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.

Clinical and laboratory differences between chromosomal and undefined causes of non-obstructive azoospermia: A retrospective study

ABSTRACT BACKGROUND: Knowledge of clinical and laboratory differences between chromosomal and undefined causes aids etiological research on non-obstructive azoospermia. OBJECTIVE: Compare clinical and laboratory differences between men with non-obstructive azoospermia due to chromosomal anomalies versus undefined causes DESIGN AND SETTING: A cross-sectional retrospective study conducted at a public university hospital in Campinas (Brazil) METHODS: All men aged 20-40 years with non-obstructive azoospermia were included in the analysis. RESULTS: The 107 cases included 14 with Klinefelter syndrome (KS) (13%), 1 with mosaic KS, 4 with sex development disorders (2 testicular XX, 1 NR5A1 gene mutation, and 1 mild androgen insensitivity syndrome) (4%), 9 with other non-obstructive azoospermia etiologies (8%), and 79 with undefined causes. The 22 chromosomal anomaly cases (14 KS, 1 mosaic KS, 2 testicular XX, 4 sex chromosome anomalies, and 1 autosomal anomaly) were compared with the 79 undefined cause cases. The KS group had lower average testicular volume, shorter penile length, and lower total testosterone levels but greater height, arm span, serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, and gynecomastia frequency (absent in the undefined group and affecting more than half of the KS group). Patients with testicular XX DSD had LH, FSH, and penile length data intermediate between the KS and undefined cause groups, testicular volume similar to the KS group, and other data similar to the undefined group. CONCLUSION: Clinical and laboratory data differentiate men with non-obstructive azoospermia and chromosomal anomalies, particularly KS and testicular XX, from those with undefined causes or other chromosomal anomalies.

Association of raised serum progesterone level with ovulation trigger and histology of endometrium in stimulated cycles

Abstract This was a forthcoming study of those patients, who undergo in-vitro fertilization (IVF) and freeze-all embryo, who acquiesce for the study. The number of participated patients (n=350) in this study, underwent for IVF. The blood sample was collected from patients to evaluate the level of serum progesterone in vacuum vials on the day of ovulation trigger. After 36 hrs of ovulation trigger, ovum picked up was done. Quantitative methods were used to estimate the level of serum progesterone through the electrochemiluminescence immunoassay and correlation of serum progesterone with embryo transfer (ET) outcomes. Main outcome of this current study was to evaluate the value of mean serum progesterone level i.e.0.868± 0.712 ng/ml and 0.88±0.723 ng/ml was found in case of pregnancy positive and negative respectively, at p=0.216 value. In antagonist (n=40) and agonist (n=310) cases, it was 8(20%) and 37(11.94%) PL occurrence was noted at p=0.143 respectively. An overall value of the premature lutenization (PL) occurrences was 13.63% and 15.25% observed in both positive and negative cases of pregnancy at p=0.216 respectively. This study concluded that 12.66% of PL occurrences were recorded in the case of IVF. Study results proved, there were no significant effect of PL on pregnancy outcomes.

Pasado presente y futuro de la estimulación ovárica en el tratamiento de la infertilidad / Past, present and future of ovarian stimulation in infertility treatment

La mejor comprensión de la fisiología reproductiva y la disponibilidad de más y mejores recursos diagnóstico/terapéuticos permiten individualizar la estimulación ovárica y hacerla más efectiva (mejores resultados), eficiente (en menos tiempo y con dosis más bajas), segura (con menos y más leves complicaciones), cómoda (menos molestias y autonomía) y accesible (para más personas, a menores costos). Con tecnología de ADN recombinante se dispone ahora de todas las gonadotrofinas e incluso algunas con formas moleculares modificadas para aumentar la duración de acción y disminuir el número de inyecciones. El esquema más utilizado es el de FSH recombinante junto con antagonistas de GnRH. Hay indicaciones específicas para agregar LH o coadyuvantes como hGH o andrógenos transdérmicos. La estimulación ovárica, además de infertilidad, se usa para la preservación de la fertilidad. Cada vez se implementan más estrategias como acumulación de óvulos, esquemas no convencionales (random start, DuoStim y otros) junto a vitrificación ovular, estudio genético preimplantatorio, transferencias embrionarias diferidas y la investigación continúa. Se pronostican mejoras en un futuro próximo, entre otras antagonistas por vía oral y estudio genético de pacientes para diagnosticar mutaciones o polimorfismos de gonadotrofinas y sus receptores. Aunque ya es factible individualizar la estimulación y volverla más efectiva, segura y amigable, así como ofrecer otras opciones a pacientes de mal pronóstico.

