Steroid Deficiency Research Articles

12466 Dual Bone Defect In Patients With Charge Syndrome

Abstract Disclosure: N. Reyes: None. R.J. Santen: None. S.M. Jan De Beur: None. R. Balasubramanian: None. Chromodomain Helicase DNA-binding protein 7 (Chd7) is an ATP-dependent chromatin modifier that mediates nucleosome remodeling. Chd7 mutations result in CHARGE syndrome characterized by coloboma, heart defects, choanal atresia, growth/developmental delay, ear abnormalities, and hypogonadotropic hypogonadism/Kallmann syndrome (IHH/KS). Testosterone has direct and indirect effects (through estrogen), to increase bone formation and decrease bone resorption. Untreated hypogonadism is associated with decreased bone density and fractures. Reports of fractures and low bone density in CHARGE syndrome patients have been attributed to sex hormone deficiency associated with hypogonadism. However, recent data from a Chd7 mouse knockout model suggests an intrinsic Chd7-related bone defect. In wild-type mice, Chd7 promotes osteogenic differentiation of mesenchymal stem cells. Chd7 deficient mice show markedly reduced osteoblasts. Thus, we propose, a dual bone defect in CHARGE syndrome resulting from impaired osteogenesis from CHD7 and sex steroid deficiency; and increased bone resorption due to lack of sex steroids. Here we present two individuals with CHARGE syndrome with markedly low bone density and literature review supporting the dual bone defect concept. Case 1 is a 30 yo male with a pathogenic CHD7 mutation, multiple congenital anomalies of CHARGE syndrome and hypogonadotropic hypogonadism. He had multiple fractures in his teen age years and a bone density Z score of -5.2 at the lumbar spine and -3.3 at the left femoral neck. Because he did not tolerate androgen therapy, a single infusion of zoledronic acid was administered with no further fractures for eight years following infusion. Case 2 is a male evaluated for IHH/KS and ultimately diagnosed with CHARGE Syndrome based on a pathogenic CHD7 mutation. Despite 7 years of testosterone therapy with full virilization, his bone density remained low at Z-score of -1.9 at the spine and -2.6 at the total hip. Results: Both patients had low bone density, one while untreated and the other after full virilization with exogenous androgens. This raises the question whether the bone defects were related to the CHD7 mutation, to androgen deficiency or both. To answer this question, a literature search examined bone density data in untreated patients with CHARGE syndrome versus IHH/KS. We found substantially lower bone density in untreated CHARGE patients Z score -3.46±0.36 (SEM) (n=13) versus IHH/KS -2.16 ±1.0 (n=4). Furthermore, the bone density was also lower in treated CHARGE patients -2.46±0.28 (n=6) versus IHH/KS -0.94±0.26 (n=140). Conclusion: These data, taken together, provide direct human evidence to support the concept that the CHD7-related CHARGE syndrome patients have a defect in both osteogenesis as well as an effect of sex steroid deficiency on bone. Presentation: 6/3/2024

