Fertilización asistida con óvulos propios en mujeres mayores de 40 años: indicaciones y resultados

Las mujeres posponen su maternidad por el deseo de superación personal y profesional. Se conoce que la cantidad y calidad de los óvulos por ciclo dependen de la edad de la paciente. Las tasas de éxito en tratamientos de reproducción asistida disminuyen con la edad, especialmente después de los 40 años. Se observan tasas más altas de nacidos vivos en mujeres más jóvenes y las tasas disminuyen significativamente en mujeres mayores debido a la disminución de la fertilidad y el aumento de abortos espontáneos. Por ello, la edad es crucial al evaluar la posibilidad de un embarazo exitoso mediante tratamientos de reproducción asistida (TRA). Las indicaciones para realizar fertilización in vitro (FIV) con óvulos propios en mujeres mayores de 40 años incluyen iniciar lo más pronto procedimientos de alta complejidad, buena evaluación de la reserva ovárica con análisis de la hormona antimülleriana y conteo de folículos antrales para realizar asesoramiento genético, proponer FIV-inyección intracitoplasmática de espermatozoides (ICSI) antes de los 44 años, generar expectativas realistas y realizar consentimiento informado, con estadisticas propias. En la REDLARA, de todos los procedimientos de FIV-ICSI, el 34% de las pacientes tienen más de 40 años; se prefiere transferir blastocistos con prueba genética preimplantacional de aneuploidías (PGT-A) para seleccionar embriones euploides. Las tasas de éxito son bajas, inclusive cuando son tasas de embarazo por transferencia de un embrión en el grupo de mujeres ≥ 40 años (18,2% sin PGT, 42,7% con PGT en el IMRCRP). Se recomienda acumular óvulos o embriones realizando múltiples estimulaciones ováricas. Se debe optar por transferir un solo embrión para evitar complicaciones obstétricas con embarazos múltiples en pacientes ≥ 40 años, por el alto riesgo debido a la edad.

Women postpone motherhood because of their desire for personal and professional improvement. It is known that the quantity and quality of oocytes per cycle depends on the patient's age. Success rates in assisted reproduction treatments decrease with age, especially after 40 years of age. Higher live birth rates are observed in younger women, and rates decrease significantly in older women due to decreased fertility and increased miscarriages. Therefore, age is crucial when assessing the possibility of a successful pregnancy through assisted reproductive treatments (ART). The indications to perform in vitro fertilization (IVF) with own ovules in women older than 40 years include starting as soon as possible highly complex procedures, good evaluation of ovarian reserve with antimüllerian hormone analysis (AMH) and antral follicle count (AFC) for genetic counseling, proposing IVF-intracytoplasmatic sperm injection (ICSI) before the age of 44 years, generating realistic expectations and informed consent, with own statistics. At REDLARA, of all IVF-ICSI procedures, 34% of patients are over 40 years old; preference is given to transfer blastocysts with preimplantation genetic testing for aneuploidy (PGT-A) to select euploid embryos. Success rates are low, even when they are pregnancy rates per embryo transfer in the group of women ≥ 40 years (18.2% without PGT, 42.7% with PGT in IMRCRP). It is recommended to bank ovules or embryos by performing multiple ovarian stimulations. A single embryo transfer should be chosen to avoid obstetric complications with multiple pregnancies in patients ≤ 40 years, because of the high risk due to age.

Ovarian reserve in adolescent girls with autoimmune thyroiditis

ABSTRACT Objectives: To assess serum anti-Müllerian hormone (AMH) levels as an ovarian reserve marker in adolescent girls with autoimmune thyroiditis (AIT) and explore the relationship of this marker with autoimmunity and thyroid function biomarkers. Subjects and methods: This study included 96 adolescent girls with newly diagnosed AIT and 96 healthy, age- and sex-matched controls. All participants were evaluated with detailed history taking and physical examination, thyroid ultrasound, and measurement of levels of thyroid-stimulating hormone (TSH), free thyroxin (FT4), free triiodothyronine (FT3), antithyroid peroxidase antibodies (TPOAb), antithyroglobulin antibody (TGAb), estradiol, total testosterone, and anti-Müllerian hormone (AMH) levels. The LH/FSH ratio was also calculated. Among 96 patients evaluated, 78 were overtly hypothyroid and 18 were euthyroid. AMH levels were significantly lower in participants with overt hypothyroidism and euthyroidism compared with controls. Results: Serum levels of AMH correlated negatively with age, body mass index (BMI) standard deviation score (SDS), and TPOAb, TGAb, and TSH levels but positively with FT4 levels. In multivariate analysis, AMH levels correlated significantly with age (odds ratio [OR] = 1.65, 95% confidence interval [CI] 1.18-2.32, p = 0.05), BMI SDS (OR = 2.3, 95% CI, 2.23-3.50, p = 0.01), TSH (OR = 2.43, 95% CI 1.5-2.8, p = 0.01), and TPOAb (OR = 4.1, 95% CI 3.26-8.75, p = 0.001). Conclusions: Ovarian reserve of adolescent girls with AIT, as measured by serum AMH levels, is affected by thyroid autoimmunity and hypothyroidism, indicating a possible need for ovarian reserve monitoring in these patients.

