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Cyclin-dependent kinase inhibitors are approved in combination with hormonal therapy for treatment of hormone receptor expressing breast cancers. Activity in hormone receptor expressing gynecologic cancers has been postulated. Granulosa cell tumor of the ovary is one such cancer, which is relatively resistant to traditional cytotoxic chemotherapy. We report a case series of 7 heavily pre-treated patients with recurrent granulosa cell tumor of the ovary with a cyclin-dependent kinase inhibitor in combination with hormonal therapy, with 3 patients demonstrating partial response and 2 with stable disease. As of the data cutoff, 3 patients remained on treatment and 5 were alive, with true medians for duration of treatment and overall survival not reached (medians at data cutoff of 64 weeks and 62 months respectively). The treatment was generally well tolerated, with 1 patient choosing to discontinue treatment due to grade 3 fatigue. This regimen represents a possible option in the treatment of granulosa cell tumor of the ovary, warranting further prospective study for this unmet need in this indolent disease which often requires many lines of treatment.

BackgroundThe contribution of genetic polymorphisms to the large inter-individual variation in mammographic density (MD) changes following starting and stopping use of estrogen and progestin combined therapy (EPT) has not been well-studied. Previous studies have shown that circulating levels of insulin-like growth factors are associated with MD and cross-talk between estrogen signaling and growth factors is necessary for cell proliferation in the breast. We evaluated single nucleotide polymorphisms (SNPs) in growth factor genes in association with MD changes after women stop EPT use.MethodsWe genotyped 191 SNPs in 13 growth factor pathway genes in 284 non-Hispanic white California Teachers Study participants who previously used EPT and collected their mammograms before and after quitting EPT. Percent MD was assessed using a computer-assisted method. Change in percent MD was calculated by subtracting percent MD of an 'off-EPT' mammogram from percent MD of an 'on-EPT' (i.e. baseline) mammogram. We used multivariable linear regression analysis to investigate the association between SNPs and change in percent MD. We calculated P-values corrected for multiple testing within a gene (Padj).ResultsRs1983210 in INHA and rs35539615 in IGFBP1/3 showed the strongest associations. Per minor allele of rs1983210, the absolute change in percent MD after stopping EPT use decreased by 1.80% (a difference in absolute change in percent MD) (Padj= 0.021). For rs35539615, change in percent MD increased by 1.79% per minor allele (Padj= 0.042). However, after applying a Bonferroni correction for the number of genes tested, these associations were no longer statistically significant.ConclusionsGenetic variation in growth factor pathway genes INHA and IGFBP1/3 may predict longitudinal MD change after women quit EPT. The observed differences in EPT-associated changes in percent MD in association with these genetic polymorphisms are modest but may be clinically significant considering that the magnitude of absolute increase in percent MD reported from large clinical trials of EPT ranged from 3% to 7%.

Germline knockout studies in female mice demonstrated an essential role for forkhead box L2 (FOXL2) in early follicle development, whereas an inducible granulosa cell (GC)-specific deletion of Foxl2 in adults has shown ovary-to-testis somatic sex reprogramming. In women, over 120 different germline mutations in the FOXL2 gene have been shown to cause blepharophimosis/ptosis/epicantus inversus syndrome associated with or without primary ovarian insufficiency. By contrast, a single somatic mutation (FOXL2C134W) accounts for almost all adult-type GC tumors (aGCTs). To test the hypothesis that FOXL2C134W differentially regulates the expression of aGCT markers, we investigated the effect of FOXL2C134W on inhibin B and P450 aromatase expression using a recently established human GC line (HGrC1), which we now show to bear two normal alleles of FOXL2. Neither FOXL2wt nor FOXL2C134W regulate INHBB messenger RNA (mRNA) expression. However, FOXL2C134W selectively displays a 50-fold induction of CYP19 mRNA expression dependent upon activin A. Mechanistically, the CYP19 promoter is activated in a similar way by FOXL2C134W interaction with SMAD3, but not by FOXL2wt. SMAD2 had no effect. Moreover, FOXL2C134W interactions with SMAD3 and with the FOX binding element located at -199 bp upstream of the ATG initiation codon of CYP19 are more sustainable than FOXL2wt. Thus, FOXL2C134W potentiates CYP19 expression in HGrC1 cells via enhanced recruitment of SMAD3 to a proximal FOX binding element. These findings may explain the pathophysiology of estrogen excess in patients with aGCT.

