United States

Background: Pheochromocytomas and paragangliomas (PPGL) are catecholamine-producing neuroendocrine tumors that arise from the adrenal medulla or ganglia and display the highest heritability rate among all human tumours. Genomic analyses allowed identification of molecular subgroups of PPGL which are organized into 2 main clusters. Cluster 1 contains SDHx- and VHL-mutated tumors which do not produce epinephrine while cluster 2 includes the epinephrine-secreting PPGL related to RET, NF1, TMEM127 and MAX mutations. PPGL must be early diagnosed and treated to prevent adrenergic crises which can be life-threatening. Detection of PPGL is particularly important during pregnancy since PPGL are associated with a high risk of either maternal or fetal complications in this context. Reciprocally, pregnancy can favor adrenergic crises in patients with previously undiagnosed or silent pheochromocytoma (PCC). These dangerous events can be triggered by tumor compression resulting from fetus growth, or labor and delivery. However, it is known that surges in plasma catecholamines may also occur during early gestation suggesting that pregnancy may also activate the secretory activity of PPGL through the involvement of non-mechanical factors, such as gestational hormones. Methods: In the present study, we report a case of silent PCC revealed in a pregnant woman by life-threatening adrenergic myocarditis occurring at 31 weeks of gestation. Analysis of PPGL susceptibility genes showed the presence of a heterozygous germline RET variant of uncertain significance. The fact that the first symptoms of catecholamine excess had appeared during the first trimester of pregnancy led us to conduct in vitro studies to investigate the effects of estradiol and the pregnancy hormone chorionic gonadotropin (hCG) on epinephrine secretion by cultured cells derived from the resected patient&#39;s tumor. Expression of luteinizing hormone/chorionic gonadotropin receptor (LHCGR) was searched for in the tumor and an additional series of 12 PCC by RT-qPCR and immunohistochemistry. LHCGR expression was also analyzed in silico in the PPGL cohorts of the COMETE and The Cancer Genome Atlas (TCGA) databases. Results: hCG stimulated epinephrine secretion by primary cultured PCC cells. The tumor expressed the LHCG receptor, which was colocalized with catecholamine-producing enzymes. A similar expression pattern of the LHCG receptor was also observed in 5 out of a series of 12 PCCs. Moreover, in silico studies revealed that PPGL display the highest expression levels of LHCGR mRNA among the 32 solid tumor types of TCGA cohort. Interestingly, expression of LHCGR was higher in cluster 2 than in cluster 1 PPGL. Conclusion: We show that PCC can express functional LHCG receptor. Consequently, pregnancy may activate catecholamine production by previously silent pheochromocytoma as early as the first trimester of gestation especially in women with gene mutations that predispose to cluster 2 epinephrine-secreting PCC.

ENDO 2022

Luteinizing Hormone-Chorionic Gonadotrophin Receptor in Pheochromocytomas

**Program**
ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

This year’s education program features:
more than 100 in-person and virtual sessions with another 70+ in-person only sessions;
six plenary sessions including plenaries on Envisioning Future Therapies for Type 1 Diabetes and Addressing Challenges in Fertility and Reproduction;
over 20 Meet the Professor sessions presented both in-person and live-streamed virtually and another 20+ presented live in Atlanta;
four Basic Science Pathways, including Diabetes and Metabolism; Neuroendocrinology; Nuclear Receptors and Signaling; and Reproductive Endocrinology; and
more than 30 oral sessions and a robust virtual poster hall for accepted scientific abstracts.

**What Programming Is Included in My Virtual Meeting Registration?**
As you build your schedule during the conference, you can select the sessions that are tagged with 'Livestreamed', so you can view virtually. These sessions are being livestreamed, so they are available in real time to our virtual audience. In addition, our in-person and livestreamed sessions will be recorded, so you can access them on demand after 72 hours. We will have over 200 hours available on demand for Standard and Premium pass registrants.

Product theaters and the Communications and Career Center will also include hybrid content delivery.

**Plenaries**
Spanning the spectrum of science, clinical care, and social implications, an outstanding slate of world-renowned speakers will showcase the most cutting-edge advances on research and medicine.

