Fetal Adrenal Gland Research Articles

S-15-04 Knowledge gaps: case studies from human fetal ovary and adrenal gland

S-15-04 Knowledge gaps: case studies from human fetal ovary and adrenal gland

Evaluation of fetal middle adrenal artery Doppler and fetal adrenal gland size in pregnancies with fetal growth restriction: a case-control study.

This study aims to evaluate sonographic measurements of fetal adrenal gland size and middle adrenal artery Doppler in pregnancies with fetal growth restriction (FGR) and in a healthy control group. This prospective study included 107 singleton pregnancies with FGR between 24 and 42weeks of gestation and 107 pregnancies with fetuses whose growth was appropriate for gestational age (AGA). Adrenal gland size and Doppler parameters of the adrenal artery were measured and the values and obstetric outcomes were compared between the study and control groups. In the study group, the Z-scores of total adrenal width-length and height, fetal zone width-length and middle adrenal artery-peak systolic velocity (MAA-PSV) were significantly higher than those in the control group (p<0.05). The Z-scores of middle adrenal artery-pulsatility index (MAA-PI) were significantly lower in the study group than in the control group (p<0.05). The rate of neonatal intensive care unit admission in fetuses with high adrenal artery PI scores was higher in the FGR group (p<0.05). In the present study, we observed decreased adrenal artery PI, increased adrenal blood flow, and increased fetal adrenal volume in fetuses diagnosed with fetal growth restriction, most likely in response to placental insufficiency and chronic hypoxia.

Relationship among anogenital distance, adrenal gland volume, and penile length and width at 22-36weeks of pregnancy.

The subject of current work was to determine the relationship of fetal ultrasonographic biomarkers, including anogenital distance (AGD), adrenal gland volume, and penile length and width in mothers with male fetuses at 22-36weeks of gestation for the assessment of the effect of fetal adrenal gland producing androgens on the male anogenital structures that are exposed to androgen effects as anogenital region and penis. This study is a prospective cross-sectional study conducted in our hospital's outpatient perinatal care unit. One hundred and seventy pregnant women with a male fetus aged 22-36weeks of gestation were included in the study. The fetal adrenal gland length, width, and depth forthe calculation of adrenal volume, AGD, and penile lengthand width were measured for each participant. The Pearson coefficients were calculated to assess the correlation among these parameters. The adrenal gland volume had a meaningful, positive moderate relationship with both the AGD (r=0.60) and penile length and width (r=0.57 and r=0.59, respectively; p<0.001). The AGD had a positive, strong correlation with the penile length and width (r=0.74 and r=0.76, respectively; p<0.001). The fetal adrenal gland as one of the androgen sources of the fetus is an influencer of the development of the anogenital and penile region. The findings of the current study support that the adrenal gland considerably affects the masculinization of male fetuses, since there were remarkable correlations among the AGD, adrenal gland volume, and penile length and width.

The Androgen Metabolome of Preterm Infants Reflects Fetal Adrenal Gland Involution

The human adrenal cortex changes with fetal-neonatal transition from the fetal to the adult organ, accompanied by changes in the steroid metabolome. As it is unclear how the observed developmental changes differ between preterm and full-term neonates, we investigated whether the involution of the fetal adrenals is following a fixed time course related to postmenstrual age or whether it is triggered by birth. Furthermore, the fetal and postnatal androgen metabolome of preterm infants was characterized in comparison to term babies. This was a prospective, longitudinal, 2-center study collecting spot urines of preterm and term infants during the first 12 to 18 months of life. Steroid metabolites were measured from spot urines by gas chromatography-mass spectrometry. Data relating were modeled according to established pre- and postnatal pathways. Fetal adrenal involution occurs around term-equivalent age in preterm infants and is not triggered by premature birth. Testosterone levels are higher in preterm infants at birth and decline slower until term compared to full-term babies. Dihydrotestosterone levels and the activity of the classic androgen biosynthesis pathway are lower in premature infants as is 5α-reductase activity. No difference was found in the activity of the alternate backdoor pathway for androgen synthesis. Human adrenal involution follows a strict timing that is not affected by premature birth. By contrast, prematurity is associated with an altered androgen metabolome after birth. Whether this reflects altered androgen biosynthesis in utero remains to be investigated.