BackgroundThe influence of estradiol (E2) on granulosa cell (GC) function has not been tested clinically in women with polycystic ovary syndrome (PCOS). The objective of this study is to determine if E2 influences GC responses to FSH in women with PCOS.MethodsThis is a two phase, single cohort study conducted over a 2-year period at a single academic center. Nine women with PCOS according to NIH criteria. In Phase 1, FSH stimulation of GC responses as measured by E2 and Inhibin B (Inh B) were assessed before and at 5 and 6 weeks after GnRH agonist administration. In Phase 2, the same protocol was employed with the addition of an aromatase inhibitor (letrozole, LET) administered daily beginning at week 4 for 2 weeks.ResultsIn Phase 1, recovery of FSH, E2 and Inh B from ovarian suppression occurred at 5 and 6 weeks after GnRH agonist injection and preceded resumption of LH and androgen secretion. In Phase 2, hormone recovery after GnRH agonist was characterized by elevated FSH and suppressed E2 levels whereas recovery of LH and androgen levels were unchanged. In Phase 1, FSH stimulated E2 and Inh B responses were unaltered during recovery from ovarian suppression. In Phase 2, E2 and Inh B fold changes after FSH were significantly reduced at weeks 5 (p

Aim: To evaluate the value of the second‐trimester fibronectin concentration, alone and in combination with other markers (e.g., mean arterial pressure, inhibin A), in the identification of women who subsequently develop severe preeclampsia. Methods: For this prospective nested case–control study, serum from pregnant women (gestational age 15–22 weeks) who underwent routine Down syndrome screening was analyzed. The women were tracked to delivery and assigned to the severe preeclampsia or control group, according to whether they developed severe preeclampsia. Each woman who later developed severe preeclampsia was paired with five healthy women with pregnancies of similar gestational age (± 1 week). Fibronectin, inhibin A, human chorionic gonadotropin, placental growth factor, cysteine, and homocysteine concentrations were measured in 44 cases in the severe preeclampsia group and 220 cases in the control group. The body mass index and mean arterial pressure were calculated. All results were compared between the two groups. Logistic regression analysis and receiver operating characteristic curve construction were conducted for markers differing significantly between two groups. Results: The second‐trimester fibronectin value was positively correlated with severe preeclampsia and predicted 67.7% of severe preeclampsia cases. The combination of fibronectin, inhibin A, and mean arterial pressure predicted 76.7% of severe preeclampsia cases; predictive values for combinations of fibronectin with mean arterial pressure or inhibin A were 75.4% and 74.6%, respectively. Combination with these other markers increased the predictive value of fibronectin. In addition, fibronectin was more powerful for the late severe preeclampsia and severe preeclampsia without fetal growth restriction subgroups. Conclusions: The second‐trimester fibronectin concentration can be used to predict severe preeclampsia. [ABSTRACT FROM AUTHOR]

Extraovarian granulosa cell tumors (GCTs) develop from ectopic gonadal tissue situated along the embryonal route of the genital ridge. Primary retroperitoneal tumors are extremely rare, with an incidence of 02% -06% and 80-85% probability of malignancy. Only eight such case reports have been published previously. We herein, report a rare case of extraovarian retroperitoneal GCT in a 55-year-old woman who presented with intermittent left lumbar region pain of one-year duration. She had a history of hysterectomy and bilateral salpingo-oophorectomy 8 years ago for uterine leiomyoma. Laparotomy revealed a retroperitoneal mass measuring 8cm x 10cm x 20cm in size, solid cystic with areas of necrosis and hemorrhage. The gross features, classical histopathology, and positive immunostaining of the retroperitoneal mass with inhibin, calretinin, PR, WT1 and immunonegativity for EMA were characteristic of adult-type GCT. Excluding any previous history of primary ovarian GCT in this patient, a de-novo retroperitoneal diagnosis was established.