**Symposia**
Our ENDO 2022 lineup of sessions offers a unique opportunity to dive into topics from nearly every major therapeutic area of endocrinology and hormone science. Listen, learn, and be inspired by world-class faculty who are at the forefront of scientific discovery and high-quality health care.

**Basic Science Pathways**

These special “meeting-within-a-meeting” tracks integrate focused discussions, poster sessions, and networking opportunities to provide you with the latest research in:
Diabetes and Metabolism
Neuroendocrinology
Nuclear Receptors and Signaling
Reproductive Endocrinology

**Meet the Professor & Meet the Scientist**
Discover insights from experts on treating a variety of endocrine conditions and emerging science in the field of endocrinology, and learn the latest in patient care and scientific research.

ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

Background: Pheochromocytomas and paragangliomas (PPGL) are catecholamine-producing neuroendocrine tumors that arise from the adrenal medulla or ganglia and display the highest heritability rate among all human tumours. Genomic analyses allowed identification of molecular subgroups of PPGL which are organized into 2 main clusters. Cluster 1 contains SDHx- and VHL-mutated tumors which do not produce epinephrine while cluster 2 includes the epinephrine-secreting PPGL related to RET, NF1, TMEM127 and MAX mutations. PPGL must be early diagnosed and treated to prevent adrenergic crises which can be life-threatening. Detection of PPGL is particularly important during pregnancy since PPGL are associated with a high risk of either maternal or fetal complications in this context. Reciprocally, pregnancy can favor adrenergic crises in patients with previously undiagnosed or silent pheochromocytoma (PCC). These dangerous events can be triggered by tumor compression resulting from fetus growth, or labor and delivery. However, it is known that surges in plasma catecholamines may also occur during early gestation suggesting that pregnancy may also activate the secretory activity of PPGL through the involvement of non-mechanical factors, such as gestational hormones. Methods: In the present study, we report a case of silent PCC revealed in a pregnant woman by life-threatening adrenergic myocarditis occurring at 31 weeks of gestation. Analysis of PPGL susceptibility genes showed the presence of a heterozygous germline RET variant of uncertain significance. The fact that the first symptoms of catecholamine excess had appeared during the first trimester of pregnancy led us to conduct in vitro studies to investigate the effects of estradiol and the pregnancy hormone chorionic gonadotropin (hCG) on epinephrine secretion by cultured cells derived from the resected patient's tumor. Expression of luteinizing hormone/chorionic gonadotropin receptor (LHCGR) was searched for in the tumor and an additional series of 12 PCC by RT-qPCR and immunohistochemistry. LHCGR expression was also analyzed in silico in the PPGL cohorts of the COMETE and The Cancer Genome Atlas (TCGA) databases. Results: hCG stimulated epinephrine secretion by primary cultured PCC cells. The tumor expressed the LHCG receptor, which was colocalized with catecholamine-producing enzymes. A similar expression pattern of the LHCG receptor was also observed in 5 out of a series of 12 PCCs. Moreover, in silico studies revealed that PPGL display the highest expression levels of LHCGR mRNA among the 32 solid tumor types of TCGA cohort. Interestingly, expression of LHCGR was higher in cluster 2 than in cluster 1 PPGL. Conclusion: We show that PCC can express functional LHCG receptor. Consequently, pregnancy may activate catecholamine production by previously silent pheochromocytoma as early as the first trimester of gestation especially in women with gene mutations that predispose to cluster 2 epinephrine-secreting PCC.