Fetal adrenal gland size and umbilical artery Doppler in growth-restricted fetuses.

In fetal growth restriction (FGR), Doppler ultrasound is the most important method for the detection and management. However, additional parameters are needed to improve the distinction between constitutionally small fetuses and fetuses affected by FGR. A total of 445 singleton pregnancies between 23 and 40weeks of gestation were included in our retrospective study, of which 67 with FGR and 378 normal fetuses. A 2D-plane of the fetal adrenal gland was obtained and the adrenal gland ratio was measured. Spearman's correlation coefficient was calculated to assess the association of fetal Doppler and adrenal gland ratio with outcome parameters. Logistic regression analysis was performed to assess the statistical significance of "PI of the umbilical artery" and "adrenal gland ratio" as prognostic factors for intrauterine growth restriction (IUGR). PI of the umbilical artery was shown to correlate with outcome parameters (WG_Delivery: r=-0.125, p=0.008; birth weight: r=-0.268, p<0.001; birth weight centile: r=-0.248, p<0.001; APGAR at 5min: r=-0.117, p=0.014). Adrenal gland ratio showed no correlation with any of the outcome parameters. In logistic regression however, both PI of the umbilical artery and the adrenal ratio were shown to be significantly associated with fetal IUGR. When combining the two parameters, predictive value was superior to the predictive value of each individual parameter (AUC 0.738 [95% CI 0.670; 0.806]). The adrenal gland ratio can be a useful addition to Doppler ultrasound when it comes to the detection of fetal FGR. Prospective studies are needed to establish references ranges and cut-off values for clinical decision-making.

The importance of fetal adrenal gland volume measurement in successful labor induction with oxytocin.

We aimed to show the predictive value of fetal adrenal gland volume (FAGV) measurement in the success of labor induction with oxytocin. This is a prospective cohort study that included a total of 103 term nulliparous. Immediately after deciding to induce labor with oxytocin, the fetal right and left adrenal gland measurements were obtained. Induction success was achieved in 89 of 103 (86.4%) pregnant women. In comparison of the FAGV values of failed induction labor group, the total volumes of right and left fetal adrenal glands and the fetal zone volumes (FZV) were found to be statistically significantly higher in the successful labor induction group (p < 0.001). In predicting induction success, the cut-off value of fetal adrenal gland volume (cFAGV) was set as >230.2 mm3 /kg and area under curve (AUC) value of 0.872 (95% confidence interval [CI], 0.736-1.000) for right total adrenal gland (p < 0.001). The cut-off value of cFAGV was set as >236.7 mm3 /kg and AUC value of 0.891(95%CI, 0.768-1.000) (p < 0.001) for left total adrenal gland. The cut-off value of cFAGV was set as >12.6 mm3 /kg and AUC value of 0.952 (95%CI, 0.905-0.999) for right FZV(p < 0.001). The cut-off value of cFAGV was set as >7.8 mm3 /kg and AUC value of 0.884 (95%CI, 0.752-1.000) for left FZV (p < 0.001). Two-dimension ultrasonographic measurement is an easy-to-access and noninvasive method that can be integrated into the algorithms to predict the success of induction based on FAGV measurement.

