Single-chain human follicle-stimulating hormone with a di-N-glycosylated linker.

The classic way to produce single-chain (sc) glycoprotein hormones is to fuse their two subunits through the carboxy-terminal peptide (CTP) from human Choriogonadotropin (hCG). The CTP confers a longer half-life to single-chain hormones thanks to its four O-glycosyl side chains. However, unlike syncytiotrophoblastic cells, most cells used for recombinant protein production do not transfer O-glycosyl chains efficiently. We thus choose to fuse the hFSH subunits with a linker comprising two N-glycosyl side chains (sc-hFSH LNN) or none (sc-hFSH L0N), that were generated using two expression systems, HEK293 and CHO K1 cells. Their production levels and biological activities were tested and compared. Both expression systems successfully produced biologically active sc-hFSH, but, in our hands, CHO K1 cells yielded about 30-fold higher amounts of recombinant protein than HEK293 cells. Moreover, sc-hFSH L0N was considerably less expressed than sc-hFSH LNN in both cell types. Our data show that sc-hFSH L0N and sc-hFSH LNN produced from both cell lines stimulate cAMP and progesterone production in mLTC cells expressing hFSH receptors and exhibit similar B/I (in vitro Bioactivity/Immuno activity) ratios. Finally, the ratio of in vivo/in vitro bioactivities for sc-hFSH LNN relative to natural pituitary heterodimeric hFSH increased 8-fold, most likely because of a longer half-life in the blood.

CPEB1 induces autophagy and promotes apoptosis in ovarian granulosa cells of polycystic ovary syndrome.

Inflammatory damage in ovarian granulosa cells (GCs) is a key mechanism in polycystic ovary syndrome (PCOS), cytoplasmic polyadenylation element binding protein-1 (CPEB1) is important in inflammatory regulation, however, its role in PCOS is unclear. We aim to research the mechanism of CPEB1 in ovarian GCs in PCOS using dehydroepiandrosterone (DHEA)-induced PCOS rat models and testosterone-incubated GC models. The pathophysiology in PCOS rats was analyzed. Quantitative-realtime-PCR, TUNEL, immunohistochemistry, and Western blot were applied for quantification. Additionally, cell counting kit-8, flow cytometry, immunofluorescence, Western blot, and Monodansylcadaverine staining were performed. We found that PCOS rat models exhibited a disrupted estrus cycle, elevated serum levels of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), increased LH/FSH ratio, and heightened ovarian index. Furthermore, reduced corpus luteum and increased follicular cysts were observed in ovarian tissue. In ovarian tissue, autophagy and apoptosis were activated and CPEB1 was overexpressed. In vitro, CPEB1 overexpression inhibited cell viability and sirtuin-1 (SIRT1), activated tumor necrosis factor-α, and interleukin-6 levels, as well as apoptosis and autophagy; however, CPEB1 knockdown had the opposite effect. In conclusion, overexpression of CPEB1 activated autophagy and apoptosis of ovarian GCs in PCOS.

Efficacy and safety of follitropin delta for ovarian stimulation in vitro fertilization/ intracytoplasmic sperm injection cycles: a systematic review with meta-analysis.