Estimulación ovárica en síndrome de Mayer-Rokitansky: reporte de caso y revisión de la literatura / Controlled ovarian stimulation in Mayer-Rokitansky syndrome: case report and literature review

Resumen El síndrome de Mayer-Rokitansky-Küster-Hauser (SMRKH) es una anomalía del tracto genital femenino caracterizada por ausencia congénita del útero y porción superior de la vagina. Ocurre en uno de cada 4,500 nacimientos y se diagnostica normalmente durante la adolescencia al presentarse amenorrea primaria. Su función ovárica está preservada, pero la información actual respecto al potencial reproductivo de estas pacientes es limitada. Se presenta el caso de una mujer con diagnóstico de SMRKH sometida a estimulación ovárica para transferencia de embriones a útero subrogado y se discute su potencial reproductivo: técnicas de reproducción asistida, intervenciones e impacto psicológico.

Abstract Mayer-Rokitansky-Küster-Hauser syndrome (MRKH) is a congenital anomaly of the female genital tract characterized by congenital absence of the uterus and upper part of the vagina. It occurs in 4,500 female births and diagnosis is usually made during adolescence when primary amenorrhea presents. They have functioning ovaries but data regarding their reproductive potential is limited. We hereby report the case of a woman diagnosed with MRKH syndrome in whom assisted reproductive techniques were used to try to achieve pregnancy by gestational surrogacy and their reproductive potential is discussed: assisted reproductive techniques, procedures, and psychological impact.

Clinical analysis of the effect of pituitrin in laparoscopic stripping of ovarian cystectomy / 中国医师进修杂志

Objective:To discusse the value of pituitin in laparoscopic ovarian cyst removal.Methods:From October 2015 to June 2018 in Dalian Medical University Affiliated Dalian Maternity Hospital, useing prospective research methods, 90 patients with unilateral ovarian cyst (except endometriomas) were randomly divided in 3 groups of pituitrin group,control group 1 and control group 2. The pituitrin group: laparoscopic cystectomy with the injection of diluted pituitrin 6 U, the total amount of diluted pituitrin 10 - 20 ml, ovarian hemostasis was achieved by sutura. The control group 1: ordinary laparoscopic cystectomy without injection suture hemostasis. The control group 2: laparoscopic cystectomy with the injection of normal saline 10 - 20 ml, ovarian hemostasis was same to pituitrin group. The operation time and the amount of bleeding were compared among the three groups. The ovarian reserve was compared between before and 3 months after operation by estradiol (E 2), follicle-stimulating hormone (FSH), luteinizing hormone (LH). Results:The amount of bleeding in the pituitrin group was less than that in the control group1: (14.00 ± 5.48) ml vs. (18.33 ± 6.99) ml, P<0.05. The operation time in the pituitrin group and control group 2 was less than that in the control group1: (43.50 ± 7.21) min, (45.00 ± 10.29) min vs. (50.17 ± 8.95) min, P<0.05. The level of FSH after operatiaon in the pituitrin group and control group 2 was less than that in the control group1: (7.20 ± 1.55) U/L, (7.43 ± 1.52) U/L vs. (8.31 ± 0.97) U/L, P<0.05. The level of E 2 3 months after operation in the pituitrin group was higher than that in the control group 1 and control group 2: (54.20 ± 10.90) ng/L vs. (46.63 ± 10.76) ng/L, (43.90 ± 18.23) ng/L, P<0.05. There was no significant difference of LH 3 months after operation among the three groups ( P>0.05). Conclusions:This study shows that diluted pituitrin decreases operation time and the amount of bleeding during operation, at the same time,the pituitrin injection is valued of ovarian reserve.

Factors affecting decreased ovarian reserve among women of childbearing age / 预防医学

Objective@#To investigate the factors affecting decreased ovarian reserve (DOR) among women of childbearing age, so as to provide insights into prevention of DOR.@*Methods@#Women with DOR at ages of 18 to 40 years that were admitted to Department of Gynecology, Ningbo Women and Children's Hospital during the period from January 2021 to June 2022 were recruited (DOR group), while healthy women at ages of 18 to 40 years during the same period served as normal controls. Participants' demographics, exercise, diet, previous medical history, childbearing history and menstruation were collected using questionnaire surveys. The follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Müllerian hormone (AMH) and estradiol (E2) levels were tested. Factors affecting DOR were identified among women of childbearing age using a multivariable logistic regression model.@*Results@#There were 200 participants in the DOR group, with a median (interquartile range) age of 32 (9) years, and 200 participants in the normal group, with a median (interquartile range) age of 29 (12) years. Multivariable logistic regression analysis showed that underweight (OR=2.935, 95%CI: 1.374-6.269), overweight/obesity (OR=2.612, 95%CI: 1.335-5.065), high-oil-high-glucose-high-salt diet (OR=2.653, 95%CI: 1.616-4.357), menstrual disorder (OR=1.977, 95%CI: 1.284-3.041) and lack of exercise (OR=3.392, 95%CI: 2.052-5.606) were statistically correlated with the development of DOR among women of childbearing age.@*Conclusions@#Underweight, overweight/obesity, high-oil-high-glucose-high-salt diet, menstrual disorder and lack of exercise are factors affecting the development of DOR among women of childbearing age.

Treatment Progress in Diminished Ovarian Reserve: Western and Chinese Medicine / 中国结合医学杂志

Diminished ovarian reserve (DOR), generally defined as a decreased number or quality of oocytes, has a significant impact on quality of life and fertility in women. In recent years, the incidence of DOR has been increasing and the ages of patients are younger. The search for an effective DOR treatment has emerged as one of the preeminent research topics in reproductive health. An effective DOR therapy would improve ovarian function, fertility, and quality of life in patients. In this review we evaluated DOR treatment progress both in Western medicine and Chinese medicine, and elucidated the characteristics of each treatment.