technical paper

Introduction: Mutations in MC2R causing familial glucocorticoid deficiency (FGD), a rare form of primary, isolated adrenal insufficiency, were first published in 1993, discovered by candidate gene sequencing (CGS). Through advances in genetic techniques from homozygosity mapping to whole exome sequencing (WES) we have linked a further five genes to adrenal insufficiency and, in conjunction with other groups, this has expanded the number of monogenic causes for isolated or syndromic adrenal insufficiency to >25.
Patients and Methods: Over the last 30 years over 400 individuals with suspected FGD, from 31 different countries, have been referred to our centre for genetic testing, ranging in age from neonates to individuals in their eighties. All cases had low or undetectable serum cortisol usually paired with an elevated plasma ACTH level. Our strategy for sequencing has evolved over time and we now routinely sequence the small, frequently mutated, candidate genes by Sanger sequencing (MC2R, MRAP, STAR and CYP11A1) before proceeding to WES as the most cost-effective route to a genetic diagnosis. In total, 369of the 400 individuals have been fully characterised either by CGS or WES. For CGS, sequences were analysed by alignment to reference sequences using BioEdit software and for WES variant call files were initially analysed using Ingenuity Variant Analysis package and/or examination of BAM files, using the Integrative Genomics Viewer, to detect exonic deletions. Rare, synonymous or predicted benign variants were further tested by an in vitro splicing assay using the pET01 vector (MoBiTec)
Results: In 308/ 369 individuals we found a definitive diagnosis in a gene known to be causal for adrenal insufficiency, giving a success rate of >81%, and identified 15 novel mutations. The aetiologies of diagnosed cases were as follows; MC2R (22%), MRAP (17%), NNT (15%), STAR (9%), CYP11A1 (7%), with the remaining 30% due to a further 13 genes.
Founder effects were clear for variants in some genes/populations, whereas in others hotspot mutations were present in multiple ethnicities. Examples include the previously described S74I in MC2R and rs6161 in CYP11A1 in the UK population, P24Rfs*4 in MCM4 in Ireland, R188C in STAR in Canada, and newly discovered associations with T731= in NNT in Sudan and R222Q in SGPL1 in Saudi Arabia. Whereas MRAP splice mutations commonly seen at the exon 3/intron 3 junction were present in individuals from many countries. The work has also highlighted a number of causal synonymous and predicted benign variants that result in splicing defects.
Conclusion: The use of CGS/WES now permits a rapid genetic diagnosis for >83% individuals with PAI improving tailored patient management. For the remaining patients it is unclear whether they have unconventional mutations in known genes or if there are further gene defects to be discovered.

A Combined Candidate Gene/Whole Exome Sequencing Approach Permits a Rapid Genetic Diagnosis for >81% Individuals with Primary Adrenal Insufficiency.

The male reproductive tract development has been predominantly dependent upon androgen action, which is mainly mediated by the androgen receptor (AR). Under the influence of androgen actions, the primitive male reproductive tract, also known as the Wolffian duct, is first stabilized then differentiates into the epididymis, vas deference and seminal vesicle. Impairment of androgen signaling during fetal programming causes a spectrum of male reproductive disorders that manifest in adulthood. Despite the dominant roles of androgen action in the male reproductive tract development, it has been noticed that androgen's capability in promoting Wolffian duct survival and development is completely lost in the absence of Wnt9b. Wnt9b belongs to the WNT family of secreted proteins. It is specifically expressed in the Wolffian duct epithelium to regulate the surrounding mesenchyme. This project aims to investigate why the androgen action fails to maintain the male reproductive tract in the absence of Wnt9b. We first examined the expression pattern of Wnt9b during the window of sexual differentiation, which was not investigated in the previous publication. We found that during sexual differentiation, Wnt9b is still specifically expressed in the Wolffian duct epithelium in both XX and XY embryos. Androgen action exists in XY but not in the XX embryos during sexual differentiation. These observations indicate that Wnt9b does not lie downstream of the androgen signaling. We are in process of collecting Wnt9b+/+ and Wnt9b-/- male embryos to examine whether expression of AR and AR downstream genes is altered in the absence of Wnt9b. In addition, WNT9B can activate two intracellular pathways under the context of target cells: β-catenin dependent and independent pathways. Since Wolffian duct mesenchyme is the major target of epithelium-derived WNT9B, we next determined which pathways WNT9B acts through in the mesenchyme by specific deletion of β-catenin in the Wolffian duct mesenchyme. Interestingly, the loss of β-catenin in the mesenchyme led to the partial degeneration of Wolffian ducts at the caudal region and cystic formations at the cranial region, the similar phenotypes observed in mesenchymal AR knockout male embryos. Taken together, our study demonstrates that the local WNT9B/β-catenin pathway provides the permissive signaling for androgen actions in Wolffian duct development.

Why Does Androgens Fail to Promote the Survival of the Wolffian Duct in the Absence of Wnt9b?

