DHEAS Levels Research Articles

LBMON231 Virilization Secondary To Androgen Producing Ovarian Serous Cystadenoma

Abstract Background Ovarian cystadenomas are classically considered as 'non-functional' tumors and among the most common benign ovarian neoplasms. Most of these tumors are asymptomatic and found incidentally on pelvic examination or with ultrasound. In rare circumstances these tumors may present as functional with secretions of excess androgens that subsequently produce virilizing features. Clinical Case A 59 year old Hispanic female G3P3(3003) presented to the clinic for receding hairline and facial hair for a duration of almost 2 years. Her medical history included total abdominal hysterectomy, due to fibroids, syphilis treated in Dominican Republic, Obesity, Vitamin D deficiency. On examination patient had hirsutism and significant hair growth on the abdomen, axilla, chest and extremities. The clitoris was enlarged, had frontal blading and increased abdominal circumference. Initial laboratory studies showed total testosterone was elevated [264 ng/mL] and free testosterone was high normal [4.2 pg/mL], DHEA-Sulfate normal [29.2 ug/mL], CA 125 unremarkable [5 U/mL]. Repeat labs were done showed elevated total testosterone and free testosterone [276 ng/mL and 4.7 pg/mL respectively] Normal levels of DHEA [87ng/dL] and DHEA-sulfate [ug/mL], 17-Hydroxyprogesterone [64 ng/mL], FSH normal [41.7 IU/L], LH normal [26.6 IU/L], morning cortisol level was normal [ 7.1 ug/mL] and a normal response to 1 mg dexamethasone suppression test. Transvaginal/Transabdominal ultrasound showed a left adnexa of 11.7×5.5×8.3 cm and simple cystic mass with no internal septations or nodularity and unremarkable right adnexa. Imaging by CAT scan showed a 9 cm left adnexal mass likely cystadenoma with unremarkable liver, spleen, pancreas and adrenals. Considering the laboratory, imaging findings and onset of symptoms the androgen production favors left adnexal cyst as the origin and not from the adrenals. Patient then underwent bilateral salphingoophorectomy without any complications and pathology reports revealed left serous cystadenoma. During her 2 week and 3 month post op follow up, patient reports no improvement of her hirsutism and virilization while repeat labs postoperatively showed normalization of total [15 ng/mL] and free testosterone [1.5 ng/mL]. Conclusion In conclusion, we report a rare case of androgen producing ovarian serous cystadenoma with virilizing features.

ODP408 Elevated DHEAS and Acute Hair Loss in an Adult Male with Trichorhinophalangeal Syndrome Type 1: a Case of Male PCOS

Abstract Background Male androgenic alopecia is a common cause of hair loss in both men and women. Although genetic and hormonal factors likely play a role, the etiology is mostly unknown. PCOS is a highly heritable disease with elevated prevalence of reproductive abnormalities in first-degree relatives (FDRs) of patients with PCOS, which may be due to an underlying genetic defect in steroidogenesis. A recent meta-analysis revealed that male FDRs of patients with PCOS had significantly increased levels of DHEAS compared with controls. We present a young adult male who developed acute hair loss with biochemical evidence of hyperandrogenism. Clinical Case A 21-year-old man presented for evaluation of hyperandrogenism after experiencing progressive loss of posterior patch of hair over 3 weeks. He also endorsed acne, intermittent headaches, striae, and difficulty losing weight for the past 2 years. He denied facial rounding, vision changes, and use of glucocorticoids or supplements. Physical examination was notable for height of 67 inches, BMI 30.5 mg/m 2, BP 120/78, recession of the frontotemporal and occipital hairline, sparse posterior scalp hair, bulbous nose, long philtrum, mild facial acne, 2, 3 toe syndactyly, and thin purple striae on bilateral flanks and axillae. Labs revealed elevated DHEAS 1065.7 mcg/dL (ref. 238.4-539.3) and normal 8 AM total testosterone of 382 ng/dL (240-871). Cosyntropin stimulation test revealed baseline cortisol level of 10.6 mcg/dL with ACTH of 22.2 pg/mL (5-46) and 60-minute cortisol level of 24.8 mcg/dL, 17-OH progesterone level 81 ng/dL (18-164), and 17-OH pregnenolone 1040 ng/dL (55-455). Workup for Cushing's revealed multiple normal midnight salivary cortisol levels and mild intermittent elevation of 24-hour urinary free cortisol levels. CT scan of the adrenals was negative for a mass. Exome sequencing revealed a heterozygous de novo pathogenic variant (c.1614_1615delTCinsAT: p. C538X) in the TRPS1 gene (NM_0141112.2). Family history was significant for a 20-year-old sister with PCOS and elevated DHEAS of 443 ug/dL (51-321). Mid-parental height was 69.6 inches. Conclusion Trichorhinophalangeal syndrome Type 1 (TRPS1) is a rare genetic disorder characterized by hair, craniofacial, and skeletal abnormalities such as androgenetic alopecia, bulbous nasal tip, and cone-shaped epiphyses. To our knowledge, the hair findings in TRPS are not associated with hyperandrogenism which prompted further investigation. Evaluation for endocrine causes of hyperandrogenism such as Cushing's disease, congenital adrenal hyperplasia, and adrenal tumor were negative. However, our patient's elevated DHEAS is likely due to male PCOS, as previously described in male FDRs of patients with PCOS. Thus, genetic susceptibility to PCOS and rare genetic syndromes should be considered in the differential diagnosis of young men with clinical and biochemical evidence of hyperandrogenism. Reference: Shan D et al. Reproductive Health in First-degree relatives of Patients with Polycystic Ovarian Syndrome: a Review and Meta-analysis. JCEM. 2022 Jan;107(1); 273-295. Presentation: No date and time listed

ODP056 The Treatment of Opioid Addiction Leading to Secondary Adrenal Insufficiency

