bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors Impacting Quality of Life in Patients With Klinefelter Syndrome: A Systematic Review with Narrative Synthesis and Meta-Analysis
Authors: Mehmet Brien , Llahana Sofia V 
Published: May 2021

Abstract
Objective: To identify how Klinefelter’s Syndrome affects patients’ quality of life (QoL) and to determine which subsections of QoL are affected guided by the WHOQOL100-tool as an overarching framework for QoL. To determine the effects and impact KS has on patients’ QoL when compared to the QoL of healthy controls and general population. DESIGN - Systematic review of studies reporting QoL factors among patients with KS which included narrative synthesis and thematic analysis of 17 studies and a meta-analysis of intelligence quotient (IQ) completed in 7 studies. QoL factors were reviewed based on the parameters of the WHOQOL-100: physical health, psychological, level of independence, social relations, environment, and religion/spirituality/personal beliefs. DATA SOURCES - Medline, Cochrane, Embase, Psychinfo, CINAHL, BASE and grey search from the reference lists of key publications. Eligibility Criteria: RCT’s, Cohort studies, cross sectional studies and Epidemiology studies involving patients with KS and reporting on QoL parameters. Only human studies published in English were considered with no limits for publication date. Results: Out of all studies included (n=1266), (87.5%) had suggested KS negatively affected the outcomes measures tested, where recorded (91.1%) of studies had small/medium/large effect sizes (Cohen’s d). Narrative synthesis suggests all subgroups of QoL excluding ‘environment’ and ‘spirituality/faith/personal beliefs’ were negatively impacted for patients with KS, whilst meta-analysis showed statistical significance (P &lt;0.00001) which identified patients with KS having lower full-scale IQ compared to healthy controls. Psychological parameters were the most affected in this patient group, showing that patients with KS experienced greater social anxiety, distress during social interactions, self-esteem, self-injuries behaviours and symptoms or traits related to Autism spectrum. Conclusions: This review identifies the significant evidence supporting that QoL is reduced in patients with KS. There is a large spectrum of symptoms and no standard phenotype for KS suggesting that multiple facets of QoL are negatively impacted in these patients due to the complex nature of KS and the severity of symptoms and phenotype associated with KS. PROSPERO REGISTRATION NUMBER - CRD4202017343
Exploring NCX4040, an Aspirin Derivative, as a Potential Treatment for Benign Prostatic Hyperplasia
Authors: Shahagadkar Preksha Vaibhav , Munirathinam Gnanasekar 
Published: May 2021

Abstract
Benign Prostatic hyperplasia (BPH) is a leading cause of lower urinary tract symptoms which affects men above 50 years of age. Chronic inflammation and abnormal proliferation of stromal and epithelial cells are implicated in BPH disease onset. The symptoms of BPH include back pain and difficulty in emptying bladder. Finasteride, sildenafil and tamsulosin are some of the drugs used to ease difficulty urinating and relax the muscles of the gland. Transurethral resection of the prostate or laser surgery can be performed to treat severe symptoms. However, these therapies have deleterious effects such as low blood pressure, ejaculatory dysfunction, and lump formation. Hence, there is an unmet need for potential drugs against BPH. Nonsteroidal anti-inflammatory drugs (NSAIDs) have proven to be effective in cancers but their applicability in BPH condition is yet to be fully explored. Aspirin, one of the NDSAIDs, has anti-tumor and anti-inflammatory properties at higher doses. NCX4040, a nitric oxide releasing derivative of aspirin, could prove to be effective against BPH, since it can inhibit abnormal cell proliferation and serve as a vasodilator. We hypothesize that NCX4040 would be an effective drug to treat BPH. BPH-1 epithelial and WPMY-1 stromal cells were used as in vitro models of BPH. MTT assay was performed to check the inhibitory effect of NCX4040 and blocking agents like catalase and N-acetyl-L-cysteine (NAC) were explored on cells after treatment. Clonogenic assay was done to explore the colony formation ability of cells. Spheroid assay was performed to analyze the anti-proliferative effect of NCX4040. Annexin V/PI and cell cycle analysis was performed to check for apoptosis and cell cycle arrest in the cells. Western blot was done to assess the signaling molecules altered by NCX4040 in BPH-1 cells. Confocal immunofluorescence was employed to analyze the dynamics of actin filaments after treatment in cells. Our studies revealed that NCX4040 inhibited the cell viability of BPH-1 and WPMY-1 in a dose dependent manner with IC50 predicted at 5µM and 2.5µM respectively. Of note, catalase and NAC blocked the effect of NCX4040 on prostate cells. Colony formation assay result implied a gradual decrease in the number of colonies of cells treated with NCX4040 with 2.5µM and 5µM doses. Spheroid assay in BPH-1 cells showed inhibitory effects after treatment. Cell cycle analysis by flowcytometry inferred that cell cycle arrest at G2/M phase and annexin V analysis indicated that activation of apoptosis in cells following treatment. Phalloidin staining showed decrease in the actin filament intensity in cells. At the molecular level, NCX4040 downregulated the expression of key markers such as RhoA, p65, COX-2, PCNA, Cyclin D3, and PDE-5 in BPH-1 cells. Taken together, NCX4040 could be used as a potential agent to manage BPH with minimal side effects, which needs further evaluation in animal models.
Fadrozole-Mediated Sex Reversal Induces PAX2+Undifferentiated Supporting Cells in Female Chicken Gonads
Authors: Estermann Martin Andres , Smith Craig Allen 
Published: May 2021