6611 ACTH deficiency due to TBX19 mutation mimics complete adrenal insufficiency in a newborn

Abstract Disclosure: T. Reinehr: None. P.M. Holterhus: None. S.A. Wudy: None. A. Richter-Unruh: None. C. Spratte: None. C. Roll: None. Isolated ACTH deficiency (IAD) is a rare cause of adrenocortical insufficiency. T-box transcription factor 19 (TBX19) mutations are responsible for more than 60% of neonatal cases of IAD. To the best of our knowledge, we present for the first time a newborn with ACTH deficiency due to a TBX19 mutation with almost steroid-free plasma and urine: At day 2 of life, the female newborn (birth weight 3190g, length 52 cm, 40+1 gestational age) was transferred to our neonatal intensive care unit for severe hypoglycemia (12 mg/dl), which responded to intravenous glucose infusion. Surprisingly, the sodium serum concentrations decreased from 140 mmol/l at day 2 of life to 126 mmol/l at day 7 of life. There were no clinical signs of adrenal insufficiency such as vomiting or hypotonia. Treatment with oral sodium-chloride 5.85% was started. Endocrine diagnostic work-up performed at day 8 of life demonstrated normal values of fT4, HGH and IGFBP-3 ruling out pituitary involvement of these axes, while ACTH serum concentrations were markedly decreased (1.5 pg/ml). Liquid- chromatography-mass spectrometry (LC-MS/MS) revealed nearly absent glucocorticoids (17-hydroxyprogesterone <0.12 nmol/l, 11-deoxycortisol <0.08 nmol/l, cortisol <4.2 nmol/l, and cortisone 1.3 nmol/l (norm value [nv]: 17-138 nmol/l)). Androgens were undetectable (testosterone <0.02 nmol/l, androstenedione <0.08 nmol/l). Mineralocorticoids were severely reduced (11-desoxycorticosterone 0.1 nmol/l (nv: 0.2-1.0 nmol/l), corticosterone 0.6 nmol/l (nv: 1-24 nmol/l), aldosterone 0.1 nmol/l (nv: 0.8-2.3 nmol/l)). In urine spot, gas chromatography-mass spectrometry (GC-MS) demonstrated subnormal excretion of C19 and C21 steroids including fetal zone steroids. Serum and urine measurements were interpreted by the labs as a typical finding similar to StAR defect. The genetic analyses revealed a normal female karyotype (46,XX) and ruled out CYP11A1 and StAR, mutations but demonstrated a homozygous missense mutation in TBX19 (c.172A>G, p.(Thr58Ala)). After 3 months of life under treatment with hydrocortisone (10mg/m² divided in 3 doses) and fludrocortisone (0.05 mg divided in 2 doses), cortisol was normal (320 nmol/l) and DHEAS was undetectable (<3 nmol/l). While androgens were in normal range (testosterone 2.6 nmol/l, androstenedione 0.28 nmol/l), 11-deoxycorticosterone was normal (0.74 nmol/l), corticosterone was undetectable (<0.5 nmol/l) and aldosterone was decreased (0.12 nmol/l nv: 0.8-1.2 nmol/l). At this time point, ACTH was <4 pg/ml, renin 1.6 mIU/l, LH 0.7 mIU/l and FSH 24.5 mIU/ml. This case demonstrated that isolated ACTH deficiency should be considered as a potential differential diagnosis in complete adrenal steroid insufficiency in newborns. Our data suggest that ACTH is not only necessary for cortisol biosynthesis but also for sufficient mineralocorticoid and androgen production by the adrenals in neonates. Presentation: 6/3/2024

Features of densitometric assessment of bone tissue parameters in the verification of osteoporotic changes in young men with Hodgkin's lymphoma

BACKGROUND: The development of osteoporosis in males is associated with a complex interaction of various factors, including: deficiency of sex hormones, heredity, physical activity, nicotine use, etc. In young men with Hodgkin's lymphoma, the development of the osteoporotic process is very multifactorial due to the influence of tumor cells, pathogenetic therapy, as well as a secondary decrease in androgens on the composition of bone tissue and a decrease in BMD. AIMS: To determine the parameters of bone mineral density in young men with Hodgkin's lymphoma and to assess the risks of osteoporosis associated with pathogenetic therapy of the disease. MATERIALS AND METHODS: The study included 26 men, of whom 14 were diagnosed with Hodgkin's lymphoma, and the control group included 12 healthy males. All patients underwent a two-adsorption X-ray scan of bone tissue in the lumbar spine, as well as the femur. The following parameters were identified and studied: MPC, Z-criterion, T-criterion for all participants in both study groups. RESULTS: The analysis of bone mineral density in patients with Hodgkin's lymphoma showed a significant decrease in the parameter in two measurement areas: the lumbar spine and the proximal femur. Significantly more often in men with Hodgkin's lymphoma, a decrease in the Z-criterion to osteopenia/osteoporosis was noted in the lumbar spine. A decrease in the T-criterion in patients with Hodgkin's lymphoma to osteopenia/osteoporosis was noted in the proximal and femoral neck. CONCLUSIONS: Young men with Hodgkin's lymphoma who have received pathogenetic therapy, including cytostatic drugs and glucocorticosteroids, are at high risk of developing the osteoporotic process and its complications. The decrease in densitometric parameters (MPC, Z-criterion, T-criterion) in patients with Hodgkin's lymphoma to osteopenia/osteoporosis, noted in the proximal part and femoral neck, indicates a high risk of fractures of this localization and requires the development of a strategy for their prevention.

