Exceptional lymph node recurrence of an unusual ovarian tumor 16 years later: a case report.

BACKGROUND: Sex cord-stromal tumors with annular tubules are a rare tumor accounting for less than 1% of all ovarian malignancies. However, they are characterized by very late recurrence, which can be as late as 30 years after diagnosis and treatment. CASE PRESENTATION: A 16-year-old female Caucasian patient was treated in our department for a stage IA ovarian sex cord-stromal tumors with annular tubules. She underwent a left salpingo-oophorectomy and ipsilateral pelvic node biopsy with no adjuvant treatment. She was seen for amenorrhea after being lost to follow up for 16 years. The diagnosis of recurrence was made by radiology and the elevation of serum inhibin B level. The patient underwent resection of the tumor, left segmental colectomy, and paraaortic lymphadenectomy because the mass was massively adherent to the left mesocolon. Histology confirmed the diagnosis with no metastatic lymph nodes. No adjuvant therapy was indicated. The patient was lost to follow-up again for 4 years and re-presented for amenorrhea. Serum inhibin B level was high. A second recurrence was suggested, and the patient underwent a laparoscopic surgery. We performed left pelvic and paraaortic lymphadenectomy, and 3 months after surgery the patient was pregnant. CONCLUSION: Sex cord-stromal tumors with annular tubules is a slow-growing ovarian tumor with a high potential for recurrence and metastasis. Surgery is the mainstay of treatment. Due to the rarity of these tumors, they are often unsuspected and thus incompletely staged before primary surgery; the diagnosis is made by histological examination. The prognosis of these patients is unknown, and they require long-term follow-up.

Combined maternal risk factors and the Quadruple test to predict late-onset preeclampsia in pregnant Thai women.

BACKGROUND: This study aimed to evaluate the predictive power of a model combining maternal risk factors and the Quadruple screen test for late-onset preeclampsia (PE). METHODS: All pregnant women that received the Quadruple test for Down syndrome at 15+ 0-20+ 6 weeks' gestation were recruited. Maternal serum α-fetoprotein, ß-human chorionic gonadotropin, unconjugated estriol, and inhibin A were measured as multiples of the median. A logistic regression model was used to identify predictors associated with late-onset PE with severe features. The receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to assess the model's predictive ability. RESULTS: Fifty-five of the 2,000 pregnant women had PE, and 31 of 55 women had late-onset PE. Multivariate analysis identified maternal age ≥ 35 years, inhibin A, history of previous PE, history of infertile, cardiac disease, chronic hypertension, and thyroid disease as significant risk factors. The area under the curve of the receiver operating characteristic curve was 0.78. The likelihood ratio to predict late-onset PE was 49.4 (total score > 60). CONCLUSIONS: Our model combining serum inhibin A with maternal risk factors was useful in predicting late-onset PE. Close monitoring of these patients is recommended.

Low Serum Inhibin B/Follicle-Stimulating Hormones and Anti-Müllerian Hormone/Follicle-Stimulating Hormones Ratios as Markers of Decreased Germ Cells in Infants with Bilateral Cryptorchidism.

PURPOSE: In cryptorchidism, germ cell development failure presents from infancy and may be reflected by altered hormonal levels produced by Sertoli cells. Our object was to assess for associations between serum hormone levels and testicular histopathology in cryptorchidism with an infertility risk according to the pretreatment undescended testicular positions. MATERIALS AND METHODS: Prepubertal cryptorchid boys aged 7-91 (median 20) months who underwent orchidopexy between 2014 and 2019 were included (122 unilateral [median 19 months {range 7-91}], 23 bilateral [24 months {11-81}]). We evaluated the pretreatment testicular position and size; serum hormone levels; and the mean number of germ cells per tubule transverse section (G/T). We also performed a subgroup analysis of boys aged ≤24 months at orchidopexy. RESULTS: Serum inhibin B levels and G/T were significantly lower in bilateral than in unilateral cryptorchid boys (median 96 [range 46-197] pg/ml vs 125 [21-354] pg/ml, p=0.026; 0.20 [0-2.59] vs 0.65 [0-4.55], p <0.001, respectively). Inhibin B/follicle-stimulating hormones (FSH) and anti-Müllerian hormone (AMH)/FSH ratios were positively correlated with G/T in bilateral cryptorchid boys aged ≤24 months (12, p=0.008 and p=0.019, respectively). Low inhibin B/FSH and AMH/FSH ratios and high FSH were predictors of impaired G/T as per receiver operating characteristic curves (p=0.019, p=0.004 and p=0.004, respectively), whereas in unilateral cryptorchid boys aged ≤24 months, serum hormone levels and G/T did not differ with the pretreatment testicular positions. CONCLUSIONS: In bilateral cryptorchid boys aged ≤24 months at orchidopexy, low inhibin B/FSH and AMH/FSH ratios may reflect impaired G/T and future infertility risk.