Abstract Background As we continue to learn about the opioid crisis in America, more patients are seeking treatment for their opioid addictions. This treatment includes buprenorphine/naloxone, a partial opioid agonist and opioid antagonist. Though there is known evidence of opioid-induced secondary adrenal insufficiency, there is scarce data regarding the effect of buprenorphine/naloxone on the hypothalamic-pituitary-adrenal (HPA) axis. Here we describe a case of secondary adrenal insufficiency in a patient who is on long-term treatment for her opioid addiction with buprenorphine/naloxone. Clinical Case A 30 year old female with a past medical history of ADHD, OCD, PTSD, and menorrhagia presented with extreme fatigue, 100-pound weight gain, hair loss, and intermittent red flushing on hands and face over the past year. Labs showed low androstenedione (21 ng/dL, n 41 - 262 ng/dL), low testosterone (6.5 ng/dL, n 10. 0 - 55. 0 ng/dL) and low DHEA-S levels (55.6 ug/dL, n 84.8 - 378. 0 ug/dL). Further history revealed that the patient had been on Buprenorphine/Naloxone for 4 years for opioid addiction. Testing revealed a low morning cortisol level (5.6 ug/dL, n 6.2 - 19.4 ug/dL). The patient was started on hydrocortisone 10mg in the morning and 5mg in the afternoon with improvement of symptoms. Repeat testing after holding hydrocortisone revealed a cortisol level (6.6 n 6.2 - 19.4 ug/dL) and an inappropriately low-normal ACTH level (16 pg/mL, n 6 - 50 pg/mL). Cosyntropin stimulation test did not show an adequate response with a baseline cortisol level of 3.4 ug/dL, (n 5. 0 - 23. 0 ug/dL), 30 minute cortisol level of 6.9 ug/dL and 60 minute cortisol level of 8.2 ug/dL (n >18. 0 ug/dL). ACTH drawn at that time was low (<5 pg/mL n 6 - 50 pg/mL). Pituitary MRI was completed and findings were insignificant. Due to continued fatigue, the hydrocortisone dose was increased to 15mg in the morning and 5mg in the afternoon with improvement in symptoms with a plan to retest the adrenal axis as she continues to wean off the Buprenorphine/Naloxone. Conclusion This case calls attention to secondary adrenal insufficiency caused by the treatment of opioid addiction with buprenorphine/naloxone. Further investigation of adrenal insufficiency secondary to buprenorphine/naloxone use is warranted given the frequency of use of this combination to treat the ongoing opiate addiction crisis in America. Presentation: No date and time listed

PMON319 A Pure Androgen Secreting Adrenal - Cortical Tumor in a 13 Year Old Female

Abstract Background Adrenal cortical adenomas are exceedingly rare representing 0.2% of pediatric malignancies and often present with signs of Cushing syndrome, virilization and mixed elevated hormones.[1] We present a rare case of a virilizing androgen only secreting adrenal cortical adenoma with resolution after surgical removal. Clinical Case A 13-year-old female was referred to endocrine clinic for 1 year history of deep masculine voice, hirsutism and elevated DHEA-S levels. She also reported facial hair requiring removal every 3 to 4 days, back hair, acne, and dull aching back pain. Pubertal changes began at age 9 with breast development and menarche at age 11 followed by amenorrhea. On physical exam, she had a significantly deep masculine voice, axillary hair, female genitalia with prominent clitoris, Tanner Stage IV pubic hair and Stage III breast development. Blood pressure was within normal limits and weight was historically consistent in the 90th percentile. Initial labs were significant for elevated 17-Hydroxypregnenolone 353 ng/dL (ref: 44-235), Androstenedione LCMS 903 ng/dL (ref: 50-170), Testosterone 100 ng/dL (ref: 15-35), DHEA 5460 ng/dL (ref: <202) and DHEA-S >1000 ug/dL (ref: 67.8–328.6). LH, FSH, Estradiol, Cortisol LCMS, and Chromogranin A were within normal limits for her sex and age. Further work up ruled out pheochromocytoma, paraganglioma, Cushing's syndrome and congenital adrenal hyperplasia. Magnetic resonance imaging revealed a well-circumscribed 5.5×5.8×6.4 cm cystic and solid left adrenal mass and displacement of the left kidney. She was referred to endocrine oncology and surgery specialists. Genetic testing showed absence of TP53 involvement. Patient underwent open left adrenalectomy, and remained hospitalized for 3 days in recovery. The surgical pathology identified an adrenal cortical adenoma Stage II (pT2, pN0, cM0) measuring 8.7×6.0×3.3cm with slight increase of ki67 index at 3.7% (average 8044 nuclei counted) and hot spot with 4.6% (1266 nuclei counted). Follow up revealed resumption of regular periods, improvement in acne and male-pattern hair growth, and voice becoming less deep beginning 3 months post-operatively. DHEA-S returned to normal ranges at 220 ug/dL (ref: 67.8–328.6). Patient did well post-operatively except for occasional sharp back pain. Discussion Rare amongst adrenal tumors are isolated androgen-secreting sub types. To our knowledge, this is one of the first documented cases of a pure androgen secreting adrenal cortical tumor without symptoms of Cushing's syndrome in the pediatric population.

The clinical and laboratory features of patients with triple A syndrome: a single-center experience in Turkey.