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. [ABSTRACT FROM AUTHOR]

• GDF-15 can be measured in urine in pregnant and non-nonpregnant women. • The GDF-15 assay detects protein harboring the common H202D polymorphism. • The GDF-9/BMP-15 heterodimer can be measured in serum. TGF-β superfamily members are important biomarkers of reproductive health in women desiring fertility and during pregnancy. TGF-β proteins derived from the ovary and/or placenta have been detected in serum in women, but there have been very few attempts to measure them non-invasively, such as in urinary samples, and to compare them to serum concentrations. We measured inhibin A, inhibin B, total inhibin, AMH, activin A, activin B, activin AB, follistatin, the GDF-9/BMP-15 complex, and GDF-15 in paired serum and urine samples from healthy reproductive aged women and in pregnant (second trimester) women. We detected all hormones in serum in both pregnant and non-pregnant women. Inhibin A, total inhibin, activin A, activin AB, follistatin, and GDF-15 were significantly higher in pregnant than in non-pregnant women. GDF-15 was the only hormone consistently detected in urine. We also measured, for the first time, the GDF-9/BMP-15 functional heterodimer and the GDF-15 protein harboring the H202D polymorphism. We report the successful measurement of the GDF-9/BMP-15 heterodimer (its native form) in serum and the ability to measure GDF-15 non-invasively, in urinary samples. This novel GDF-15 assay also captures the antigen in the presence of a common genetic variant. [ABSTRACT FROM AUTHOR]

Objective: To assess whether serum inhibin A at 14-20 weeks of gestation is associated with the occurrence of pre-eclampsia., Methods: A retrospective cohort study using propensity score matching was conducted on 11 682 singleton pregnant women with established deliveries at the Obstetrics and Gynecology Hospital of Fudan University between January 2017 and July 2019. We investigated serum inhibin A levels at 14-20 weeks of gestation and calculated the relative risk between inhibin A and pre-eclampsia by multifactorial logistic regression analysis. Smoothed, fitted curves were used to observe the effect of inhibin A in relation to the occurrence of pre-eclampsia., Results: The risk of pre-eclampsia occurrence increased with elevated serum inhibin A. After full adjustment for confounders, the risk ratio for pre-eclampsia in the group of pregnant women with high inhibin A was 2.92 (95% confidence interval [CI] 2.08-4.11) compared with those with normal inhibin A. The results of sensitivity analysis suggested a consistent effect of inhibin A on the risk of pre-eclampsia in different populations., Conclusion: Elevated serum inhibin A at 14-20 weeks of gestation is associated with pre-eclampsia and may provide an early warning signal for pregnancy outcomes associated with pre-eclampsia., (© 2023 International Federation of Gynecology and Obstetrics.)