Photothermal tissue reconstruction and the use of phytoestrogens in the treatment of genitourinary menopausal syndrome

Introduction. Genitourinary syndrome of menopause (GSM) is a complex of symptoms resulting from changes to the vulvovaginal region, urethra and bladder due to estrogen and other sex steroid deficiency. Vulvovaginal atrophy is one of its manifestations, and vaginal dryness, dyspareunia, burning and itching are the most common symptoms.Aim. To analyse 20 clinical cases of the use of innovative laser procedures combined with phytoestrogens in patients with vulvovaginal atrophy as a symptom of GSM vs the standard systemic protocol for menopausal hormone therapy.Materials and methods. A clinical case-control study was conducted among 20 postmenopausal women. The age of the subjects ranged from 50 to 65 years with amenorrhea for at least 1 year, a follicle-stimulating hormone level of >30 IU/L and various presentations of GSM. The women were divided into two groups: group 1 (n = 10) received laser therapy combined with phytoestrogens, group 2 (n = 10) received systemic menopausal hormonal therapy. To evaluate the results, a survey with a specialized international vulvovaginal symptom questionnaire (VSQ) was carried out to determine the vaginal health index scores before and after treatment.Results. After treatment, both groups showed significant improvement in the form of the reduction or disappearance of symptoms of vulvovaginal atrophy. The prescription of phytoestrogens provided an additional positive effect after 3 sessions of carbon dioxide laser treatment.Conclusion. The carbon dioxide laser exposure resulted in the reduction or disappearance of the local symptoms of climacteric syndrome in the form of GSM, and the use of phytoestrogens as part of Mense BAA supplemented the treatment of psychoemotional and neurovegetative changes, which allowed us to make a conclusion about the feasibility, high efficiency and safety of the complex treatment for women, who do not wish to take menopausal hormone therapy and (or) have absolute contraindications. However, further research on the laser technologies and other non-hormonal techniques to treat GSM is required to carry out a more complete and accurate assessment of the effectiveness and safety of these treatments.

Sex Steroid Levels in Women With Hypopituitarism: A Case-controlled Observational Study.

Women with hypopituitarism remain at increased risk of morbidity and mortality. Insufficient replacement of sex steroids has been suggested as a contributing factor, but sex steroid levels in women with hypopituitarism have not been comprehensively mapped. To quantify sex steroids in women with hypopituitarism by a high-sensitivity assay. Using a combination of clinical and biochemical criteria, women with hypopituitarism (n = 104) who started GH replacement in 1995 to 2014 at a single center were categorized as eugonadal or having hypogonadotropic hypogonadism (HH). A population-based cohort of women (n = 288) served as controls. Eugonadal women and controls were categorized as pre-/postmenopausal and HH women as younger/older (≤ or >52 years). Dehydroepiandrosterone (DHEA), androstenedione, testosterone, dihydrotestosterone, progesterone, 17αOH-progesterone, estradiol, and estrone were analyzed by a validated liquid chromatography-tandem mass spectrometry assay. Among both premenopausal/younger and postmenopausal/older women, women with HH had lower levels of sex steroid precursors (DHEA, androstenedione) and androgens (testosterone and dihydrotestosterone) than controls. Progesterone, 17αOH-progesterone, estrone, and estradiol showed similar patterns. Women with HH and ACTH deficiency had markedly lower concentrations of all sex hormones than those without ACTH deficiency. This study demonstrates for the first time a broad and severe sex steroid deficiency in both younger and older women with HH, particularly in those with combined gonadotropin and ACTH deficiency. The health impact of low sex steroid levels in women with hypopituitarism requires further study, and women with combined gonadotropin and ACTH deficiency should be a prioritized group for intervention studies with sex hormone replacement.

Could sex-specific subtypes of hand osteoarthritis exist? A retrospective study in women presenting to secondary care.