The utility of serum inhibin B, anti-Müllerian hormone and insulin growth factor-1 in predicting a positive response to GnRH analogs for diagnosing central precocious puberty in girls.

OBJECTIVES: The use of inhibin B (INHB), anti-Müllerian hormone (AMH) and insulin-like growth factor-1 (IGF-1) in differentiating central precocious puberty (CPP) from non-CPP was evaluated. METHODS: In total, 115 Chinese girls were recruited (CPP: 44, non-CPP: 71). The diagnostic performance of INHB, AMH and IGF-1 in differentiating CPP from non-CPP was analyzed using receiver operating characteristic (ROC) curves. RESULTS: INHB levels were higher in the CPP group than in the non-CPP group (55.56 ± 22.42 vs. 32.97 ± 15.59 pg/mL; p<0.001). AMH levels were similar in the CPP and non-CPP groups (6.63 ± 3.74 vs. 5.70 ± 3.15 pg/mL; p=0.158), and IGF-1 levels were much higher in the CPP group than in the non-CPP group (290.75 ± 79.78 vs. 200.10 ± 54.01 pg/mL; p<0.001). The area under the ROC curve (AUC) was greatest for INHB (0.819, standard error (SE) 0.041), followed by IGF-1 (0.809, SE 0.047) and AMH (0.567, SE 0.057). Among the ROC curves including combinations of these parameters, the AUC for INHB + IGF-1 was 0.849 and that for INHB + AMH was 0.768. CONCLUSIONS: Serum INHB and IGF-1 measurements could predict positive responses to gonadotropin-releasing hormone (GnRH) analog stimulation in girls with precocious puberty.

A technical and clinical evaluation of the new ThermoFisher BRAHMS unconjugated estriol and inhibin-A assays and their use in second trimester Down syndrome screening.

To evaluate second-trimester Down syndrome screening performance of the new ThermoFisher BRAHMS GOLD unconjugated estriol (uE3) and inhibin-A assays. Serum samples were analyzed for levels of uE3 and inhibin-A using the ThermoFisher BRAHMS GOLD immunoanalyzer and compared to other platforms. Levels were transformed to multiples of the median (MoM) in unaffected pregnancies. Log10 MoM distributions in unaffected and Down syndrome pregnancies were assessed for central tendency (mean) and dispersion (SD). Empirical and estimated screening performances were determined. Correlation between BRAHMS and AutoDELFIA® uE3 and inhibin-A were 0.63 and 0.97, respectively, the respective mean difference was 31.3% [95%CI 50.2% to -112.8%] and -23.3% [95%CI -41.9% to -4.7%]. Passing-Bablok indicated significant systematic (-2.78 [95%CI -3.57 to -2.04]) and proportional bias (1.30 [95%CI 1.15 to -1.47]) between uE3 assays and significant proportional bias (0.71[95%CI 0.65-0.78]) between inhibin-A assays. The uE3 and inhibin-A log10 MoM distribution mean [SD] in unaffected and Down syndrome pregnancies were 0.0024 [SD = 0.2341] and -0.0001 [SD = 0.2078], and -0.2028 [SD = 0.2495] and 0.3645 [SD = 0.2576], respectively. The new BRAHMS uE3 and inhibin-A assays had an 81-83% detection rate for Trisomy21 for a 5% false-positive rate. The new BRAHMS assays achieved the expected screening performance provided the risk estimation model is adjusted to account for the higher BRAHMS uE3 MoM measurement distribution variance.