Triple-A Syndrome (TAS) is a rare autosomal recessive disorder characterized by adrenal insufficiency, achalasia, and alacrimia. This disorder is caused by mutations in the AAAS gene. The aim of this study is to discuss the clinical, laboratory and molecular genetic analysis results of 12 patients with TAS. We evaluated 12 patients from 8 families. Clinical and laboratory data were retrospectively collected from the medical records of the patients in the database for the period 2015-2020. All exons and exon-intron junctions of the AAAS gene were evaluated by next-generation sequencing method. Detected variants were classified according to American Collage of Medical Genetics criteria. Alacrimia was found in all patients (100%); achalasia was found in 10 patients (83.3%) and adrenal insufficiency was found in 10 patients (83.3%). In addition, hyperreflexia(6/12), learning disability(5/12), hypernasal speech(5/12), muscle weakness(8/12), delayed walking(7/12), delayed speech(6/12), excessive sweating(7/12), optic atrophy(1/12), epilepsy(1/12), palmoplantar hyperkeratosis(5/12), multiple dental caries(9/12), atrophy of the thenar/hypothenar muscles(4/12) and short stature(4/12) were detected. The DHEA-S levels were measured in 10 patients and were found to be low in 8 of them. In all patients, the sodium and potassium levels were found to be normal. AAAS gene sequencing revealed four previously reported c.1066_1067del (p.Leu356fs*8), c.1432 C > T (p.Arg478*), c.688 C > T (p.Arg230*), and c.1368_1372del (p.Gln456fs*38) variants and two novel homozygous c.1250-1 G > A and c.398_399 + 2del variants in the AAAS gene. We detected two novel variants in the AAAS gene. While the classic triad is present in 66.7% of the cases, neurological dysfunction, skin and dental pathologies also occur quite frequently. The earliest and most common finding of TAS is alacrimia. Therefore, adrenal insufficiency should be investigated in all patients with alacrimia and if necessary, genetic analysis should be performed for TAS. In addition, TAS should be followed up with a multidisciplinary approach since it involves many systems.

Longitudinal evaluation of dehydroepiandrosterone (DHEA), its sulfated form and estradiol with cancer-related cognitive impairment in early-stage breast cancer patients receiving chemotherapy

The purpose of this study is to elucidate how patient-reported cognitive symptoms manifest from variations in hormone levels or precursors such as dehydroepiandrosterone (DHEA) and its sulfated form [collectively termed as DHEA(S)] and to investigate their association in breast cancer survivors. Levels of estradiol and DHEA(S) were compared between early-stage breast cancer patients with and without cancer-related cognitive impairment (CRCI) during adjuvant chemotherapy. Data were analyzed from 242 patients (mean age ± SD = 50.8 ± 9.2 years) who had completed FACT-Cog v.3.0, blood draws and questionnaires. Regression model was used to fit the magnitude of change in each respective biomarker levels against overall cognitive impairment status while adjusting for clinically important covariates. There was reduction in mean plasma levels of estradiol and DHEAS during and towards the end of chemotherapy (p-values < 0.001). Compared to non-impaired patients, smaller magnitude of decline was observed in DHEA(S) levels in patients reporting CRCI, with significant association between decline in DHEAS levels and acute onset of CRCI at 6 weeks from baseline (adjusted β of 0.40, p-value of 0.02). In contrast, patients reporting CRCI showed greater magnitude of decline in estradiol compared to non-impaired patients, although this was not found to be statistically significant. There was an association between magnitude of change in biomarker levels with self-reported CRCI which suggests that the hormonal pathway related to DHEAS may be implicated in acute CRCI for breast cancer survivors. Our findings help to improve biological understanding of the pathway from which DHEAS may correlate with cognitive dysfunction and its impact on cancer survivors.

Neighborhood walkability and sex steroid hormone levels in women

BackgroundNeighborhood walkability (NW) has been linked to increased physical activity, which in turn is associated with lower concentrations of sex hormones and higher concentration of SHBG in women. However, no study has directly examined the association of NW with female sex hormone levels. ObjectiveWe conducted a cross-sectional study to evaluate the association between NW and circulating levels of sex hormones and SHBG in pre- and post-menopausal women. MethodsWe included 797 premenopausal and 618 postmenopausal women from the New York University Women's Health Study (NYUWHS) who were healthy controls in previous nested case-control studies in which sex hormones (androstenedione, testosterone, DHEAS, estradiol and estrone) and SHBG had been measured in serum at enrollment. Baseline residential addresses were geo-coded and the Built Environment and Health Neighborhood Walkability Index (BEH-NWI) was calculated. Generalized Estimating Equations were used to assess the association between BEH-NWI and sex hormone and SHBG concentrations adjusting for individual- and neighborhood-level factors. ResultsIn premenopausal women, a one standard deviation (SD) increment in BEH-NWI was associated with a 3.5% (95% CI 0.9%–6.1%) lower DHEAS concentration. In postmenopausal women, a one SD increment in BEH-NWI was related to an 8.5% (95% CI 5.4%–11.5%) lower level of DHEAS, a 3.7% (95% CI 0.5%–6.8%) lower level of testosterone, a 1.8% (95% CI 0.5%–3.0%) lower level of estrone, and a 4.2% (95% CI 2.7%–5.7%) higher level of SHBG. However, the associations with respect to DHEAS and estrone became apparent only after adjusting for neighborhood-level variables. Sensitivity analyses using fixed effects meta-analysis and inverse probability weighting accounting for potential selection bias yielded similar results. ConclusionOur findings suggest that NW is associated with lower concentrations of androgens and estrone, and increased SHBG, in postmenopausal women, and lower levels of DHEAS in premenopausal women.

AN OVERVIEW OF DHEA-S LEVELS IN CHRONIC STRESS-PROSPECTIVE STUDY

Background: Increased stress levels are associated with various health issues due to the dysregulation of HPA axis, more so when the stress is chronic in nature.As the DHEA-S is a catabolic hormone the chronic stress levels may be involved with long term diseases like early ageing, hypertension, cancer and various other diseases Objectives: The aim of this study was to see the effect of perceived chronic stress in a subset of healthy population of male and female volunteers who willingly participated in the study. The selected male and female population was than stratified into age and stress matched groups and then one time DHEA-S levels were ascertained to see for changes in the DHEA-S values. Methods: DHEA-S levels were measured within 6 hours of collection of the Blood Samples, randomly collected at different time points in the day by Chemiluminescence method which was than statistically evaluated by using Mini Tab statistical tool. Results: There was no significant correlation in both genders when age and stress matched.