Due to an increased understanding of reproductive physiology and to the availability of more and better diagnostic/therapeutic agents, ovarian stimulation through individualization, has become more effective (improved results), efficient (shorter span and lower doses), safe (less and milder complications), comfortable (less discomfort and dependance) and affordable (for more people at lower cost). All gonadotrophins are now available by recombinant DNA technology, including some modified compounds for specific purposes such as longer action and fewer injections. The most popular ovarian regime uses recombinant FSH and GnRH antagonist. There are precise indications for adding LH or adjuncts like hGH or transdermal androgens. Besides infertility, ovarian stimulation is also indicated for fertility preservation. Strategies like oocyte accumulation, non-conventional stimulation protocols (random start, DuoStim and others), oocyte vitrification, preimplantation genetic testing, freeze-all, deferred embryo transfer for particular cases are becoming popular, and the research still goes on. Future advances like oral GnRH antagonists, and the study of mutations and polymorphisms for gonadotropins and its receptors are foreseen. Today through individualization, ovarian stimulation is safe, effective and friendly, also we can offer good options to bad prognosis patients

Impact of trigger timing of gonadotropin-releasing hormone antagonist regimen for infertility patients of various ages / 中华妇产科杂志

Objective:To investigate the impact of trigger timing of gonadotropin- releasing hormone (GnRH) antagonist regimen for infertility patients of various ages.Methods:This was a retrospective study, 1 529 infertility patients who receiving GnRH antagonist regimen in Chongqing Health Center for Women and Children from January 2017 to December 2018 were divided into the advance trigger group and the standard trigger group, and further divided into three subgroups according to age:<35 years, 35-40 years,>40 years. The number of retrieved oocytes and transplantable embryos, the clinical pregnancy rate and the live birth rate among patients in the advance trigger group and standard trigger group in various age subgroups were compared.Results:(1) The gonadotropin (Gn) days among the three age subgroups were significantly shorter in the advance trigger group compared to the same-aged standard trigger group (all P<0.01), but only in the 35－40 years and >40 years subgroups, the Gn doses in the advance trigger group [(2 702±551) and (2 780±561) U] were significantly less than those in the standard trigger group (all P<0.01). In the <35 years subgroup, the number of oocytes retrieved and transplantable embryos of the advance trigger group (6.6±4.8 and 2.6±2.7) were significantly less than those of the standard trigger group (all P<0.01), but there was no difference in the number of top-quality embryos ( P=0.580); however, in the 35－40 years and >40 years subgroups, there were no significant differences between advance and standard trigger groups in terms of the afore mentioned 3 indicators (all P>0.05), only the numbers of top-quality embryos in the advance trigger group (0.6±1.0 and 0.6±0.9) were significantly higher than those in the standard trigger group (all P<0.01). (2) In the <35 years and 35－40 years subgroups, no significant differences were noted between the advance trigger group and standard trigger group with regard to the clinical pregnancy rate and live birth rate (all P>0.05); but in the >40 years subgroup, the clinical pregnancy rate of the advance trigger group was significantly higher than that of the standard trigger group [33.0% (30/91) vs 19.2% (25/130), P=0.020], and there was no statistical difference in the live birth rate ( P=0.064). (3) Multivariate logistic regression analysis showed that trigger timing was an independent predictor of clinical pregnancy rate in the >40 years subgroup ( OR=0.334, 95% CI: 0.119-0.937, P=0.037), but not an independent predictor of live birth rate ( P>0.05). Conclusions:Advance trigger in the GnRH antagonist protocol for infertility patients >40 years old could effectively reduce Gn times and Gn dosage, increase the number of top-quality embryos, and improve the clinical pregnancy rate. Therefore, compared with patients ≤40 years of age, patients >40 years might benefit more from advance trigger.

Evaluation of gonadotropin-replacement therapy in male patients with hypogonadotropic hypogonadism / 亚洲男科学杂志(英文版)

Hypogonadotropic hypogonadism (HH) is a rare disease in which medical treatment has a high success rate to achieve fertility. This study aimed to analyze the efficacy of hormone replacement therapy and determine predictive factors for successful spermatogenesis and spontaneous pregnancy in patients with idiopathic HH. A total of 112 patients with low testosterone (T), luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and normal prolactin levels were diagnosed with HH and administered LH and FSH analogs as hormone replacement therapy. During treatment, 96 (85.7%) patients had sperm present in ejaculate samples. Among these patients, 72 were married and wanted a child. Of these 72 patients, 48 (66.7%) of couples had pregnancies from natural conception. After initiation of treatment, the mean time for the appearance of sperm in semen was 9.48 months. There were no significant differences between baseline FSH, T, and LH levels; however, older age, larger testicular size, and low rate of undescended testes were favorable factors for successful spermatogenesis. Larger testicular size and older age were also the main predictive factors for natural conception. We found that patients with undescended testes had a younger age, smaller testes, and lower T levels compared with patients exhibiting descended testes. The rate of sperm found in the ejaculate was not significantly decreased in patients with undescended compared with descended testis (73.7% vs 87.6%, P = 0.261). The medical approach for males with HH and azoospermia provides a successful treatment modality in regard to successful spermatogenesis and achievement of pregnancy.