Abstract 6215: The immune cell atlas of human neuroblastoma

Abstract Our current knowledge of the different immune cells in neuroblastoma is based on in vitro and in vivo studies mainly focusing on a single cell type. Different studies have conveyed conflicting results and despite the use of anti-GD2 immunotherapy in the clinic, a comprehensive immune cell overview at the single-cell level is still missing and understanding the complete composition of immune cells neuroblastoma will be crucial for the development of novel immunotherapeutics against the disease. In this study, we performed single-cell RNA-sequencing on human neuroblastoma coupled with multiplex immunohistochemistry and survival analysis to provide a complete cellular and molecular immune cell landscape of human neuroblastoma. Further, we contrasted the neuroblastoma data with single-cell RNA-sequencing data from normal fetal adrenal gland to characterize cell-state changes from normal tissue to neuroblastoma. Our analysis revealed 27 immune cell subtypes including distinct subpopulations of myeloid, NK, B and T cells that were associated with a survival benefit. Multiple subtypes of B and NK cells, not seen in neuroblastoma before, were identified. We propose the presence of tertiary lymphoid structures and showed that Active NK cells correlated with improved survival. In contrast to adult cancers, we detected no difference in cytotoxicity and exhaustion score for cytotoxic T cells, nor Treg activity. However, we demonstrated an increase in inflammatory monocyte signature score from normal to tumor derived myeloid cells. Finally, we performed receptor-ligand interaction analysis between tumor, stroma and immune cells, where we highlight several interactions that we suggest for future studies of how to exploit immune cells as a therapeutic option in neuroblastoma. Our findings significantly broaden the understanding of the immune composition in neuroblastoma and provides a resource for the development of novel immunotherapeutics. Citation Format: Bronte Manouk Verhoeven, Shenglin Mei, Thale K. Olsen, Karin K. Gustafsson, Anders Valind, Axel Lindström, David G. Nord, Shahrzad S. Fard, Catharina Hagerling, Peter V. Kharchenko, Per Kogner, John I. Johnsen, Ninib Baryawno. The immune cell atlas of human neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6215.

Tissue concentration of aldosterone in fetal adrenals of intrauterine death cases.

Fetal adrenals are one of the main organs responsible for maturation and survival. Extant literature is not clear about whether second trimester fetal adrenals are capable of synthesizing secreting aldosterone. We have taken 20 adrenals from fetuses of intrauterine death cases. None of the fetuses had any external malformations and obstetric history was unremarkable. The organs were weighed and homogenized. The supernatant was used for aldosterone estimation by ELISA. We consistently detected aldosterone in all the cases including second trimester. However, we did not see any correlation between aldosterone concentration and gestational age. It is striking to note that there are wide variations in the tissue levels of aldosterone across different gestational ages and also same period. Tissue aldosterone levels in second trimester can be possibly induced by stress preceding intrauterine deaths. It is possible that functional status of adrenal is different in intrauterine death cases as opposed to elective abortions in second trimester.

Longitudinal patterns in progesterone metabolites in pregnant and non-pregnant Steller sea lions (Eumetopias jubatus)

Similar to the several pinniped and a few terrestrial carnivore species, the Steller sea lion has a seasonal synchronized mating scheme enabled by a female reproductive cycle that includes embryonic diapause, delayed implantation, and pseudopregnancy (a state in which the corpus luteum produces progesterone for approximately as long as in pregnant females). Due to this, circulating systemic progesterone concentrations cannot be used to differentiate pregnant and nonpregnant females during early gestation. With the use of advanced measurement technologies such as liquid chromatography tandem mass spectrometry (LC-MS/MS) additional steroid hormones are measurable which can provide additional information on the endocrine pathways throughout gestation. Our objectives were to further characterize endocrine patterns in female Steller sea lion pregnancy by 1) quantifying longitudinal profiles of hormone metabolites in pregnant and non-pregnant female sera, and 2) evaluating hormone profiles to identify pregnant animals within the early stage of gestation. Three gestation stages were delineated based on what is believed to be the period of implantation (September-October): EARLY (August– November), MID (December-February), and LATE (March to May). Five steroids, Progesterone (P4), 5α-dihydroprogesterone (DHP), 17αOH-progesterone (17OHP), 20αOH-progesterone (20OHP), and androstenedione (A4), were detected in both pregnant and non-pregnant animals. A significant difference in P4 concentrations was measured between EARLY and MID gestation (p ≤ 0.01) in both pregnant and non-pregnant animals. During MID gestation there was a significant difference (p ≤ 0.05) between pregnant and non-pregnant animals in all pregnanes measured. Significant patterns of correlation between P4 and 17OHP and between P4 and DHP were detected during EARLY and MID gestation in non-pregnant animals. While those significant correlations also exist in EARLY pregnant animals, this pattern was lost by MID gestation. This loss of correlation suggests a potential shift in progesterone metabolism from ovarian to alternative tissue (e.g. fetal gonads or adrenal glands) by MID gestation in Steller sea lions. We were unable to identifying a steroid hormone biomarker capable of differentiating pseudopregnancy from pregnant animals and conclude that such a biomarker likely falls outside of the traditional progesterone metabolic pathway.