Editorial: The relationship between sarcopenia and metabolic diseases: Its formation mechanism and intervention means

hormone and DHEAS levels in elderly men. If the study is confirmed in a larger population, the results obtained may shift the paradigm of drug intervention strategy of sarcopenia [22] . The Ghrelin secret-promoting agent capromorelin increases weight and muscle mass in older adults and improves walking and stair climbing [23,24] . These data suggest that Ghrelin has a potential therapeutic effect on sarcopenia, but more prospective studies are needed to confirm it. Other drugs, such as metformin, anti-Myostain Activin ⅱ receptor, estrogen, and angiotensin converting enzyme inhibitors, are all being studied for intervention of sarcopenia [21] . Other potential targets include PGC-1A, phosphodiesterase inhibitors (PDE), skeletal muscle stem cells, and gene recombination [21,23,24] .In summary, the research on sarcopenia is still in its exploratory stage, and the pathogenesis of sarcopenia is not well understood. For future studies, it is necessary to enhance the efforts on elucidating the underlying cellular and molecular mechanisms, developing validate biomarkers, improving the accuracy of diagnostic tests, solving the problem of consistency of diagnostic criteria, and designing effective strategies for the prevention and treatment of sarcopenia. The editors thank all authors and reviewers for their scientific contributions.

Association between hair steroid hormone levels and cardiometabolic risk factors in a group of women participating in the national CVD prevention program: A cross-sectional study

Background and Aims : Cardiovascular disease (CVD) is the major cause of death worldwide. Although women develop CVD later than men, women’s morbidity and mortality from CVD are similar compared with men. Such a high prevalence of CVD cannot be explained completely by conventional risk factors. Recent studies indicate that chronic stress may be an independent CVD risk factor. Thus, we aimed to investigate the relationship between the biomarkers of chronic stress (hair cortisol, cortisone, DHEA levels) and traditional cardiovascular risk factors, as well as Systematic COronary Risk Evaluation (SCORE2) index, in a group of women (50-64 years) participating in the national CVD prevention program.

Assessment of DHEAS, cortisol, and DHEAS/cortisol ratio in patients with COVID-19: a pilot study.

PurposeDehydroepiandrosterone sulfate (DHEAS) is observed to be decreased in sepsis and inflammatory conditions. In the present study, we assessed the levels of DHEAS and cortisol and the DHEAS/cortisol ratio and their association with inflammatory markers in patients with COVID-19.MethodsThe study recruited 76 RT-PCR-positive COVID-19-positive patients and 79 healthy controls. The blood samples were collected and were analyzed for cortisol and DHEAS.ResultsWe observed decreased levels of DHEAS and DHEAS/cortisol ratio and increased levels of cortisol in cases when compared with controls. DHEAS and DHEAS/cortisol ratio showed a decreasing trend with the increase in disease severity.ConclusionThe present study is the first of its kind comparing DHEAS levels and DHEAS/cortisol ratio in COVID-19 patients and control subjects. DHEAS, with its inhibitory effect on IL6 and activation of Tregs, may play a crucial role in immune defense mechanisms against COVID-19.Supplementary InformationThe online version contains supplementary material available at 10.1007/s42000-022-00382-x.

Study of LHCGR gene variants in a sample of colombian women with polycystic ovarian syndrome: A pilot study

PurposeTo evaluate the association between polymorphisms of the LHCGR gene and PCOS in a sample from Colombian women. MethodsWe included 49 Colombian women with PCOS and 49 healthy women. Genotype distributions between groups were compared, and phenotype-genotype association analysis was performed in the PCOS group. Identification of five SNP’s in the LHCGR gene was carried out through the iPLEX and MassARRAY system (Agena Bioscience). ResultsOur results showed that the rs7371084 variant was negatively associated with PCOS under the codominant, dominant, and overdominant models. Women with the TC + TT genotypes in rs2293275 had shorter menstrual cycles (p = 0.026), and women with the CT + CC genotypes in rs6732721 showed a decrease in the number of antral follicles (p = 0.038).Within the endocrine parameters, we identified associations between GA + GG genotypes in rs13405728 and CT + CC genotypes in rs6732721, and the decrease in LH levels (p = 0.013; p = 0.04, respectively). Women with TC + TT genotypes in rs2293275 had increased DHEAS (p = 0.047) and androstenedione (p = 0.045) levels. Regarding metabolic parameters, we identified associations between GA + GG genotypes in rs13405728 and CT + CC genotypes in rs6732721, and an increase in fasting glucose levels (p = 0.028; p = 0.017, respectively). ConclusionWe found that the rs7371084 variant was negatively associated with PCOS. Also, we identify associations between combined genotypes of the LHCGR gene and the phenotypic traits of PCOS, such as shorter menstrual cycle length, fewer follicles, lower LH levels, and increased DHEAS, androstenedione, and fasting glucose levels. The results of this pilot study provide a basis to clarify the genetics and pathophysiology of PCOS in the Colombian population. Future large-scale studies are recommended for this population.