Abstract:
Background: Hypergonadotropic hypogonadism can be caused by congenital or acquired causes. These can range from chromosomal abnormalities, enzymatic defects or mutations that cause gonadotropin resistance, trauma, chemotherapy, infections etc. It is uncommon in females other than in Turner syndrome and not all the genetic etiologies are known.
Clinical Case: A 15 10/12 year old female with primary amenorrhea and absent pubertal development presented with FSH and LH levels of 35.24 mIU/mL and 14.38 mIU/mL, respectively and non-pubertal estradiol levels of 4 pg/mL consistent with hypergonadotropic hypogonadism. Her evaluation showed a normal 46,XX female karyotype and no evidence of hyperandrogenism or thyroid dysfunction. Ultrasound showed no evidence of ovaries and a rudimentary uterus measuring 0.9 cm x 1.4 cm x 1.2 cm with a delayed bone age of 12 years. Family history was positive for mother having delayed puberty with menarche at 16.5 years of age. Patient was started on hormone replacement therapy with transdermal estrogen. Four months after treatment she developed breast buds and vaginal discharge. After 1.5 years, the uterus measurements were 5.7 cm x3.7 cm x2.2 cm although no ovarian tissue or follicles were identified on MRI. Her biochemical profile also showed decreases in FSH (3.48 mIU/mL) and LH (0.99 mIU/mL) and an increase in estradiol (38pg/mL).
Exome sequencing was performed and revealed biallelic missense variants c.766C>T, p.(Pro256Ser) and c.1036G>C p.(Gly346Arg) in exon 2 of the INHA (NM_002191) gene. Both variants are rare in the human population, seen in a heterozygous state with a global allele frequency (gnomADv2.1) of 0 and 0.00002790 (rs780833794), respectively, and predicted to be damaging by bioinformatic tools. INHA, a member of the transforming growth factor-β (TGF-β) superfamily, encodes the alpha subunit of glycoprotein hormones inhibin A and B. Studies in animal models indicate that inhibin A negatively regulates follicle stimulating hormone (FSH) secretion by suppressing FSHR expression and plays a crucial role in ovarian steroid hormone production, follicular development, proliferation and apoptosis of granulosa cells, and oocyte maturation.
Heterozygous pathogenic variants in the INHA gene have been reported in patients with primary ovarian insufficiency (POI) and secondary amenorrhea¹, while our patient with biallelic variants in INHA is affected by gonadal dysgenesis, primary amenorrhea, absence of puberty, a more severe POI phenotype.

Conclusion: To our knowledge, this is the first case of biallelic mutations in INHA gene leading to a severe phenotype (gonadal dysgenesis, primary amenorrhea and absence of puberty) compared to heterozygous mutations that lead to POI with secondary amenorrhea.
¹References: Marozzi A, Porta C, et al. 2002. Mutation analysis of the inhibin alpha gene in a cohort of Italian women affected by ovarian failure. Human Reproduction Vol. 17 No.7 1741-1745

Biallelic variants in the INHA gene are the cause of gonadal dysgenesis, primary amenorrhea and absence of puberty in the setting of hypergonadotropic hypogonadism

BACKGROUND: Kisspeptin is a critical activator of hypothalamic gonadotrophin releasing hormone (GnRH) neurons and has significant potential to treat common reproductive disorders. To date, kisspeptin has solely been administered to humans via the intravenous or subcutaneous routes, however intranasal administration could offer a novel non-invasive delivery route, which is preferred by patients. We therefore sought to determine the effects of intranasal kisspeptin on reproductive hormone release in humans for the first time.

METHODS: Randomised, double-blinded, placebo-controlled, cross-over study in 12 healthy men (mean±SEM age 28.3±1.7 yrs; BMI 24.5±0.7 kg/m²). After monitored self-administration of intranasal kisspeptin-54 (3.2, 6.4, 12.8 and 25.6 nmol/kg) or 0.9% saline, serum reproductive hormone levels were measured every 15 minutes for four hours. Subsequently, four women (mean age 29.8±3.7 yrs; BMI 21.2±1.1 kg/m²) with hypothalamic amenorrhoea (HA) attended for the same protocol comparing intranasal kisspeptin-54 (12.8 nmol/kg) and 0.9% saline. Mean ±SEM was presented unless otherwise stated. Time profiles of hormone levels during the four-hour study were compared using two-way ANOVA with Bonferroni's multiple comparison test. Multiple means were compared using one-way ANOVA with Bonferroni's multiple comparison test.

