United States

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.

ENDO 2022

The Human Metabolic Profile of Estetrol

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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. 

technical paper

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.

Reversal of Graves' Disease Associated Facial Volume Expansion and Eyelid Changes Following Teprotumumab Therapy

Clinical manifestations of thyroid eye disease (TED) are mainly caused by the binding of immunoglobulin G (IgG) thyrotropin receptors (TSHR) autoantibodies (TSHR-Ab) on orbital fibroblasts. Batoclimab (IMVT-1401) is an anti-neonatal Fc receptor (FcRn) human monoclonal antibody that prevents normal IgG recycling, leading to reduced levels of circulating IgG. Thus, batoclimab may provide benefit for patients with TED by reducing pathogenic anti-TSHR-Ab. In this Phase 2b, double-blind, randomized study (NCT03938545), subjects with active and moderate-to-severe TED received weekly subcutaneous (SC) injections of batoclimab (680mg, 340mg, 255mg) or placebo for 12-weeksSixty-five subjects were randomized and received batoclimab (680mg [n=18], 340mg [n=19], 255mg [n=10]) or placebo (n=18). Recruitment and treatment were stopped because of an unanticipated increase in LDL cholesterol levels, not included in subject informed consent. Hence, forty-five of 77 planned subjects completed the 12-week treatment period. Serum IgG and anti-TSHR-Ab were reduced from baseline to Week-12 with batoclimab (680mg [-77.9%; -65.5%], 340mg [-65.8%; -70.1%], 255mg [-56.6%; -42.1%]) versus placebo (-4.67%; -3.23%), respectively. Substantial reductions were also observed at Week-12 in stimulatory anti-TSHR-Ab. Fifty-one of 65 subjects had proptosis ≥ upper level of normal at baseline. At Week-12 (primary outcome), greater proportions of 680mg (30%; p=0.2197) and 340mg (30.8%; p=0.1311) subjects were proptosis responders (≥2mm reduction) versus placebo (8.3%). Absolute risk reduction (ARR [95% CI]) versus placebo was 21.4 (-11.3, 54.1) for 680mg and 24.2 (-4.8, 53.2) for 340mg at Week 12. Earlier proptosis responses were statistically different from placebo for 680mg at Weeks-four (35.7%; ARR [95% CI] 36.0 [10.9, 61.1]), five (42.9%; 43.0 [17.1, 68.9]), and 11 (41.7%; 34.5 [3.4, 65.6]) and for 340mg at Weeks-five (29.4%; 29.6 [7.9, 51.3]), nine(35.7%; 30.6 [3.0, 58.2]), and 11 (46.2%; 40.2 [10.2, 70.1]) (all p<0.05). Changes in clinical activity at Week-12 were not significantly different from placebo.The proportion of subjects with an adverse event (AE) were similar across treatment groups; most were mild or moderate in severity. Two subjects reported serious AEs not related to treatment (optic neuropathy, autoimmune encephalitis [occurring after treatment period]). No subjects withdrew from the study due to an AE during the 12-week treatment period. There was a reversible dose-dependent reduction in serum albumin during the treatment period. Post-hoc lipid analysis demonstrated a reversible increase in mean serum LDL during treatment (680-mg: 58.7%; 340-mg: 30.8%; 255-mg: 19.0%) vs placebo (-3.9%),.In conclusion, batoclimab reduced circulating IgG and especially the pathogenic anti-TSHR-Ab. Although the proptosis response was not statistically significant at the primary endpoint, significance was seen at earlier time points. This is probably related to early study termination which reduced the numbers of patients available for efficacy assessment at the primary endpoint.

Double-Blind, Randomized, Placebo-controlled, Multicenter, Phase 2b Study of Batoclimab in Active and Moderate-to-Severe Thyroid Eye Disease