Clinical application value of Inhibin B alone or in combination with other hormone indicators in subfertile men with different spermatogenesis status: A study of 324 Chinese men.

BACKGROUND: In this study, we investigated the clinical value of serum Inhibin B alone or in combination with other hormone indicators in subfertile men. METHODS: This is a multicenter study involving 324 men from different cities in China. Testicular volume, routine semen analysis, serum Inhibin B, anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, estradiol, and prolactin were measured. Testicular tissue samples were also analyzed in 78 of 129 patients with azoospermia to distinguish impaired spermatogenesis from obstructive azoospermia. RESULTS: The concentration of Inhibin B, FSH, and AMH is related to spermatogenesis. For men with impaired spermatogenesis, including mild-to-moderate oligozoospermia (IMO) and severe oligozoospermia (ISO), serum levels of Inhibin B and FSH are highly correlated with sperm counting. However, in patients with idiopathic moderate oligozoospermia or severe oligozoospermia, there was no significant correlation between Inhibin B (or FSH) and sperm concentration. The upper cutoff value of Inhibin B to diagnose ISO is 58.25 pg/ml with a predictive accuracy of 80.65%. To distinguish between nonobstructive azoospermia (NOA) and obstructive azoospermia (OA), the area under the curve (AUC) for AMH + Inhibin B + FSH is very similar to Inhibin B (0.943 vs. 0.941). The cutoff level of Inhibin B to diagnose nonobstructive azoospermia is 45.9 pg/ml with a positive and negative prediction accuracy of 97.70% and 85.71%, respectively. CONCLUSION: In summary, Inhibin B is a promising biomarker alone or in combination with other hormone indicators for the diagnosis of testicular spermatogenesis status, helping clinical doctors to distinguish NOA from OA.

Serum Inhibin-A and PAPP-A2 in the prediction of pre-eclampsia during the first and second trimesters in high-risk women.

OBJECTIVES: Maternal serum inhibin-A, pregnancy associated plasma protein-A (PAPP-A) and PAPP-A2 together with placental growth factor (PlGF), maternal risk factors and uterine artery pulsatility index (UtA PI) were analysed to study their ability to predict pre-eclampsia (PE). STUDY DESIGN: Serial serum samples for the nested case-control study were collected prospectively at 12-14, 18-20 and 26-28 weeks of gestation from 11 women who later developed early-onset PE (EO PE, diagnosis < 34 + 0 weeks of gestation), 34 women who developed late-onset PE (LO PE, diagnosis ≥ 34 + 0 weeks) and 89 controls. MAIN OUTCOME MEASURES: Gestational age -adjusted multiples of the median (MoM) values were calculated for biomarker concentrations. Multivariate regression analyses were performed to combine first trimester biomarkers, previously reported results on PlGF, maternal risk factors and UtA PI. Area under curve (AUC) values and 95% confidence intervals (CIs) for the prediction of PE and its subtypes were calculated. RESULTS: A high first trimester inhibin-A predicted PE (AUC 0.618, 95%CI, 0.513-0.724), whereas PAPP-A and PlGF predicted only EO PE (0.701, 0.562-0.840 and 0.798, 0.686-0.909, respectively). At 26-28 weeks PAPP-A2 and inhibin-A predicted all PE subtypes. In the multivariate setting inhibin-A combined with maternal pre-pregnancy body mass index, prior PE and mean UtA PI predicted PE (0.811,0.726-0.896) and LO PE (0.824, 0.733-0.914). CONCLUSIONS: At first trimester inhibin-A show potential ability to predict not only EO PE but also LO PE whereas PlGF and PAPP-A predict only EO PE. At late second trimester inhibin-A and PAPP-A2 might be useful for short-term prediction of PE.

Can Inhibin B Reflect Ovarian Reserve of Healthy Reproductive Age Women Effectively?