Effect of electroacupuncture at different acupoints on follicle development and related factors in serum and ovary tissues of PCOS rats / 针刺研究

OBJECTIVE: To observe the effect of electroacupuncture (EA) at different acupoints on follicle development, expression of gonadotropins and their receptors and anti-Müllerian hormone(AMH), inhibin B(INHB) in polycystic ovarian syndrome (PCOS) rats, so as to explore its mechanisms underlying improvement of PCOS. METHODS: Sixty female SD rats were randomized into six groups: control, model, Zusanli(ST36), Sanyinjiao(SP6), Guanyuan(CV4) and combination (ST36+SP6+CV4, n=10 rats/group). The PCOS model was established by gavage of Letrozole solution (1.0 mg/kg) once daily for 21 consecutive days. Rats of the control group were given 1% Carboxymethyl Cellulose (CMC, 1 mg/kg). EA (2 Hz) was applied to ST36, SP6, or/and CV4 for 20 min, once daily for 14 consecutive days. The number of follicles was counted, and the ovarian structure and follicular development were observed under light microscope after H.E. stain, and the contents of serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), AMH, and INHB were assayed by enzyme-linked immunosorbent assay, and the ratio of LH/FSH was calcula-ted. The immunoactivity of LH receptor (LHR) and FSH receptor (FSHR) proteins was detected by immunohistochemistry. RESULTS: After modeling, the number of follicles at the growth stage, contents of serum LH, AMH and INHB, and ratio of LH/FSH were significantly increased, and serum FSH level and FSHR, LHR immunoactivity were remarkably decreased in the model group relevant to the control group (P0.05). CONCLUSION: EA of CV4, SP6, ST36 and ST36+CV4+SP6 can reduce the number of follicles at the growth stage and regulate the expression levels of gonadotropins in PCOS rats. The effects of EA of CV4 and ST36 are evidently better than those of EA of SP6 in up-regulating serum FSH content and in down-regulating LH/FSH ratio, and serum AMH and INHB levels, and EA of SP6 is evidently superior to EA of CV4 down-regulating LH level, but without synergistic effect among the 3 acupoints.

An in vitro prototype of a porcine biomimetic testis-like cell culture system: A novel tool for the study of reassembled Sertoli and Leydig cells / 亚洲男科学杂志(英文版)

At present, there is no reliable in vitro assembled prepubertal testis.like biomimetic organ culture system designed to assess the functional effects of human gonadotropins on Sertoli and Leydig cells. Spermatogenesis is regulated by endocrine, paracrine, and juxtacrine factors (testicular cross-talk), mainly orchestrated by gonadotropins such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH) that play a pivotal role by stimulating Leydig and Sertoli cells, respectively. The aim of our study was to set up an in vitro prepubertal porcine bioengineered construct as a new model for experimental studies on reassembled Sertoli and Leydig cells. We have evaluated Sertoli and Leydig cells obtained from 15- to 20-day-old neonatal pig testes in terms of purity and function. Subsequently, purified Sertoli and enriched Leydig cells were subjected to coincubation to obtain an in vitro prepubertal porcine testis-like culture system. We performed enzyme-linked immunosorbent assay (ELISA) for anti-Müllerian hormone (AMH), inhibin B, and testosterone secretion in the medium, and Real-Time PCR analysis of AMH, inhibin B, FSH-r, aromatase, LHr, and 3β-HSD mRNA expression levels. This in vitro testis-like system was highly responsive to the effects of human gonadotropins and testosterone. AMH mRNA expression and secretion declined, and inhibin-B increased, while FSH-receptor expression was downregulated upon FSH/LH exposure/treatment. Finally, the production of testosterone was increased selectively upon LH treatment. In summary, our proposed model could help to better determine the action of human gonadotropins on Sertoli and Leydig cells. The potential usefulness of the system for shedding light into male infertility-related issues is evident.

