Staged Treatment with Chinese Herbal Medicine in a Controlled Ovarian Hyperstimulation of In Vitro Fertilization-Embryo Transfer Programme / 中医杂志

It is believed that kidney deficiency is the fundamental pathogenesis while liver constraint and spleen deficiency， and disharmony of chong （thorough vessel， 冲脉）and ren （conception vessel， 任脉） is the key pathogenesis of infertility patients who adopted controlled ovarian hyperstimulation of in vitro fertilization-embryo transfer （IVF-ET） programme. Therefore， the method of tonifying the kidneys dominantly and treating the liver and spleen simultaneously is proposed， and Chinese herbal medicine is suggested to be used in adjuvant treatment of staged IVF-ET controlled ovrian hyperstimulation. In the regulation stage， modified Liuwei Dihuang Pill （六味地黄丸） can be used to tonify kidney and supplement essence， fortify spleen and nourish liver； in the ovulation promotion stage， modified Wenjing Decoction （温经汤） should be used to warm kidney and assist yang， dispel stasis and nourish blood； in the pre-transplantation endothelial preparation stage， modified Shenling Baizhu Powder （参苓白术散） is suggested to fortify spleen and replenish qi， invigorate blood and resolve stasis； after the transplantation stage， modified Shoutai Pill （寿胎丸） or Taiyuan Decoction （胎元饮） can be taken to fortify spleen and tonify kidney， benefit qi and nourish blood.

Manejo del Síndrome de Hiperestimulación Ovárica / Management of Ovarian Hyperstimulation Syndrome

INTRODUCCIÓN: El síndrome de hiperestimulación ovárica es una respuesta exagerada del ovario a los tratamientos hormonales para estimular la formación de óvulos. OBJETIVO: Describir el caso clínico de una mujer con síndrome de hiperestimulación ovárica; revisar el abordaje, manejo, tratamiento y cómo prevenirlo. CASO CLÍNICO: Paciente femenina de 37 años, multigesta, en tratamiento con metformina por Síndrome de ovario poliquístico , que presenta infertilidad secundaria a factor tubárico, que desarrolló un cuadro moderado de síndrome de hiperestimulación ovárica como consecuencia de la aplicación de las técnicas de fertilización in vitro (Folitropina alfa humana recombinante (GONAL-F®) y Cetrolerelix (CETROTIDE®); al cuarto día del procedimiento de aspiración folicular presenta dolor pélvico intenso, disuria, deposiciones diarreicas, ecografía abdominal y vaginal evidencia líquido libre en cavidad alrededor de 1000cc, además de ovarios tanto derecho e izquierdo con volumen de 102 mL y 189 mL respectivamente. Paciente es ingresada para realizar tratamiento hidratación parenteral, Enoxaparina 40mg subcutánea, Cabergolina 0.5mg vía oral, alta a las 72 horas. DISCUSIÓN: Las claves para la prevención del síndrome de hiperestimulación ovárica son la experiencia con la terapia de inducción de la ovulación y el reconocimiento de los factores de riesgo para el síndrome de hiperestimulación ovárica. Los regímenes de inducción de la ovulación deberían ser altamente individualizados, monitorizados cuidadosamente y usando dosis y duración mínimas del tratamiento con gonadotropinas para conseguir la meta terapéutica. CONCLUSIONES: El síndrome de hiperestimulación ovárica constituye la complicación más temida durante el uso de inductores de la ovulación; el conocimiento de factores de riesgo, puede prevenir o evitar que llegue a ser de un caso severo, lo cual puede causar mayor morbilidad o hasta mortalidad. La vitrificación se convierte en la técnica que permite prevenir el síndrome de hiperestimulación ovárica, junto con esta técnica hay 2 alternativas: la inducción con análogo de la hormona liberadora de gonadotropina o el uso de agonistas dopaminérgicos.

INTRODUCTION: Ovarian hyperstimulation syndrome is an exaggerated response of the ovary to hormonal treatments to stimulate egg formation. OBJECTIVE: To describe the clinical case of a woman with ovarian hyperstimulation syndrome; to review the approach, management, treatment and how to prevent it. CLINICAL CASE: 37-year-old female patient, multigestation, under treatment with metformin for polycystic ovary syndrome, presenting infertility secondary to tubal factor, who developed a moderate picture of ovarian hyperstimulation syndrome as a consequence of the application of in vitro fertilization techniques (recombinant human follitropin alfa (GONAL-F®) and Cetrolerelix (CETROTIDE®); On the fourth day of the follicular aspiration procedure she presents intense pelvic pain, dysuria, diarrheic stools, abdominal and vaginal ultrasound shows free fluid in the cavity of about 1000cc, in addition to right and left ovaries with a volume of 102 mL and 189 mL respectively. Patient was admitted for parenteral hydration treatment, Enoxaparin 40mg subcutaneous, Cabergoline 0.5mg orally, discharged after 72 hours. DISCUSSION: The keys to prevention of ovarian hyperstimulation syndrome are experience with ovulation induction therapy and recognition of risk factors for ovarian hyperstimulation syndrome. Ovulation induction regimens should be highly individualized, carefully monitored, and using minimal doses and duration of gonadotropin therapy to achieve the therapeutic goal. CONCLUSIONS: Ovarian hyperstimulation syndrome constitutes the most feared complication during the use of ovulation inducers; knowledge of risk factors, may prevent or avoid it from becoming a severe case, which may cause increased morbidity or even mortality. Vitrification becomes the technique that allows preventing ovarian hyperstimulation syndrome, along with this technique there are 2 alternatives: induction with gonadotropin-releasing hormone analog or the use of dopaminergic agonists.