BACKGROUND: Follitropin delta is a novel recombinant follicle stimulating hormone preparation uniquely expressed in a human fetal retinal cell line by recombinant DNA technology. To date, no systematic review was available about the safety and the efficacy of the follitropin delta. The objective of this study was systematically reviewing the available literature and to provide updated evidence regarding the efficacy-safety profile of follitropin delta when compared to other gonadotropin formulations for ovarian stimulation in in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) cycles. METHODS: An extensive search was performed to identify phase 1, phase 2 and phase 3 RCTs in humans focused on follitropin delta use for ovarian stimulation in IVF/ICSI cycles. The risk of bias and the overall quality of the evidence was analyzed. All data were extracted and analyzed using the intention-to-treat principle and expressed per woman randomized. RESULTS: A total of 7 RCTs (1 phase 1 RCT, 2 phase 2 RCTs and 4 phase 3 RCTs) were included in the qualitative analysis, whereas data of three phase 3 RCTs were meta-analyzed. All trials compared personalized recombinant follitropin delta treatment versus conventional recombinant follitropin alfa/beta administration in potentially normo-responder patients who receive ovarian stimulation in GnRH antagonist IVF/ICSI cycles. No difference between two regimens was detected for clinical pregnancy rate [odds ratio (OR) 1.06; 95% confidence intervals (CI): 0.90, 1.24; P = 0.49; I2 = 26%], ongoing pregnancy rate (OR 1.15; 95%CI: 0.90, 1.46; P = 0.27; I2 = 40%), and live birth rate (OR 1.18; 95%CI: 0.89, 1.55; P = 0.25; I2 = 55%). No data were available regarding cumulative success rates. The rate of adoption of strategies to prevent ovarian hyperstimulation syndrome (OHSS) development (OR 0.45; 95%CI: 0.30, 0.66; P < 0.0001; I2 = 0%), and the rate of both early OHSS (OR 0.62; 95%CI: 0.43, 0.88; P = 0.008; I2 = 0%) and all forms of OHSS (OR 0.61; 95%CI: 0.44, 0.84; P = 0.003; I2 = 0%) were significantly lower in the group of patients treated with personalized follitropin delta treatment compared to those treated with conventional follitropin alfa/beta administration. CONCLUSION: Personalized follitropin delta treatment is associated with a lower risk of OHSS compared to conventional follitropin alfa/beta administration in potentially normo-responder patients who receive ovarian stimulation in GnRH antagonist IVF/ICSI cycles. The absence of cumulative data does not allow definitive conclusions to be drawn regarding the comparison of the effectiveness of the two treatments. PROTOCOL STUDY REGISTRATION: CRD42023470352 (available at http://www.crd.york.ac.uk/PROSPERO ).

Pineal cysts may promote pubertal development in girls with central precocious puberty: a single-center study from China.

Introduction: Pineal cysts have long been considered a benign intracranial variation. However, in our clinical practice, it has been observed that some children with central precocious puberty (CPP) who have pineal cysts experience rapid progression in adolescent development. In recent years, there has been a significant increase in the prevalence of CPP in girls, leading to more diagnoses of CPP among children with pineal cysts. Despite this, there is no consensus regarding whether pineal cysts contribute to CPP as one of its organic factors. This study aimed to analyze the clinical characteristics of pineal cysts in children with CPP and explore the potential effects of pineal cysts on puberty development. Methods: This single-center study retrospectively analyzed clinical data from girls aged 3 to 10 years who underwent head/pituitary magnetic resonance imaging at the Children's Hospital Affiliated to Zhengzhou University between 2019 and 2022. The study categorized the detection rates of pineal cysts based on systematic disease classification and compared the rates of cyst detection between girls diagnosed with CPP and those without CPP. Subsequently, CPP-diagnosed girls with pineal cysts were examined. Among CPP-diagnosed girls meeting the study's criteria, those with pineal cysts formed the 'cyst group,' while those without cysts were matched in a 1:1 ratio based on age and body mass index to form the 'non-cyst group.' Comparative analyses were conducted to assess the clinical characteristics between these two groups. CPP-diagnosed girls with cysts were further subdivided into three groups according to cyst size (≤5 mm, 5.1-9.9 mm, and ≥10 mm) to investigate potential differences in clinical characteristics among these subgroups. The study involved an analysis of clinical data from girls diagnosed with CPP and included imaging follow-ups to explore the progression of pineal cysts over time. Results: Among the 23,245 girls who underwent head/pituitary magnetic resonance imaging scans, the detection rate of pineal cysts was 3.6% (837/23,245), with most cases being associated with endocrine diseases. The detection rate of pineal cysts in CPP patients was 6.4% (262/4099), which was significantly higher than the 3.0% (575/19,146) in patients without CPP. In comparison to the non-cyst group, the cyst group exhibited statistically significant increases in estradiol levels, peak luteinizing hormone (LH) levels, peak LH/follicle-stimulating hormone (FSH) ratios, uterine body length, and cervix length (P < 0.001). As cyst size increased, there were significant rises in LH peak, peak LH/FSH ratio, uterine body length, and cervical length (P < 0.01). Estradiol levels and left ovarian volume also showed an increasing trend (P < 0.05). Among girls who underwent follow-up imaging, 26.3% (5/19) exhibited an increase in cyst size. Conclusion: Pineal cysts are relatively common in children with CPP. They may affect the pubertal development process, with larger cysts correlating to faster pubertal development. Therefore, the authors hypothesize that pineal cysts may trigger CPP in some cases, especially when the cysts are larger than 5 mm in size, as indicated by our data.