Tasas de embarazo en el primer ciclo de inseminación intrauterina en pacientes estimuladas con gonadotropinas según el desarrollo folicular y edad / Pregnancy rates in the first cycle of intrauterine insemination with gonadotropin stimulation in relation to number of follicles and age

Resumen OBJETIVO: conocer la tasa de embarazo clínico en el primer ciclo de inseminación intrauterina en pacientes estimuladas con gonadotropinas, según la cantidad de folículos maduros desarrollados y la edad, así como la influencia de los antagonistas de GnRH en su desarrollo y en la tasa de embarazo. MATERIALES Y MÉTODOS: estudio analítico y retrospectivo efectuado para evaluar el primer ciclo de inseminación intrauterina en las pacientes atendidas en el Instituto Nacional de Perinatología Isidro Espinosa de los Reyes entre enero de 2015 y diciembre de 2016, con diferentes protocolos de gonadotropinas. La muestra se dividió en grupos: menores de 35 y mayores de esta edad e indicación o no de antagonista de GnRH. RESULTADOS: se estudiaron 171 pacientes; 60.4% menores de 35 años (grupo 1) y 65.1% mayores de esta edad (grupo 2) que desarrollaron de 2 a 4 folículos maduros. La tasa de embarazo clínico en el grupo 1 fue de 27.7 y 28.5% en el grupo 2. Con 1 (54.5%) y 4 (57.4%) folículos maduros desarrollados y relación proporcional entre el número de éstos y la tasa de embarazo. La tasa de embarazo en curso fue de 19.8% en el grupo 1 y 13.3% en el grupo 2. El uso de antagonista de GnRH no parece relacionarse con mejores tasas de embarazo en ciclos con más de un folículo maduro. CONCLUSIONES: se encontró asociación entre la cantidad de folículos maduros desarrollados y la tasa de embarazo clínico y en curso, pero sin diferencia significativa al momento de asociar estas variables con la edad o con el uso de un antagonista de GnRH. Sin embargo, sí se encontró una tendencia clara de mejores tasas de embarazo en las pacientes tratadas con antagonista de GnRH.

Abstract OBJECTIVE: To determine the clinical pregnancy rate in the first cycle of intrauterine insemination with gonadotropin stimulation in relation to number of mature follicles and age and the use of GnRH antagonist on its development. MATERIALS AND METHODS: Analytic, retrospective study, we evaluated the first IUI cycle in 171 women stimulated with different protocols of ovarian stimulation in a period of two years. The patients were divided into two groups: <35 and ≥35 years old and the use of GnRH antagonist. RESULTS: 60.4 and 65.1% of patients <35 and ≥35 years old respectively, developed 2 to 4 mature follicles; the clinical pregnancy rate <35 and ≥35 years old was 27.7 y 28.5% and 54.5 and 57.4% with 1 and 4 mature follicles developed, we found a proportional relation between mature follicles and pregnancy rates. The ongoing pregnancy rates was 19.8 y 13.3% in <35 y ≥35 years respectively. The use of antGnRH does not appear to be related to better pregnancy rates in cycles with more than one mature follicle. CONCLUSIONS: we found a proportional relation between mature follicles and pregnancy rates. The use of antGnRH does not appear to be related to better pregnancy rates in cycles with more than one mature follicle. The target in ovarian stimulation and IUI must be the development of 2 or 3 matures follicles.

Reduction of the cetrorelix dose in a multiple-dose antagonist protocol and its impact on pregnancy rate and affordability: A randomized controlled multicenter study / 대한생식의학회지

OBJECTIVE: To determine whether reducing the cetrorelix dose in the antagonist protocol to 0.125 mg had any deleterious effects on follicular development, the number and quality of retrieved oocytes, or the number of embryos, and to characterize its effects on the affordability of assisted reproductive technology. METHODS: This randomized controlled study was conducted at the Fertility Unit of Tanta Educational Hospital of Tanta University, the Egyptian Consultants' Fertility Center, and the Qurrat Aien Fertility Center, from January 1 to June 30, 2017. Patients' demographic data, stimulation protocol, costs, pregnancy rate, and complications were recorded. Patients were randomly allocated into two groups: group I (n=61) received 0.125 mg of cetrorelix (the study group), and group II (n=62) received 0.25 mg of cetrorelix (the control group). RESULTS: The demographic data were comparable regarding age, parity, duration of infertility, and body mass index. The dose of recombinant follicle-stimulating hormone units required was 2,350.43±150.76 IU in group I and 2,366.25±140.34 IU in group II, which was not a significant difference (p=0.548). The duration of stimulation, number of retrieved oocytes, and number of developed embryos were not significantly different between the groups. The clinical and ongoing pregnancy rates likewise did not significantly differ. The cost of intracytoplasmic sperm injection per cycle was significantly lower in group I than in group II (US $494.66±4.079 vs. US $649.677±43.637). CONCLUSION: Reduction of the cetrorelix dose in the antagonist protocol was not associated with any significant difference either in the number of oocytes retrieved or in the pregnancy rate. Moreover, it was more economically feasible for patients in a low-resource country.