Zuogui Pills and Yougui Pills in differential treatment of diminished ovarian reserve based on metabolomics / 中国中药杂志

Based on the metabolomics, this paper systematically analyzed the metabolic substance basis of Zuogui Pills and Yougui Pills in syndrome differentiation and treatment of diminished ovarian reserve(DOR), so as to provide a scientific basis for the traditional Chinese medicine(TCM) syndrome differentiation and treatment of DOR. Patients with DOR of kidney-Yin deficiency syndrome were collected from outpatient department of hospitals and treated with Zuogui Pills for 12 weeks. And kidney-Yang deficiency syndrome were treated with Yougui Pills for 12 weeks. Based on the non-targeted metabolomic research techniques, the potential biomarkers of Zuogui Pills and Yougui Pills in the treatment of DOR with kidney-Yin deficiency and kidney-Yang deficiency, respectively, were screened out, and metabolic pathways of biomarkers were analyzed. The pregnancy rate, basic serum hormone levels [basal follicle-stimulating hormone(bFSH), basal-luteinizing hormone(bLH), basal-estradiol(bE_2), and anti-Müllerian hormone(AMH)], TCM syndrome type score, and Kupperman score were recorded and statistically analyzed after treatment. The results showed that 23 patients with DOR of kidney-Yin deficiency syndrome and 25 patients of kidney-Yang deficiency syndrome were collected. Twenty-six differential metabolites, including L-carnitine, acetyl-CoA, coenzyme A, and coenzyme Q_(10)(CoQ10), were mapped to 12 metabolic pathways in patients with kidney-Yin deficiency treated with Zuogui Pills. Twenty-two differential metabolites, such as adipoyl-CoA, L-lysine, lysine arginine, and α-tocopherol, were mapped to 11 metabolic pathways in patients with kidney-Yang deficiency. After treatment, bFSH and bLH of patients with DOR were significantly lower than those before treatment(P<0.05). Although the comparison of bE_2 and AMH had no significant differences, there was a improvement trend. The TCM syndrome type score and Kupperman score of patients with DOR after TCM treatment were significantly lower than those before treatment(P<0.05).

Mechanism of Liuwei Dihuang Pills in treatment of mice with diminished ovarian reserve based on proteomics / 中国中药杂志

This study aims to investigate the efficacy and possible mechanism of Liuwei Dihuang Pills in the treatment of diminished ovarian reserve(DOR) by using proteomic techniques. Firstly, cyclophosphamide(60 mg·kg~(-1)) combined with busulfan(6 mg·kg~(-1)) was injected intraperitoneally to establish the mouse model of DOR. After drug injection, the mice were continuously observed and the success of modeling was evaluated by the disturbance of the estrous cycle. After successful modeling, the mice were administrated with the suspension of Liuwei Dihuang Pills by gavage for 28 days. At the end of the gavage, four female mice were selected and caged together with males at a ratio of 2∶1 for the determination of the pregnancy rate. Blood and ovary samples were collected from the remaining mice on the next day after the end of gavage. Hematoxylin-eosin(HE) staining and transmission electron microscopy(TEM) were then employed to observe the morphological and ultrastructural changes in the ovaries. The serum levels of hormones and oxidation indicators were measured by enzyme-linked immunosorbent assay. Quantitative proteomics techniques were used to compare the ovarian protein expression before and after modeling and before and after the intervention with Liuwei Dihuang Pills. The results showed that Liuwei Dihuang Pills regulated the estrous cycle of DOR mice, elevated the serum levels of hormones and anti-oxidation indicators, promoted follicle development, protected the mitochondrial morphology of ovarian granulosa cells, and increased the litter size and survival of DOR mice. Furthermore, Liuwei Dihuang Pills negatively regulated the expression of 12 differentially expressed proteins associated with DOR, which were mainly involved in lipid catabolism, inflammatory response, immune regulation, and coenzyme biosynthesis. These differentially expressed proteins were significantly enriched in sphingolipid metabolism, arachidonic acid metabolism, ribosomes, ferroptosis, and cGMP-PKG signaling pathway. In summary, the occurrence of DOR and the treatment of DOR with Liuwei Dihuang Pills are associated with multiple biological pathways, mainly including oxidative stress response, inflammatory response, and immune regulation. "Mitochondria-oxidative stress-apoptosis" is the key to the treatment of DOR by Liuwei Dihuang Pills. YY1 and CYP4F3 may be the key upstream targets that trigger mitochondrial dysfunction and ROS accumulation, and the metabolism of arachidonic acid is the main signaling pathway of drug action.