Background: The effects of novel non-cytotoxic and immunotherapy drugs for cancer treatment on human testicular function have not been studied systematically., Objectives: The present study aimed to characterize effects of non-cytotoxic and immunotherapy drugs in patients with cancers who had not been previously treated with gonadotoxic chemo- or radiotherapy., Materials and Methods: This study involved 34 men, not previously treated with gonadotoxic regimens, in a mixed longitudinal (Cohort 1: 19 men about to start and approximately 1 year on non-cytotoxic and immunotherapy treatment) and cross-sectional (Cohort 2: 15 men already on non-cytotoxic and immunotherapy treatment) study using data modeling to estimate within-person time-course changes in testicular exocrine and endocrine functions. Cohort 1 provided 45 paired semen and blood samples (34 prior to and nine during treatment) and Cohort 2 provided 45 sets of samples (15 pre-treatment, 30 on treatment), including six men in Cohort 2 who had pre-treatment spermatozoa cryostorage prior to the study. Men on non-cytotoxic and immunotherapy treatment had undergone a median of 33.5 months long-term treatment., Results: Spermatozoa output and concentration were reduced by about 50%, with corresponding increases in serum follicle-stimulating hormone and decreases in serum inhibin B. Serum testosterone, luteinizing hormone, and sex hormone-binding globulin were unaffected by non-cytotoxic and immunotherapy treatment., Conclusion: Within limits of the present study of sample size and duration of on-non-cytotoxic and immunotherapy treatment, non-cytotoxic and immunotherapy drugs have a modest effects on testicular exocrine function (sperm production) or its hormonal correlates (follicle-stimulating hormone, inhibin B), with minimal impact on testicular endocrine (testosterone, luteinizing hormone) function., (© 2023 Commonwealth of Australia. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Gonadotropin inhibitory hormone (GnIH) is essential for regulating the reproduction of mammals and inhibiting testicular activities in mice. This study aimed to explore the mechanism of GnIH on spermatogenesis and steroidogenesis by acting through the hypothalamus-pituitary-testis axis of mice. Mice were subcutaneously injected with different doses of GnIH (1 μg/150 μL, 3 μg/150 μL, 6 μg/150 μL, 150 μL saline, twice daily) for 11 days. Subsequently, luteinizing hormone (LH), testosterone (T), and inhibin B (INH B) levels of peripheral blood were determined, and the expression of GnRH synthesis-related genes (GnRH-1, Kiss-1, NPY) and gonadotropin synthesis-related genes (FSH β, LH β, GnRH receptor) in the hypothalamus and pituitary gland were respectively detected. Additionally, the expression of steroidogenesis-related genes/proteins (P450scc, StAR and 3β-HSD) and spermatogenesis-related proteins/genes including LH receptor (LHR), androgen receptor (AR), heat shock factor-2 (HSF-2) and INH B were analyzed using western blot and q-PCR. Results showed that GnIH treatment significantly reduced the concentration of LH in the peripheral blood. Further analysis revealed that GnIH treatment markedly reduced the expression of GnRHImRNA and Kiss-1 mRNA in the hypothalamus, and mRNA levels of FSH β, LH β, and GnRHR genes in the pituitary. We also observed that GnIH treatment significantly decreased T levels and expression of the P450scc, StAR, and 3β-HSD proteins in the testis. Furthermore, GnIH treatment down-regulated LHR, AR proteins, and HSF-2 gene in the testis. Importantly, the INH B concentration of and INH βb mRNA levels significantly declined following GnIH treatment. Additionally, GnIH treatment may induce germ cell apoptosis in the testis of mice. In conclusion, GnIH may suppress spermatogenesis and steroidogenesis by acting through the hypothalamus-pituitary-testis axis in mice., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Rats are multiparous rodents that have been used extensively in research; however, the low reproductive performance of some rat strains hampers the broader use of rats as a biomedical model. In this study, the possibility of increasing the litter size after natural mating in rats through superovulation using an anti-inhibin monoclonal antibody (AIMA) was examined. In outbred Wistar rats, AIMA increased the number of ovulated oocytes by 1.3-fold. AIMA did not affect fertilization and subsequent embryonic development, resulting in a 1.4-fold increase in litter size and a high pregnancy rate (86%). In contrast, conventional superovulation by eCG/hCG administration decreased the pregnancy rate to 6-40% and did not increase the litter size. In inbred Brown Norway rats, AIMA increased the litter size by 1.2-fold, and the pregnancy rate increased more than twice (86% versus 38% in controls). AIMA also increased the litter size by 1.5-fold in inbred Tokai High Avoiders and Fischer 344 rats. AIMA increased the efficiency of offspring production by 1.5-, 2.7-, 1.4-, and 1.4-fold, respectively, in the four rat strains. Thus, AIMA may consistently improve the reproductive performance through natural mating in rats, which could promote the use of AIMA in biomedical research., (© 2024. The Author(s).)

We describe the pathology of 5 patients with germline PRKACA copy number gain and Cushing syndrome: 4 males and 1 female, aged 2 to 43 years, including a mother and son. Imaging showed normal or slightly enlarged adrenal glands in 4 patients and a unilateral mass in the fifth. Biochemically, the patients had corticotropin-independent hypercortisolism. Four underwent bilateral adrenalectomy; unilateral adrenalectomy was performed in the patient with the adrenal mass. Pathologically, 3 patients, including the 1 with the tumor (adenoma), had primary pigmented nodular adrenocortical disease with extranodular cortical atrophy and mild intracapsular and extracapsular extension of cortical cells. The other 2 patients had cortical hyperplasia and prominent capsular and extracapsular micronodular cortical hyperplasia. Immunoperoxidase staining revealed differences for synaptophysin, inhibin-A, and Ki-67 (nuclei) in the atrophic cortices (patients 1, 2, and 3) and hyperplastic cortices (patients 4 and 5) and for Ki-67 (nuclei) and vimentin in the extracortical nodules in the 2 groups of patients. β-Catenin stained the cell membrane, cytoplasm, and nuclei of the adenoma. The patients were well at follow-up (1-23 years); 24-hour urinary cortisol excretion was elevated in the patient who had unilateral adrenalectomy.