Cryopreservation as a strategy for prevention of ovarian hyperstimulation syndrome in a public assisted reproduction service in São Paulo - Brazil

SUMMARY OBJECTIVE: This study aimed to evaluate the prevalence of ovarian hyperstimulation syndrome (OHSS) and associated risk factors in patients undergoing fertilization cycles at risk of OHSS (≥15 antral follicles or ≥15 oocytes aspirated) and submitted to cryopreservation of all embryos in the Human Reproduction Service of the Pérola Byington Hospital (Referral Center for Women's Health) in São Paulo, SP, Brazil. METHODS: This cross-sectional, institutional, descriptive study of secondary data from patients' charts enrolled in the Assisted Reproduction Service of the Pérola Byington Hospital at risk of OHSS after controlled ovarian stimulation and submitted to cryopreservation of all embryos was conducted between January 2015 and September 2017. RESULTS: OHSS occurred in 47.5% of cycles, all with mild severity, and there were no moderate or severe cases of OHSS. CONCLUSION: The cryopreservation of all embryos is associated with a reduction in moderate and severe forms of OHSS. Risk factors for OHSS should be evaluated prior to initiation of treatment, with less intense stimulation protocols accordingly.

Aflibercept suppresses ovarian hyperstimulation syndrome: an experimental study in rats

SUMMARY OBJECTIVE: In this study, we aimed to determine the impact of the antiangiogenic medications, namely, aflibercept and cabergoline in the prevention and treatment of ovarian hyperstimulation syndrome in a rat model. METHODS: A total of 36 female Wistar rats were randomly allocated to one of the five groups, including disease-free and ovarian hyperstimulation syndrome controls: Group no OHSS (control, n=6) received saline only intraperitoneally (i.p.); group just OHSS (ovarian hyperstimulation syndrome only, n=6) received 10 IU pregnant mare serum gonadotropin and 30 IU human chorionic gonadotropin subcutaneously to produce ovarian hyperstimulation syndrome; group cabergoline+OHSS (cabergoline+ovarian hyperstimulation syndrome, n=8) received 100 μg/kg oral cabergoline; group aflibercept (12.5 mg/kg)+OHSS (aflibercept+ovarian hyperstimulation syndrome, n=8) received 12.5 mg/kg i.p. aflibercept; and group aflibercept (25 mg/kg)+OHSS (aflibercept+ovarian hyperstimulation syndrome, n=8) received 25 mg/kg i.p. aflibercept. The groups were compared for ovarian weight, immunohistochemical vascular endothelial growth factor expression, spectrophotometric vascular permeability evaluated with methylene blue solution in peritoneal lavage, and body weight growth. RESULTS: Vascular endothelial growth factor immunoexpression was substantially greater in the just OHSS group (22.00±10.20%) than in the aflibercept (12.5 mg/kg)+OHSS (7.87±6.13%) and aflibercept (25 mg/kg)+OHSS (5.63±4.53%) groups (p=0.008 and p=0.005, respectively). Post-hoc tests indicated that cabergoline, 12.5 mg/kg aflibercept, and 25 mg/kg aflibercept decreased vascular permeability compared to the untreated ovarian hyperstimulation syndrome group (p=0.003, p=0.003, and p=0.001, respectively). JOH group had the heaviest ovaries, whereas aflibercept (25 mg/kg)+OHSS group had the lightest. In terms of body weight gain, cabergoline+OHSS group was substantially greater than the aflibercept (12.5 mg/kg)+OHSS and aflibercept (25 mg/kg)+OHSS groups (p=0.006 and p=0.007, respectively). CONCLUSION: Aflibercept, an antiangiogenic medication, decreased ovarian hyperstimulation syndrome by lowering the vascular permeability and vascular endothelial growth factor expression.

Clinical characteristics of severe late-onset ovarian hyperstimulation syndrome and its impact on the live birth outcome of IVF-ET / 中华妇产科杂志

Objective:To investigate the correlation between different clinical features and live birth in patients with severe late-onset ovarian hyperstimulation syndrome (OHSS) after in vitro fertilization-embryo transfer (IVF-ET).Methods:The clinical information of 330 patients who were pregnant after IVF-ET and referred to medical treatments diagnosed as late-onset severe OHSS in Peking University Third Hospital from January 2016 to December 2020 was retrospectively analyzed. The patients were divided into live birth achieved group ( n=287) and non-live birth achieved group ( n=43) according to pregnancy outcomes, and live birth achieved group was further divided into two subgroups, full-term birth group ( n=222) and early-term birth group ( n=65) according to gestational week at delivery for better analysis. Single factor and multi-factor analysis were utilized to clarify the influencing factors of both live birth and early-term birth. Results:Among all the patients who received IVF-ET, the incidence of severe OHSS was 0.67% (673/100 758). Among 330 severe late-onset OHSS patients, 42.4% (140/330) had pleural effusion, the incidence of abnormal liver function was 69.4% (229/330), and the live birth rate was 87.0% (287/330). Among the 287 patients who achieved live birth, 55.4% (159/287) had no pleural effusion, 18.5% (53/287) had a small amount of pleural effusion, and 26.1% (75/287) had medium or massive pleural effusion; in the non-live birth achieved group, there were more patients without pleural effusion and less patients with a small amount of pleural effusion; the difference was statistically significant ( χ2=6.213, P=0.045). The rate of selective fetal reduction in live birth achieved group was 16.0% (46/287), which was significantly higher than that in the non-live birth achieved group, which was 2.3% (1/43; χ2=5.749, P=0.017). Multivariate logistic regression analysis revealed that moderately abnormal liver function was an independent risk factor for live birth ( OR=3.15, 95% CI: 1.60-6.19), while selective fetal reduction was an independent protective factor for live birth ( OR=0.13, 95% CI: 0.02-0.96). Additionally, subgroup analysis suggested that twin birth was an independent risk factor for preterm birth ( OR=8.54, 95% CI: 4.31-16.91). Conclusions:Moderate hepatic dysfunction may be associated with adverse pregnancy outcomes in patients with severe late-onset OHSS. Selective fetal reduction and singleton pregnancy are recommended to ameliorate live birth rate, full-term delivery rate, also the maternal and neonatal prognosis for patients with multiple pregnancies.