RESULTS: In healthy men, intranasal kisspeptin dose-dependently increased mean luteinising hormone (LH) levels at doses between 3.2-12.8 nmol/kg (p=0.008 and <0.0001 for 6.4 and 12.8 nmol/kg vs saline, respectively), with the maximal rises occurring at 30-45 minutes post-administration. Correspondingly, the area under the curve (AUC) for the LH change was significantly elevated following all doses of kisspeptin compared to saline (saline: -25.4±70.5 h.IU/L; 3.2 nmol/kg: 172.2±64.2 h.IU/L [p=0.03]; 6.4 nmol/kg: 300.2±79.2 h.IU/L [p=0.002]; 12.8 nmol/kg: 595.7±98.3 h.IU/L [p=0.001]; 25.6 nmol/kg: 549.0±108.6 h.IU/L [p<0.0001]). Follicle stimulating hormone (FSH) levels followed a similar trajectory to LH in response to intranasal kisspeptin. Moreover, kisspeptin at 12.8 nmol/kg increased serum testosterone from 120 minutes onwards (p=0.02), with a maximal change from baseline of 4.9±0.7 nmol/L (p=0.03).
In women with HA, intranasal kisspeptin increased mean LH (p=0.002 vs saline), with the peak levels occurring at 30-45 minutes post-administration. The AUC for the LH change was 508.4±77.5 h.IU/L (p=0.02 vs saline AUC for LH). The maximal LH change from baseline was 4.1±0.9 IU/L compared to 0.2±0.4 IU/L for saline (p=0.03). Intranasal kisspeptin increased mean FSH (p=0.01 vs saline). No significant changes in downstream serum oestradiol or progesterone were observed during the acute four-hour study.

CONCLUSION: We report the first investigation of the effects of intranasal kisspeptin delivery on reproductive hormone release in humans. Our results demonstrate that intranasal kisspeptin robustly and dose-dependently stimulates reproductive hormone release in healthy men and crucially in a patient-group of women with hypogonadism. Given the ongoing development of kisspeptin therapeutics, intranasal kisspeptin therefore offers a novel, safe, effective and non-invasive route of administration for the management of reproductive disorders.

Reproductive Hormone Secretion is Increased by Intranasal Kisspeptin in Humans

Objectives: Estetrol (E4), a native estrogen produced by the fetal human liver, has four hydroxyl-groups, making it structurally distinct from other estrogens. We determined the human metabolic profile of E4, which is recently marketed combined with drospirenone as a novel contraceptive and is currently in development for the relief of menopausal symptoms.
Method: We studied the in vitro metabolism of E4 using human hepatocytes, human liver microsomes and recombinant CYP enzymes in reaction phenotyping studies to evaluate the role of human cytochrome P450 enzymes, UDP-glucuronosyltransferases (UGT) and sulfotransferases (SULT). Furthermore, we evaluated the in vivo metabolism of E4 in an open-label, non-randomised phase 1 human absorption, distribution, metabolism, and excretion study, in which six healthy postmenopausal participants received a single oral solution containing 15 mg [¹⁴C]-E4. We analysed blood (up to 240h), urine and faecal samples (up to 312h). Metabolite profiling and identification was performed using liquid chromatography with tandem mass spectrometry.
Results: The in vitro studies showed that E4 undergoes extensive phase 2 metabolism to form glucuronide and sulphate conjugates. UGT2B7 is the key enzyme catalysing the direct glucuronidation of E4 and SULT1E1 is the dominant sulfotransferase for sulphate conjugation in vitro. Unlike for other estrogens, oxidative phase 1 metabolism by P450 enzymes does not play a major role in the metabolism of E4. Following oral administration of E4 to humans, the major metabolites observed in human plasma were E4-16-glucuronide, E4-3-glucuronide and E4-glucuronide-sulfate (respectively 62%, 17% and 9% of radioactivity at the time of maximum plasma concentration [Tmax]). At Tmax, unchanged E4 accounts for only 7.5% of plasma radioactivity. Main metabolites quantified in urine during the first 6 hours after administration were E4-16-glucuronide and E4-3-glucuronide (respectively 77.4% and 16.5% of urine radioactivity). Approximately 69% of the total administered radioactivity was recovered in urine and 22% in faeces. Mass spectrometry showed that E4 was not present in urine but was detected in faeces and that E4 is not converted back into one of the other natural estrogens (estriol, estradiol, estrone).
Conclusions: Altogether, these data suggest that E4 has a unique metabolic profile. E4 is a terminal end-product of estrogen metabolism, which is not converted back, in vivo, into active metabolites like estriol, estradiol or estrone. Unlike for other estrogens, CYP450 enzymes do not play a major role in the metabolic pathway of E4.