BACKGROUND: Endocrine measures of ovarian reserve before breast cancer treatment may predict postchemotherapy ovarian function, providing prognostic information at the time of cancer diagnosis. The objectives of this study were 1) to determine whether prechemotherapy levels of antimullerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B (inhB) are associated with the return of ovarian function after chemotherapy and 2) to generate a prognostic score for ovarian recovery in young women with breast cancer. METHODS: A prospective cohort study recruited 109 participants (median age, 39 years; age range, 23-45 years) before chemotherapy from 2 breast clinics and followed them longitudinally. By using time-to-event analysis, the authors tested the association between prechemotherapy AMH, FSH, and inhB levels and the time to return of ovarian function, as measured by menstrual pattern. RESULTS: After a median follow-up of 163 days (range, 4-1009 days) after chemotherapy, 62 participants (57%) experienced return of ovarian function. In adjusted analyses, AMH levels >0.7 ng/mL (hazard ratio, 2.9; 95% confidence interval, 1.5-5.6) and FSH levels ≤10 IU/L (hazard ratio, 4.7; 95% confidence interval, 1.3-16.8) were associated with a shorter time to ovarian recovery, whereas inhB levels were not related. A prognostic score based on age 0.7 ng/mL, and body mass index ≥25 kg/m2 was used to estimate the timing of recovery. CONCLUSIONS: In reproductive-aged women with newly diagnosed breast cancer, prechemotherapy AMH and FSH levels were associated with the return of ovarian function, independent of age. A novel prognostic score incorporating AMH, age, and body size was capable of estimating the time to ovarian recovery. Pending validation, these data support using prechemotherapy ovarian reserve measures, particularly AMH, to prospectively counsel young patients on future ovarian function. Because ovarian function is not equivalent to fertility, follow-up studies on predicting fertility are needed. © 2014 American Cancer Society.

Di-n-Butyl (DBP) and Di-(2-EthylHexyl) (DEHP) phthalates can leach from daily-use products resulting in environmental exposure. In male rodents, phthalate exposure results in reproductive effects. To evaluate effects on the immature primate testis, testis fragments from 6-month-old rhesus macaques were grafted subcutaneously to immune-deficient mice, which were exposed to 0, 10, or 500 mg/kg of DBP or DEHP for 14 weeks or 28 weeks (DBP only). DBP exposure reduced the expression of key steroidogenic genes, indicating that Leydig cell function was compromised. Exposure to 500 mg/kg impaired tubule formation and germ cell differentiation and reduced numbers of spermatogonia. Exposure to 10 mg/kg did not affect development, but reduced Sertoli cell number and resulted in increased expression of inhibin B. Exposure to DEHP for 14 week also affected steroidogenic genes expression. Therefore, long-term exposure to phthalate esters affected development and function of the primate testis in a time and dosage dependent manner.

ObjectiveTo determine whether granulosa cells contribute to excess androgen production, by assessing inhibin B (Inh B) responses to hCG in women with polycystic ovary syndrome (PCOS) and in normal women.DesignProspective study.SettingAcademic medical center.Patient(s)Twenty women with PCOS and 16 normal women.Intervention(s)Blood samples obtained before and 24 hours after injection of 25 μg recombinant hCG (r-hCG).Main outcome measure(s)Basal and stimulated Inh B, E2, androstenedione (A), and T responses after r-hCG administration.Result(s)In normal and PCOS women, r-hCG induced a significant reduction of Inh B levels. Lowered Inh B responses were not related to body mass index, PCOS status, or age by multivariate regression. Recombinant hCG significantly increased serum A and E2 in both normal and PCOS women.Conclusion(s)In normal and PCOS women, Inh B production was decreased following r-hCG administration. These findings strongly suggest that in PCOS women androgen excess is not enhanced by LH-stimulated Inh B production.Clinical trial registration numberNCT00747617.