Nonlinear relationship between gonadotropin total dose applied and live birth rates in non-PCOS patients: a retrospective cohort study.

The purpose of this article is to explore the relationship between the total dose of follicle-stimulating hormone (FSH) applied during controlled ovulation stimulation and the live birth rates (LBRs) in non-PCOS population. Many studies have found no difference between the dose of FSH application and pregnancy outcomes such as clinical pregnancy rates after fresh embryo transfer. However, a recent large retrospective analysis found a negative correlation between live birth rates and increasing dose of FSH. It is still controversial about the association between FSH dose and LBRs. In addition, no studies have yet explored the nonlinear relationship between FSH and LBRs. This cohort study included a total of 11,645 patients who had accepted IVF/intracytoplasmic sperm injection (ICSI) at the second hospital of Hebei medical university between December 2014 to December 2019. PCOS was identified by Rotterdam PCOS criteria. We researched the association between FSH total dose and live birth rates (LBRs) using multivariate regression analysis. In addition, a model for nonlinear relationships based on a two-part linear regression was applied. The analysis of threshold effects indicated that LBR increased with every 1000 IU FSH when the concentration of FSH was lower than 1410 IU (OR 1.55, 95% CI [1.05, 2.28]); however, a negative association between FSH dose and LBR (OR 0.94, 95% CI [0.89, 0.99]) was found when the FSH total dose was higher than 1410 IU. It is worth noting that the relationship between LBR and FSH dose varied among patients of different ages (OR 0.92 vs 1.06, P for interaction < 0.05).

The follicle-stimulating hormone triggers rapid changes in mitochondrial structure and function in porcine cumulus cells.

Oocyte maturation is a key process during which the female germ cell undergoes resumption of meiosis and completes its preparation for embryonic development including cytoplasmic and epigenetic maturation. The cumulus cells directly surrounding the oocyte are involved in this process by transferring essential metabolites, such as pyruvate, to the oocyte. This process is controlled by cyclic adenosine monophosphate (cAMP)-dependent mechanisms recruited downstream of follicle-stimulating hormone (FSH) signaling in cumulus cells. As mitochondria have a critical but poorly understood contribution to this process, we defined the effects of FSH and high cAMP concentrations on mitochondrial dynamics and function in porcine cumulus cells. During in vitro maturation (IVM) of cumulus-oocyte complexes (COCs), we observed an FSH-dependent mitochondrial elongation shortly after stimulation that led to mitochondrial fragmentation 24 h later. Importantly, mitochondrial elongation was accompanied by decreased mitochondrial activity and a switch to glycolysis. During a pre-IVM culture step increasing intracellular cAMP, mitochondrial fragmentation was prevented. Altogether, the results demonstrate that FSH triggers rapid changes in mitochondrial structure and function in COCs involving cAMP.

A direct healthcare cost analysis of recombinant LH versus hMG supplementation on FSH during controlled ovarian hyperstimulation in the GnRH-antagonist protocol.

PURPOSE: We have previously published a retrospective matched-case control study comparing the effect of recombinant LH (r-hLH) versus highly purified human menopausal gonadotropin (hMG) supplementation on the follicle-stimulating hormone (FSH) during controlled ovarian hyperstimulation (COH) in the GnRH-antagonist protocol. The result from that study showed that the cumulative live birth rate (CLBR) was significantly higher in the r-hLH group (53% vs. 64%, p = 0.02). In this study, we aim to do a cost analysis between these two groups based on our previous study. METHODS: The analysis consisted of 425 IVF and ICSI cycles in our previous study. There were 259 cycles in the r-hFSH + hMG group and 166 cycles in the r-hFSH + r-hLH group. The total cost related to the treatment of each patient was recorded. Probabilistic sensitivity analysis (PSA) and a cost-effectiveness acceptability curve (CEAC) were performed and created. RESULTS: The total treatment cost per patient was significantly higher in the r-hFSH + r-hLH group than in the r-hFSH + hMG group ($4550 ± 798.86 vs. $4290 ± 734.6, p = 0.003). However, the mean cost per live birth in the r-hFSH + hMG group was higher at $8052, vs. $7059 in the r-hFSH + r-hLH group. The CEAC showed that treatment with hFSH + r-hLH proved to be more cost-effective than treatment with r-hFSH + hMG. Willingness-to-pay was evident when considering a hypothetical threshold of $18,513, with the r-hFSH + r-hLH group exhibiting a 99% probability of being considered cost-effective. CONCLUSION: The cost analysis showed that recombinant LH is more cost-effective than hMG supplementation on r-hFSH during COH in the GnRH-antagonist protocol.