Evaluation of activity of hypothalamo-pituitary-gonadal axis in postmenopausal women suffering from severe acute illness.

Background & objectives: Postmenopausal women constitute an ideal model for studying the extent of hypothalamo-pituitary gonadal (HPG) axis suppression in critical illness as the gonadotropins are normally high and non-cyclical in them. The objective was to assess the impact of acute severe illness in postmenopausal women on the HPG axis and the activities of the hypothalamo-pituitary-adrenal (HPA), the hypothalamo- pituitary-thyroid (HPT) axes; and levels of serum prolactin, by comparison between critically ill postmenopausal women and otherwise healthy postmenopausal women. Methods: Thirty five consecutive postmenopausal women older than 60 yr admitted to medical intensive care with a Simplified Acute Physiology Score II (SAPS II) more than 30 were included. On day five of their in-hospital stay, blood samples were collected for oestradiol, luteinizing hormone (LH), follicle stimulating hormone (FSH), cortisol, androstenedione, prolactin and thyroid profile. Thirty five apparently healthy postmenopausal women were selected as controls. Results: Levels of LH, FSH, thyrotropin, free thyroxin (fT4) and free tri-iodothyronine (fT3) were lower while oestradiol, cortisol and dehydroepiandrosterone were higher among patients in comparison to healthy controls. Prolactin levels were similar in patients and controls. Among sick patients both FSH and fT4 showed a negative correlation (P<0.05) with the SAPS II score. Interpretation & conclusions: In critically ill postmenopausal women, paradoxically elevated oestrogen levels despite gonadotropin suppression suggests a non-ovarian origin. Prolactin remained unaltered in patients despite their illness, possibly reflecting atrophy of lactotrophs in menopause.

Association between serum gonadotropin level and insulin resistance-related parameters in Korean women with polycystic ovary syndrome

OBJECTIVE: To evaluate the relationship between serum gonadotropin level and parameters related to insulin resistance in Korean women with polycystic ovary syndrome (PCOS). METHODS: This retrospective study included 138 women aged 18 to 35 years who were newly diagnosed with PCOS according to the Rotterdam consensus. Participants were divided into three groups based on the serum luteinizing hormone to follicle-stimulating hormone (LH/FSH) ratio in the early follicular phase: group 1 (LH/FSH 2.0), and group 3 (LH/FSH ≥2.0). The correlations between the LH/FSH ratio and various metabolic parameters were evaluated using Pearson correlation coefficients. RESULTS: Patients with higher LH/FSH ratios showed higher total antral follicle counts and higher total ovarian volume. In the comparison of anthropometric and biochemical parameters among the three groups, the waist to hip ratio was the only parameter that differed significantly among the groups (P=0.003). Correlation analysis revealed no significant correlations between serum LH/FSH ratios and biochemical parameters related to insulin resistance. However, after adjustments for age and body mass index, a significant correlation between total cholesterol level and serum LH/FSH ratio was observed (r=0.221, P=0.018). CONCLUSION: Most parameters related to insulin resistance, with the exception of total cholesterol level, are unrelated to the inappropriate pattern of serum gonadotropin secretion in Korean women with PCOS.

Effects of hydro-alcoholic extract of Launaea acanthodes on serum gonadotropin and testosterone levels and the structure of seminiferous tubules in hyperglycemic rats / 中国结合医学杂志

<p><b>OBJECTIVE</b>To investigate the effects of hydro-alcoholic extract of Launaea acanthodes, a blood glucose lowering plant in folk medicine of Iran, on the structure of seminiferous tubules and serum gonadotropin and testosterone levels in hyperglycemic rats.</p><p><b>METHODS</b>Twenty-four Wistar rats were randomly allocated into 4 groups (n=6): control, streptozotocin (STZ), STZ + insulin [STZ + Ins, 5 IU/(kg•day)], and STZ + Launaea acanthodes extract [STZ + Ext, 150 mg/(kg•day)]. Blood samples were collected at the 2nd and 4th weeks for detection of testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH) with enzyme-linked immuno sorbent assay (ELISA), and the right testes of rats were removed at the 7th week for the evaluation of diameter and wall thickness of seminiferous tubules and number of Leydig cells using unbiased stereological techniques.</p><p><b>RESULTS</b>In comparison with the control group, at the 2nd week FSH (0.45 vs 0.03, 0.02, 0.02 IU/L in STZ, STZ + Ins and STZ + Ext groups, respectively) and LH (1.02 vs 0.37, 0.2, 0.29 IU/L) showed significant decreases (all P<0.05) and testosterone (4.2 vs 8.37, 7.78, 11.8 ng/mL) showed a remarkable increase (all P<0.05). The levels of these hormones became closer in the STZ + Ext and the STZ + Ins groups to the control at the 4th week. A significant decrease in diameter and wall thickness of seminiferous tubules and number of Leydig cells were observed in the STZ group as compared with the control (P<0.01).</p><p><b>CONCLUSIONS</b>Administration of Launaea extract demonstrated a beneficial impact on the protection of testis from pathogenic and degenerative effects of hyperglycemia which may be partly due to its potential antioxidative effects.</p>