Introduction: Thyroid hormones play a major role in the regulation of testicular maturation and growth and in the control of Sertoli and Leydig cell functions in adulthood. When naturally occurring, hypothyroidism causes male hypogonadotropic hypogonadism and Sertoli cell function disorders, but when iatrogenic and methimazole-induced its influence on the pituitary-testicular axis function with respect to Sertoli cells is poorly known.

The objective of the present study was to investigate the potential role of immunization against INH on follicular development, serum reproductive hormone (FSH, E 2 , and P 4 ) concentrations, and reproductive performance in beef cattle. A total of 196 non-lactating female beef cattle (4-5 years old) with identical calving records (3 records) were immunized with 0.5, 1.0, 1.5, or 2.0 mg [(T1, n = 58), (T2, n = 46), (T3, n = 42) and (T4, n = 36), respectively] of the pcISI plasmid. The control (C) group (n = 14) was immunized with 1.0 mL 0.9% saline. At 21d after primary immunization, all beef cattle were boosted with half of the primary immunization dose. On day 10 after primary immunization, the beef cattle immunized with INH DNA vaccine evidently induced anti-INH antibody except for the T1 group. The T3 group had the greatest P/N value peak among all the groups. The anti-INH antibody positive rates in T2, T3 and T4 groups were significantly higher than that in C and T1 groups. RIA results indicated that serum FSH concentration in T2 group increased markedly on day 45 after booster immunization; the E 2 amount in T3 group was significantly increased on day 10 after primary immunization, and the levels of E 2 also improved in T2 and T3 groups after booster immunization; the P 4 concentration in T2 group was significantly improved on day 21 after primary immunization. Ultrasonography results revealed that the follicles with different diameter sizes were increased, meanwhile, the diameter and growth speed of ovulatory follicle were significantly increased. Furthermore, the rates of estrous, ovulation, conception, and twinning rate were also significantly enhanced. These findings clearly illustrated that INH DNA vaccine was capable of promoting the follicle development, thereby improving the behavioral of estrous and ovulation, eventually leading to an augment in the conception rates and twinning rate of beef cattle., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Meng, Li, Xiao, Liu, Gao, Gong, Lan and Wang.)