Effectiveness, safety and cost of urinary follicle stimulating hormone in controlled ovarian stimulation in China: multi-center retrospective cohort study of 102 061 in vitro fertilization cycles / 中华妇产科杂志

Objective:To explore the effectiveness, safety and cost between urinary follicle stimulating hormone (uFSH) and recombinant follicle stimulating hormone (rFSH) in controlled ovarian stimulation (COS) in China.Methods:Data were collected from 16 reproductive centers in China covering oocytes collection time from May 1, 2015 to June 30, 2018. Eligible patients were over 18 years old, adopting COS with uFSH (uFSH group) or rFSH (rFSH group) as start gonadotropins (Gn), and using in vitro fertilization (IVF) and (or) intracytoplasmic sperm injection for fertilisation, excluding frozen embryo recovery cycle. Generalised estimating equation was used to address the violation of independency assumption between cycles due to multiple IVF cycles for one person and clustering nature of cycles carried out within one center. Controlling variables included age, body mass index, anti-Müllerian hormone level, cause of infertility, ovulation protocol, type of fertilisation, number of embryos transferred, number of days of Gn use.Results:Totally 102 061 cycles met eligibility criteria and were included in the analyses. In terms of effectiveness, after controlling relevant unbalanced baseline characteristics, compared with rFSH group, the high oocyte retrieval (>15 oocytes was considered high retrieval) rate of uFSH group significantly decreased in gonadotropin-releasing hormone agonist protocol ( OR=0.642, P<0.01) and in gonadotropin-releasing hormone antagonist protocol ( OR=0.556, P=0.001), but the clinical pregnancy rate per transfer cycle and the live birth rate per transfer cycle significantly increased ( OR=1.179, OR=1.169, both P<0.01) in both agonist and antagonist protocols. For safety, multiple analysis result demonstrated that in the agonist protocol, compared with rFSH group, the incidence of moderate to severe ovarian hyperstimulation syndrome of uFSH group significantly decreased ( OR=0.644, P=0.002). The differences in ectopic pregnancy rate and multiple pregnancy rate between the uFSH and rFSH groups were not significant ( P=0.890, P=0.470) in all patients. In terms of cost, compared with rFSH group, the uFSH group had lower total Gn costs for each patient ( P<0.01). Conclusion:For patients who underwent COS, uFSH has better safety, and economic profiles over rFSH in China.

Effects of Transcutaneous Electrical Acupoint Stimulation on Ovarian Responses and Pregnancy Outcomes in Patients Undergoing IVF-ET: A Randomized Controlled Trial / 中国结合医学杂志

OBJECTIVE@#To evaluate the influence of different transcutaneous electrical acupoint stimulation (TEAS) modes on ovarian responses and pregnancy outcomes in patients with infertility undergoing in vitro fertilization and embryo transfer (IVF-ET).@*METHODS@#Two hundred infertility patients undergoing IVF-ET were divided randomly into experimental groups (TEAS groups: E-I, E-II, E-III, and E-IV, 40 cases each group) and a control group (mock TEAS group, 40 patients) using the random number method. The patients in the experimental groups received TEAS treatment of 20, 30, 40 and 50 mA for the E-I, E-II, E-III and E-IV groups, respectively. The control group received a treatment of 5 mA. TEAS was applied at acupoints of Guanyuan (RN 4), Zhongji (RN 3), Sanyinjiao (SP 6), Zigong (EX-CA 1), and Taixi (KI 13), once a day for 30 min each time for a treatment period of 10-13 d. Treatment effect was assessed using the following indicators: endometrial thickness on the 6th day of gonadotropin treatment (GN6 day), endometrial thickness on the day on chorionic gonadotropin administration (HCG day), number of ovarian follicles on HCG day, number of ova captured, amount of estrogen required for each harvested ova, number of mature ova divided by the total number of ova, percentage of high-quality embryos, and clinical pregnancy.@*RESULTS@#Endometrial thickness in the experimental groups on the HCG day was significantly better than that of the control group after TEAS stimulation (P=0.01). TEAS exhibited a greater impact on the number of ova captured (P=0.003). However, the effect of TEAS stimulation on the high-quality embryo rate and clinical pregnancy in patients was not statistically significant (P>0.05).@*CONCLUSIONS@#TEAS is an effective method in improving the ovarian state. When the stimulus intensity was at 40 mA and above, it could be helpful to improve the patient's endometrial condition and endometrial receptivity and to retrieve more oocytes. (Trial registration No. ChiCTR-TRC-11001780).