Objective: The reference range and potential value of inhibin B are still unclear and controversial. This study aimed to define the variation trend of inhibin B in healthy women with age and explore its value in the reflection of ovarian reserve. Methods: A total of 2524 healthy reproductive age women from eight medical institutes nationwide were recruited. The variation tendency of inhibin B with age was primarily established in the first group of 948 women and validated in another 605. We evaluated the relationship between inhibin B and classic ovarian reserve and function markers. The potency of inhibin B in predicting AFC <5-7 was also estimated and compared with FSH. Results: The nomogram showed that serum levels of inhibin B rapidly decreased after the age of 40. Inhibin B was positively correlated with AMH (R = 0.57, P < 0.001), AFC (R = 0.34, P < 0.001) and testosterone (R = 0.10, P = 0.002), and negatively correlated with FSH (R = -0.41, P < 0.001) and LH (R = -0.20, P < 0.001) and FSH/LH (R=-0.18, P < 0.001), while no correlation was found with PRL. Unexpectedly, Inhibin B (AUC = 0.74, P < 0.001 for the establishment population; AUC = 0.78, P < 0.001 for the validation population) had a slightly higher value than FSH (AUC = 0.71, P < 0.001 for the establishment population; AUC = 0.72, P < 0.001 for the validation population) in diagnosing AFC <5-7. Conclusions: For healthy reproductive age women, the decline of inhibin B can reflect decreased ovarian reserve effectively, having a good consistency with AMH and AFC. More importantly, inhibin B had an advantage in predicting AFC <5-7 compared with FSH, which suggested the potential of inhibin B in predicting ovarian response. These results will be helpful to the clinical application of inhibin B in the evaluation of female ovarian reserve and the assessment of their reproductive capacity. Trial registration: http://clinicaltrials.gov; NCT02294500.

Ethnic-specific reference range affects the efficacy of quadruple test as a universal screening for Down syndrome in a developing country.

OBJECTIVE: To evaluate the efficacy of the quadruple test for potential use as a Thai national policy for Down syndrome (DS) screening and establish an accurate equation for risk estimation of Down syndrome based on gestational age, weight and the ethnic-specific reference range of our population. METHODS: A prospective study was conducted on singleton pregnancies at 14 to 21 weeks of gestation to evaluate the efficacy of quadruple DS screening using the automatically calculated Western European descent factor (WF) in our population and the impact of screening using a specific Thai ethnic factor as well as to establish an equation for the risk estimation of DS based on gestational age, weight and a local Thai ethnic factor to correct for the impact of ethnic factor on the screening efficacy. RESULTS: Of a total of 5,515 women, 12 cases of DS and 8 cases of other aneuploidies were found. The detection rate, false positive rate and specificity were 75.0%, 9.1% and 90.9%, respectively, by automatic calculation with the widely used WF; the screening efficacy was lower when used in Asian populations than in other studies. The best-fitted regression equation of serum quadruple screening of AFP, free ß-hCG, uE3 and inhibin A was established by adjustment for gestational age (GA) in days, maternal weight and our Thai-specific ethnic reference range which was created for this study. Calculations with our Thai-specific ethnic model gave a better detection rate of 83.3%, a false positive rate of 9.6% and specificity of 90.4%. CONCLUSION: The serum quadruple test had a lower detection rate than expected when the risk estimation was based on the WF reference range. The serum quadruple test using WF had significantly different levels when corrected with our ethnic-specific factor. Using our local ethnic specific model could increase the detection rate of DS screening in Thailand with a minimal increase in false positive rates. Our findings indicate that DS screening should be adjusted with an appropriate individual ethnic factor when used for national screening.

Interactions between serum FSH, inhibin B and antral follicle count in the decline of serum AMH during the menstrual cycle in late reproductive age.

Objective: To investigate the hormonal interrelationships during the menstrual cycle in women of late reproductive age with suppressed serum AMH and antral follicle count (AFC). Methods: Serum hormones (AMH, FSH, LH, estradiol, progesterone, inhibin A, inhibin B), AFC (2-10 mm) and AMH/AFC ratio (an estimate of AMH/follicle) were assessed every 2-3 days across the menstrual cycle in 26 healthy ovulatory women aged 18-50 years. Results: An 11-fold fall in AMH/AFC was observed in women aged ≥45 years compared to those 18-45 years (P < .001). Although women ≥45 years exhibited normal menstrual cycle patterns of serum estradiol, progesterone, LH and inhibin A, FSH was elevated (P < .001) and inhibin B suppressed (P < .001) compared to the younger group. Overall FSH was inversely correlated (r = .55, P < .05) and AMH directly correlated (r = .88, P < .01) with AFC; however, these relationships were curvilinear and more pronounced when AFC was low. Inhibin B was directly linearly correlated (r = .70, P < .01) with AFC across both high and low AMH/follicle groups. Conclusions: It is hypothesized that the marked fall in AMH/follicle in late reproductive age is attributed to the change in the hormonal interplay between the pituitary and ovary. The fall in AFC leads to a decrease in inhibin B and a concomitant increase in FSH by a recognized feedback mechanism. It is postulated the elevated FSH suppresses AMH either directly or indirectly through oocyte-specific growth factors leading to a marked fall in AMH/follicle. We propose that pituitary-ovarian and intra-ovarian regulatory systems underpin the accelerated fall in AMH/follicle during the transition to menopause.