The Human Metabolic Profile of Estetrol

Primary ovarian insufficiency (POI) is characterized by a heterogeneous genetic background. Moreover, the etiology of most POI cases remains unclear. Herein, our goal was to investigate the presence of rare deletions or duplications in patients presenting with POI, which could lead to identification of novel chromosomal regions and/or genes potentially associated with disease risk. Patients and Methods: Sixty-six patients presenting idiopathic POI were evaluated; 44 had primary amenorrhea and 22 secondary amenorrhea. Chromosomal microarray analysis was performed to detect copy number variants (CNVs) using array-CGH or SNP-array. Identified CNVs were validated by population databases of either health individuals (Database of Genomic Variants - DGV) or patients carrying chromosomal structural alterations (DECIPHER). A set of rare CNVs was selected and annotated in regard to gene content and clinical associations using bioinformatic tools (RefSeq, OMIM, PubMed, Ovarian Kaleidoscope Database, and Mouse Genome Informatics). Results: Fifteen rare CNVs were found in 13 patients, ten of them with primary amenorrhea. The identified CNVs comprised four deleted and 11 duplicated regions, in which the break points occurred intragenic in 8 of them. Most of the CNVs were mapped in the autosomes. Seven CNVs identified in 5 patients were classified as pathogenic or probably pathogenic; three were novel variants containing candidate genes associated with ovarian development [19q13.43 (NLRP5) and Xq13.2 (XIST)] or function [(2q37.3 (PER2)]. The other pathogenic CNVs were previously implicated in POI etiology; two of them [Xq27.2q28 del (14.5 Mb) and Xq22.1q27.1 dup (41.4 Mb)] were encompassed in a complex chromosome rearrangement, associated with 20p13 dup (2.7 Mb), and the last region was 15q25.2 deletion. Four VUS containing genes associated with ovarian development [2p23.1 (XDH and EHD3), 9p24.1 (KDM4C), 22q12.1 (ZNRF3)] or function [1p31.1 (PTGFR)] were identified. Conclusion: CNVs analysis indicated a genetic etiology in 10% of these POI patients. New candidate genes associated with ovarian development and function were revealed.

Copy Number Variant Analysis Reveals Novel Candidate Genes Associated with Primary Ovarian Insufficiency