Sudden death of an egg donor during oocyte retrieval due to ovarian hyperstimulation syndrome

ABSTRACT Ovarian Hyperstimulation Syndrome (OHSS) is uncommon among oocyte donors during in vitro fertilization (IVF) procedure and is rarely associated with death. We report a case of a 23-year-old oocyte donor who suddenly died on the operation table during oocyte retrieval. She had no risk factors in her menstrual history, laboratory, or clinical parameters. The antagonist cycle, triggered with the GnRH agonist protocol, was carried out. The cause of death at autopsy was attributed to respiratory failure due to acute massive pulmonary edema, which developed due to the complication of OHSS. Only a few autopsy cases associated with OHSS have been published, but, as far as we know, no clinical or autopsy cases of sudden death caused by OHSS have been reported.

Pleuropatía secundaria a inductores de la ovulación / Pleuropathy secondary to ovulation inducers

Introducción: Se denomina derrame pleural al acúmulo de líquido en el espacio pleural por encima de 5 y 15 mL en un hemitórax. Diferentes etiologías son las responsables de su aparición, pero un grupo estas están dadas por la etiología medicamentosa. El síndrome de hiperestimulación ovárica constituye una complicación secundaria al uso de la terapia con inductores de la ovulación. Es poco conocida en la literatura médica la asociación del tratamiento con inductores de la ovulación en la génesis del derrame pleural. Objetivo: Revisar los aspectos clínico-fisiopatológicos más importantes reportados sobre la pleuresía en el síndrome de hiperestimulación ovárica. Desarrollo: Se realizó una revisión a propósito de un caso clínico de una paciente de 34 años de edad con antecedentes de salud, seguida en consulta de fertilidad, a la cual se le aplicó tratamiento con citrato de clomifeno y desarrolló un síndrome de hiperestimulación ovárica moderado e inmediato, cuya expresión clínica fue un derrame pleural derecho de moderada cuantía. La pleuresía es poco frecuente, depende de la predisposición genética individual de la paciente y la susceptibilidad a los medicamentos; la incidencia varía entre 0,6 y 10 por ciento. Se han descrito diferentes factores de riesgo de presentarlo, aunque cualquier mujer sometida a estos tratamientos lo puede desarrollar. El tratamiento es sintomático restituyendo el volumen intravascular con la administración de cristaloides y/o albúmina. Conclusiones: La asociación del síndrome de hiperestimulación ovárica y la pleuropatía secundaria al tratamiento con citrato de clomifeno no es frecuente(AU)

Introduction: Pleural effusion is called the accumulation of fluid in the pleural space above 5 and 15 mL in a hemithorax. Different etiologies are responsible for its appearance but a group of them are given by drug etiology. Ovarian hyperstimulation syndrome is a secondary complication to the use of ovulation inducer therapy. The association of treatment with ovulation inducers in the genesis of pleural effusion is little known in the medical literature. Objective: To review the most important clinical-pathophysiological aspects reported on pleurisy in ovarian hyperstimulation syndrome. Methods: A review was carried out on the purpose of a clinical case of a 34-year-old patient with a medical history, followed in a fertility consultation. She was treated with clomiphene citrate and she developed an immediate moderate ovarian hyperstimulation syndrome. The clinical expression was a moderate right pleural effusion. Pleurisy is rare. It depends on the individual genetic predisposition of the patient and the susceptibility to drugs; the incidence varies between 0.6 and 10 percent. Different risk factors have been described, although any woman subjected to these treatments can develop it. Treatment is symptomatic, restoring the intravascular volume with the administration of crystalloids and / or albumin. Conclusions: The association of ovarian hyperstimulation syndrome and pleuropathy secondary to treatment with clomiphene citrate is not frequent(AU)

Resultados de la preinducción con Misofar en el Hospital Carlos Manuel de Céspedes. Enero - diciembre 2018 / Results of pre-induction with Misofar at the Carlos Manuel de Céspedes Hospital. January - December 2018 / Resultados da pré-indução com Misofar no Hospital Carlos Manuel de Céspedes. Janeiro - dezembro de 2018

RESUMEN Introducción: en la obstetricia moderna se establece la necesidad de aumentar las alternativas para vencer la constante de resistencia del cuello del útero a la actividad uterina durante todo el periodo gestacional. La preinducción con misofar fue introducido en la práctica clínica entre los procedimientos de aceleración en la madurez del cuello uterino. Objetivo: identificar los resultados perinatales con el uso del misofar en la preinducción del parto durante un año en el Hospital Carlos Manuel de Céspedes. Métodos: se realizó un estudio observacional descriptivo transversal con 732 en el Hospital Universitario "Carlos Manuel de Céspedes" de Bayamo, provincia Granma en el año 2018 a las que se le aplicaron de una a tres dosis de misofar como tratamiento facilitador para la preinducción del parto. Resultados: el índice de cesáreas en este grupo de pacientes fue de alrededor del 13%. Más del 50% de pacientes tuvieron parto Eutócico con la 1ª dosis. Se reportaron solo un 0.8% complicaciones relacionadas con hiperestimulación del útero, que resolvieron con medidas generales sin causar morbilidad en la madre ni el feto. Conclusiones: la administración de una dosis de 25 µg diaria por 3 días, es efectiva para lograr la remodelación cervical y pasar a la fase activa y alcanzando un test cervical igual o mayor de 7, considerado un criterio de éxito.