Regional and ethnic differences in semen quality and reproductive hormones in Russia: A Siberian population-based cohort study of young men.

BACKGROUND: This is the first large-scale Russian study describing semen quality and reproductive hormone levels among young men. OBJECTIVES: The aim of the study was to compare semen quality and reproductive hormone levels in young men of four cities and three ethnic groups living in the Siberian region of Russia and to find out ethnic or environmental reasons for regional differences. MATERIALS AND METHODS: The study population consisted of 1291 young men from Novosibirsk, Kemerovo, Ulan-Ude, and Yakutsk, including 1013 men of three most numerous ethnic groups: Slavs, Buryats, and Yakuts. Each participant provided one sperm and blood sample, information about lifestyle and ethnicity. Anthropometric parameters, semen quality and reproductive hormone levels, were evaluated. RESULTS: Significant regional and ethnic differences were detected for semen and reproductive hormone parameters. Median sperm concentrations in Novosibirsk, Kemerovo, Ulan-Ude, and Yakutsk were 54.6, 39.9, 34.7, 33.1 × 106 /ml; total sperm counts-202.5, 138.7, 97.9, 93.4 × 106 ; percentages of morphologically normal spermatozoa-7.8%, 6.5%, 6.3%, 5.0%, respectively. Median sperm concentrations in Slavs, Buryats, and Yakuts were 43.7, 37.0, 30.6 × 106 /ml; total sperm counts-150.0, 102.3 and 74.8 × 106 ; percentages of morphologically normal spermatozoa-6.8%, 6.8%, 4.8%, respectively. DISCUSSION: The young men in Novosibirsk and Kemerovo, populated by Slavs, had a higher semen quality compared to Ulan-Ude and Yakutsk, populated by Buryats and Yakuts, apparently due to the higher testicular function in Slavic compared to Asian ethnicity. Impaired spermatogenesis in young men in Kemerovo compared to Novosibirsk, located in the same climatic zone and having a socio-cultural and ethnic identity, may be due to the influence of a polluted environment. CONCLUSION: The findings suggest that ethnic composition and environment may be responsible for regional differences in semen and reproductive hormone parameters.

RANKL regulates male reproductive function.

Infertile men have few treatment options. Here, we demonstrate that the transmembrane receptor activator of NF-kB ligand (RANKL) signaling system is active in mouse and human testis. RANKL is highly expressed in Sertoli cells and signals through RANK, expressed in most germ cells, whereas the RANKL-inhibitor osteoprotegerin (OPG) is expressed in germ and peritubular cells. OPG treatment increases wild-type mouse sperm counts, and mice with global or Sertoli-specific genetic suppression of Rankl have increased male fertility and sperm counts. Moreover, RANKL levels in seminal fluid are high and distinguishes normal from infertile men with higher specificity than total sperm count. In infertile men, one dose of Denosumab decreases RANKL seminal fluid concentration and increases serum Inhibin-B and anti-Müllerian-hormone levels, but semen quality only in a subgroup. This translational study suggests that RANKL is a regulator of male reproductive function, however, predictive biomarkers for treatment-outcome requires further investigation in placebo-controlled studies.

Ovarian Reserve Markers in Premature Ovarian Insufficiency: Within Different Clinical Stages and Different Etiologies.