A 71-year-old male presented to the endocrine clinic for evaluation of hypothyroidism which has recently been difficult for his primary care physician to control.  He initially developed hypothyroidism in 1990 after neck radiation for squamous cell carcinoma of his sternocleidomastoid muscle. He was previously controlled for many years on levothyroxine 150mcg daily with TSH readings in the normal reference range.  Patient was infected with COVID-19 in 2020 and was hospitalized for 10 days. He was treated with 5 days of Remdesivir and 10 days of Decadron. 6 months after the infection he received mRNA COVID-19 vaccination.  Upon his first visit to the endocrine clinic post COVID-19 infection and vaccination, his TSH was elevated at 90 uIU/mL with a free thyroxine that was elevated at 1.8 ng/dL even after multiple attempts by his primary care physician to increase his Levothyroxine which was up to 225 mcg daily before he was referred to endocrinology. He is compliant with his levothyroxine and takes it on an empty stomach first thing in the morning without any of his other medications. He is not taking iron supplements, biotin or any other supplements or new medications. TSH values had been normal 1 month prior to his COVID-19 infection and was first noted to be abnormal 8 months after his COVID-19 infection and 2 months after his mRNA COVID-19 vaccine.  There was no TSH drawn between when he had COVID-19 and when he received his vaccine. It was suspected that he may have a factitious elevation in his TSH due to antibody interference.  Labs were drawn for a TSH with human anti-mouse antibodies (HAMA) treatment which resulted with a markedly suppressed TSH at 0.007 uIU/mL with an elevated free thyroxine of 1.94 ng/dL.  HAMA antibodies came back elevated at 552 ng/mL.
Reference:
Klee, G., 2000. Human Anti-Mouse Antibodies. Archives of Pathology & Laboratory Medicine, 124(6), pp.921-923.
Koshida, S., Asanuma, K., Kuribayashi, K., Goto, M., Tsuji, N., Kobayashi, D., Tanaka, M. and Watanabe, N., 2010. Prevalence of human anti-mouse antibodies (HAMAs) in routine examinations. Clinica Chimica Acta, 411(5-6), pp.391-394.

A Case of COVID-19 Infection; COVID-19 mRNA-Based Vaccine Induced Human Anti-Mouse Antibodies (HAMA) Interfering With TSH Testing

Background: In 2011, Shoenfeld and Agmon-Levin described a distinct clinical entity called the autoimmune/inflammatory syndrome induced by adjuvants (ASIA). Adjuvants are primarily used in vaccines for directing the adaptive immune response. However, adjuvants sometimes trigger undesirable autoimmune effects, especially in genetically predisposed individuals such as those with DRB1 allele mutations. The mRNA vaccine may exert "self-adjuvant" properties through activation of tumor necrosis factor, interferon-alpha and other cytokines secreted by immune cells or cross reactivity of mRNA targeting CoV-2 spike protein with thyroid tissue antigens. With the recent widespread use of SARS-CoV-2 mRNA vaccine, cases of vaccine associated thyroid disorders are becoming more apparent.Case Summary: A 45-year-old male with well controlled hypertension and type 2 diabetes mellitus was evaluated for abnormal thyroid function tests with a TSH of 0.078 uIU/mL and Free T4 of 2.17 ng/dl. He reported a history of Hashimoto's chronic thyroiditis. He received the second dose of mRNA COVID-19 vaccine one month prior to presentation. He denied any change in the size of his thyroid gland. He also reported no local neck symptoms, dysphagia, odynophagia or change in voice. A nuclear thyroid uptake and scan showed mildly asymmetric thyroid lobes with markedly decreased 24-hour uptake of 0.7 %.  Based on his clinical presentation, labs and nuclear imaging he was diagnosed with painless thyroiditis. His thyroid function normalized to a TSH of 0.96uIU/ml and Free T4 of 1.29 ng/dl within 2 months without any intervention. There is a strong possibility that the SARS-CoV-2 vaccine accentuated his underlying Hashimoto's chronic thyroiditis enough to cause this transient episode of painless thyroiditis, particularly considering the close interval between the vaccine and onset of his thyroid abnormalities.Conclusion: Autoimmune thyroid abnormalities induced by vaccines have been historically associated with protein vaccines for protection from HPV, HBV, seasonal influenza, etc. The spectrum of these disorders can potentially manifest as a transient side effect or even years later with non-specific findings. The SARS-CoV-2 mRNA vaccine may incite similar immunogenicity though yet unestablished, and physicians should be mindful of this phenomenon. Due to limited data, more rigorous studies are needed to fully understand the underlying pathogenesis of thyroiditis following SARS-CoV-2 vaccine in future. As there have been minimal cases of thyroiditis reported, SARS-CoV-2 vaccine should still be strongly recommended.References
Bragazzi NL, Hejly A, Watad A, Adawi M, Amital H, Shoenfeld Y. ASIA syndrome and endocrine autoimmune disorders. Best Pract Res Clin Endocrinol Metab. 2020 Jan;34(1): 101412. doi: 10.1016/j.beem.2020.101412. Epub 2020 Mar 11. PMID: 32265102.
Watad A, David P, Brown S, Shoenfeld Y. Autoimmune/Inflammatory Syndrome Induced by Adjuvants and Thyroid Autoimmunity. Front Endocrinol (Lausanne). 2017 Jan 24;7: 150. doi: 10.3389/fendo.2016.00150. PMID: 28167927; PMCID: PMC5256113.

The Human Metabolic Profile of Estetrol

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

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