Hand osteoarthritis is more common in women, and its risk increases around the time of the menopause. We set out to describe the timing between menopause and the onset of symptomatic hand osteoarthritis (OA), and associations with the use of hormone replacement therapy (HRT) or its discontinuation, describing any identifiable subgroups of women. Retrospective healthcare-records study of sequential women referred to a specialist hand OA clinic, 2007-2015. Confirmation of hand OA diagnosis was by clinican, by accepted criteria. Demographics and clinical variables were from healthcare-records, recorded by standardised proforma. Outcomes of interest were reported age of onset of hand symptoms, reported age at final menstrual period (FMP), time from FMP to reported onset of hand symptoms and time from cessation of HRT to reported onset of hand symptoms. Exposure categories for systemic HRT use were never users, current users, previous users. Analysis of Variance compared groups; linear regression analysed associations of exposure with outcome. 82/92(89%) of eligible women were post-menopausal, mean age at FMP 49.9 years (SD5.4). In these post-menopausal women, median time from FMP to hand symptom onset was 3 years. 48/82 (59%) developed hand symptoms within the defined peri-menopausal period (FMP ± 4 years), whilst some women developed their symptoms before or after (range -25, 30 years). In women who discontinued HRT prior to symptom onset, the median time from HRT cessation to onset of hand symptoms was 6 months. Past HRT users were older at hand symptom onset than women who had not taken HRT [coeff.4.7 years (0.92, 8.39); P = 0.015]. This study adds to evidence associating the menopause/sex hormone deficiency with hand OA symptom onset in a sizeable subgroup of women (but not all). HRT use/cessation appears to influence the timing of onset of hand OA symptoms. It is not possible to interpret from this type of study whether sex hormone deficiency is causative of disease or modulates its symptoms. It is also not possible to judge whether painful hand osteoarthritis in post-menopausal women is a subtype of disease. Further investigation is indicated of sex-specific subtypes and potential for personalised medicine for post-menopausal women with hand osteoarthritis, as a clearly definable high-risk subgroup.

Plasma steroid concentrations reflect acute disease severity and normalise during recovery in people hospitalised with COVID-19.

Endocrine systems are disrupted in acute illness, and symptoms reported following coronavirus disease 2019 (COVID-19) are similar to those found with clinical hormone deficiencies. We hypothesised that people with severe acute COVID-19 and with post-COVID symptoms have glucocorticoid and sex hormone deficiencies. Samples were obtained for analysis from two UK multicentre cohorts during hospitalisation with COVID-19 (International Severe Acute Respiratory Infection Consortium/World Health Organisation [WHO] Clinical Characterization Protocol for Severe Emerging Infections in the UK study), and at follow-up 5 months after hospitalisation (Post-hospitalisation COVID-19 study). Plasma steroids were quantified by liquid chromatography-mass spectrometry. Steroid concentrations were compared against disease severity (WHO ordinal scale) and validated symptom scores. Data are presented as geometric mean (SD). In the acute cohort (n = 239, 66.5% male), plasma cortisol concentration increased with disease severity (cortisol 753.3 [1.6] vs. 429.2 [1.7] nmol/L in fatal vs. least severe, p < .001). In males, testosterone concentrations decreased with severity (testosterone 1.2 [2.2] vs. 6.9 [1.9] nmol/L in fatal vs. least severe, p < .001). In the follow-up cohort (n = 198, 62.1% male, 68.9% ongoing symptoms, 165 [121-192] days postdischarge), plasma cortisol concentrations (275.6 [1.5] nmol/L) did not differ with in-hospital severity, perception of recovery, or patient-reported symptoms. Male testosterone concentrations (12.6 [1.5] nmol/L) were not related to in-hospital severity, perception of recovery or symptom scores. Circulating glucocorticoids in patients hospitalised with COVID-19 reflect acute illness, with a marked rise in cortisol and fall in male testosterone. These findings are not observed 5 months from discharge. The lack of association between hormone concentrations and common post-COVID symptoms suggests steroid insufficiency does not play a causal role in this condition.

How do we make progress in phenotyping patients with LUT such as OAB and underactive detrusor, including using urine markers and microbiome data, in order to personalize therapy? ICI-RS 2023: Part 1.

Overactive bladder (OAB) and Underactive bladder (UAB) could be associated with metabolic syndrome, affective disorders, sex hormone deficiency, changes in urinary microbiota, functional gastrointestinal disorders, or autonomic nervous system dysfunction. The aim of this Think Tank was to provide a guide on how to investigate OAB and/or detrusor underactivity (DU) patients to better clarify the underlying pathophysiology and possibly personalize the treatment. A compendium of discussion based on the current evidence related to phenotyping patients with OAB or DU investigating metabolic, neurogical, psychological and gastrointestinal aspects with the aim to personalize the treatment. The article emphasizes the critical significance of adopting a comprehensive yet tailored approach to phenotyping patients with lower urinary tract symptoms, such as OAB and UAB. The intricate interplay between the lower urinary tract and various factors, metabolic, neurological, psychological, and gastrointestinal can define unique LUT profiles, enabling personalized therapies to replace the one-size-fits-all approach.