Objective: To characterize the ovarian reserve indicators for premature ovarian insufficiency (POI) at different disease stages and with various etiologies. Methods: According to different FSH levels and menstrual conditions, patients with normal ovarian reserve (NOR with 5 IU/L40 IU/L, n=454) were retrospectively screened and their records were abstracted from Reproductive Hospital Affiliated to Shandong University between 2014 and 2019. Based on the known etiologies, POI patients were subdivided into genetic, iatrogenic, autoimmune and idiopathic subsets according to the known etiologies. The phenotypic features were compared within different subgroups, and the predictive value of ovarian reserve markers was analyzed. Results: The ovarian reserve indicators consecutively deteriorated with the progress of ovarian insufficiency, indicated as an increase of FSH and LH but decrease of AMH, inhibin B, AFC, E2 and T (P<0.01). Most of them changed significantly from NOR to pre-POI while remained relatively stable at a low level or even undetectable at early POI and POF stage. AMH showed the highest predictive value for pre-POI (AUC 0.932, 95% CI 0.918-0.945) and POI (AUC 0.944, 95% CI 0.933-0.954), and the combination of AMH and AFC was highly promising for early prediction. Additionally, significant differences existed in AMH, inhibin B and AFC among women with different etiologies of POI (P<0.05), and the genetic POI presented the worst hormone status. Conclusions: Our study indicated a high heterogeneity of POI in both endocrine hormones and etiological phenotypes. The quantitative changes and cutoff values of AMH and AFC could provide new insights in the prediction and early diagnosis of POI.

Hormonal markers as noninvasive predictors of sperm retrieval in non-obstructive azoospermia.

Non-obstructive azoospermia (NOA) is one of the leading causes of male factor infertility, which results from impaired spermatogenesis. Currently, the sole feasible therapeutic option for men with NOA to father their biologic children is sperm retrieval by testicular sperm extraction (TESE) approaches followed by an intracytoplasmic sperm injection program. Nevertheless, the rate of sperm retrieval from NOA men following TESE has remained as low as 50%, leading to a significant number of unsuccessful TESE operations. Given that TESE is associated with multiple side effects, the prediction of TESE outcome preoperatively can abolish unnecessary operations and thereby prevent NOA patients from sustaining adverse side effects. As the process of spermatogenesis is under the regulation of hormones, the hormonal profile of serum and/or seminal plasma may contain useful information about spermatogenesis status and can potentially predict the chance of sperm retrieval from NOA patients. A large body of literature is available on the predictive capability of different serum and seminal plasma hormones such as FSH, LH, testosterone, inhibin B, AMH, estradiol, prolactin, and leptin in a stand-alone basis or combinational fashion with respect to the TESE outcome. The present review aimed to evaluate the potential of these hormonal markers as noninvasive predictors of sperm retrieval in men with NOA.

Serum INHB levels and ACE gene I/D polymorphism with increased risk for unexplained infertility.

Angiotensin converting enzyme (ACE) has a significant role in the angiogenesis of ovarian endothelium and the resumption of meiosis and folicular growth. However, there is no any study concerning ACE polymorphism and unexplained infertility (UI). The main aim of this study is that both identify ACE polymorphism and measure the serum ACE, anti-Mullerian hormone (AMH) and inhibin-B (INHB) levels in UI patients and controls in Turkish population. Forty-seven UI patients and 41 controls were involved in this study. To determine the ACE polymorphisms, DNA isolation and PCR were performed. Then, serum ACE, AMH and INHB levels were measured spectrophotometrically. Patients with UI had significantly higher serum INHB levels compared with controls (P < 0.05). Serum ACE levels were decreased, compared to controls; however, the decrease was not significant. Serum AMH levels did not significantly differ from controls. When the relationship was analysed between ACE insertion/deletion (I/D) polymorphism and infertility risk, and ID genotype was chosen as reference, it was found to be 2.33 times more risk of UI than the women have DD genotype [DD versus ID: odds ratio = 2.33, 95% confidence interval (0.88-6.19); P = 0.086]. This finding indicates that DD genotype may be high risk for UI. Further studies are warranted to confirm this finding, especially with a larger population.

Predictive value of quad serum markers for adverse pregnancy outcome in antiphospholipid antibody syndrome.