Can AMH levels predict the need to step up FSH dose for controlled ovarian stimulation following a long GnRH agonist protocol in PCOS women?

BACKGROUND: To explore the role of anti-Mullerian hormone (AMH) in predicting the need to step up recombinant FSH (rFSH) dose following long GnRH agonist protocol in IVF/ICSI cycles of polycystic ovarian syndrome (PCOS) women. METHODS: This is a retrospective cohort study of 825 PCOS women undergoing long GnRH agonist protocol enrolled from Jan 2019 to Dec 2021. The daily rFSH dose at which the first response to rFSH were recorded. The dose at which the first response to rFSH was based on folliculometry during follow up in which two or more follicles reached ≥ 11 mm. A receiver operating characteristic (ROC) curve analysis was done to investigate the ability of AMH to predict the need to step up initial rFSH dose. RESULTS: PCOS women who needed to step up initial rFSH dose had a significantly higher AMH compared with those didn't step up initial rFSH dose (11.37 ± 3.25ng/ml vs. 8.69 ± 3.16ng/ml, p < 0.001). In multivariate logistic regression analysis, increased AMH level was an independent factor for the need to step up initial rFSH dose in PCOS patients after adjusted for confounding factors. ROC curve analysis showed AMH could predict the need to step up initial rFSH dose (AUC = 0.738, 95%CI: 0.704-0.773), having 75.4% specificity and 63% sensitivity when the threshold AMH concentration was 9.30ng/ml. 58.8% PCOS women with AMH > 9.30 ng/ml required increased rFSH dose compared to 18.8% of women with AMH ≤ 9.30ng/ml (p < 0.001). Although the clinical pregnancy rate and live birth rate were not significantly different, there was a higher incidence of OHSS among women with AMH > 9.30 ng/ml vs. AMH ≤ 9.30ng/ml (20.8% vs. 15.3%, p = 0.043). CONCLUSION: PCOS women with AMH > 9.30 ng/ml were resistant to rFSH stimulation and require increased dose for the cycle recruitment of ovarian follicles.

Sequential 2.5 mg letrozole/FSH therapy is more effective for promoting pregnancy in infertile women with PCOS: a pragmatic randomized controlled trial.

Study question: In infertile women with polycystic ovary syndrome (PCOS), is the sequential use of letrozole 2.5 mg/follicle stimulating hormone(FSH) more effective than letrozole 5 mg/FSH in stimulating ovulation and promoting pregnancy? Research design and methods: The study was designed as a prospective, single-center, randomized, controlled pragmatic clinical trial. 220 infertile women between the ages of 20 and 40, who matched the Rotterdam criteria for PCOS and had no other identified reasons for infertility were enrolled from April 2023 to July 2023.The participants were randomly assigned to two groups in a 1:1 ratio. One group received 2.5 mg of letrozole on cycle days 3-7 with a sequential injection of 75 IU FSH on cycle days 8-10 (n = 110), while the other group received 5 mg of letrozole on cycle days 3-7 with a sequential injection of 75 IU FSH on cycle days 8-10 (n = 110). The duration of FSH treatment varied depending on the follicular development stage. Each participant underwent one to three treatment cycles until achieving pregnancy.The primary outcome was the cumulative pregnancy rate of all the participants. Secondary outcomes included characteristics and clinical pregnancy rates of all the intervention cycles. Results: For all 220 participants, the sequential letrozole 2.5 mg/FSH treatment group had a significantly higher cumulative pregnancy rate compared to the letrozole 5 mg/FSH treatment group (72.7% versus 59.1%, RR (95%CI) = 1.23 (1.02, 1.49), P-value = 0.033). For all 468 intervention cycles, letrozole 2.5 mg/FSH group had a significantly higher clinical pregnancy rate than the letrozole 5 mg/FSH group (36.2% versus 26.3%, P-value = 0.021), no statistically significant differences were observed in ovulation rates or adverse effects. Conclusions: The data indicate that the sequential letrozole 2.5mg/FSH protocol may be more effective than the sequential letrozole 5mg/FSH protocol for promoting pregnancy in infertile women with PCOS. Clinical trial registration: www.chictr.org.cn, identifier ChiCTR2300069638.