Effects of Zishen Yutai Pills on in vitro Fertilization-Embryo Transfer Outcomes in Patients with Diminished Ovarian Reserve: A Prospective, Open-Labeled, Randomized and Controlled Study / 中国结合医学杂志

OBJECTIVE@#To explore the effects of Zishen Yutai Pills (ZYPs) on the quality of oocytes and embryos, as well as pregnancy outcomes in patients with diminished ovarian reserve (DOR) receiving in vitro fertilization-embryo transfer (IVF-ET). The possible mechanisms, involving the regulation of bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9), were also investigated.@*METHODS@#A total of 120 patients with DOR who underwent their IVF-ET cycle were randomly allocated to 2 groups in a 1:1 ratio. The patients in the treatment group (60 cases) received ZYPs from the mid-luteal phase of the former menstrual cycle by using gonadotropin-releasing hormone (GnRH) antagonist protocol. The patients in the control group (60 cases) received the same protocol but without ZYPs. The primary outcomes were the number of oocytes retrieved and high-quality embryos. Secondary outcomes included other oocyte or embryo indices as well as pregnancy outcomes. Adverse events were assessed by comparison of the incidence of ectopic pregnancy, pregnancy complications, pregnancy loss, and preterm birth. Contents of BMP15 and GDF9 in the follicle fluids (FF) were also quantified with enzyme-linked immunosorbent assay.@*RESULTS@#Compared with the control group, the numbers of oocytes retrieved and high-quality embryos were significantly increased in the ZYPs group (both P<0.05). After treatment with ZYPs, a significant regulation of serum sex hormones was observed, including progesterone and estradiol. Both hormones were up-regulated compared with the control group (P=0.014 and 0.008), respectively. No significant differences were observed with regard to pregnancy outcomes including implantation rates, biochemical pregnancy rates, clinical pregnancy rates, live birth rates, and pregnancy loss rates (all P>0.05). The administration of ZYPs did not increase the incidence of adverse events. The expressions of BMP15 and GDF9 in the ZYPs group were significantly up-regulated compared with the control group (both P<0.05).@*CONCLUSIONS@#ZYPs exhibited beneficial effects in DOR patients undergoing IVF-ET, resulting in increments of oocytes and embryos, and up-regulation of BMP15 and GDF9 expressions in the FF. However, the effects of ZYPs on pregnancy outcomes should be assessed in clinical trials with larger sample sizes (Trial reqistration No. ChiCTR2100048441).

Effect of laparoscopic ovarian cystectomy on ovarian reserve and the outcomes of in vitro fertilization patients with benign ovarian cysts / 中华妇产科杂志

Objective:To investigate the effect of laparoscopic ovarian cystectomy on anti-Mullerian hormone (AMH) level, ovarian response to gonadotropin stimulation and pregnancy rate for in vitro fertilization (IVF) patients with benign ovarian cysts.Methods:Patients with benign ovarian cysts who were admitted for cystectomy and had undergone IVF treatment were enrolled in the study. There were 373 participants with ovarian cysts underwent laparoscopic ovarian cystectomy in the experimental group. According to duration of post-surgery, there were four sub-groups: 1 year post-surgery (1Y POST), 2 years post-surgery (2Y POST), 4 years post-surgery (4Y POST) and ≥5 years post-surgery (≥5Y POST) in the experimental group. According to histopathologic types of ovarian cysts, there were two sub-groups: ovarian endometriotic cysts and ovarian non-endometriotic cysts. Two hundreds and three patients with no history of ovarian cysts and ovarian surgery were in the control group. The level of AMH and basic concentrations of follicle stimulating hormone (FSH), luteinizing hormone (LH), progesterone (P), estradiol (E 2) were measured. Antral follicle counts (AFC) were calculated. There were other study variables: total dose of gonadotropins, duration of ovarian stimulation, the number of oocyte retrieved, the number of embryo obtained, blastocyst transfer rate and pregnancy rate. Results:The control group was matched as closely as possible to the experimental group, including age, body mass index and menstrual cycle (all P>0.05). Compared to the women in control group, the women in ovarian endometriotic cystectomy sub-group had significantly higher levels of basal FSH and basal P, lower level of AMH (all P<0.05); the women in ovarian endometriotic cysts sub-group had significantly higher dose of gonadotropins (all P<0.05); the women in ovarian endometriotic cysts ≥5Y POST sub-group had significantly lower number of oocyte retrieved, lower number of embryo obtained, lower blastocyst transfer rate, and lower pregnancy rate (all P<0.05). Compared to the women in control group, the women in ovarian non-endometriotic cysts sub-group had a significantly higher level of basal FSH and basal P (all P<0.05). The women in ovarian non-endometriotic cysts sub-group had lower level of AMH, higher dose of gonadotropins, lower number of oocyte retrieved, lower number of embryo obtained, lower rate of blastocyst transfer and lower rate of pregnancy than the control group but there were no statistically significant differences among them (all P>0.05). The women with unilateral ovarian endometriotic cysts had significantly lower number of oocyte retrieved on the side of surgery than another side ( P<0.05). Conclusions:In short term laparoscopic ovarian cystectomy has no significant effect on ovarian reserve. But with long-term follow-up ovarian reserve, ovarian response to gonadotropin stimulation and pregnancy rate are decreased. The effect of laparoscopic ovarian cystectomy in benign cysts on ovarian is associated with whether or not it is the surgical side.

Prevention and Treatment of Age-related Ovarian Hypofunction with Traditional Chinese Medicine： A Review / 中国实验方剂学杂志

Age-related ovarian hypofunction includes a decrease in follicle quantity and quality as well as alterations in the ovarian microenvironment，the mechanisms of which are mainly related to mitochondrial dysfunction，free radical and antioxidant systems，telomere and telomerase alterations，and apoptosis，and is one of the major factors contributing to infertility in advanced maternal age （AMA）. Despite the tremendous progress in assisted reproductive technology in recent decades，few breakthroughs have been made in alleviating age-related ovarian hypofunction and improving reproductive outcomes for AMA. In recent years，there has been an increasing number of studies on the multi-level and multi-targeted mechanisms of traditional Chinese medicine （TCM） to improve age-related ovarian hypofunction by modulating mitochondrial homeostasis，alleviating oxidative stress，and inhibiting apoptosis，while more high-quality randomized controlled trials have demonstrated the clinical efficacy of TCM in assisted reproductive technology. Given this，this article presented a systematic review of recent research and randomized controlled trials on the mechanism of Chinese medicine active ingredients，single Chinese medicine， and Chinese medicine compounds in delaying age-related ovarian hypofunction，to clarify the current status and shortcomings of the research. This paper provides medication management of TCM for effectively alleviating age-related ovarian hypofunction and improving reproductive outcomes for AMA.