O-244 Androgen levels and their predictive value in women with different ovarian responses

Abstract Study question Do androgen levels impact oocyte yield during ovarian stimulation and how predictive are they for distinct ovarian response? Summary answer Testosterone positively correlates with the number of oocytes retrieved in all patients. DHEA-S appears more specific by only correlating significantly in poor responding women. What is known already Androgens are involved in the initiation of primordial follicle recruitment and early development. Testosterone and DHEA-S increase the number of growing follicles by reducing follicular atresia. A reduction in androgen levels can be observed with diminished ovarian reserve and advanced age. To standardize the definition of POR Bologna criteria have been elaborated including age, laboratory or sonographic ovarian reserve and low ovarian response in previous stimulations. The mentioned markers have been reviewed concerning its predictive power for POR by the POSEIDON analysis and divided into four subgroups. To date androgen levels are not raised to stratify POR in these classifications. Study design, size, duration All women were recruited in the division for reproductive medicine at the University Hospital Heidelberg. The patients’ files were retrospectively analyzed for androgen levels before ovarian stimulation and outcome. A classification between poor and normal response was performed according to Bologna criteria. Participants/materials, setting, methods All patients provided written informed consent. Blood samples were analyzed from serum drawn on day 2 to 5 of the menstrual cycle before ovarian stimulation. Statistical analysis was performed with SPSS; statistical significance was set to p &amp;lt; = 0.05. Main results and the role of chance Valid data for analysis was available in 335 cycles, 238 were scaled in normal (NOR), 97 in poor ovarian response (POR). Statistics in both subgroups were performed concerning age, AMH, count of retrieved oocytes, DHEA-S and testosterone with significant lower AMH as well as androgen levels, oocyte yields and a higher median age in the POR group. An expected significant positive correlation between AMH and retrieved oocytes was confirmed in both subgroups (p=.000 and .004). Increasing age negatively correlates with the number of retrieved oocytes after ovarian stimulation in NOR (p=.003), but not in POR (p=.441) patients suggesting age as less powerful predictive marker for oocyte yield in those patients. In addition, a positive correlation for testosterone and retrieved oocytes merely reached significance in all analyzed cycles independently of different ovarian responses. On the contrary DHEA-S levels and oocyte counts cohered with a marginal significance (p=.05) only in POR patient cycles. Serum levels for DHEA-S positively correlated with the variable “oocyte count ≥ 3” in the POR group (OR 1.006, 95% CI, 0.999- 1.014 Limitations, reasons for caution The results are based on a limited sample size. Therefore, results need to be proven in further studies including further aspects affecting ovarian response. Wider implications of the findings The significant correlation between pre-stimulatory DHEA-S levels in POR for oocyte yield on the contrary to NOR, supports the experimental supplementation with DHEA in this subgroup, aiming to improve outcomes during ovarian stimulation. Testosterone is less specific for estimating ovarian response in both subgroups. Trial registration number n.A.

P-681 Balance of Estrogen:Androgen ratio (Estradiol E2: Dehydroepiandrosterone-sulphate DHEAS) and its symbiotic correlationship with Vascular-Endothelial Growth-Factor (VEGF) critically foments implantation and pregnancy outcomes in IVF cycles

Abstract Study question Is the estrogen/androgen balance vital for implantation and does this E2:DHEAS ratio coordinate with neoangiogenesis/neovascularisation (VEGF) to facilitate establishment of viable pregnancy in IVF cycles? Summary answer The Estradiol E2:DHEAS ratio independently as well as in symbiotic correlationship with VEGF is strongly predictive of invasive implantation and pregnancy outcomes in IVF cycles What is known already Decidualization of endometrial stroma and vascularization at feto-maternal interface is necessary for implantation. Estrogen Estradiol E2 is among the factors widely known to regulate these processes. Androgen Dehydroepiandrosterone (DHEA) is the designated primary precursor for natural estrogens. DHEA-induced PCOS mice have demonstrated adverse impacts on Embryo implantation and decidualization. However, role of DHEA/S in human implantation has not yet been explored. Vascular-Endothelial growth-factor (VEGF) is known to influence vascularization, angiogenesis, endometrial receptivity. Higher VEGF expression in endometrium is associated with pregnancy. However endometrial-biopsy for VEGF estimation is an invasive method for implantation studies and cannot be applied to ongoing cycles. Study design, size, duration Prospective study of n = 235 (Power of study&amp;gt;85%) non-PCOS, normal-responder infertile females (mean age 31.77±2.42 years, BMI 24.4±4.1, W/H ratio 0.82±0.07) undergoing fresh IVF treatment cycles using standard antagonist stimulation protocol at our fertility clinic during January 2019-December 2020. Elderly women (age&amp;gt;35 years), women with polycystic-ovaries, endometriosis and frozen-thawed cycles were excluded.7 cycles were cancelled owing to no embryo transfer (ET). Day3-cleavage stage or day5-blastocyst stage embryos were transferred (n = 228). Luteal-phase was supported with Micronized progesterone. Participants/materials, setting, methods Serum levels of Estradiol E2 and DHEAS were measured by Radio-Immunoassay and VEGF estimation by ELISA on day ET, day7, day14 post ET. Cycles were divided into Pregnant (P:n=73) and Non-Pregnant (NP=n=155) groups. Main outcome measures: Clinical Pregnancy (CPR:n=70=30.70%), Live-Birth (LBR:28.94%) rates. Secondary outcome measures: Biochemical-pregnancy (BCP:n=3=1.31%), Early-Miscarriage (EM:n=4=1.75%) rates. Pregnant=Serum βhCG&amp;gt;50 on d14ET. BCP=No exponential rise/tapering βhCG levels post d14ET, CP=positive cardiac activity at 6-8 weeks gestation, EM=non-viable intra-uterine pregnancy upto 12 weeks gestation. Main results and the role of chance dET: E2 did not differ significantly (780±50 vs. 750±30 pg/ml;p=0.61) whereas DHEAS = (212±11 vs. 170±6 ng/dL;p=0.0005), E2:DHEAS = (3.72±0.13 vs. 4.65±0.17;p=0.0011), VEGF = (658±20 vs. 495±16;p&amp;lt;0.0001) differed significantly between P vs. NP groups; indicating importance of E2/DHEAS ratio. D7ET: E2 = (790±57 vs. 222±19;p&amp;lt;0.0001), DHEAS = (381±28 vs. 1262±70;p&amp;lt;0.0001), E2:DHEAS = (2.37±0.25 vs. 0.30±0.029;p&amp;lt;0.0001), VEGF = (636±23.61 vs. 480±10.13;p&amp;lt;0.0001) displayed statistically robust differences between P vs. NP groups. d14ET: E2 = (855±73.45 vs. 193.2±13.31;p&amp;lt;0.0001), VEGF = (544.2±15.80 vs. 452.3±16.77;p=0.0011) displayed statistically robust differences between P vs. NP groups. Interestingly, although DHEAS = (685±41.05 vs. 806±55.37;p=0.18) did not differ significantly, E2:DHEAS = (1.643±0.26 vs. 0.45±0.048;p&amp;lt;0.0001) showed highly significant difference; again highlighting importance of E2/DHEAS balance. Ratio E2:DHEAS on d7ET correlated strongly with d7VEGF (Pearson r = 0.31,p&amp;lt;0.0001). ROC curve for d7 E2:DHEAS had AUC 78%, p &amp;lt; 0.0001 Hormone values and their rising trends (d/ET to d7/ET to d14/ET) varied with pregnancy outcome status E2= LB:(d/ET:780±50 to d7/ET:790±57 to d14/ET:855±73.45) vs. BCP:(d/ET:723.3±157.6 to d7/ET:743.3±159 to d14/ET:770±153) vs. EM:(d/ET:906.3±104 to d7/ET:1150±113 to d14/ET:1758±127) DHEAS= LB:(d/ET:212±11 to d7/ET:381±28 to d14/ET:685±41.05) vs. BCP:(d/ET:248.3±55 to d7/ET:266.7±71.2 to d14/ET:400±120.3) vs. EM:(d/ET:243.8±27 to d7/ET:303.8±11.43 to d14/ET:391.3±49) E2:DHEAS= LB:(d/ET:3.72±0.13 to d7/ET:2.37±0.25 to d14/ET:1.643±0.26) vs. BCP:(d/ET:2.93±0.15 to d7/ET:2.97±0.4 to d14/ET:2.12±0.32) vs. EM:(d/ET:3.78±0.40 to d7/ET:3.77±0.26 to d14/ET:4.68±0.59) Decreasing E2:DHEAS ratio (d/ET-d7/ET-d14/ET) is vital for successful implantation/Live-birth VEGF= LB:(d/ET:658±20 to d7/ET:636±23.61 to d14/ET:544.2±15.80) vs. BCP:(d/ET:513.3±37.56 to d7/ET:628.3±40.45 to d14/ET:468.3±35.63) vs. EM:(d/ET:647.5±78.8 to d7/ET:887.5±60 to d14/ET:1138±94.4) Limitations, reasons for caution This study is limited by small sample size and is not a randomized controlled trial. We have taken only representative molecules into consideration. There is a plethora of factors involved during the implantation process. Multi-centric systematic studies are needed to corroborate these findings and account for the probable confounding factors. Wider implications of the findings This novel study explores and highlights significance of maintenance of a critical estrogen/androgen ratio (E2:DHEAS), rather than individual estrogen or androgen markers, in the implantation process. We have also underscored how this ratio coordinates symbiotically with VEGF as a critical non-invasive determinant of implantation and pregnancy-outcomes in ongoing IVF cycles. Trial registration number Not Applicable