Evaluation of central precocious puberty treatment with GnRH analogue at the Triangulo Mineiro Federal University (UFTM)

Objective To report our experience of treating central precocious puberty (CPP) with a GnRH analogue with respect to the final heights (FH) attained in patients who completed treatment. Subjects and methods Among 105 records of children diagnosed with precocious puberty, 62 cases (54 girls and 8 boys), who were treated with leuprolide acetate/3.75 mg/monthly, were selected, and divided into 4 groups: group 1 (G1), 25 girls who attained FH; group 2 (G2), 18 girls who completed treatment but did not reach FH; group 3 (G3), 11 girls still under treatment; and group 4 (G4), 8 boys, 5 of which attained FH. Treatment was concluded at a bone age of 12 years, and follow-up continued until FH was achieved. Results In both G1 and G2 groups, height standard deviation score (SDS), weight-SDS and percentile of body mass index (PBMI) did not show intra/intergroup differences at the beginning and at interruption of treatment, but when added, G1+G2, height-SDS and weight-SDS differed significantly (p = 0.002 and 0.0001, respectively). In G1, 19 of 25 cases attained TH, and average height gain was 16.7 cm (7.7- 27.1); there was significant difference between FH and prediction of FH at the start (PFH at start) (p = 0.0001), as well as between PFH at interruption vs TH and vs FH (p = 0.007) with FH higher than TH (p = 0.004). Significant correlation was identified between FH and height gain after treatment. Conclusion As shown by some studies, GnRH analogue treatment was effective in children with CPP reaching FH near the genetic target.

Experiencia de la Unidad de Medicina Reproductiva Clínica Monteblanco con el uso de corifollitropin alfa en ciclos de fecundación in vitro / Experience of the Monteblanco Clinical Reproductive Medicine Unit with the use of corifollitropin alfa in in vitro fertilization cycles

ANTECEDENTES: La hiperestimulación ovárica controlada (HEOC) es uno de los componentes fundamentales de los ciclos de fecundación in-vitro (FIV). HEOC se ha realizado con gonadotrofinas exógenas de uso diario, agregando un componente de estrés adicional al tratamiento. La aparición de una FSH recombinante de depósito (corifollitropin alfa) permite disminuir el estrés asociado. Los estudios publicados no han mostrados diferencias en el número de ovocitos recuperados ni en las tasas de embarazo clínico. Los estudios existentes han sido financiados en su mayoría por la industria farmacéutica. OBJETIVO: Presentar la experiencia de la Unidad de Medicina Reproductiva Monteblanco con el uso de corifollitropin alfa en ciclos de FIV autólogos en pacientes no seleccionadas. MÉTODO: Se analizaron el número de ovocitos recuperados y la proporción de ovocitos en metafase 2 en pacientes sometidas a HEOC con corifollitropin alfa, FSH recombinante diaria (rFSH), y la combinación de FSH recombinante y urinaria. RESULTADOS: Se analizaron 727 ciclos de FIV: 270 con corifollitropin alfa, 33 con rFSH y 333 con combinación de FSH. No hubo diferencias significativas en la recuperación de ovocitos ni en la proporción de ovocitos en metafase 2. Al corregir por edad de la mujer y tipo de esquema de HEOC, encontramos que la edad de la mujer se asoció negativamente con el número de ovocitos recuperados, no así el tipo de esquema de HEOC. CONCLUSION: El uso de corifollitropin alfa en ciclos de FIV autólogos, no se diferencia significativamente de los otros esquemas de HEOC en la media de ovocitos recuperados ni en la media de ovocitos en metafase 2 obtenidos.