Principales disruptores endocrinos vinculados con salud reproductiva femenina: bases biológicas de su asociación / Main endocrine disruptors related to female reproductive health: biological basis of their association

Resumen Se denominan disruptores endocrinos (DEs) a aquellas sustancias químicas capaces de interferir con la homeostasis hormonal, alterando la síntesis, función, almacenamiento y/o metabolismo de las hormonas. Estas sustancias se encuentran en el ambiente y en una amplia variedad de productos de uso diario, por lo que la exposición humana es permanente. Experimentos con animales han confirmado la capacidad de los DEs para inducir desórdenes reproductivos, por lo que se ha sugerido que podrían ser un factor importante como causa de subfertilidad humana. El bisfenol A, los ftalatos y los compuestos orgánicos persistentes son tres tipos de DEs presentes en el medio ambiente y asociados con alteraciones reproductivas. Consultando las bases de datos MEDLINE y PubMed, en la presente revisión, se reúne bibliografía de los últimos 20 años donde se evalúan los efectos provocados por la exposición a los DEs mencionados en mujeres durante la vida adulta. Se resumen los efectos sobre marcadores de reserva ovárica y los resultados de tratamientos de fertilización in vitro. Por otro lado, se evalúa la evidencia a nivel molecular de los efectos provocados por los DEs sobre la fisiología reproductiva en estudios in vitro e in vivo.

Abstract Endocrine disruptors (EDs) are those chemical substances capable of interfering with hormonal homeostasis, altering the synthesis, function, storage and / or metabolism of hormones. These substances are found in the environment and in a wide variety of products for daily use, so human exposure is permanent. Animal experiments have confirmed the capacity of EDs to induce reproductive disorders, which is why it has been suggested that they could be an important factor in causing human subfertility. Bisphenol A, phthalates and persistent organic compounds are three types of EDs present in the environment and associated with reproductive disorders. Consulting the MEDLINE and PubMed databases, in this review, a bibliography of the last 20 years is gathered where the effects caused by exposure to the mentioned EDs in women during adult life are evaluated. The effects on ovarian reserve markers and the results of in vitro fertilization treatments are summarized. On the other hand, the evidence at the molecular level of the effects caused by EDs on reproductive physiology is evaluated in in vitro and in vivo studies.

Prevention of Premature Ovulation by Administration of Gonadotropin Releasing Hormone Antagonist the day After Ovulation Triggering in Diminished Ovarian Reserve Patients / Prevenção da ovulação prematura por meio da administração de antagonismo de liberação de gonadotropismo no dia seguinte à ovulação

Abstract Objective The aim of the present retrospective study was to investigate the effectiveness of single-dose gonadotropin releasing hormone (GnRH) antagonist administration, the day after human chorionic gonadotropin (hCG) triggering for final oocyte maturation, on the prevention of premature luteinization in patients with diminished ovarian reserve in in-vitro fertilization (IVF) cycles. The secondary objective of the study was to search the effect of this protocol on pregnancy outcomes. Methods This is a retrospective study including 267 infertile patients who have single antral follicle seen with ultrasonography on the 2nd or 3rd day of the menstrual cycle before starting IVF treatment. We randomized patients into two groups. The case group comprised patients who had single-dose GnRH antagonist injection the day after hCG triggering formed, and the patients who had the standard treatment regime formed the control group. In both groups, the oocytes were collected 36 hours after hCG injection. Results The premature ovulation rate was significantly low in the case group compared with the control group (6.86 versus 20.6% per scheduled cycle) (p=0.022). Also, the oocyte retrieval rate (93.14 versus 67.87% per scheduled cycle) (p=0.013), the oocyte maturity rate (79.42 versus 47.87%) (p=0.041), the fertilization rate (65.68 versus 34.54%) (p=0.018), and the embryo transfer rate per scheduled cycle (44.11 versus 18.78%) (p=0.003) were higher in the GnRH antagonist group than in the control group. Conclusion The administration of GnRH antagonist the day after hCG trigger in IVF treatments of patients with diminished ovarian reserve enabled a significant decrease in the rate of premature ovulation but had no effect on live birth rate.