Efficacy, efficiency and effectiveness of gonadotropin therapy for infertility treatment / Eficácia, eficiência e efetividade da terapia gonadotrófica para o tratamento da infertilidade

Gonadotropin therapy is an essential element in infertility treatments involving assisted reproductive technology. In recent years there have been outstanding advances in the development of new gonadotropins, particularly with the production of gonadotropins using biotechnological resources. Recombinant gonadotropins have higher specific activity compared with urinary counterparts, thus allowing subcutaneous administration of minimal amounts of glycoprotein. As a result, recombinant formulations have a better safety profile despite an overall similarity in terms of efficacy for pregnancy, as reported in many randomized controlled trials and meta-analyses. Gonadotropins stimulate the ovaries to develop follicles and oocytes, which are the raw material for fertilization and embryo production. The resulting embryos are transferred (fresh or frozen-thawed) to achieve pregnancy. The efficiency of a gonadotropin should therefore measured by the amount of drug used, the number of oocytes/embryos produced, and the number of pregnancies achieved by transferring fresh and/or frozen-thawed embryos to the uterus (cumulative pregnancy). Comparisons between different gonadotropin preparations should also take into account other important quality indicators in reproductive medicine, such as safety and patient-centeredeness. Altogether, the aforementioned quality indicators favor biotech gonadotropins over biologic products in infertility therapy.

RESUMO A terapia gonadotrófica é elemento essencial nos tratamentos de infertilidade que envolvem tecnologia de reprodução assistida. Nos últimos anos houve avanços notáveis no desenvolvimento de novas gonadotrofinas, principalmente com a produção de gonadotrofinas via recursos biotecnológicos. As gonadotrofinas recombinantes têm maior actividade específica em comparação com os suas homólogas urinárias, permitindo, assim, a administração subcutânea de quantidades mínimas de glicoproteína. Como resultado, as formulações recombinantes tem um melhor perfil de segurança, apesar de semelhança em termos de eficácia para a gravidez, como relatado em diversos ensaios clínicos randomizados e meta-análises. As gonadotrofinas estimulam os ovários a desenvolver folículos e ovócitos, que são a matéria-prima para a fertilização e produção de embriões. Os embriões resultantes são transferidos (frescos ou congelados/descongelados) para produzir gravidez. Comparações entre as gonadotrofinas devem, portanto, ser medidas não somente pela eficácia clínica de produzir gravidezes pela transferência de embriões a fresco, mas sobremaneira pela eficiência na produção de ovócitos e embriões em relação à quantidade de droga administrada, e efetividade na obtenção de gravidezes pela transferência de embriões frescos e congelados/descongelados (taxa de gravidez cumulativa). As comparações entre diferentes preparações de gonadotrofinas também devem levar em conta outros indicadores importantes de qualidade em medicina reprodutiva, como a segurança e o interesse do paciente. Estes indicadores de qualidade favorecem as gonadotrofinas biotecnológicas em relação aos produtos biológicos na terapia da infertilidade.

Atividade dos neurônios do núcleo anterovental periventricular e sua participação no envelhecimento reprodutivo de ratas / Activity of anteroventral periventricular nucleus neurons in reproductive aging of female rats

Alterações do eixo hipotálamo-hipófise-gônadas em fêmeas determinam a transição de ciclos reprodutivos regulares para irregulares, com perda da fertilidade. Interação dos neurônios GnRH e esteróides gonadais está interligado pelas alças de retroalimentação e alterações nesse mecanismo estão relacionados com a senescência reprodutiva. Estímulos da noradrenalina (NA) e neurônios da área pré-óptica (APO) são essenciais para liberação das gonadotrofinas, pois neurônios GnRH expressam receptores para estrógeno β e progesterona. O objetivo deste estudo foi avaliar a atividade das células neuronais da APO no período de transição para a estropausa em ratas Wistar. Ratas Wistar cíclicas (4-5 meses) no dia do estro e acíclicas (17-18 meses) em constante estro (CE) foram perfundidas ou decapitadas às 10, 14 e 18 horas. Encéfalos perfundidos foram processados por imunohistoquímica para avaliação da imunorreatividade para antígenos relacionados ao Fos da APO. Após a decapitação, o encéfalo foi retirado e realizado microdissecção da APO e determinação do conteúdo de NA e seu metabolito; o plasma foi utilizado para dosagens de LH, FSH, E2 e P4. Os resultados obtidos evidenciaram secreção plasmática maior de LH e menor de FSH e E2 no grupo de ratas acíclicas. O número de neurônios FRA-IR foi maior em ratas acíclicas, nos horários das 10 (p<0,001) e das 18 (p<0,05) em relação ao grupo de animais com ciclo regular. Nas ratas acíclicas, o conteúdo armazenado de NA foi menor às 14h e 18h (p<0,001) e o metabólito foi constante e maior às 18h, comparada com o mesmo horário das ratas do grupo cíclica (p<0,05). Conclui-se que alterações neurais e ovarianas que ocorrem no CE determinam o declínio para a ocorrência da ciclicidade dos ciclos e caracterizam o período de periestropausa.