The immune cell atlas of human neuroblastoma

SummaryUnderstanding the complete immune cell composition of human neuroblastoma (NB) is crucial for the development of immunotherapeutics. Here, we perform single-cell RNA sequencing (scRNA-seq) on 19 human NB samples coupled with multiplex immunohistochemistry, survival analysis, and comparison with normal fetal adrenal gland data. We provide a comprehensive immune cell landscape and characterize cell-state changes from normal tissue to NB. Our analysis reveals 27 immune cell subtypes, including distinct subpopulations of myeloid, NK, B, and T cells. Several different cell types demonstrate a survival benefit. In contrast to adult cancers and previous NB studies, we show an increase in inflammatory monocyte cell state when contrasting normal and tumor tissue, while no differences in cytotoxicity and exhaustion score for T cells, nor in Treg activity, are observed. Our receptor-ligand interaction analysis reveals a highly complex interactive network of the NB microenvironment from which we highlight several interactions that we suggest for future therapeutic studies.

Vitamin D receptor hypermethylation as a biomarker for pediatric adrenocortical tumors.

Pediatric adrenocortical tumors (pACT) display complex genomic backgrounds, lacking robust prognostic markers and targeted therapeutic options. Vitamin D3 receptor (VDR) promoter hypermethylation and underexpression were reported in adrenocortical carcinomas from adult patients. In this study, we aimed to investigate VDR expression levels and methylation status in pACT and their clinical and prognostic significance. Retrospective cross-sectional study enrolling pediatric patients with ACT from two tertiary referral institutions. We evaluated clinicopathological features, VDR mRNA (qPCR) and protein (immunohistochemistry) expression, and VDR-wide methylation of ACT samples from 108 pediatric patients. Fourteen pediatric and 32 fetal and postnatal normal adrenals were used as controls. Unlike in pre- and post-natal normal adrenals, most pACT lacked nuclear VDR expression and had reduced mRNA levels, especially the carcinomas. Unsupervised analysis of VDR methylation data revealed two groups of pACT with distinct disease features and outcomes. Tumors with high VDR methylation presented lower mRNA levels, and the respective patients presented advanced disease and reduced disease-free and overall survival. VDR has a role in normal adrenocortical development and homeostasis, which is impaired during tumorigenesis. VDR hypermethylation and underexpression may be both predictive and prognostic biomarkers for pACT.

Association between Fetal Adrenal Gland Ultrasound Measurements in the 9th Month and Mode of Delivery.

Several studies have previously assessed the value of changes in the fetal adrenal gland to predict preterm labor. The aim of this study is to evaluate the correlation between fetal adrenal gland measurements after 36 weeks and obstetrical outcomes. Abdominal two-dimensional (2D) ultrasound is used to measure in the transversal plane the length of fetal zone (D1), the width (D2), and the length (D3) of fetal adrenal gland, and, subsequently, the fetal zone enlargement (FZE), in 98 primigravida women after 36 weeks. Labor and delivery outcomes were assessed and compared with these measurements. FZE changes had no association with spontaneous onset of labor. No association was found between all adrenal gland measurements and delivery onset. There was a significant relationship between D1, D2, and D3 and the delivery method. Patients delivered by cesarean section had smaller fetal adrenal gland dimensions, defining D1= 0.16 cm, D2 = 0.7 cm, and D3 = 2.37 cm as cutoff levels based on receiver operator characteristics curves. The 2D measurement of the fetal adrenal gland after 36 weeks seems to predict the delivery method in low-risk primigravida women. · We evaluate fetal adrenal gland measurements after 36 weeks versus the obstetrical outcome.. · No association was found between all adrenal gland measurements and delivery onset.. · Patients delivered by cesarean section had smaller fetal adrenal gland dimensions..