BACKGROUND: Controlled ovarian hyperstimulation (COH) is a main component of in-vitro fertilization (IVF) cycles. COH have been performed with daily exogenous gonadotropins administered, adding to treatment an additional component of stress. The appearance of a depot recombinant FSH (corifollitropin alfa) helps to reduce stress in patients undergoing IVF. No studies have shown differences in the number of retrieved oocytes or clinical pregnancy rates; however these studies have been funded by the pharmaceutical industry. AIMS: To show the experience of Reproductive Medicine Unit Monteblanco with the use of corifollitropin alpha in autologous IVF cycles, in unselected patients. METHODS: Our main outcome was the mean number of oocytes retrieved, and the proportion of oocytes in metaphase 2 in patients undergoing COH with corifollitropin alpha, daily recombinant FSH (rFSH), and a combination of rFSH and urinary gonadotropin. RESULTS: We analyzed 727 IVF cycles: 270 cycles with corifollitropin alpha, 33 exclusive rFSH and 333 cycles with rFSH combination and urinary gonadotropins. We did not found any statistically significant difference in the mean number of oocytes recovered nor the proportion of metaphase two oocytes obtained. After adjusting for age, we did not find that the COH protocol influenced the mean number of oocytes recovered. CONCLUSION: We concluded that the use of corifollitropin alpha in autologous IVF cycles does not alter the mean number of oocytes recovered, nor the proportion of oocytes in metaphase 2.

Avaliação dos níveis basais de FSH em pacientes inférteis com endometriose profunda de ovário tratadas cirurgicamente / Evaluation of basal FSH serum levels in infertile patients with deep ovarian endometriosis who underwent surgery

OBJETIVO: avaliar a reserva ovariana de pacientes inférteis portadoras de endometriose profunda de ovário, submetidas à cirurgia excisional dos endometriomas, atendidas entre os meses de Fevereiro e Novembro de 2008. MÉTODOS: estudo prospectivo que incluiu 30 pacientes portadoras de endometriose graus III e IV com comprometimento profundo de ovário submetidas à cirurgia excisional dos endometriomas e 30 pacientes portadoras de endometriose graus I e II que foram alocadas como Grupo Controle. A reserva ovariana foi avaliada indiretamente a partir do valor do hormônio folículo estimulante (FSH) basal (U/L), entre o terceiro e quinto dias do ciclo, após um período de 12 meses da cirurgia. O índice de massa corpórea (IMC) foi calculado conforme a fórmula de Quetelet [peso (kg)/estatura (cm²)]. Para a comparação das variáveis "idade", "IMC" e "valores de FSH basal" entre os grupos, foi utilizado o teste não paramétrico U de Mann-Whitney. RESULTADOS: não foi encontrada diferença significativa entre os grupos em relação à idade e ao IMC. Em relação ao FSH basal, observou-se que, no grupo das pacientes com endometriose profunda, o valor médio foi de 7,0 U/L, enquanto que, no Grupo Controle, foi de 5,6 U/L (p=0,3), o que demonstra que a diferença no valor médio de FSH encontrado nos dois grupos não foi significativa. CONCLUSÕES: a cirurgia não influenciou de forma deletéria a reserva ovariana das pacientes com endometriose profunda de ovário.

PURPOSE: to evaluate the ovarian reserve of infertile patients with severe ovarian endrometriosis, submitted to excisional surgery of endometriomas and attended from February to November, 2008. METHODS: prospective study, including 30 patients with endometriosis grades III and IV, with severe ovarian impairment, submitted to excisional surgery of the endometriomas, and 30 patients with endometriosis grades I and II, allocated as a Control Group. The ovarian reserve was indirectly assessed, through the basal (U/L) follicle stimulating hormone (FSH), between the third and fifth days of the cycle, 12 months after the surgery. The body mass index (BMI) was calculated according to Quetelet's formula [weight (kg)/height(cm²)]. The Mann-Whitney non-parametric U test was used to compare the variables "age", "BMI" and "basal SFH" between the groups. RESULTS: there was no significant difference between the groups about age and BMI. Concerning basal FSH, in the group of patients with severe endometriosis, the average value was 7.0 U/L, while in the Control Group, it was 5.6 U/L (p=0.3), what demonstrates that the difference between the two groups was not significant. CONCLUSIONS: the surgery did not affect the ovarian reserve of patients with severe ovarian endometriosis.