Resumo Objetivo O objetivo do presente estudo retrospectivo foi investigar a eficácia da administração do antagonista do hormônio liberador da gonadotrofina (GnRH) em dose única no dia seguinte ao desencadeamento da gonadotrofina coriônica humana (hCG) para a maturação final do oócito, na prevenção da luteinização prematura em pacientes com diminuição do ovário reserva em ciclos de fertilização in vitro (FIV). O objetivo secundário do estudo foi pesquisar o efeito deste protocolo nos resultados da gravidez. Métodos Trata-se de um estudo retrospectivo incluindo 267 pacientes inférteis que apresentam um único folículo antral visto por ultrassonografia no 2° ou 3° dia do ciclo menstrual antes de iniciar o tratamento de FIV. Nós randomizamos os pacientes em dois grupos. Os pacientes que receberam injeção de antagonista de GnRH em dose única no dia seguinte ao desencadeamento do hCG formaram o grupo caso, e os pacientes que receberam o regime de tratamento padrão formaram o grupo controle. Em ambos os grupos, os oócitos foram coletados 36 horas após a injeção de hCG. Resultados A taxa de ovulação prematura foi significativamente baixa no grupo caso em comparação com o grupo controle (6,86 versus 20,6% por ciclo programado) (p=0,022). Além disso, a taxa de recuperação de oócitos (93,14 versus 67,87% por ciclo programado) (p=0,013), a taxa de maturidade do oócito (79,42 versus 47,87%) (p=0,041), a taxa de fertilização (65,68 versus 34,54%) (p=0,018) e a taxa de transferência de embriões por ciclo programado (44,11 versus 18,78%) (p=0,003) foram maiores no grupo antagonista de GnRH do que no grupo controle. Conclusão A administração de antagonista de GnRH, no dia seguinte ao desencadeamento de hCG em tratamentos de FIV de pacientes com reserva ovariana diminuída permitiu uma redução significativa na taxa de ovulação precoce,mas não teve efeito na taxa de nascidos vivos.

Ovarian Tissue Culture to Preserve Fertility in Transgender Male Patients after Hormonal Treatment / Cultura de tecido ovariano para preservação da fertilidade em pacientes transexuais masculinos após tratamento hormonal

Abstract Objective To evaluate the reproductive and histological characteristics of fresh cultured ovarian tissue from transgender male patients. Methods An in vitro pilot study in which samples were collected during sex reassignment surgery for transgender male patients. The ovarian cortex was cut into fragments of 2 mm, 3mm, and 4 mm, and placed in a 96-well plate suitable for cultivation at days 0, 2, 4, 6, and 8, when the histology was analyzed. Results Stromal hyperplasia was observed in all samples, and it was not associated with the obtainment of primordial or primary follicles. Peripheral reduction in cell count was also a recurrent finding. Primordial and primary follicles were identified with a heterogeneous pattern in fragments from the same patient and from different patients, and follicles in more advanced stages of development (secondary and antral) were not found. There was an association between the diameter of the ovarian fragments and the identification of primary follicles (p=0.036). The number of days in culture was associated with histological signs of tissue damaging in the fragments (p=0.002). The total number of follicles identified in the samples with 2mm in diameter was significantly lower than in those that measured 4mm in diameter (p=0.031). Conclusion A diameter of 4mm is suitable for ovarian tissue culture with the benefit of ease of handling. Even after prolonged exposure to testosterone, the ovarian fragments presented primordial and primary follicles, maintaining viability throughout the days they were exposed to the culture. Freezing the ovarian cortex of transgender patients who will undergo surgery for gender reassignment would be an interesting option, in the future, for the preservation of fertility.

Resumo Objetivo Avaliar as características reprodutivas e histológicas de tecido ovariano cultivado a fresco de pacientes transexuais masculinos. Métodos Estudo experimental in vitro e piloto, no qual amostras foram coletadas durante a cirurgia de redesignação de sexo para pacientes transexuais masculinos. O córtex ovariano foi cortado em fragmentos de 2mm, 3mm, e 4mm, e colocado em placa de 96 poços própria para cultivo nos dias 0, 2, 4, 6 e 8, quando a histologia foi analisada. Resultados Hiperplasia estromal foi observada em todas as amostras, e não esteve associada à obtenção de folículos primordiais ou primários. A redução periférica no número de células também foi um achado recorrente. Folículos primordiais e primários foramidentificados com padrão heterogêneo emfragmentos domesmo paciente e em fragmentos de pacientes diferentes, não sendo encontrados folículos em estágios mais avançados de desenvolvimento (secundários e antrais). Houve associação entre o diâmetro dos fragmentos ovarianos e a identificação dos folículos primários (p=0,036). O número de dias de cultura esteve associado a sinais histológicos de lesão tecidual nos fragmentos (p=0,002). O número total de folículos identificados nas amostras de 2mm de diâmetro foi significativamente menor do que nas de 4mm de diâmetro (p=0,031). Conclusão O diâmetro de 4mm parece ser mais adequado para a cultura de tecido ovariano com a vantagem de fácil manejo. Mesmo após exposição prolongada à testosterona, os fragmentos ovarianos apresentavam folículos primordiais e primários, e manteve a viabilidade ao longo dos dias de exposição à cultura. No futuro, o congelamento da cortical do ovário de pacientes transgêneros que se submeterão à cirurgia de redesignação sexual poderia ser uma opção interessante para a preservação da fertilidade.

Analysis of related factors and prediction of poor ovarian response in patients with controlled ovarian stimulation / 中华妇产科杂志