Changes of the hypothalamic-pituitary-gonadal axis in females determine the transition from regular to irregular reproductive cycles, with a loss of fertility. Interaction of GnRH neurons and gonadal steroid is connected by feedback and changes in this mechanism are related to reproductive senescence. Noradrenaline (NE) stimulation and preoptic area (POA) neurons are essential for release of gonadotropins, as GnRH neurons express receptors for estrogen β and progesterone. The objective of this study was to evaluate the activity of neurons in POA nuclei, in transition period for estropause in Wistar rats. Cyclic Wistar rats (4-5 months) on the day of estrus and acyclic (17-18 months) in estrus constant (CE) were decapitated or perfused at 10, 14 and 18 hours. Perfused brains were processed for immunohistochemistry to evaluate the immunoreactivity to antigens related to the Fos in POA. After decapitation, the brain was removed and carried microdissection of POA and determining the content of NE and its metabolite; Plasma was used for measurements of LH, FSH, E2 and P4. The results showed higher plasma secretion of LH, FSH and E2 lower in the group of acyclic rats. The number of FRA-IR neurons was higher in acyclic rats in the 10 hours (p <0.001) and 18 (p <0.05) compared to the group of animals with regular cycle. In rats acyclic, the stored contents of NE was lower at 14h and 18h (p <0.001), and the metabolite was constant and greater at 18h compared to the same time of the rats of the cyclic group (p <0.05). It follows that neural and ovarian changes that occur in the CE decline to determine the occurrence of cyclicity of cycles and featuring periestropausa period.

Congenital Hypogonadotropic Hypogonadism and Kallmann Syndrome: Past, Present, and Future

The proper development and coordination of the hypothalamic-pituitary-gonadal (HPG) axis are essential for normal reproductive competence. The key factor that regulates the function of the HPG axis is gonadotrophin-releasing hormone (GnRH). Timely release of GnRH is critical for the onset of puberty and subsequent sexual maturation. Misregulation in this system can result in delayed or absent puberty and infertility. Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are genetic disorders that are rooted in a GnRH deficiency but often accompanied by a variety of non-reproductive phenotypes such as the loss of the sense of smell and defects of the skeleton, eye, ear, kidney, and heart. Recent progress in DNA sequencing technology has produced a wealth of information regarding the genetic makeup of CHH and KS patients and revealed the resilient yet complex nature of the human reproductive neuroendocrine system. Further research on the molecular basis of the disease and the diverse signal pathways involved will aid in improving the diagnosis, treatment, and management of CHH and KS patients as well as in developing more precise genetic screening and counseling regime.

Advances in male hormonal contraception.

Contraception is a basic human right for its role on health, quality of life and wellbeing of the woman and of the society as a whole. Since the introduction of female hormonal contraception the responsibility of family planning has always been with women. Currently there are only a few contraceptive methods available for men, but recently, men have become more interested in supporting their partners actively. Over the last few decades different trials have been performed providing important advances in the development of a safe and effective hormonal contraceptive for men. This paper summarizes some of the most recent trials.

In vitro fertilization outcome in women with endometriosis & previous ovarian surgery.

Background & objectives: Women with endometriosis often need in vitro fertilization (IVF) to concieve. there are conflicting data on the results of IVF in patients with endometriosis. This study was undertaken to elucidate the influence of endometriosis on IVF outcome to give the best counselling for infertile patient with this problem. Methods: Tthe outcome measures in 78 patients with surgically confirmed endometriosis were compared with 157 patients with tubal factor infertility, all of whom have undergone IVF. The groups were matched for age and follicle stimulating hormone (FSH) levels. Outcome measures included number of follicles, number of ocytes, peak oestradiol (E2) concentrations and mean number of ampoules of gonadotropins. Cumulative pregnancy, miscarriage and live birth rates were calculated in both the groups. Results: Higher cancelation rates, higher total gonadotropin requirements, lower peak E2 levels and lower oocyte yield were found in women with endometriosis and previous surgery compared with those with tubal factor infertility. However, no differences were found in fertilization, implantation, pregnancy, miscarriage, multiple births and delivery rates between the endometriosis and tubal factor infertility groups. Interpretation & conclusions: Tthe present findings showed that women with endometriosis and previous surgery responded less well to gonadotropins during ovarian stimulation and hence the cost of treatment to achieve pregnancy was higher in this group compared with those with tubal factor infertility. However, the outcome of IVF treatment in patients with endometriosis was as good as in women with tubal factor infertility.