How do we make progress in phenotyping patients with lower urinary tract such as overactive bladder and underactive detrusor, including using urine markers and microbiome data, to personalize therapy? ICI-RS 2023-Part 2.

Overactive bladder (OAB) and underactive bladder (UAB) could be associated with metabolic syndrome, affective disorders, sex hormone deficiency, changes in urinary microbiota, functional gastrointestinal disorders, or autonomic nervous system dysfunction. The aim of this Think Tank was to provide a guide on how to investigate OAB and/or detrusor underactivity (DU) patients to better clarify the underlying pathophysiology and possibly personalize the treatment. A compendium of discussion based on the current evidence related to phenotyping patients with OAB or DU using urodynamic tests, functional neuro-imaging, urinary markers, and microbiome. The article emphasizes the critical significance of adopting a comprehensive yet tailored approach to phenotyping patients with lower urinary tract (LUT) symptoms, such as OAB and UAB. The intricate interplay between the LUT and various factors, metabolic, neurological, psychological, and gastrointestinal can define unique LUT profiles, enabling personalized therapies to replace the one-size-fits-all approach.

The role of lipotropic factors in the correction of metabolic disorders in women during the perimenopausal period

In women during perimenopause, changes in metabolic parameters are detected, such as weight gain, which triggers a cascade of pathological reactions leading to the formation of metabolic disorders (lipid, carbohydrate metabolism) and endothelial dysfunction, during the development of which a deficiency of sex hormones plays a certain role in the onset of menopause. There is a connection between hormonal changes and an increase in the amount of abdominal and/or visceral fat, which is accompanied by a weakening of oxidative processes in adipose tissue, a decrease in energy consumption and a predisposition to the development of metabolic syndrome. As a nutritional correction, it is advisable to introduce into the diet lipotropic substances that help catalyze the breakdown of fats and ensure the processes of hydroxylation and methylation of toxic substances in the liver, such as methionine, inositol and choline. Each of the lipotropic substances affects the mobilization of fats, and their combination can provide a synergistic effect and increase the natural metabolic function of the liver.

Cadmium facilitates the formation of large lipid droplets via PLCβ2-DAG-DGKε-PA signal pathway in Leydig cells

Cadmium (Cd) exposure damages the reproductive system. Lipid droplets (LDs) play an important role in steroid-producing cells to provide raw material for steroid hormone. We have found that the LDs of Leydig cells exposed to Cd are bigger than those of normal cells, but the effects on steroidogenesis and its underlying mechanism remains unclear. Using Isobaric tag for relative and absolute quantitation (iTARQ) proteomics, phosphodiesterase beta-2 (PLCβ2) was identified as the most significantly up-regulated protein in immature Leydig cells (ILCs) and adult Leydig cells (ALCs) derived from male rats exposed to maternal Cd. Consistent with high expression of PLCβ2, the size of LDs was increased in Leydig cells exposed to Cd, accompanied by reduction in cholesterol and progesterone (P4) levels. However, the high PLCβ2 did not result in high diacylglycerol (DAG) level, because Cd exposure up-regulated diacylglycerol kinases ε (DGKε) to promote the conversion from DAG to phosphatidic acid (PA). Exogenous PA, which was consistent with the intracellular PA concentration induced by Cd, facilitated the formation of large LDs in R2C cells, followed by reduced P4 level in the culture medium. When PLCβ2 expression was knocked down, the increased DGKε caused by Cd was reversed, and then the PA level was decreased to normal. As results, large LDs returned to normal size, and the level of total cholesterol was improved to restore steroidogenesis. The accumulation of PA regulated by PLCβ2-DAG-DGKε signal pathway is responsible for the formation of large LDs and insufficient steroid hormone synthesis in Leydig cells exposed to Cd. These data highlight that LD is an important target organelle for Cd-induced steroid hormone deficiency in males.