ABSTRACT Introduction: in modern obstetrics, the need to increase the alternatives to overcome the constant resistance of the cervix to uterine activity is established throughout the gestational period. Preinduction with misofar was introduced in clinical practice among acceleration procedures in the maturity of the cervix. Objective: to identify the perinatal results with the use of misofar in the pre-induction of labor for one year at the Carlos Manuel de Céspedes Hospital. Methods: a cross-sectional descriptive observational study was carried out with 732 at the "Carlos Manuel de Céspedes" University Hospital of Bayamo, Granma province in 2018, to which one to three doses of misofar were applied as a facilitating treatment for the preinduction of the Birth. Results: the cesarean section rate in this group of patients was around 13%. More than 50% of patients had Eutocic delivery with the 1st dose. Only 0.8% complications related to hyperstimulation of the uterus were reported, which resolved with general measures without causing morbidity in the mother or the fetus. Conclusions: the administration of a dose of 25 µg daily for 3 days is effective to achieve cervical remodeling and move to the active phase and reaching a cervical test equal to or greater than 7, considered a criterion of success.

RESUMO Introdução: na obstetrícia moderna, a necessidade de aumentar as alternativa para superar a resistência constante do colo do útero à atividade uterina se estabelece ao longo do período gestacional. A pré-indução com misofar foi introduzida na prática clínica entre os procedimentos de aceleração na maturidade do colo do útero. Objetivo: identificar os resultados perinatais com o uso de misofar na pré-indução do parto durante um ano no Hospital Carlos Manuel de Céspedes. Métodos: foi realizado um estudo transversal observacional descritivo com 732 pessoas no Hospital Universitário "Carlos Manuel de Céspedes" de Bayamo, província de Granma em 2018, ao qual foram aplicadas de uma a três doses de misofar como tratamento facilitador da pré-indução do Nascimento. Resultados: a taxa de cesárea neste grupo de pacientes foi em torno de 13%. Mais de 50% dos pacientes tiveram parto eutócico com a 1ª dose. Foram relatadas apenas 0,8% de complicações relacionadas à hiperestimulação do útero, que se resolveram com medidas gerais sem causar morbidade na mãe ou no feto. Conclusões: a administração de uma dose de 25 µg ao dia por 3 dias é eficaz para conseguir a remodelação cervical e passar para a fase ativa chegando a um teste cervical igual ou superior a 7, considerado critério de sucesso.

Outcomes of frozen-thawed embryo transfer cycles of progestin-primed ovarian stimulation protocol compared with other three ovulation hyperstimulation protocols / 解剖学报

Objective To analyze the clinical outcomes of progestin primed ovarian stimulation (PPOS) compared with the other three different controlled ovarian hyperstimulation (COH) protocols in fresh embryo transfer (ET) and frozen-thawed embryo transfer (FET) cycles. Methods A total of 430 oocyte pick-up cycles and 272 FET cycles were retrospectively analyzed. Number of oocytes retrieved, laboratory indexes and pregnancy outcome of FET were compared. Results The mean oocytes retrieved (11.1±7.3), fertilization rate (85.6%), cleavage rate (95.1%) and excellent embryo rate (20.2%) as well as transplantable embryo rate (4. 5 ±3.1) of the PPOS group did not show significant differences compared with the other 3 subgroups (all P<0.05) in fresh cycle. As for pregnancy outcomes in FET cycles, no statistically significant differences were observed among the four groups in embryo implantation rate (26.2%), clinical pregnancy rate (63.0%) and abortion rate (11.8%) (all P<0.05). However, embryo implantation rate, clinical pregnancy rate was higher in PPOS group compared with the other groups. Conclusion Compared with the other three ovulation stimulation programme, PPOS might be used as a new alternative for controlled ovulation stimulation protocols.

Is there a perfect protocol for patients with low ovarian reserve: a retrospective study comparing antagonist or agonist protocol in patients with low ovarian reserve

Background: The high prevalence of infertility has made it a major healthcare problem in the present era. A majority of patients presenting with infertility have poor ovarian reserve (POR). Patients with POR are challenging to treat due to reduced treatment success and high cycle cancellation rate as there is no uniform definition and treatment protocol for these patients. The present retrospective study was performed to compare the pregnancy outcome between a long agonist protocol and flexible antagonist protocol in patients with POR. Patients with AMH ≤1.5 ng/mL and AFC ≤4 was included in the study. Controlled ovarian hyperstimulation is the basis of any in vitro fertilisation (IVF) procedure. There is no universally accepted ideal stimulation protocol for patients with POR, and it remains a challenge.Methods: This was a retrospective study covering the period from May 2019 to March 2020. Ninety-nine patients with low ovarian reserve (AMH ≤1.5 ng/mL and AFC ≤4) were included in the study. The patients underwent GnRH agonist/GnRH antagonist stimulation protocol using recombinant FSH. Demographic characteristics like age, BMI, duration of infertility was comparable. Total days of stimulation, total Gonadotropin dose used and clinical pregnancy rate in both the protocols was analyzed. Difference between the two groups was considered statistically significant at p-value <0.05.Results: Fifty-three patients underwent antagonist stimulation protocol and forty-six long agonist protocol. The clinical pregnancy rate was 37.7% (20/53) and 32.6% (15/46) in antagonist and agonist protocol respectively (p-value=0.5983). Pregnancy rate was higher in the antagonist group but the difference was not statistically significant.Conclusions: Antagonist protocol could marginally increase pregnancy rate in patients with low ovarian reserve. However, patients with poor ovarian reserve require a tailor-made protocol.