Objective:To explore the related factors of poor ovarian response (POR) in patients receiving controlled ovarian stimulation (COS) and to establish the nomogram for predicting POR in patients who received in vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI).Methods:In this retrospective research, clinical data of 17 164 cycles of patients who received IVF/ICSI treatment at Henan Provincial People′s Hospital from September 1st, 2016 to September 1st, 2020 were analyzed. Independent correlative factors affecting the occurrence of POR were screened by logistic regression, which were the model enrollment variables in the prediction model. Totally 13 266 cycles with well-record of enrollment variables were screened, and these data were randomly divided into model group (9 896 patients) and validation group (3 370 patients) according to 3∶1. The nomogram was established according to the regression coefficient of the relevant variables. The prediction accuracy of the nomogram was evaluated by calculating area under the receiver operating characteristic curve (AUC).Results:Multivariate logistic regression analysis showed age, infertility type, body mass index, anti-Müllerian hormone, basal follicle stimulating hormone, basal estrogen, antral follicle number, previous times of POR, history of ovarian surgery, ovulation stimulation protocol and average amount of gonadotropin were independent correlative factors affecting the occurrence of POR (all P<0.05). In the model group, according to the above factors, the prediction model and nomogram of POR risk were constructed and the validation group verified the model. The AUC of the model group was 0.893 (95% CI: 0.885-0.900), and the AUC of the validation group was 0.890 (95% CI: 0.878-0.903). Conclusion:The influencing factors of POR after COS in patients treated by IVF/ICSI are screened, and the nomogram for predicting POR established in this study is proved to be effective, simple, intuitive and clear in predicting the occurrence of POR.

The value of serum anti-Mullerian hormone combined with transvaginal color Doppler ultrasonography in predicting ovarian reserve function in infertility patients / 中国医师进修杂志

Objective:To investigate the predictive value of serum anti-Mullerian hormone (AMH) combined with transvaginal color Doppler ultrasonography (vaginal color ultrasound) for ovarian reserve function in infertility patients.Methods:A total of 105 infertility patients diagnosed and treated in Dezhou People′s Hospital from January 2018 to October 2020 were selected as study subjects. Among them, 32 patients with less than 5 eggs obtained after the first treatment (low ovarian response) were included in group A, and 73 patients with 5 to 15 eggs obtained (normal ovarian response) were included in group B. Serum AMH levels were measured, antral follicle count (AFC), ovarian volume (OV), and ovarian stromal peak diastolic systolic velocity (PSV) were recorded by vaginal ultrasound. The levels of above index in A, B groups, patients aged > 35 years old, and those aged ≤35 years old were compared. Moreover, the correlation among serum AMH level and aged, ultrasonic parameters were analyzed. The efficacy of serum AMH level and AFC, OV and PSV in predicting low ovarian response was analyzed by receiver operating characteristic (ROC) curve.Results:The levels of serum AMH, AFC, OV and PSV in group A were lower than those in group B: (0.69 ± 0.28) μg/L vs. (1.43 ± 0.44) μg/L, (8.52 ± 2.29) eggs vs. (11.15 ± 2.56) eggs, (3.12 ± 0.70) cm 3 vs. (4.50 ± 1.31) cm 3, (8.80 ± 2.14) cm/s vs. (15.80 ± 4.43) cm/s, the differences were statistically significant ( P<0.05). The levels of serum AMH, AFC, OV and PSV in aged > 35 years old group were lower than those in aged ≤35 years old group: (0.64 ± 0.20) g/L vs. (1.71 ± 0.46) μg/L, (8.35 ± 2.68) eggs vs. (12.17 ± 2.79) eggs, (3.05 ± 0.78) cm 3 vs. (5.02 ± 1.26) cm 3, (9.01 ± 3.04) cm/s vs. (17.90 ± 4.19) cm/s, the differences were statistically significant ( P<0.05). Serum AMH level was negatively correlated with age ( r = -0.317, P<0.05), and positively correlated with AFC, OV and PSV ( r = 0.288, 0.326, 0.370, P<0.05). The sensitivity and specificity for the evaluation of low ovarian response by AMH+AFC+OV+PSV were 96.90% and 100.00% respectively. Conclusions:The sensitivity and specificity of serum AMH combined with vaginal color ultrasound for the evaluation of ovarian reserve function in infertility patients are both high.

Effect of Siwutang on Diminished Ovarian Reserve in Rats Based on 16S rRNA Sequencing of Intestinal Flora / 中国实验方剂学杂志

ObjectiveTo study the effect of Siwutang （SWT） on intestinal flora in rats with diminished ovarian reserve （DOR） induced by Tripterygium wilfordii polyglycoside （TWP） based on 16S rRNA sequencing. MethodTwenty 8-week-old female SD rats were randomly assigned into four groups： blank group， model group， SWT high-dose group， and SWT low-dose group. Except the blank group， the other three groups were underwent intragastric administration of TWP tablets at a dose of 50 mg·kg-1 for 14 days. On day 15， the high-dose group was administrated at 3 times of the human dosage （40 g/person/day）， the low-dose group at 1.5 times of the human dosage， and the model group and the blank group with the same volume of normal saline for 18 days. Then， feces were collected for 16S rRNA sequencing. One hour after administration， blood was sampled from abdominal aorta after anesthesia for the measurement of hormone levels by radioimmunoassay， and ovaries were sampled， embedded， sliced， and stained with haematoxylin-eosin （HE） for pathological observation. ResultThe model group had higher level of luteinizing hormone （LH， P<0.05） and lower level of estradiol （E2， P<0.05） than the blank group. The SWT high-dose group and low-dose group had lower LH levels （P<0.05） and higher E2 levels than the model group （P<0.05）. SWT reversed the elevation in follicle-stimulating hormone （FSH） and LH levels and the decline in E2 and progesterone （P） levels caused by TWP to some extent. There were a large number of follicles at different developmental stages in the blank group， while atretic follicles increased significantly in the model group. A large number of mature follicles， secondary follicles， and primary follicles were observed in the high-dose SWT group， and primordial follicles， secondary follicles， and increased corpus luteum in the low-dose SWT group. Compared with that in the blank group and the administration group， the abundance of Verrucomicrobia and Epsilonbacteraeota in the model group significantly reduced. Compared with the blank group， the model group had different intestinal flora in phylum， class， order， family， and genus levels. Specifically， the model group had increased proportions of Firmicutes and Bacteroidetes. After TWP modeling， the abundance of Lachnospiraceae decreased significantly while that of Ruminococcaceae UCG-005 increased significantly. SWT groups， blank group， and model group can be clearly distinguished， and SWT groups had a tendency to approach the blank group. ConclusionSWT may improve the ovarian function of rats with TWP-induced DOR by regulating intestinal flora diversity.