Current trends in the prevention and treatment of genitourinary menopausal syndrome

Genitourinary menopausal syndrome is still a widespread problem that significantly affects the quality of life in postmenopause. The cause of this state is hypoestrogenism that is associated with menopause and the following change in the vaginal microflora due to the elimination of lactobacilli. The disturbance of the vulval and vaginal microflora provides risks for the invasion of pathogenic microorganisms, and the deficiency of sex hormones is associated with atrophy of the epithelium of the urogenital tract. An analysis of published clinical studies using a combination of L. acidophilus and 0.03 mg estriol (Gynoflor® E) in postmenopausal women with vulvovaginal atrophy, breast cancer survivors, in postmenopausal women with breast cancer on aromatase inhibitors was performed. Treatment with a combination of L. acidophilus and 0.03 mg of estriol (Gynoflor® E) can be evaluated as safe without risk of endometrial effects or other systemic effects. Local estrogen therapy in postmenopausal women can restore the vaginal epithelium, and a useful lactobacillus flora is needed to prevent urogenital infections. Local application of estriol is preferable, as it causes a local proliferative response and has no stimulating effect on the endometrium. This method of therapy may also be considered for hormone-sensitive women with breast cancer on aromatase inhibitors. However, today, there are not enough clinically validated studies proving the absolute safety of this treatment method among breast cancer women. The effect of this therapy is achieved due to the synergistic action of estriol and lactobacilli.

SAT336 A Successful Ovulation Induction And Embryo Generation In A Woman With P450-oxidoreductase Deficiency From Mutation G539R, Which Preferentially Impairs 17,20-lyase Activity

Abstract Disclosure: S. Charoensri: None. M. Thakur: None. R.J. Auchus: None. Introduction: Cytochrome P450 oxidoreductase (POR) deficiency is an autosomal recessive disorder causing decreased activity of several P450 enzymes, including CYP21A2, CYP17A1, and CYP19A1 that are essential for steroidogenesis in the adrenals and gonads. Female POR deficiency patients are typically manifested with genital ambiguity, abnormal menstruation, and infertility. Very few pregnancies have been documented from these patients. Case presentation: During an evaluation for infertility, a 35-year-old woman with late menarche, irregular cycles, and unruptured ovarian follicles was diagnosed with POR deficiency due to compound heterozygous pathogenic variant c.1615G&amp;gt;C (G539R) and a large deletion c.1669+5_1669+32del in the POR gene. Because mutation G539R preferentially impairs the 17,20-lyase activity of CYP17A1, she underwent in-vitro fertilization (IVF) with the protocol that has been used successfully to achieve pregnancy in incomplete 17-hydroxylase deficiency. Oral dexamethasone of 0.5 mg/day was given to suppress the adrenal-derived progesterone. After one menstrual cycle induced with estradiol and progesterone priming, leuprolide acetate was used to down-regulate endogenous gonadotropin secretion, then the oocyte maturation was induced with recombinant follicle-stimulating hormone (rFSH) and highly purified menotrophin. In the first cycle, 6 eggs were retrieved, 2 that were mature and fertilized with intracytoplasmic sperm injection (ICSI); however, none advanced to the blastocyst stage. She underwent the same protocol in a second IVF cycle with higher rFSH dosing. Despite increasing dexamethasone to 1.5 mg/day, progesterone rose to 4.9 ng/mL, while estradiol peaked at 120 pg/mL, consistent with progesterone accumulation in the developing ovarian follicles due to POR deficiency. From 6 eggs retrieved, 5 eggs were mature and all fertilized, and 3 developed past day 3. On day 6, one embryo (grading 5BB) was biopsied for preimplantation genetic testing and frozen. The second phase of the treatment plan is to lower adrenal-derived progesterone with a combination of hydrocortisone and prednisolone, prepare the endometrium with estradiol followed by progesterone, and perform embryo transfer. Conclusions: Very few examples of pregnancy in women with POR deficiency have been reported, and we describe the first example of successful ovulation induction and embryo generation in a woman with POR deficiency caused by the G539R mutation, which preferentially impairs 17,20-lyase activity. The complex array of steroid excess and deficiencies, from both adrenal and ovarian origin, must be systematically managed during assisted reproduction treatment for these women. Presentation: Saturday, June 17, 2023

THU186 A Case Of 3beta-hydroxysteroid Dehydrogenase Type2 Deficiency Diagnosed By Whole Genome Sequencing In A Patient With Congenital Adrenal Hyperplasia