The Relationship of Fetal Adrenal Gland Size with Fetal Liver Length and Fetal Abdominal Wall Fat Thickness in Mothers with and Without Gestational Diabetes

Background: Given the possible association between maternal diabetes status and metabolic disorders in the fetus, such as hepatic dysfunction or subcutaneous fat mass, it is expected that there is a close relationship between fetal adrenal gland volume and these two indicators. Aim: We decided to examine the relationship of fetal adrenal gland size with fetal liver length and fetal abdominal wall fat thickness in mothers with gestational diabetes and to compare it with non-diabetic mothers. Methods: This cross-sectional study was performed on 40 pregnant women in the third trimester of pregnancy suffering gestational diabetes under insulin therapy as the cases and 40 age and gestational age-matched pregnant women without diabetes as the controls. An ultrasound was performed for all participants in the third trimester of pregnancy to assess adrenal gland size, liver dimensions and fetal abdominal wall fat thickness. Results: The fetuses in diabetic group was found to have adrenal glands with significantly higher mean width, but with lower height leading similarity in mean adrenal volume as compared to non-diabetic group. The mean fetal abdominal wall fat thickness was significantly higher in diabetic than in non-diabetic groups. In diabetic groups, we found a direct association between height of adrenal gland and fetal abdominal wall fat thickness (p = 0.001). The length of adrenal gland was also positively associated with abdominal wall fat thickness (p = 0.001). However, in non-diabetic group, we found no association between adrenal height and fetal abdominal wall fat thickness. Measuring liver length in the two groups showed significantly higher mean value in diabetic than in non-diabetic groups. No association was revealed between adrenal volume and liver length in diabetic group. In non-diabetic group, there was a significant direct association between adrenal volume and liver length (p = 0.008). Conclusion: Gestational diabetes is directly associated with increasing fetal abdominal wall fat thickness and liver length in fetus. The dimensions of adrenal gland in fetus are also associated with fetus abdominal wall fat thickness and liver length probably independent to maternal diabetic status.

Steroids, steroid associated substances and gestational diabetes mellitus.

As gestational diabetes mellitus (GDM) is both a frequent and serious complication, steroid levels in pregnancy are extremely elevated and their role in pregnancy is crucial, this review focuses on the role of steroids and related substances in the GDM pathophysiology. Low SHBG levels are associated with insulin resistance and hyperinsulinemia, while also predicting a predisposition to GDM. Other relevant agents are placental hormones such as kisspeptin and CRH, playing also an important role beyond pregnancy, but which are synthesized here in smaller amounts in the hypothalamus. These hormones affect both the course of pregnancy as well as the synthesis of pregnancy steroids and may also be involved in the GDM pathophysiology. Steroids, whose biosynthesis is mainly provided by the fetal adrenal glands, placenta, maternal adrenal glands, and both maternal and fetal livers, are also synthesized in limited amounts directly in the pancreas and may influence the development of GDM. These substances involve the sulfated ?5 steroids primarily acting via modulating different ion channels and influencing the development of GDM in different directions, mostly diabetogenic progesterone and predominantly anti-diabetic estradiol acting both in genomic and non-genomic way, androgens associated with IR and hyperinsulinemia, neuroactive steroids affecting the pituitary functioning, and cortisol whose production is stimulated by CRH but which suppresses its pro-inflammatory effects. Due to the complex actions of steroids, studies assessing their predominant effect and studies assessing their predictive values for estimating predisposition to GDM are needed.