Comparative Study between Timed Intercourse and Intrauterine Insemination in Ovulation Stimulated Cycles in Unexplained Infertile Couples

Background and Objectives: It cannot be stressed enough that infertility is a problem of the couple and not an individualalone. IUI as a mode of artificial insemination is widely used in treating couples with unexplained infertility. The present studywas done with the objective of comparing the effectiveness of TI and IUI with husband’s sperm in couples with unexplainedinfertility undergoing superovulation with clomiphene.Methodology: In this cross-over study, a total of 60 couples with unexplained infertility were subjected to controlled ovarianhyperstimulation with clomiphene and prospectively randomized to receive either TI (Group A) or IUI (Group B). The groupswere interchanged when pregnancy was not achieved in either group after three cycles of each intervention.Results: A positive pregnancy test was seen in both IUI and TI after cross-over. There were seven pregnancies (four in IUI andthree in TI), out of which 6 (85.71%) were viable pregnancies, while one was non-viable (14.29%). Both IUI and TI had threeviable pregnancies each. The one non-viable pregnancy was from the IUI group.Interpretation and Conclusions: The findings of the present study showed that both TI and IUI are effective treatment modalitiesfor women with unexplained infertility. Although the addition of IUI to ovulation induction does increase the cycle fecundability,it does not improve the fecundity.

A prospective randomized comparative study of the efficacy of sustained release vaginal insert versus intracervical gel in primigravidae at term pregnancy

vBackground: Induction of labour is the intentional initiation of labour before spontaneous onset for the purpose of delivery of fetoplacental unit. Failure of induction is responsible for increased incidence of caesarean delivery. This study performed to assess and compare the clinical effects of sustained release vaginal insert versus intracervical gel in primiparous women with term pregnancy in terms of improvement of Bishop’s score, Induction delivery interval, incidence of hyperstimulation, maternal and neonatal outcomes.Methods: A total 100 consecutive term pregnant women who underwent labor induction for fetal or maternal indications were divided randomly into two groups. Group A - sustained release Vaginal insert and Group B - Intracervical gel. Informed consent was taken from each patient.Results: Statistically significant increase in final Bishop’s score (p=0.008) and hyperstimulation (p=0.04) was seen in Vaginal insert group as compared to Intracervical gel group, while there were no statistically significant differences in maternal outcomes, neonatal outcomes and need for oxytocin augmentation in both groups.Conclusions: In this study we found that insert did not improve the induction delivery interval or rate of successful induction, nor did it have any advantage in terms of neonatal outcome although it did improve the Bishops score – Its advantage was in terms of single application, few prevaginal examinations, longer duration of action and immediate retrieval in case of hyperstimulation. Its main drawback remained the maintenance of cold chain without which its efficacy decreases. Another significant observation was the dropout rate of insert (16%).

Letrozole versus gonadotropin-releasing hormone antagonist during luteal phase in the prevention of ovarian hyperstimulation syndrome: a randomized controlled trial / 中华妇产科杂志

Objective@#To explore and compare the preventive effect of using letrozole and gonadotropin-releasing hormone (GnRH) antagonist during luteal phase of patients at high risk for ovarian hyperstimulation syndrome (OHSS).@*Methods@#A total of 99 infertile women undergoing in vitro fertilization and embryo transfer or intracytoplasmic sperm injection with high risk for OHSS were enrolled in this randomized controlled trial.The letrozole group (n=51) received letrozole of 7.5 mg daily for 3 days;the GnRH antagonist group (n=48) were given cetrorelix of 0.25 mg subcutaneously daily for 3 days. Both groups received support therapy combined with embryo cryopreservation. The incidence of OHSS was surveyed. And the serum concentration of estradiol, LH and progesterone on days 3, 5 and 8 after oocytes retrieval were measured.@*Results@#There were no statistical differences in terms of baseline characteristics of patients and outcomes of controlled ovarian hyperstimulation between the two groups.The incidence of moderate and severe OHSS was found no significantly difference between letrozole group [11.8%(6/51)] and GnRH antagonist group [10.4%(5/48);P>0.05]. The estradiol concentration of the indicated days on days 3,5 and 8 after oocytes retrieval in letrozole group and GnRH antagonist group were (1 417±3 543) versus (15 210±9 921) pmol/L, (1 692±4 330) versus (18 680±11 567) pmol/L, (239±336) versus (3 582±5 427) pmol/L, respectively;compared with GnRH antagonist group, the estradiol level was significantly lower in the letrozole group (all P<0.01). The luteinizing hormone level in the letrozole group were (0.46±0.40), (0.56±0.55)and (0.67±0.58) U/L on days 3,5 and 8 after oocytes retrieval, which were significantly higher than those of GnRH antagonist group [(0.28±0.28), (0.30±0.19) and (0.45±0.37) U/L, respectively; all P<0.05]. There was no obvious differences on progesterone levels between letrozole group and GnRH antagonist group (all P>0.05),and on days 8 after oocytes retrieval,the level of progesterone in each group were significantly lower than those on day 3 and 5 after oocytes retrieval (P<0.05).@*Conclusion@#Letrozole has the same efficiency as GnRH antagonist for the prevention of OHSS, faster and cheaper to use, but its efficacy seems not to be related to the suppression of steroidogenic during the luteal phase.