P-652 Contribution of the D19S884 allele 8 of the FBN3 gene and the Hippo signaling to the reproductive and metabolic phenotype of PCOS patients

Abstract Study question Does exist a correlation between the presence of D19S884 allele 8 (A8) and Hippo pathway dysregulation with the metabolic and ovarian PCOS profiles? Summary answer The presence of the A8 allele affects insulin resistance and hyperandrogenism. Moreover, PCOS ovarian phenotype could be related to a dysregulation of Hippo pathway genes. What is known already The specific D19S884 A8 allele of the FBN3 gene has been associated with an increased probability of polycystic ovarian syndrome (PCOS). D19S884 participates in FBN3 alternative splicing and produces Asprosin-3 and Fibrilin-3 proteins that may be related to PCOS clinical manifestations. Asprosin-3 has been recently identified as a glucose modulator and could be related to metabolic profiles of PCOS. Fibrilin-3 is an extracellular matrix protein, and together with a dysregulation of the Hippo pathway, could be responsible for constraining follicular growth in the PCOS ovaries. Study design, size, duration Descriptive and cross-sectional study with 93 women (25-37 years old) undergoing an IVF cycle between 2019 and 2021 at Hospital la Fe (Valencia, Spain). Thirty patients were considered PCOS while the remaining sixty-three were non-PCOS controls. After recruitment women were screened for A8 allele, metabolic status, hormone profile and Hippo pathway genes. The IVF cycle parameters were recorded to determine their relationship with study variables. Participants/materials, setting, methods Patients with two or more Rotterdam-criteria or with polycystic ovarian morphology (PCOM) were considered as PCOS. After signed informed consent, blood samples and cumulus cells were obtained at egg retrieval. Hormone and metabolic parameters were analyzed and the homeostasis model assessment of insulin resistance (HOMA-IR) established. Genomic DNA was isolated to assess the presence of A8 allele by capillary electrophoresis. The expression of Hippo pathway genes, BIRC1 and CCN2, was analyzed by Taqman qPCR assay. Main results and the role of chance PCOS patients showed increased body mass index (Control:23.2±3.7; PCOS:25.3±4.5, p = 0.04) antimüllerian hormone levels (Control:17.7±7.7pmol/L; PCOS:39.7±22.9pmol/L, p = 0.00), antral follicle count (Control:15±7; PCOS:27±13, p = 0.001) and a reduced number of good quality embryos (Control:1.3±0.9; PCOS:0.8±1.0, p = 0.02). The A8 allele was detected in 15% of the recruited patients, with a 13% incidence in controls and 19% in PCOS. Interestingly, PCOS A8+ patients presented the PCOM phenotype. Women with the A8 allele (A8+) showed higher DHEAS levels (A8-:1899.7±1256.9; A8+:2642.5±555.2, p = 0.046) and free androgen index (A8-:1.1±0.8; A8+:2.0±1.2, p = 0.046) when compared to A8- ones. Similar results were obtained when the comparison was made according to clinical diagnose (Control A8+ vs. Control A8- and PCOS A8+ vs PCOS A8-). Moreover, the overall A8+ patients associated an increase in glucose levels (A8-:85.7±10.9mg/dL; A8+:93.0±6.01mg/dL, p = 0.02) and HOMA-IR (A8-:1.7±1.1; A8+:2.5±1.2). These metabolic findings were observed in control women with the allele but not in PCOS. The PCOS group showed a downregulation of CCN2 (Fold-change (FC): -3.8±9.1, p = 0.02) in cumulus cells. Interestingly, those women with the A8 allele showed downregulated BIRC1 levels (FC A8+: -2.7±4.8 and A8-: 0.2±2.7; p = 0.04). These gene dysregulations could be related with a deficient oocyte-cumulus communication, abnormal follicular growth and an ovarian stroma stiffness alteration. Limitations, reasons for caution These promising results need to be confirmed in a larger population of PCOS to allow validation of the observed effects according to PCOS sub-phenotypes. Moreover, transcriptomic analysis and functional enrichment assays should be carried out to clarify the contribution of Hippo pathway and A8 allele to PCOS pathogenesis. Wider implications of the findings The obtained results suggest that the presence of the A8 allele influences the metabolic profile related to insulin resistance and androgen levels, as well as the activation status of Hippo pathway. Moreover, this signaling pathway seems to be dysregulated in PCOS patients, suggesting its possible role in the ovarian phenotype. Trial registration number Not applicable