Steroids, steroid associated substances and gestational diabetes mellitus

As gestational diabetes mellitus (GDM) is both a frequent and serious complication, steroid levels in pregnancy are extremely elevated and their role in pregnancy is crucial, this review focuses on the role of steroids and related substances in the GDM pathophysiology. Low SHBG levels are associated with insulin resistance and hyperinsulinemia, while also predicting a predisposition to GDM. Other relevant agents are placental hormones such as kisspeptin and CRH, playing also an important role beyond pregnancy, but which are synthesized here in smaller amounts in the hypothalamus. These hormones affect both the course of pregnancy as well as the synthesis of pregnancy steroids and may also be involved in the GDM pathophysiology. Steroids, whose biosynthesis is mainly provided by the fetal adrenal glands, placenta, maternal adrenal glands, and both maternal and fetal livers, are also synthesized in limited amounts directly in the pancreas and may influence the development of GDM. These substances involve the sulfated Δ5 steroids primarily acting via modulating different ion channels and influencing the development of GDM in different directions, mostly diabetogenic progesterone and predominantly anti-diabetic estradiol acting both in genomic and non-genomic way, androgens associated with IR and hyperinsulinemia, neuroactive steroids affecting the pituitary functioning, and cortisol whose production is stimulated by CRH but which suppresses its pro-inflammatory effects. Due to the complex actions of steroids, studies assessing their predominant effect and studies assessing their predictive values for estimating predisposition to GDM are needed.

Fetal adrenal gland biometry as a prediction tool in labor induction.

Due to previous evidence showing that fetal adrenal gland parameters can serve as predictors of delivery in women with preterm uterine contractions, the objective of this study was to assess the association between fetal adrenal length and width to success of induction of labor.

A COMPARATIVE STUDY OF FETAL ADRENAL GLAND BIOMETRY AND CERVICAL LENGTH AS A PREDICTOR OF PRETERM BIRTH

Background: Preterm birth is an important challenge in obstetrics and contemporary perinatology in India. Timely recognition, intervention and appropriate management is integral in curbing the upsurge in its incidence and consequent poor perinatal outcome. This study was conducted taking into account the potential mechanism of preterm labor: premature activation of the placental-adrenal endocrine axis wherein elevation of maternal cortisol leads to an increased production of placental corticotrophin releasing hormone which causes an increase in dehydroepiandrosterone produced by the fetal zone of the adrenal gland and its enlargement. This activates a cascade leading to early loss of uterine quiescence, consequently causing cervical modelling, ripening and preterm birth.&#x0D; Aim and Objectives: To assess fetal adrenal gland volume, fetal zone enlargement and cervical length on ultrasound and compare their efficacy in the prediction of preterm birth. &#x0D; Methods: This was a hospital based prospective study in which pregnant women with an uncomplicated live singleton pregnancy between 28 to 34 weeks of gestation were subjected to obstetric ultrasonography wherein fetal adrenal gland volume, fetal zone enlargement and cervical length was measured. They were then followed up until their delivery, whether term or preterm and its correlation with fetal adrenal gland parameters and cervical length was assessed. &#x0D; Result: Corrected fetal adrenal gland volume showed the highest sensitivity of 90.0% and a specificity of 96.7% with a cut off value of 632.50 mm3/kg while fetal zone enlargement showed a sensitivity and specificity of 72.7% and 60.9% respectively. Cervical length was found to be the least important marker for predicting the preterm birth as having the least AUC as 0.209, sensitivity as 36.4 % and specificity as 76.1%.&#x0D; Conclusion: This study concludes that fetal adrenal gland biometry can be used as a noninvasive, cost effective and potential new marker for the prediction of preterm birth and is a better predictor than cervical length.&#x0D; Keywords: Preterm, Cervical length, Adrenal biometry.