Qilin pills prevent ovarian hyperstimulation syndrome of patients after IVF-ET by regulating plasma-related indicators / 中国临床药理学与治疗学

AIM: To study the preventive effect of Qilin pill on ovarian hyperstimulation syndrome (OHSS) after in vitro fertilization and embryo transfer (IVF-ET) and its effects on vascular endothelial growth factor (VEGF), tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in plasma. METHODS: Sixty-four patients undergoing IVF-ET treated in our hospital from January 2016 to January 2019 were selected. On the day of ovulation induction injection of human chorionic gonadotropin (HCG), 32 patients with high risk factors of OHSS were randomly divided into two groups. The control group received western medicine therapy, while the observation group received extra Qilin pill. The incidence of mild to moderate OHSS, fresh cycle transplant cancellation rate, plasma VEGF, TF, TFPI levels, and clinical outcomes of patients undergoing IVF-ET (HCG positive rate, biochemical pregnancy rate, clinical pregnancy rate) were compared between the two groups.RESULTS:There was no severe OHSS occurred in the two groups, the incidence of OHSS in the observation group (12.50%) and the cancellation rate of fresh cycle transplantation (15.63%) were lower than those in the control group (50.00%, 43.75%)(χ2=6.063,P=0.014); The levels of VEGF and TF in the observation group on the day of egg retrieval and embryo transfer were [(368±103) pg/mL, (392±91) pg/mL],[(24±4)pg/ mL,(29±4) pg/mL], which were lower than the control group [(436±117) pg/mL, (448±108) pg/mL],[(26±4) pg/mL, (31±4) pg/mL] (t=2.450,2.237,4.093,5.204,P=0.017,0.029,<0.001,<0.001); The plasma TFPI levels in the observation group on the day of egg retrieval and embryo transfer were [(73±18) ng/mL,(66±12) ng/mL], higher than the control group [(62±16)ng/mL, (58±10) ng/mL](t=2.550,3.032,P=0.014,0.004); The biochemical pregnancy rate in the observation group (8.70%) was lower than that in the control group (42.86%) (χ2=4.147, P=0.042),the clinical pregnancy rate (91.30%) was higher than that of the control group (57.14%) (χ2=4.147,P=0.042).CONCLUSION:Qilin pill can prevent the occurrence of severe OHSS after IVF-ET, reduce the occurrence of mild to moderate OHSS, decrease the cancellation rate of fresh cycle transplantation and improve the pregnancy outcome after IVF-ET; Its mechanism may be related to the regulation of the expression of VEGF, TF and TFPI.

Controlled ovarian hyperstimulation alters mice placental function / 解放军医学杂志

Objective To observe and assess the effect of controlled ovarian hyperstimulation (COH) on fetal weight and placental function of mouse model. Methods In vitro fertilized (IVF) blastocysts were transferred to non-stimulated pseudopregnant mice (NSP group, n=6) and superovulated pseudopregnantt mice (SOP group, n=6). At 18.5 d of embryonic age (E18.5 d), the fetal weight and placental weight were examined. The areas of labyrinth layer and junction layer of placenta were measured using microscopic image software. The apoptosis in the placenta was detected by TUNEL. The levels of glutathion (GSH) and malonaldehyde (MDA) in placenta were detected separately by spectrophotometry and barbiturate method. The expression levels of amino acid transporter Snat1, Snat2, Snat4, Lat1, Lat2, Cd98, and Taut mRNA in placenta were detected by qRT-PCR. The SNAT2 protein levels in microvillous membrane (MVM) of placenta were detected by Western blotting. Results At E18.5d, compared with the mice in SOP group to those in NSP group, the mean weights of fetal and placenta were significantly lower [(1.37±0.13) g vs. (1.75±0.13) g; (0.14±0.02) g vs. (0.17±0.01) g, P<0.001)]. The apoptosis rates increased in both labyrinth layer and junction layer of placenta [(7.57±1.23) % vs. (4.62±0.91) %, P<0.001; (5.28±0.99) % vs. (3.27±0.69) %, P=0.002]. The GSH level in placenta decreased obviously [(5.21±1.55) μmol/g prot vs. (8.45±1.60) μmol/g prot, P=0.005], while the concentration of MDA increased markedly [(1.35±0.52) nmol/g prot vs. (0.56±0.19) nmol/g prot, P=0.005]. The levels of Snat1, Snat2, Lat2 and Tau mRNA in the placenta were down regulated (0.77±0.13, 0.65±0.18, 0.69±0.18, 0.73±0.07, P<0.001), and the SANT2 protein levels in placental MVM were decreased significantly [(0.32±0.01) vs. (0.65±0.15), P<0.001]. Conclusion Controlled ovarian hyperstimulation may alter placental function, and induced placental oxidative stress might be a critical factor of abnormal placental function.