PLASMA STEROID PROFILE IN WOMEN WITH FIBROMUSCULAR DYSPLASIA - THE ARCADIA-GYN STUDY

Objective: Fibromuscular dysplasia(FMD) mostly affects women in reproductive age. It has been suggested that FMD might be related to female hormone levels or contraceptive use. Therefore, the aim of the ARCADIA-POL substudy ARCADIA-GYN was to perform detailed, prospective obstetrics and gynaecological evaluation of women with FMD. Design and method: We enrolled in the ARCADIA-GYN study 42 women with FMD, ages between 18–46 years old and 45 age-matched healthy, normotensive women who have regular menstruation. By means of LC-MS/MS we analysed plasma steroid profile: estrogen, progesterone, testosterone, aldosterone, cortisol, 18-oxo-cortisol, 18-hydrocortisol, cortisone, 11-deoxycortisol, 21-deoxycortisol, corticosterone, 11-deoxycortisone, progesterone, 17-OH progesterone, pregnenolone, androstenedione, DHEA, DHEA-SO4. Blood samples in all subjects were collected in luteal phase while women stayed without any hormonal contraceptive. FMD was diagnosed based on ARCADIA-POL protocol as published previously. No signs of arterial lesions and/or disturbances in blood flow were found in Doppler duplex evaluations of carotid and renal arteries in control subjects. Results: 42 patients with FMD (34.2 ± 8.1years), predominantly with renal FMD, were compared to 45 healthy, normotensive women (34.0 ± 5.4years; p = 0.88). Hypertension was diagnosed in 88.1% (37) women with FMD. In women with FMD we found lower plasma levels of progesterone (5.1 inter quartile range [IQR] 2.0–8.2 vs 7.6 IQR 3.3–12.5ng/ml;p = 0.017),testosterone (0.20 IQR 0.15–0.28 vs 0.25 IQR 0.18–0.36ng/ml; p = 0.036), DHEA (3.6 IQR 2.6–4.3 vs 4.5 IQR 2.9–6.6ng/ml;p = 0.012), DHEAS04 (1167 IQR 819–1535 vs 1579 IQR 1197–1980ng/ml;p = 0.04) and 11-deoxycortisol (0.09 IQR 0.05–0.12 vs 0.14 IQR 0.09–0.18ng/ml;p = 0.002) as compared to control group. There were no significant differences in other analyzed hormones. There were no differences in steroid profile evaluations between patients with unifocal and multifocal FMD. Conclusions: Women with FMD as compared to healthy controls are characterized by hormonal alterations including lower plasma progesterone level. Taking into consideration previous findings of abnormal balance between estrogen and progesterone receptors in renal artery samples of FMD our results suggest that female hormonal disturbances may have a role in FMD development.