Evidência da resposta folicular ao FSH pelo hormônio antimülleriano em mulheres ovulatórias / Evidence of follicle responsiveness to FSH by antimüllerian hormone in ovulating women

OBJETIVO: examinar a hipótese de que o nível sérico do hormônio antimülleriano (AMH) reflete a resposta dos folículos antrais à administração do FSH. MÉTODOS: estudo prospectivo, no qual foram incluídas 116 pacientes normo-ovulatórias inférteis submetidas à hiperestimulação ovariana controlada com agonista de GnRH e FSH. Depois de atingir a supressão pituitária e antes da administração de FSH (dia basal), o nível sérico de AMH foi mensurado. O número de folículos antrais foi determinado pela ultrassonografia no dia basal (folículos antrais precoces; 2 a 8 mm) e no dia da administração do hCG (dhCG; folículos pré-ovulatórios; >16 mm). A resposta folicular ao FSH foi determinada pela percentagem de folículos antrais precoces que atingiram os estágios pré-ovulatórios em resposta ao FSH (taxa de maturação). Foram estudadas as correlações do AMH com a idade das pacientes, número total de folículos antrais precoces e pré-ovulatórios, oócitos coletados, dose total de FSH na estimulação ovariana controlada e a taxa de maturação folicular. Para análise estatística, foram usados a regressão simples e o teste de Spearman's, com nível de significância de 5%. RESULTADOS: o nível sérico de AMH foi positivamente correlacionado com o número de folículos antrais precoces no dia basal (r=0,64; p<0,0001) e folículos pré-ovulatórios em dhCG (r=0,23; p=0,01). Excepcionalmente, o nível sérico de AMH foi negativamente correlacionado com a taxa de maturação (r=-0,24; p<0,008). CONCLUSÕES: o AMH atenua o desenvolvimento folicular em resposta à administração do FSH.

PURPOSE: to test the hypothesis that the anti-müllerian hormone (AMH) serum level reflects the antral follicles' response to the administration of FSH. METHODS: prospective study, including 116 normo-ovulatory infertile patients submitted to controlled ovarian hyperstimulation with GnRH and FSH agonists. The AMH serum level was measured after reaching the pituitary suppression and before the FSH administration (basal day). The number of antral follicles was determined by ultrasonography at the basal day (precocious antral follicles; 2 to 8 mm) and at the day of hCG administration (dhCG; pre-ovulatory follicles; >16 mm). The follicle response to FSH was determined by the percentage of precocious antral follicles which reached pre-ovulatory stage in response to FSH (maturation rate). The correlation of AMH with the patients' age, the total number of precocious antral and pre-ovulatory follicles, collected oocytes, total dose of FHS in the controlled ovarian stimulation and the rate of follicular maturation was studied. For the statistical analysis, it simple regression analysis and the Spearman's test were used, at a 5% significance level. RESULTS: The serum level of AMH was positively correlated with the number of precocious antral follicles at the basal day (r=0.64; p<0.0001) and pre-ovulatory follicles in dhCG (r=0.23; p=0.01). Exceptionally, the serum level of AMH was negatively correlated with the maturation ratio (r=-0.24; p<0.008). CONCLUSIONS: AMH attenuates the follicular development caused by FSH administration.

Hormônio anti-mulleriano: um marcador mais fidedigno da reserva ovariana? / Anti-mullerian hormone: a better marker of ovarian reserve?

O Hormônio anti-mulleriano (HAM) é uma glicoproteína dimérica, membro da super família TGF (transforming growth factor), descoberto em 1947 por Alfred Jost. Além da produção de HAM pelas células de Sertoli testiculares, as células da granulosa dos folículos ovarianos sintetizam HAM em discretas quantidades a partir de 32 semanas de vida intra-uterina, com níveis séricos variáveis ao longo da vida reprodutiva. O HAM parece ter ação regulatória no desenvolvimento folicular com ação inibitória sobre o crescimento de folículos primordiais e crescimento folicular induzido pelo FSH. Por estas razões, acredita-se que o HAM tenha relação direta com o pool folicular apontando como novo marcador de reserva ovariana. Foi realizada revisão na literatura dos principais estudos sobre o HAM e suas implicações na regulação do desenvolvimento folicular, marcador de reserva ovariana, preditor de desfecho em ciclos de fertilização in vitro e de ocorrência da menopausa, associação com amenorréia secundária e neoplasias. O HAM parece ser um marcador mais fiel e fidedigno para avaliação da reserva ovariana, sendo melhor do que o FSH e Inibina B e correlacionando-se com a contagem de folículos antrais, apesar de ainda dispormos de poucos estudos para abordarmos sua dosagem como rotina.

