KNDy) play a critical role in the control of gonadotrophin-releasing hormone (GnRH) and luteinising hormone (LH) secretion. In sheep, KNDy neurones mediate both steroid-negative- and -positive-feedback during pulsatile and preovulatory surge secretions of GnRH/LH, respectively. In addition, KNDy neurones receive glutamatergic inputs expressing vGlut2, a glutamate transporter that serves as a marker for those terminals, from both KNDy neurones and other populations of glutamatergic neurones. Previous work reported higher numbers of vGlut2-positive axonal inputs onto KNDy neurones during the LH surge than in luteal phase ewes. In the present study, we further examined the effects of the ovarian steroids progesterone (P) and oestradiol (E2 ) on glutamatergic inputs to KNDy neurones. Ovariectomised (OVX) ewes received either no further treatment (OVX) or steroid treatments that mimicked the luteal phase (low E2 + P), and early (low E2 ) or late follicular (high E2 ) phases of the oestrous cycle (n = 4 or 5 per group). Brain sections were processed for triple-label immunofluorescent detection of NKB/vGlut2/synaptophysin and analysed using confocal microscopy. We found higher numbers of vGlut2 inputs onto KNDy neurones in high E2 compared to the other three treatment groups. These results suggest that synaptic plasticity of glutamatergic inputs onto KNDy neurones during the ovine follicular phase depend on increasing levels of E2 required for the preovulatory GnRH/surge. These synaptic changes likely contribute to the positive-feedback action of oestrogen on GnRH/LH secretion and thus the generation of the preovulatory surge in the sheep.
Assuntos
Dinorfinas/fisiologia , Estradiol/fisiologia , Fase Folicular/fisiologia , Glutamatos/fisiologia , Kisspeptinas/fisiologia , Neurocinina B/fisiologia , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Animais , Estradiol/metabolismo , Feminino , Hormônio Liberador de Gonadotropina/sangue , Fase Luteal/efeitos dos fármacos , Hormônio Luteinizante/sangue , Ovariectomia , Ovinos , Proteína Vesicular 2 de Transporte de Glutamato/metabolismoRESUMO
BACKGROUND: It remains under subject of debate regarding the optimal route of luteal support for hormone replacement therapy- frozen embryo transfer (HRT-FET) cycles. We compared efficacy of vaginal progesterone gel combined with oral dydrogesterone and intramuscular progesterone for HRT-FET lutein support. METHODS: This is a retrospective observational study. After matching for propensity score of getting vaginal + oral treatment, a total of 208 FET cycles in the vaginal progesterone combined with oral dydrogesterone and 624 cycles in the intramuscular progesterone group were enrolled. Pregnancy outcomes and neonatal outcomes including chemical pregnancy rate, clinical pregnancy rate, implantation rate, spontaneous abortion rate, live birth rate, gestational weeks, pre-term delivery, birth weight, and congenital anomalies rate were compared. RESULTS: No significant differences were observed in patient characteristics such as age, duration of infertility, type of infertility, or hormone level after matching. Chemical pregnancy rate (68.3 % versus 70.5 %), clinical pregnancy rate (64.9 % versus 64.4 %), implantation rate (52.3 % versus 50.2 %), spontaneous abortion rate (21.5 % versus 18.4 %), and live birth rate (49.0 % versus 51.3 %) were similar in both group without statistically significant difference. No significant differences in neonatal outcomes were observed between the two groups. CONCLUSION: We observed similar pregnancy outcomes in both vaginal progesterone gel combined with oral dydrogesterone and intramuscular progesterone protocol. Vaginal progesterone gel combined with oral dydrogesterone can be substituted for intramuscular progesterone given that vaginal plus oral use has good safety and is more convenient and may be associated with less side effect caused by intramuscular injection.