FETAL ADRENAL GLAND BIOMETRY: A POTENTIAL PREDICTOR OF PRETERM BIRTH

Background: Preterm birth is an important challenge in obstetrics and contemporary perinatology in India. Timely recognition, intervention and appropriate management is integral in curbing the upsurge in its incidence and consequent poor perinatal outcome. This study was conducted taking into account the potential mechanism of preterm labor: premature activation of the placental-adrenal endocrine axis wherein elevation of maternal cortisol leads to an increased production of placental corticotrophin releasing hormone which causes an increase in dehydroepiandrosterone produced by the fetal zone of the adrenal gland and its enlargement. This activates a cascade leading to early loss of uterine quiescence, consequently causing cervical modelling, ripening and preterm birth.&#x0D; Aim and Objectives: To assess fetal adrenal gland volume and fetal zone enlargement on ultrasound and evaluate its efficacy in the prediction of preterm birth. &#x0D; Methods: This was a hospital based prospective study in which pregnant women with an uncomplicated live singleton pregnancy between 28 to 34 weeks of gestation were subjected to obstetric ultrasonography wherein fetal adrenal gland volume and fetal zone enlargement was measured. They were then followed up until their delivery, whether term or preterm and its correlation with fetal adrenal gland parameters was assessed. &#x0D; Result: Corrected fetal adrenal gland volume showed the highest sensitivity of 90.0% and a specificity of 96.7% with a cut off value of 632.50 mm3/kg while fetal zone enlargement showed a sensitivity and specificity of 72.7% and 60.9% respectively. &#x0D; Conclusion: This study concludes that fetal adrenal gland biometry can be used as a noninvasive, cost effective and potential new marker for the prediction of preterm birth.

Triadimefon suppresses fetal adrenal gland development after in utero exposure

Triadimefon is a broad-spectrum antifungal agent, which is widely used in agriculture to control mold and fungal infections. It is considered an endocrine disruptor. Whether triadimefon exposure can inhibit the development of fetal adrenal glands and the underlying mechanism remain unclear. Thirty-two pregnant female Sprague-Dawley rats were randomly divided into four groups. Dams were gavaged triadimefon (0, 25, 50, and 100 mg/kg/day) daily for 10 days from gestational day (GD) 12 to GD 21. Triadimefon significantly reduced the thickness of the zona fasciculata of male fetuses at 100 mg/kg, although it did not change the thickness of the zona glomerulosa. It significantly reduced the serum aldosterone levels of male fetuses at a dose of 100 mg/kg, and significantly reduced serum corticosterone and adrenocorticotropic hormone levels at doses of 50 and 100 mg/kg. Triadimefon significantly down-regulated the expression of Agtr1, Mc2r, Star, Cyp11b1, Cyp11b2, Igf1, Nr5a1, Sod2, Gpx1, and Cat, but did not affect the mRNA levels of Scarb1, Cyp11a1, Cyp21, Hsd3b1, and Hsd11b2. Triadimefon markedly reduced AT1R, CYP11B2, IGF1, NR5A1, and MC2R protein levels. Triadimefon significantly reduced the phosphorylation of AKT1 and ERK1/2 at 100 mg/kg without affecting the phosphorylation of AKT2. In contrast, it significantly increased AMPK phosphorylation at 100 mg/kg. In conclusion, exposure to triadimefon during gestation inhibits the development of fetal adrenal cortex in male fetuses. This inhibition is possibly due to the reduction of several proteins required for the synthesis of steroid hormones, and may be involved in changes in antioxidant contents and the phosphorylation of AKT1, ERK1/2, and AMPK.

Adrenal neuroblastoma

The fetal adrenal glands can be seen by ultrasonography by the end of the first trimester of pregnancy.1 They appear as pyramidal hypoechoic structures superior to the hyperechoic kidney. During the second trimester of pregnancy, corticomedullary differentiation can be observed with a hypoechoic cortex and hyperechoic medulla. The size of the gland increases throughout gestation but remains smaller than the kidney. During the third trimester of pregnancy, the appearance of the fetal adrenal glands is similar to that of the neonatal adrenal glands.