Impact of Kuntai Capsules on LIF, IGF-1 and EGF expression in the implantation window of endometrium in mice / Impacto de cápsulas de Kuntai en la expresión de LIF, IGF-1 y EGF en la ventana de implantación de endometrio en ratones

To investigate the influence of Kuntai capsules on the expression level of leukemia inhibitory factor (LIF), insulin-like growth factor-I (IGF-1)and epidermal growth factor (EGF) during the mouse's implantation window of superovulation period and controlled ovarian hyperstimulation period. 90 female mice were randomly divided into six groups in control, superovulation and controlled ovarian hyperstimulation (COH) conditions. The RNA expression of EGF, LIF and IGF-1 in the endometrium on the 4th day of pregnancy was detected, and the relative expression was compared. mRNA expression of these three factors in endometrium was significantly lower in superovulation and COH groups than control group (p<0.001). mRNA expression of these three factors in endometrium remained obviously lower in superovulation plus kuntai capsule group and COH plus kuntai capsule group than control group (p<0.01). mRNA expression of these three factors in endometrium was lower in control group than in the NS plus kuntai capsule group (p<0.05). Kuntai capsule cannot completely reverse the endometrial damages caused by superovulation and COH. Thus Kuntai capsule could partially improve a mouse's endometrial receptivity during the implantation window.

Para investigar la influencia de las cápsulas de Kuntai en el nivel de expresión del factor inhibidor de la leucemia (LIF), el factor de crecimiento similar a la insulina I (IGF-1) y el factor de crecimiento epidérmico (EGF) durante la ventana de implantación del ratón del período de superovulación y la hiperestimulación ovárica controlada período, se dividieron aleatoriamente 90 ratones hembra en seis grupos en condiciones de control, superovulación e hiperestimulación ovárica controlada (COH). Se detectó la expresión de ARN de EGF, LIF e IGF-1en el endometrio al cuarto día de embarazo, y se comparó la expresión relativa. La expresión de ARNm de estos tres factores en el endometrio fue significativamente menor en los grupos de superovulación y COH que en el grupo control (p<0,001). La expresión de ARNm de estos tres factores en el endometrio permaneció más baja en el grupo de cápsulas de superovulación más Kuntai y en el grupo de cápsulas de COH más Kuntai respecto del grupo control (p<0,01). La expresión de ARNm de estos tres factores en el endometrio fue menor en el grupo control que en el grupo de cápsula NS más Kuntai (p<0,05). La cápsula de Kuntai no pudo revertir completamente los daños endometriales causados por la superovulación y la COH. Por lo tanto, se sugiere que la cápsula de Kuntai podría mejorar parcialmente la receptividad endometrial de un ratón durante la ventana de implantación.

Prediction of efficacy of gonadotropin releasing hormone agonist trigger for final oocyte maturation through post-trigger 12-hour luteinizing hormone, follicle stimulating hormone and progesterone levels in COS: a prospective study

Background: Circulating levels of luteinizing hormone (LH), follicle stimulating hormone (FSH) and progesterone (P4) in serum after administration of gonadotropin releasing hormone agonist (GnRHa) trigger for final oocyte maturation are found to be predictive of oocyte maturity. This prospective study was conducted at a tertiary care centre to evaluate relationship between serum LH, FSH and P4 levels at 12-h post-trigger and oocyte maturity rate and to predict which hormone has maximum sensitivity and specificity for appropriate oocyte maturation.Methods: Women at risk of ovarian hyper-stimulation syndrome who underwent either autologous or donor IVF cycle treated with flexible GnRH antagonist protocol were taken as participants of the study. GnRHa as trigger for final oocyte maturation was given. After 12 hours of agonist trigger, blood sample was drawn to assess LH, FSH and P4 levels in serum. Continuous variables were expressed as mean±SD. Independent sample t test was used for continuous variables which were normally distributed and Mann-Whitney U test for data not normally distributed. Main outcome measures were number of oocytes retrieved, oocyte maturity rate, fertilization rate, cleavage rate and grade of embryos.Results: There was a statistically significant reduction in number of retrieved oocytes, maturity rate, fertilization rate and grade 1 embryos with a concentration of serum LH and P4 less than the cut off value (p < 0.05).Conclusions: Serum LH and P4 level less than the cut off value at 12-hour post-trigger with GnRHa is associated with a dramatically less oocyte maturity rate and fertilization rate.

Correlation between follicular fluid sRAGE level and ovarian responsiveness in non-PCOS patients undergoing controlled ovarian hyperstimulation / 南方医科大学学报

OBJECTIVE@#To investigate the correlation between soluble receptor for advanced glycation end products (sRAGE) level in the follicular fluid and ovarian responsiveness in non-PCOS patients undergoing controlled ovarian hyperstimulation.@*METHODS@#Ninety non-PCOS patients underwent IVF/ICSI using a short-acting long protocol for ovarian stimulation with a GnRH agonist. For each patient, the level of sRAGE in the follicular fluid was measured by enzyme linked immunosorbent assay (ELISA), and the data including the clinical baseline state, hormone level, number of oocytes obtained and the fertilization rate were collected.@*RESULTS@#Follicular fluid sRAGE level showed significant negative correlations with basal FSH level (=0.0036) and Gn dose ( 15) than in cases with oocytes obtained within the range of the target numbers (7-15) and below the target number (< 7) ( < 0.0001 and =0.0012, respectively).@*CONCLUSIONS@#Follicular fluid sRAGE level can reflect ovarian reserve function in non-PCOS patients, the number of oocytes obtained and the fertilization rate, and can thus predict ovarian responsiveness during controlled hyperstimulation in nonPCOS patients.