The regulation of ovarian reserve function by Zuogui pills combined with cetrorelix / 药学学报

The purpose of this study was to investigate how Zuogui pills from the Kidney-tonifying and Nourishing Yin formula, in combination with the gonadotrophin-releasing hormone antagonist cetrorelix, affected the ovarian local oxidative stress response in decreasing ovarian reserve (DOR) mice. All animal experiments were carried out in accordance with the guidelines and standards established by Jinan University's Experimental Animal Management Committee. Cyclophosphamide (CTX)-treated DOR mice were given Zuogui pills, cetrorelix, or a combination of the two drugs intragastrically. After treatment, there were changes in the estrous cycle, serum sex hormone levels, oxidative stress-related indexes, growth biochemical factor levels, and SIRT1/P53/P21 expression. In comparison to the model group, the Zuogui pills and the cetrorelix+Zuogui pills group had significantly prolonged estrous periods and shortened interestrous periods, and the cetrorelix+Zuogui pills group had a significantly shortened cycle length. Follicle-stimulating hormone (FSH) decreased and estradiol (E2) increased in all treatment groups compared to the model group, oxidative stress indexes nitric oxide synthase (NOS), nitric oxide (NO), and reactive oxygen species (ROS) decreased, growth biochemical factors brain derived neurotrophic factor (BDNF) and growth differentiation factor 9 (GDF-9) concentrations increased significantly, and leukemia inhibitory factor (LIF) showed no significant change. SIRT1/P53/P21 immunohistochemical results revealed that, when compared to the model group, the expression of SIRT1 increased while the expression of P53 and P21 proteins decreased in all treatment groups, with the cetrorelix+Zuogui pills group having the largest decrease, with significant differences in all indicators. We conclude that cetrorelix combined with Zuogui pills for kidney nourishing and Yin recipe improved the oxidative stress response in the follicle by regulating the SIRT1/P53/P21 pathway, reducing peroxide product production, protecting ovarian function, and regulating ovarian hormone secretion, and its efficacy is superior to that of cetrorelix or Zuogui pills alone.

Effects of Bushen Yiqi Huoxue Decoction in Treatment of Patients with Diminished Ovarian Reserve: A Randomized Controlled Trial / 中国结合医学杂志

OBJECTIVE@#To explore the therapeutic effect of Bushen Yiqi Huoxue Decoction BYHD) in patients with diminished ovarian reserve (DOR).@*METHODS@#A total of 180 patients with DOR diagnosed from December 2013 to December 2014 were equally assigned into progynova and duphaston (E+D) group, Zuogui Pill group and BYHD group with 60 cases in each by computerized randomization. Patients received E+D, Zuogui Pill or BYHD for 12 months, respectively. Follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), anti-Müllerian hormone (AMH), antral follicle count (AFC), ovarian volume, endometrial thickness, and the resistance indices (RIs) of ovarian arteries and uterine arteries were observed before and after treatment.@*RESULTS@#Nine women (4 from the E+D group, 3 from the Zuogui Pill group, and 2 from the BYHD group) withdrew from the study. After 6 months, Zuogui Pill and BYHD significantly decreased FSH and LH and increased endometrial thickness and AMH (all P<0.01). BYHD also resulted in E2 elevation (P<0.05), ovary enlargement (P<0.05), AFC increase (P<0.01), and RI of ovarian arteries decrease (P<0.05). After 12 months, further improvements were observed in the Zuogui Pill and BYHD groups (all P<0.01), but BYHD showed better outcomes, with lower FSH, larger ovaries and a thicker endometrium compared with the Zuogui Pill group (all P<0.01). However, E+D only significantly increased endometrial thickness (P<0.01) and no significant improvements were observed in the RI of uterine arteries in the three groups.@*CONCLUSIONS@#BYHD had a favorable therapeutic effect in patients with DOR by rebalancing hormone levels, promoting ovulation, and repairing the thin endometrium. The combination of tonifying Shen (Kidney), benefiting qi and activating blood circulation may be a promising therapeutic strategy for DOR.

LIU Zhi-shun's experience in treatment of infertility with decreasing ovarian reserve with electroacupuncture / 中国针灸

To summarize LIU Zhi-shun's clinical experience in treatment of infertility with decreasing ovarian reserve (DOR) with electroacupuncture. LIU Zhi-shun believes that the location of infertility with DOR is the uterus, mainly involving the kidney, thoroughfare and conception vessels. He advocates to select acupoints by combining "disease-symptom-position" with prescription, and selects acupoint prescription of Bushen Tiaochong Zhuyun included Guanyuan (CV 4), Zigong (EX-CA 1), Tianshu (ST 25), Sanyinjiao (SP 6), Ciliao (BL 32) and Zhongliao (BL 33) for electroacupuncture treatment. The key points of operation are accurate positioning and deep acupuncture, focusing on regulating mind and getting qi, adopting electroacupuncture treatment and low frequency stimulation and treating slowly for long-term disease.