Several reports describing a rare primary liver tumor with histologic features reminiscent of follicular thyroid neoplasms have been published under a variety of descriptive terms including thyroid-like, solid tubulocystic, and cholangioblastic cholangiocarcinoma. Although these tumors are considered to represent histologic variants, they lack classic features of cholangiocarcinoma and have unique characteristics, namely immunoreactivity for inhibin and NIPBL::NACC1 fusions. The purpose of this study is to present clinicopathologic and molecular data for a large series of these tumors to better understand their pathogenesis. We identified 11 hepatic tumors with these features. Immunohistochemical and NACC1 and NIPBL fluorescence in situ hybridization assays were performed on all cases. Four cases had available material for whole-genome sequencing (WGS) analysis. Most patients were adult women (mean age: 42 y) who presented with abdominal pain and large hepatic masses (mean size: 14 cm). Ten patients had no known liver disease. Of the patients with follow-up information, 3/9 (33%) pursued aggressive behavior. All tumors were composed of bland cuboidal cells with follicular and solid/trabecular growth patterns in various combinations, were immunoreactive for inhibin, showed albumin mRNA by in situ hybridization, and harbored the NIPBL::NACC1 fusion by fluorescence in situ hybridization. WGS corroborated the presence of the fusion in all 4 tested cases, high tumor mutational burden in 2 cases, and over 30 structural variants per case in 3 sequenced tumors. The cases lacked mutations typical of conventional intrahepatic cholangiocarcinoma. In this report, we describe the largest series of primary inhibin-positive hepatic neoplasms harboring a NIPBL::NACC1 fusion and the first WGS analysis of these tumors. We propose to name this neoplasm NIPBL:NACC1 fusion hepatic carcinoma., Competing Interests: Conflicts of Interest and Source of Funding: This work was supported by the Englander Institute for Precision Medicine and by the Department of Pathology and Laboratory Medicine at Weill Cornell Medicine. The work at Memorial Sloan Kettering Cancer Center was funded in part by the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, the Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute under award number P30CA008748. M.F.L., J.S.M.M., and E.P. are employees at Isabl, Inc. G.G. is a consultant for Isabl. For the remaining authors none were declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To investigate the diagnostic value of anti-Mullerian hormone (AMH) and Inhibin B (InhB) in menopausal women with osteoporosis from the Chinese Daur ethnic group., Methods: A total of 175 menopausal women were selected and divided into the osteoporosis group ( N = 90) and the control group ( N = 85). BMD was measured by dual-energy X-ray absorptiometry, and laboratory indicators of osteoporosis, for example, serum osteocalcin (OC), β-collagen special sequence (β-CTX), and procollagen type I amino-terminal propeptide (PINP), bone alkaline phosphatase (BALP), AMH, and InhB were measured by commercial kits. The relationship between osteoporosis and AMH or InhB was analyzed. The predictive values of AMH and InhB were reflected by the ROC curve and logistic regression., Results: The level of BMD was decreased and the levels of OC, β-CTX, PINP, and BALP of the menopausal osteoporosis group were increased. The concentration of AMH and InhB in the menopausal osteoporosis group was decreased and they had connections with each other. AMH and InhB could be used as independent indicators for the occurrence of osteoporosis in menopausal women and their combination had a higher diagnostic value., Conclusion: AMH and InhB measurements in menopausal women had a certain clinical significance in the detection of osteoporosis. The occurrence of osteoporosis was related to BMD, OC, β-CTX, BALP, AMH, and InhB., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The severe acute respiratory syndrome coronavirus 2 can affect the hypothalamic-pituitary-gonadal axis (HPG) due to the expression of the angiotensin-converting enzyme 2 receptor., Objectives: To assess the prevalence of hypogonadism and Sertoli cell dysfunction in coronavirus disease 2019 (COVID-19) male survivors., Method: Male subjects recovered from acute COVID-19 infection were prospectively observed. The primary outcomes included the proportion of hypogonadism, defined biochemically as serum testosterone<230 ng/dL or CFT of<6.4 ng/mL if the total testosterone is between 230-320 ng/m. Sertoli cell dysfunction was defined as inhibin-B level<54.5 pg/mL. Subjects with hypogonadism were followed up at 12 months to assess the recovery of the HPG axis., Results: Eighty-three subjects aged≥18 years were evaluated at a median of 120 (±35) days post-recovery. Their mean age was 49.50±12.73 years, and the mean BMI was 26.84±5.62 kg/m 2 . Low testosterone was detected in 21 (24.71%) and low inhibin-B was detected in 14 (19.71%) out of 71 subjects at 3 months. Subjects with low testosterone were younger, with a mean age of 43.29±12.03 years (P-0.08) and higher BMI (P-0.012). The severity of COVID-19 infection, duration of hospitalization, and other factors were not significantly associated with low testosterone. At 12 months, 18 out of 21 subjects came for follow-up, of which 9 (50%) showed persistently low testosterone, suggestive of hypogonadism., Conclusion: Following COVID-19 infection, testosterone levels recovered over time; however, a significant proportion of subjects had low levels at 12-month follow-up. These findings have long-term implications for the management of COVID-19 subjects., Competing Interests: The authors declare no competing interests., (Thieme. All rights reserved.)

Secondary amenorrhea is not uncommon in the adolescent female population. There are multiple etiologies to consider, and a comprehensive evaluation is often pursued. Sometimes, however, despite a thorough workup, the diagnosis remains unclear. Here, we report an unusual cause of secondary amenorrhea in a 15-year-old girl. Our patient presented with secondary amenorrhea after a 4-year history of regular menstrual cycles. Her evaluation was notable for very low FSH and low estradiol but normal LH; pregnancy, adrenal, thyroid, prolactin studies, and brain magnetic resonance imaging scan did not reveal a cause of her amenorrhea. Her transabdominal ultrasound showed an enlarged right ovary, initially suggestive of a hemorrhagic cyst. Inhibin A and B were measured because of the persistently low FSH; these were found to be very elevated, concerning for an inhibin-producing tumor. The patient had surgical removal of her right ovary; pathology revealed a juvenile granulosa-cell tumor. Postoperatively, the patient had normalization of serum inhibin A and B and resumption of normal menstrual cycles. This report illustrates that careful consideration of laboratory findings and other studies is essential for correctly identifying the underlying cause of secondary amenorrhea, particularly when the results are not consistent with common causes of this condition. [ABSTRACT FROM AUTHOR]

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