PURPOSE: We investigated the validity of quad serum markers for the prediction of adverse pregnancy outcome (APO) in women with antiphospholipid antibody syndrome (APS). METHODS: We included 75 women with APS delivered at our institution. APO was defined as stillbirth, small for gestational age (SGA), severe preeclampsia, or preterm delivery. First, we compared clinical characteristics between patients with or without composite APO. Second, we compared the rate of APO according to abnormal level of quad serum markers. Lastly, receiver operating characteristic (ROC) curve analysis was performed. RESULTS: APS mothers with APO showed higher median α-fetoprotein (AFP) and inhibin A compared with those without APO. They were also associated with higher rates of positive risk of Down syndrome and neural tube defect. Elevated AFP, human chorionic gonadotropin (hCG), and inhibin A level was associated with higher rates of stillbirth, SGA, preterm delivery, and composite APO. ROC curve for prediction of stillbirth revealed an area under the curve of 0.835 for AFP, 0.781 for hCG, and 0.932 for inhibin A. For composite APO, the area under the ROC curve was 0.692 for AFP and 0.810 for inhibin A. CONCLUSION: Elevated AFP, hCG, and inhibin A in women with APS demonstrated a high predictive value for APO, especially stillbirth.

Serum Insulin-like Factor 3 Levels Are Reduced in Former Androgen Users, Suggesting Impaired Leydig Cell Capacity.

CONTEXT: Illicit use of anabolic androgenic steroids (AAS) is frequently observed in men and is associated with subsequent testosterone deficiency although the long-term effect on gonadal function is still unclear. Serum insulin-like factor 3 (INSL3) has been suggested to be a superior biomarker of Leydig cell secretory capacity compared to testosterone. OBJECTIVE: This study aimed to investigate serum INSL3 concentrations in AAS users. METHODS: This community-based, cross-sectional study included men aged 18 to 50 years, involved in recreational strength training and allocated to 1 of 3 groups: never-AAS users as controls (n = 44), current (n = 46), or former AAS users (n = 42) with an average duration since AAS cessation of 32 (23 ; 45) months. RESULTS: Serum INSL3 was lower in current AAS users and former AAS users than in controls, median (interquartile range), 0.04 µg/L (nondetectable [ND]-0.07 µg/L) and 0.39 µg/L (0.24-0.62 µg/L) vs 0.59 µg/L (0.45-0.72 µg/L), P less than .001. Former AAS users exhibited lower serum INSL3 levels than controls in a multivariable linear regression even after adjusting for serum total testosterone (TT) and other relevant confounders, (B) (95% CI), -0.16 µg/L (95% CI, -0.29 to -0.04 µg/L), P equal to .011. INSL3 and TT were not associated in the model, P equal to .821. Longer accumulated AAS duration (log2) was associated with lower serum INSL3 in former AAS users, (B) (95% CI), -0.08 (95% CI, -0.14 to -0.01), P equal to .022. Serum INSL3, but not inhibin B or testosterone, was associated with testicular size in a multivariate linear regression, (B) (95% CI); 4.7 (95% CI, 0.5 to 8.9), P equal to .030. CONCLUSION: Serum INSL3 is reduced years following AAS cessation in men, independently of testosterone, suggesting persistently impaired Leydig cell capacity.

Juvenile granulosa cell tumor of the ovary: A comprehensive clinicopathologic analysis of 15 cases.