Abstract Disclosure: S. Chang: None. C. Kim: None. 3β-hydroxysteroid dehydrogenase type 2 deficiency (3βHSD2D) is a very rare type of congenital adrenal hyperplasia (CAH) caused by HSD3B2 gene mutations. The estimated prevalence is less than 0.5% of all CAH and less than 1/1,000,000 at birth. It is a disorder of impaired steroidogenesis and sex steroid deficiency characterized by variable degrees of salt wasting, hypoglycemia, male incomplete masculinization and female virilization. Some newborns with 3βHSD2D have increased level of 17-hydroxyprogesterone (17OHP) that clinicians misdiagnose them as having classic 21-hydroxylase deficiency. A male newborn was referred to our hospital for generalized hyperpigmentation. Laboratory test showed hyponatremia, hyperkalemia and hypoglycemia. Hormonal study showed high level of adrenocorticotropic hormone, 17OHP, progesterone, renin activity, dehydroepiandrosterone (DHEA), androstenedione and low level of aldosterone. Clinically diagnosing with CAH, we administered glucocorticoid and mineralocorticoid replacement. We performed PCR sequencing for CYP21A2 gene mutation to confirm 21 hydroxylase deficiency but revealed normal result. After follow-up for 17 years with replacement treatment, he happened to have the opportunity to perform whole genome sequencing. Whole genome sequencing allowed to detect two pathogenic mutations in the HSD3B2 gene, described in compound heterozygosity (p.Arg249Ter and c.-149_143-1766del). One mutation (c.-149_143-1766del) is inherited from his father and the mother was not done for gene study. While there have been less than 100 cases of 3βHSD2D reported worldwide, in our best knowledge, this is the first case of genetically confirmed 3βHSD2D in Korea. Presentation: Thursday, June 15, 2023

Vaginal treatment with solid state non ablative laser 1470 nm for vaginal atrophy in post menopausal women

One of the most common menopausal symptoms is vaginal dryness. Menopausal sex hormone deficiency causes changes in the urogenital tract, where estrogens are the primary regulators of vaginal physiological functions. Many treatments have been developed over the years, but the majority of them are ineffective or have potential side effects. Actually, laser therapy has the highest efficacy with the fewest (or none) side effects. Thermal energy acting on the vaginal wall has been shown in studies to stimulate collagen synthesis, induce neovascularization, enrich the glycogen epithelium, improve vaginal lubrication, and treat urinary incontinence. However, not all lasers are created equal. The majority of published studies describe the data from CO2 laser therapy, Erbium laser therapy, and radiofrequency. Less is known about the new 1470 nm solid state laser. This is a retrospective study in which 16 women with vaginal dryness were treated with a 1470 nm solid state vaginal laser. All of the patients were cured of vaginal dryness with no pain, bleeding, scarring, or other side effects.

Halogenated bisphenol A derivatives potently inhibit human, rat, and mouse gonadal 3β-hydroxysteroid dehydrogenases: Structure-activity relationship and in silico molecular docking analysis

Bisphenol A (BPA) is a widely used plastic material, and halogenated BPA derivatives are formed either by synthesis or environmental processes. However, the effect of halogenated bisphenols on steroidogenesis remains unclear. The aim of this study was to compare inhibition of 6 BPA derivatives on gonadal 3β-hydroxysteroid dehydrogenases (3β-HSDs) in three species (human, rat, and mouse). The inhibition on human 3β-HSD2 was tetrabromo BPA (TBBPA, IC50, 1.01 μM)>trichloro BPA (TrCBPA, 3.95 μM)>tetrachloro BPA (TCBPA, 4.14 μM)>monochloro BPA (MCBPA, 4.74 μM)>others with TrCBPA of competitive, TBBPA of noncompetitive and MCBPA/TCBPA of mixed inhibition. The inhibition on rat 3β-HSD1 was TCBPA (1.68 μM)>TrCBPA (1.72 μM)>MCBPA (2.80 μM)>BPA>others with mixed inhibition. The inhibition on mouse 3β-HSD6 was TrCBPA (1.59 μM) >MCBPA (3.36 μM)>TCBPA (3.72 μM)>others with mixed inhibition. Molecular docking analysis showed that TBBPA, TrCBPA, and TCBPA bind to steroid active sites, contacting with catalytic residue Tyr154 of human 3β-HSD2. MCBPA, TrCBPA, and TCBPA bind to steroid active site of rat 3β-HSD1. MCBPA and TrCBPA bind to active site of mouse 3β-HSD6. Regression of lowest binding energy values with Ki values revealed a significant negative linear regression (P < 0.05). In conclusion, halogenated BPA derivatives are more potent inhibitors of three 3β-HSDs than BPA and there is structure-dependent inhibition. SynopsisChlorinated bisphenol derivatives after water chlorination process and other halogenated bisphenols effectively inhibit human and rat 3β-HSD activity, thereby leading to steroid hormone deficiency.