Endometriosis is a common gynecological inflammatory disorder, which is characterized by immune system dysregulation with initiation and progression. It affects 5% to 15% of reproductive-age women and is present in as many as 30% to 50% of patients with infertility and/or pain. In previous studies, including ours, have demonstrated that several cytokines have been associated with the evolution of endometriosis, including tumor necrosis factor-a (TNFa). TNFa is a non-glycosylated protein which has potent inflammatory, cytotoxic, and angiogenic potential. Therefore, in the current studies, we examined the effects of TNFa over a time course in the regulation of proinflammatory and proangiogenic microRNAs (miRNAs) in primary cultures of normal endometrial stromal cells (NESC) and compared with the untreated cells derived from eutopic endometrium of endometriosis subjects (EESC). miRNAs are short, 18- to 22-nucleotide– size, non-coding RNAs that act as post-transcriptional modulators of gene expression and are involved in the pathogenesis of endometriosis. Using NanoString nCounter-based assays and quantitative RT-PCR, we have identified levels of several proinflammatory and proangiogenic miRNAs higher in EESC than NESC. NESC treatment with TNFa significantly altered the expression of proinflammatory and proangiogenic miRNAs in a time-dependent manner. Notably, TNFa significantly decreased phosphorylation of the PI3K, AKT, and ERK signaling pathways. Moreover, treatment of EESC and NESC with curcumin (diferuloylmethane, CUR), an anti-inflammatory folk medicine in Asian countries, significantly increased the expression of anti-inflammatory and anti-angiogenic miRNAs in a dose- and time-dependent manner. These findings demonstrate higher inflammatory, and proangiogenic miRNA production in EESC may be due to a higher concentration of TNFa than NESC under basal conditions. Therefore, suppressing TNFa may reduce the inflammatory and angiogenic miRNA associated with endometriosis.
Sources of Research Support: This study was supported in part by National Institutes of Health Grants 1SC3 GM113751, U01, 1SC1 GM130544, HD66439, 1R01HD057235, U54 CA118948, HD41749, S21MD000101 and G12-MD007602. This investigation was conducted in a facility constructed with support from Research Facilities Improvement Grant #C06 RR018386 from NIH/NCRR.

TNFa-induced altered miRNA expression links to inflammation in endometriosis

The process of gender transitioning includes the employment of gender-affirming hormone therapy (GAHT) to attenuate gender dysphoria. Although considered relatively safe, there is still debate whether GAHT may increase the risk of cardiovascular disease (CVD) in transgender men (TM). Non-conventional subclinical cardiovascular (CV) risk markers, such as inflammation or coagulation markers, endothelial activity-related substances, and the use of ultrasound-assisted vascular function evaluation, may improve CV risk prediction in specific populations. Therefore, we conducted a systematic review to summarize the available findings regarding GAHT and its effects on these non-conventional cardiovascular risk markers in TM. Medline, LILACS, SCOPUS, and Embase databases were searched for cross-sectional, case-control, cohort, or randomized clinical trial studies published until July 2020. The selection criteria for the studies were as follows: ≥ 18 years old transgender male, no established CVD, using GAHT (androgens) for at least 2 months and compared with cis women or untreated transmen or before and during/after treatment for cohort studies. From 152 studies initially identified, 7 studies (3 cohorts and 4 case-control) were included in the systematic review. Some of these studies assessed different CV risk markers in the same group of participants. No changes were found in t-PA PAI-1, ICAMs, and PCR-us after 4 and 12 months of GAHT. Fibrinogen did not differ either in TM with or with no GAHT. Three studies evaluated flow-mediated-vasodilation (FMD) of the brachial artery. The only cohort study found no changes in FMD after 12 months of GAHT. One case-control study observed significant impaired FMD, and another one showed impaired FMD- after-nitroglycerin in transmen compared with cis women. One study reported increased homocysteine and higher carotid intima-media thickness (C-MIT) after 12 months of hormone use. Further, one study observed testosterone did not affect distensibility (DC) or compliance (CC) coefficient after 12 months, but the changes in fasting insulin levels were negatively associated with changes in the CC and DC. One study assessed the vascular function using brachial-ankle pulse wave velocity (baPWV) and observed a higher risk in TM with GAHT versus the untreated group. The results of the present systematic review suggest that GAHT may be associated with worse subclinical cardiovascular markers in TM. Further studies assessing long-term clinical follow-up of transgender men using GAHT could positively impact the prevention of CVD and management strategies for this population.

The Effect of Gender Affirming Hormone Therapy (GAHT) on Non-Conventional Cardiovascular Risk Markers in Transgender Men: A Systematic Review