Gonadotropin therapy in assisted reproduction: an evolutionary perspective from biologics to biotech

Gonadotropin therapy plays an integral role in ovarian stimulation for infertility treatments. Efforts have been made over the last century to improve gonadotropin preparations. Undoubtedly, current gonadotropins have better quality and safety profiles as well as clinical efficacy than earlier ones. A major achievement has been introducing recombinant technology in the manufacturing processes for follicle-stimulating hormone, luteinizing hormone, and human chorionic gonadotropin. Recombinant gonadotropins are purer than urine-derived gonadotropins, and incorporating vial filling by mass virtually eliminated batch-to-batch variations and enabled accurate dosing. Recombinant and fill-by-mass technologies have been the driving forces for launching of prefilled pen devices for more patient-friendly ovarian stimulation. The most recent developments include the fixed combination of follitropin alfa + lutropin alfa, long-acting FSH gonadotropin, and a new family of prefilled pen injector devices for administration of recombinant gonadotropins. The next step would be the production of orally bioactive molecules with selective follicle-stimulating hormone and luteinizing hormone activity.

Avanços na etiologia, no diagnóstico e no tratamento da puberdade precoce central / Advances in the etiology, diagnosis and treatment of central precocious puberty

O início da puberdade caracteriza-se pelo aumento de amplitude e frequência dos pulsos do hormônio secretor de gonadotrofinas (GnRH) após um período de relativa supressão hormonal durante a infância. A reemergência da secreção pulsátil do GnRH resulta em aumento na secreção de gonadotrofinas, hormônio luteinizante (LH) e folículo estimulante (FSH), pela hipófise anterior e consequente ativação gonadal. A ativação prematura do eixo hipotálamo-hipófise-gonadal resulta em puberdade precoce dependente de gonadotrofinas, também conhecida como puberdade precoce central (PPC), e se caracteriza pelo desenvolvimento dos caracteres sexuais secundários antes dos 8 anos nas meninas e 9 anos nos meninos. O início do desenvolvimento puberal provém da interação complexa de fatores genéticos, nutricionais, ambientais e socioeconômicos. O diagnóstico clínico da PPC baseia-se em reconhecimento de desenvolvimento puberal progressivo, concentrações púberes de LH em condição basal e/ou após estímulo com GnRH e avanço de idade óssea. A ressonância magnética de encéfalo é útil no estabelecimento de diagnóstico diferencial entre as formas orgânica ou idiopática. Os análogos de GnRH de ação prolongada representam o tratamento de escolha da PPC. O componente genético da PPC foi recentemente fortalecido pela evidência de mutações no gene MKRN3, localizado no braço longo do cromossomo 15, em crianças com PPC familial. Nessa revisão, dados clínicos e terapêuticos da PPC serão amplamente discutidos, visando à atualização e à conduta criteriosa dessa condição clínica de grande relevância na endocrinologia pediátrica.

The onset of puberty is first detected as an increase in the amplitude and frequency of pulses of gonadotropin-releasing hormone (GnRH) after a quiescent period during childhood. The reemergence of pulsatile GnRH secretion leads to increases in the secretion of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) by the pituitary gland, and the consequent activation of gonadal function. Early activation of the hypothalamic–pituitary–gonadal axis results in gonadotropin-dependent precocious puberty, also known as central precocious puberty (CPP), which is clinically defined by the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. Pubertal timing is influenced by complex interactions among genetic, nutritional, environmental, and socioeconomic factors. CPP is diagnosed on the basis of clinical signs of progressive pubertal development before the age of 8 years in girls and 9 years in boys, pubertal basal and/or GnRH-stimulated LH levels, and advanced bone age. Magnetic resonance imaging of the central nervous system is essential for establishing the CPP form as organic or idiopathic. Depot GnRH-analogues represent the first-line of therapy in CPP. Very recently, the genetic component of CPP was demonstrated by the evidence that the deficiency of the MKRN3 gene, located on long arm of chromosome 15, causes familial CPP in humans. In this current review, clinical and therapeutic aspects of the CPP will be discussed, contributing to adequate diagnosis and criterious approach of this relevant condition of pediatric endocrinology.