Modificações dos níveis de gonadotrofinas durante a vida reprodutiva / Gonadotropin level changes during the reproductive life

As modificações nas concentrações das gonadotrofinas ao longo da vida reprodutiva dependem de amadurecimento funcional harmônico entre conexões neurais, neurônios-GnRH no hipotálamo, gonadotropos hipofisários e células da granulosa e teca da parede folicular. As concentrações de LH e FSH sofrem variações com o período do dia, fase do ciclo menstrual e idades ginecológica e cronológica. A variação circadiana é marcante para o LH e ocorre na fase puberal, quando os pulsos têm maior freqüência e amplitude no período noturno. Na fase puberal tardia, os pulsos das gonadotrofinas ocorrem também durante o dia e perdem a variação noite-dia, permanecendo discretas alterações durante as 24 horas do dia. No ciclo menstrual, durante os anos reprodutivos, o FSH eleva-se no final da fase lútea tardia, declina na fase folicular média, eleva-se bruscamente na fase ovulatória e permanece em níveis basais até a fase lútea tardia. O LH permanece em níveis constantes durante toda a fase folicular, eleva-se no pico ovulatório e declina a níveis basais na fase lútea. Na quarta década, há modificações hipotálamo-neurais na secreção de GnRH, atenuação do retrocontrole positivo exercido pelo estradiol e diminuição na freqüência e prolongamento dos pulsos de GnRH. A hipófise responde com diminuição na densidade de receptores-GnRH, perda da sensibilidade do gonadotropo, secreção de gonadotrofinas mais básicas com maior meia-vida, diminuição na freqüência e maior amplitude dos pulsos de LH e FSH e secreção preferencial de FSH. Estas modificações, associadas à aceleração no consumo folicular, explicam a elevação monotrópica mais rápida de FSH após os 37-38 anos e a manutenção de níveis quase constantes de LH até o final do período reprodutivo. Estudos consistentes mostram que a elevação seletiva dos níveis basais de FSH na fase folicular precoce na verdade é gradual, sendo observada já na terceira década de vida. A discordância entre pulsos e níveis basais de FSH...

Changes in the levels of gonadotropins throughout the reproductive life depend on a fine tuned functional development of neural pathways and GnRH-neurones, pituitary gonadotrophs and granulosa-theca cells of the follicular wall. Both, LH and FSH levels change according to the day-time, menstrual cycle phase, and gynecological age. Initiating the puberty, changes in LH pulses are remarkable, showing higher frequency and amplitude at night. Later in puberty, the pulses of LH are also maintained during the day, remaining its levels with very little variation within the 24 hours period. During the menstrual cycle, the FSH levels increase at the end of the luteal phase, decrease during the medium and late follicular phase, increase rapidly in the ovulatory phase and remain at low basal levels until the late luteal phase. The levels of LH remain unaltered during the whole follicular phase, increase in the ovulatory surge, and decrease to the basal levels in the luteal phase. At the forth decade of life, the GnRH secretion changes, with hypothalamic loss of sensitivy to the estradiol positive feedback and decrease in frequency and prolongation of the GnRH pulses. The pituitary response is atenuated due to decrease in the density of GnRH receptors on gonadotroph cells, loss of gonadotroph sensitivity, secretion of more basic FSH and LH molecules, decrease in frequency and increase in amplitude of LH and FSH pulses. These modifications result in monotropic increase of the FSH secretion. Current studies show that the selective increase in the FSH levels in the early follicular phase is gradual, beginning as early as the third decade of life. These alterations in FSH are associated with an accelerated follicular depletion in women after 37-38 years old. On the other side, the LH levels remain almost constant up to the end of reproductive life. The different levels of FSH and LH seen throughout the reproductive years may be due to yet unknown regulatory...