Background: Clinical evaluation of proptosis is measured by an exophthalmometer. Hertel exophthalmometer has long been considered a standard instrument for measurement of eye protrusion. The reading may be subject to error while the examiners read through the integral reflection mirrors. Luedde exophthalmometer, which is a ruler correcting for parallax, is easier to use and less expensive than Hertel exophthalmometer. Since CT scan of orbits or brain provides the most objective assessment of proptosis measurements, we aim to study the correlation between Luedde and Hertel exophthalmometers in comparison with the CT scan for the evaluation of proptosis in normal subjects.Methods: This prospective study was carried out between November 2020 and January 2021. Sixty-three patients were enrolled from a single tertiary hospital. All patients underwent CT scan of brain for medical reasons. On the same day, proptosis was measured with Hertel and Dual Luedde exophthalmometer by two independent examiners. Measurement of proptosis from CT scan was performed by one experienced neuroradiologist, using 2 reference measurement techniques. Correlation coefficients between proptosis values measured by each exophthalmometer and CT scan were compared.Results: The mean age of the participants was 63 years old and 54% were female. For the right eye, mean proptosis measurement was 14.9+/-1.6 mm by Hertel exophthalmometer, 14.1+/-2.3mm by Luedde exophthalmometer, 16.6+/-2.3 mm by first CT technique, and 13.1 +/- 2.2 mm by second CT technique. For the left eye, mean proptosis measurement was 15.5 +/-1.5mm by Hertel exophthalmometer, 13.7+/-2.3 mm by Luedde exophthalmometer, 16.6+/-2.3 mm by first CT technique and 13.1 +/- 2.2 mm by second CT technique. The Intraclass correlation coefficient (ICC) of Hertel exophthalmometer for proptosis measurement compared to first CT technique and second CT technique were 0.63 and 0.60 for right eye; 0.61 and 0.55 for left eye, respectively. The ICC of Luedde exophthalmometer for proptosis measurement compared to first CT technique and second CT technique were 0.78 and 0.74 for right eye; 0.77 and 0.74 for left eye, respectively.Conclusion: There is a good correlation between Hertel and Luedde exophthalmometers in evaluation of proptosis. However, proptosis measured by Luedde exophthalmometer shows superior correlation with CT scan. The result suggests that Luedde exophthalmometer can be routinely used for measurement of proptosis in place of Hertel exophthalmometer, given the simplicity and the inexpensiveness of the instrument.

Comparative Study of Hertel Exophthalmometer and Luedde Exophthalmometer Versus Computed Tomography for Measurement of Proptosis in Normal Subjects

Background: Thyroid eye disease (TED) causes orbital soft tissue expansion. Teprotumumab, a monoclonal antibody to the IGF-1R reduces orbital soft tissue swelling in TED. In this study, we quantified the changes to pan facial soft tissue volumes, following treatment with Teprotumumab.
Methods: In this prospective longitudinal study, all patients presenting at our institution for the treatment of TED were considered for study eligibility. Patients who were currently on any other medical therapy for TED were excluded. Further, patients who had any plans to embark on a weight loss regime, or medications that might cause weight loss were excluded. The primary outcome measure was a change in soft tissue volume of the face from baseline to within 3 weeks of the final infusion. Secondary outcome measures included changes in proptosis, clinical activity score and body weight. All patients had 3D facial imaging using the Vectra H2 (Canfield, USA). The use of this system to quantify volumetric change in facial soft tissue has previously been shown to be reliable and accurate.
We also used the Mimics (Materialise) software to build 3D reconstructions of the face from CT scans, allowing us to calculate the volume of muscle and fat tissue pre and post treatment. Relationships between continuous variables were analyzed using bivariate and multivariate analysis. Intraobserver and Interobserver variability was calculated by two observers doing all calculations twice on two separate days.
Results: Forty-three patients with confirmed euthyroid status at the time of study were included. The mean duration of TED was 30 months (34). Following Teprotumumab therapy, the mean (SD) decrease in volume for each region was 0.74 mL (0.82) in the upper face, 1.9 mL (1.2) in the periorbital region, 0.18 mL (0.6) in the temples, 1.73 mL (2.2) in the midface and 2.84 mL (4.7) in the lower face. The mean (SD) decrease in the volume of the full face was 8.4 mL (8.5) (figure 2). There was a significant correlation between 3D facial imaging and volumetric study using CT scans (p < 0.05). Mean (SD) weight prior to therapy was 75 kg (12) and 69 kg (15) following therapy (p < 0.05). There was no relationship between previous steroid use and total body weight reduction and changes in facial volume.
Conclusion: The results of this study expand the borders of TED, suggesting its sequelae may reach beyond that of the orbit and periorbital tissues, to include changes across the entire face. Teprotumumab significantly reduces these changes.

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