OBJECTIVE: Juvenile granulosa cell tumor(JGCT) is an uncommon ovarian sex-cord stromal tumor, with diverse clinical, radiological and histopathologic features. The present study describes the clinicopathological and histomorphological spectrum of JGCTs, and highlights the key differentiating features from its mimics. METHODS: A retrospective analysis of all cases reported as JGCTs during 2011-19 (8 years) was performed with detailed evaluation of clinical, histopathologic data and follow-up details. RESULTS: Of a total 115 GCTs reported during the study period, 15(13%) were reported as JGCTs. The mean age at presentation was 17 years. Abdominal pain and distension were the most common clinical presentations. Five patients were pre-menarchal with 3 exhibiting precocious puberty. Majority of tumors were unilateral(left>right), solid-cystic, ranging in size from 4 to 20 cm. Microscopically, macrofollicular architecture was most frequent (n = 12;80%). The tumor cells depicted variable nuclear pleomorphism, small distinct nucleoli and moderate-abundant pale eosinophilic-clear/vacuolated cytoplasm. Mitotic activity ranged from 1 to 10/10HPFs. Uncommon histopathologic features included microcystic and tubulo-cystic architecture, myxoid degeneration, bizarre tumor giant cells, hob-nailing of the tumor cells, intracytoplasmic hyaline globules, multifocal calcification and thick hyalinized blood vessels. Majority(n = 12;80%) presented in stage I. Surgical treatment included unilateral salpingo-oophorectomy without any adjuvant chemotherapy, bilateral salpingo-oophorectomy (BSO) and total abdominal hysterectomy with BSO with adjuvant BEP chemotherapy (Bleomycin, etoposide, cisplatin). CONCLUSIONS: JGCT is a rare ovarian tumor affecting young women and children with diverse histopathologic features. Despite an aggressive histopathology, these tumors have a good outcome, when diagnosed at an early stage.

Ovarian Reserve Biomarkers and Menstrual Cycle Length in a Prospective Cohort Study.

CONTEXT: While age-related changes in menstrual cycle length are well known, it is unclear whether anti-Müllerian (AMH) or other ovarian reserve biomarkers have a direct association with cycle length. OBJECTIVE: To determine the association between biomarkers of ovarian reserve and menstrual cycle length. METHODS: Secondary analysis using data from time to conceive (TTC), a prospective time to pregnancy cohort study. The age-independent association between cycle length and biomarkers of ovarian reserve was analyzed using linear mixed and marginal models. Study participants were TTC-enrolled women aged 30-44 years with no history of infertility who were attempting to conceive for <3 months were enrolled. Serum AMH, follicle-stimulating hormone, and inhibin B levels were measured on cycle day 2, 3, or 4. Participants recorded daily menstrual cycle data for ≤4 months. The primary outcome was menstrual cycle length; follicular and luteal phase lengths were secondary outcomes. RESULTS: Multivariable analysis included 1880 cycles from 632 women. Compared with AMH levels of 1.6 to 3.4 ng/mL, women with AMH <1.6 ng/mL had cycles and follicular phases that were 0.98 (95% CI -1.46, -0.50) and 1.58 days shorter (95% CI -2.53, -0.63), respectively, while women with AMH >8 ng/mL had cycles that were 2.15 days longer (95% CI 1.46, 2.83), follicular phases that were 2 days longer (95% CI 0.77, 3.24), and luteal phases that were 1.80 days longer (95% CI 0.71, 2.88). CONCLUSION: Increasing AMH levels are associated with longer menstrual cycles due to both a lengthening of the follicular and the luteal phase independent of age.

Risk of Severe Maternal Morbidity or Death in Relation to Prenatal Biochemical Screening: Population-Based Cohort Study.

OBJECTIVE: This study aimed to examine whether prenatal biochemical screening analytes are associated with an increased risk of severe maternal morbidity (SMM) or maternal mortality. STUDY DESIGN: This population-based cohort study includes all women in Ontario, Canada, who underwent prenatal screening from 2001 to 2011. Increasing fifth percentiles of the multiple of the median (MoM) for alphafetoprotein (AFP), total human chorionic gonadotropin, unconjugated estriol (uE3), dimeric inhibin-A (DIA), and pregnancy-associated plasma protein A were evaluated. An abnormally high concentration (>95th percentile MoM) for each analyte, individually and combined, was also evaluated. The main outcome assessed was the adjusted relative risk (aRR) of SMM or maternal mortality from 20 weeks' gestation up to 26 weeks thereafter. RESULTS: Among 748,972 pregnancies, 11,177 resulted in SMM or maternal mortality (1.5%). Except for uE3, the aRR of SMM or maternal mortality increased in association with increasing fifth percentiles of the MoM for all analytes. AFP (aRR: 2.10; 95% confidence interval [CI]: 1.97-2.25) and DIA (aRR: 2.33; 95% CI: 1.98-2.74) > 95th versus ≤ 5th percentile of the MoM were especially associated with SMM or death. CONCLUSION: Women with abnormally high concentrations of certain prenatal biochemical analytes may be at a higher risk of SMM or death in pregnancy or postpartum.