Glutathione limits RUNX2 oxidation and degradation to regulate bone formation.

Reactive oxygen species (ROS) are natural products of mitochondrial oxidative metabolism and oxidative protein folding. ROS levels must be well controlled, since elevated ROS has been shown to have deleterious effects on osteoblasts. Moreover, excessive ROS is thought to underlie many of the skeletal phenotypes associated with aging and sex steroid deficiency in mice and humans. The mechanisms by which osteoblasts regulate ROS and how ROS inhibits osteoblasts are not well understood. Here, we demonstrate that de novo glutathione (GSH) biosynthesis is essential in neutralizing ROS and establish a proosteogenic reduction and oxidation reaction (REDOX) environment. Using a multifaceted approach, we demonstrate that reducing GSH biosynthesis led to acute degradation of RUNX2, impaired osteoblast differentiation, and reduced bone formation. Conversely, reducing ROS using catalase enhanced RUNX2 stability and promoted osteoblast differentiation and bone formation when GSH biosynthesis was limited. Highlighting the therapeutic implications of these findings, in utero antioxidant therapy stabilized RUNX2 and improved bone development in the Runx2+/- haplo-insufficient mouse model of human cleidocranial dysplasia. Thus, our data establish RUNX2 as a molecular sensor of the osteoblast REDOX environment and mechanistically clarify how ROS negatively impacts osteoblast differentiation and bone formation.

The Unique Relationship between Neuro-Critical Care and Critical Illness-Related Corticosteroid Insufficiency : Implications for Neurosurgeons in Neuro-Critical Care.

The brain houses vital hormonal regulatory structures such as the hypothalamus and pituitary gland, which may confer unique susceptibilities to critical illness-related corticosteroid insufficiency (CIRCI) in patients with neurological disorders. In addition, the frequent use of steroids for therapeutic purposes in various neurological conditions may lead to the development of steroid insufficiency. This abstract aims to highlight the significance of understanding these relationships in the context of patient care and management for physicians. Neurological disorders may predispose patients to CIRCI due to the role of the brain in hormonal regulation. Early recognition of CIRCI in the context of neurological diseases is essential to ensure prompt and appropriate intervention. Moreover, the frequent use of steroids for treating neurological conditions can contribute to the development of steroid insufficiency, further complicating the clinical picture. Physicians must be aware of these unique interactions and be prepared to evaluate and manage patients with CIRCI and steroid insufficiency in the context of neurological disorders. This includes timely diagnosis, appropriate steroid administration, and careful monitoring for potential adverse effects. A comprehensive understanding of the interplay between neurological disease, CIRCI, and steroid insufficiency is critical for optimizing patient care and outcomes in this complex patient population.

The Unique Relationship between Neuro-Critical Care and Critical Illness-Related Corticosteroid Insufficiency : Implications for Neurosurgeons in Neuro-Critical Care.

The brain houses vital hormonal regulatory structures such as the hypothalamus and pituitary gland, which may confer unique susceptibilities to critical illness-related corticosteroid insufficiency (CIRCI) in patients with neurological disorders. In addition, the frequent use of steroids for therapeutic purposes in various neurological conditions may lead to the development of steroid insufficiency. This abstract aims to highlight the significance of understanding these relationships in the context of patient care and management for physicians. Neurological disorders may predispose patients to CIRCI due to the role of the brain in hormonal regulation. Early recognition of CIRCI in the context of neurological diseases is essential to ensure prompt and appropriate intervention. Moreover, the frequent use of steroids for treating neurological conditions can contribute to the development of steroid insufficiency, further complicating the clinical picture. Physicians must be aware of these unique interactions and be prepared to evaluate and manage patients with CIRCI and steroid insufficiency in the context of neurological disorders. This includes timely diagnosis, appropriate steroid administration, and careful monitoring for potential adverse effects. A comprehensive understanding of the interplay between neurological disease, CIRCI, and steroid insufficiency is critical for optimizing patient care and outcomes in this complex patient population.

Is it feasible to treat painful hand osteoarthritis with menopausal hormonal treatment? Results from a randomised controlled trial (the HOPE-e study)

Background: Hand osteoarthritis (OA) is more common in females and relative risk increases around the menopause, implicating sex hormone deficiency. We ran a feasibility randomised controlled trial (RCT) of a form of MHT (conjugated estrogens (CE)-bazedoxifene) in post-menopausal women with painful hand OA.