ORAL OVULOGENS IN CURRENT SCENERIO

Objectives:- Oral ovulogens are the most commonly used intervention in a subfertile couple. A reproductive endocrinologist or infertility specialist commonly performs ovulation induction. Infertility affects up to 15% of couples in their reproductive years around the world. The overall prevalence of primary infertility in India is estimated to be between 3.9 and 16.8%, according to the World Health Organization. Infertility rates vary by state in India, ranging from 3.7 percent in Uttar Pradesh, Himachal Pradesh, and Maharashtra to 5% in Andhra Pradesh and 15% in Kashmir, and incidence differs by tribe and caste within the same region. Anovulation, polycystic ovarian syndrome (PCOS), thyroid disorders (both hyperactive and underactive thyroid glands can inhibit ovulation), and premature ovarian failure are the most common causes of infertility in females. Overall, the prevalence of anovulatory cycles ranged from 3.4 percent to 18.6 percent.Anovulatory infertility is caused by polycystic ovarian syndrome in 80 percent of patients. Its an endocrine and reproductive condition that affects 0.6-3.4 percent of infertile couples. Subclinical hypothyroidism (SCH), 0.2–4.5 percent for overt hypothyroidism (OH), 0.3–1 percent for hyperthyroidism, and 5–10 percent for thyroid autoimmunity are the most common thyroid disorders in women aged 20–45 years. Premature ovarian failure affects 1 to 5.5 percent of women. The most often used medications for ovulation induction are oral ovulogens like Clomiphene citrate, third generation aromatase inhibitors like letrozole and anastrozole, and selective oestrogen receptor modulators like tamoxifen. Trials have been undertaken in women with anovulatory PCOS to examine if clomiphene citrate and metformin benefit from one another. Metformin has been used as an adjuvant to treat polycystic ovarian syndrome for a long time (PCOS). Sitagliptin has recently been shown to improve ovarian cycles and ovulation in PCOS patients. Both have ovulation rates of 70-80% and a pregnancy rate of 20-25 percent per cycle. Dexamethasone is a fertility supplement that helps with raised DHEAS androgen levels and is a highly successful adjuvant to clomiphene citrate in women with PCOS. Methods:- This systematic review comprises of articles from pubmed, cohrane, google scholar, medline. Results:.- A total of 20 articles from 2016 to 2021 were included .Infertility causes modification at both endocrine and immune system at both cellular and tissue level. Conclusion:- Clomiphene citrate plays an important role in mildly stimulating infertile patients because it has the property of preventing premature LH surges. Aromatase inhibitors such as letrozole and anastrozole have also had limited success in the use of IVF. Tamoxifen may be an option for clomiphene citrate in some patients who do not ovulate or become pregnant due to its beneficial effects on cervical mucus and endometrium. Recently, sitagliptin has been reported to improve the ovarian cycle and ovulation of PCOS. Dexamethasone is an additional drug for infertility and is beneficial for elevated DHEAS and androgen levels. This review describes the science behind anovulation and treatment guidelines for promoting follicle recruitment and ovulation using multiple oral ovulogens.

The effect of oral contraceptive use on sympatic nerve activity in patients with polycystic ovary syndrome

Objective High sympathetic nerve activity, is thought to be a cardiovascular risk factor, has been shown to correlate with circulating high testosterone levels. However its role on the pathophysiology of the polycystic ovarian syndrome has not been clearly established. The aim of our study is to compare the sympathetic nerve activity between polycystic ovarian syndrome and control group and to determine whether the use of oral contraceptives for contraception has any effect on this activity. Materials and methods Our study has designed as a prospective, case–control study including patients diagnosed with polycystic ovarian syndrome. Antropometric measurements were calculated, hormone levels were measured and sympathetic skin response and heart rate variability measurements were performed in the laboratory to assess sympathetic activity before starting oral contraceptive pill therapy and at the end of 1 month follow up. Results In the baseline condition LH/FSH ratio, LH, DHEAS, and total testosterone levels were significantly higher in women with PCOS. After 1 month of treatment, reductions in Ferriman–Gallwey score, ovarian volumes, number of follicles, LH/FSH ratio, LH, and androgen hormone levels were statistically significant. The mean values of sympathetic skin response amplitude and R–R analysis-Valsalva test were higher in PCOS group as compared to the control group. However, these differences were not statistically significant. Similarly, no statistically significant difference in SSR latency and R–R analysis-standup test were demonstrated between PCOS and control groups. Conclusion In conclusion, our study supports the increased sympatovagal activity in patients with polycystic ovarian syndrome.

Assessment of salivary cortisol and dehydroepiandrosterone as oral biomarkers to assess stress in patients with recurrent aphthous stomatitis

Background: Recurrent aphthous stomatitis is a chronic inflammatory disease characterized by recurrent bouts of one or several shallow, rounded or ovoid, painful ulcers of oral mucosa that recur at intervals of a few days or up to 2–3 months and is of unknown etiology. The present study evaluated salivary cortisol and dehydroepiandrosterone as oral biomarkers to assess stress in patients with recurrent aphthous stomatitis (RAS). Materials &amp; Methods: 84 patients of recurrent aphthous stomatitis (RAS) were randomly divided into 2 groups of 41 each. Group I were RAS patients and group II were healthy control subjects. In all salivary cortisol and DHEA levels were measured. Results: DHEA levels 48–61 pg/ml was seen in 44% in group I and 10% in group II, &lt;48 pg/ml in 24% in group I and 86% in group II, &gt;61 pg/ml was seen in 32% in group I and 4% in group II. Salivary cortisol level &gt;3 ng/ml was seen in 83% in group I and 28% in group II and between 1.2–3 ng/mL in 15% in group I and 74% in group II. Conclusion: RAS patients exhibited higher salivary cortisol and DHEA levels as compared to the healthy controls.

Is there a correlation between heart rate recovery and androgen parameters in polycystic ovary syndrome? Heart rate recovery in polycystic ovary syndrome

Objectives: In our preliminary study, we assessed heart rate recovery (HRR) in patients with polycystic ovary syndrome (PCOS) and controls by subjecting them to moderate exercise and estimating androgen levels, and examined the correlation between HRR and androgen levels. Methods: 30 newly diagnosed cases of PCOS and 30 controls with comparable anthropometric measurements performed isotonic moderate exercise. Serum testosterone and DHEAS levels were measured. The HRR was calculated as the difference between the maximum heart rate and the 1st, 5th and 10th minute after the end of the exercise. Results: Heart rate recovery at 1 minute (p=0.001) and 5 minutes, (p=0.002) was significantly impaired in PCOS patients. Testosterone (p=0.100) and DHEAS (p=0.061) were elevated in PCOS patients compared to normal controls, although this was not statistically significant. A positive correlation was observed between HRR and androgen levels (testosterone: r=0.318; p=0.08, DHEAS: r=0.064; p=0.07). Conclusion: Decreased cardiovascular fitness and increased androgen levels have been observed in PCOS patients. Impaired HRR, reflecting sympathetic overactivity, has also been observed in newly diagnosed cases of PCOS. We therefore suggest that HRR is an accurate and sensitive marker to detect early signs of cardiovascular impairment and enables timely measures to avoid further morbidity.