Abstract
During early embryogenesis, the undifferentiated gonad is bipotential and subsequently commits to an ovarian or testicular fate. In birds, double dose of the Z-linked gene DMRT1 is required for testicular differentiation in male embryos (genetically ZZ). In female birds, estrogen plays a key role in ovarian differentiation. 17β-estradiol (E2) induces gonadal feminization when applied to male embryos (ZZ). Conversely, inhibition of estrogen synthesis with the drug fadrozole (FAD) results in testicular development in genetically female embryos (ZW). However, activation of male markers in sex-reversed ZW embryos is typically delayed, raising the possibility that FAD-treated embryos may transition through an undifferentiated state before masculinization. Recently, PAX2 was identified as a marker of undifferentiated supporting cells in the chicken embryo, being downregulated in both sexes at the onset of gonadal sex determination. To investigate the supporting cell differentiation process in estrogen-mediated sex reversal, we injected 1 mg of fadrozole in 100µl of PBS or vehicle into embryonic day 3.5 (E3.5) chicken eggs. Eggs were incubated until E9.5, genotypically sexed (ZZ or ZW) and processed for qRT-PCR and immunofluorescence. Quantitative RT-PCR confirmed that sex reversal had occurred in FAD-treated females, showing a reduction of pre-granulosa cell markers aromatase (P&lt;0.005) and FOXL2 (P&lt;0.05), compared to the control. Interestingly, PAX2 mRNA expression was up-regulated (P&lt;0.05) in sex-reversed females, suggesting an increase in undifferentiated supporting cells (n=6). To confirm this observation, immunofluorescence was used to detect aromatase, SOX9 (male marker) and PAX2. In FAD-treated females, both SOX9+ (male) and aromatase+ (female) cells co-existed in the same gonad, but in separated defined regions. Aromatase positive cells were located in the most apical region of the gonad whereas SOX9 positive cells were detected in the basal region. We detected an increase in PAX2 positive cells in the gonadal medulla between the SOX9 and aromatase positive supporting cells. No SOX9 or PAX2 positive cells were detected in control female gonads (n=3). For feminization experiments 100µl of a 1mg/ml solution of E2 or vehicle (Oil) was injected into E3.5 chicken eggs. No significant increase in PAX2 was detected by qRT-PCR (p&gt;0.05, n=6) and no PAX2 positive cells were detected in E2 treated gonads at E9.5. These results suggest that in fadrozole-mediated masculinization (but not in estrogen-induced feminization) there is an increase in undifferentiated supporting cells. The absence of both estrogens (feminizing) and elevated DMRT1 (masculinizing) could explain why the supporting cells remain in an undifferentiated state in ZW (genetically female) embryos. Further research is required to evaluate the fate of these undifferentiated cells in gonadal sex differentiation.
Lack of Association Between ACE2 Expression and Serum Testosterone Concentrations in Peripheral Mononuclear Cells in Males
Authors: Ling Guyou , Campbell Robert , Bruno Jonathan , Goffinet Aaron , Krebs Joseph , Jain Ajay , Dhindsa Sandeep S 
Published: May 2021

Abstract
Background: Male sex is a risk factor for developing severe COVID-19 illness, hospitalization, and mortality. It is possible that the male sex hormone, testosterone, contributes to the morbidity from COVID-19. SARS-CoV2 viruses use cell membrane protein Angiotensin-Converting Enzyme 2 (ACE2) receptor and undergo S protein priming by the Type II Transmembrane Serine Protease (TMPRSS2) to enter the cells. Hence, the expression level of ACE2 and TMPRSS2 may affect disease susceptibility and possible severity. TMPRSS2 is regulated by the androgen receptor. We, therefore, examined if an association exists between serum testosterone concentrations and ACE2 or TMPRSS2 expression level in men.
Methods: We analyzed fasting serum samples and peripheral blood mononuclear cells (MNC) from 42 men. Total and free testosterone and estradiol were measured by liquid chromatography/equilibrium dialysis. Sex hormone binding globulin (SHBG) was measured by chemiluminescence. mRNA was prepared from MNC. Quantitative RT-PCR was conducted using commercially available, pre-designed TaqMan primers and probes targeting ACE2. The ACE2 relative level was calculated after normalization to beta Actin and GAPDH, with lowest ACE2 level being set to 1.
Results: Subjects’ age ranged from 20 to 65 years. Type 2 diabetes was present in 74% of the men and the mean HbA1 was 7.2±1.6% (mean ± S.D.). Fifteen subjects had subnormal free testosterone (&lt;50 pg/ml). Compared to the 27 subjects with normal free testosterone, they were older (49±12 vs 40±13 years, p=0.03) but had similar BMI (36±10, 35±10 kg/m2, p=0.71). As expected, they had lower total testosterone (Median [25th, 75th percentile]; 222 [171-266] vs 431 [335, 618] ng/dl, p&lt;0.001) and free testosterone concentrations (39 [21, 44] vs 72 [59, 92], p&lt;0.001). Total estradiol was also lower in this group (19±1 vs 29±13 pg/ml, p=0.03) but free estradiol (0.44±0.33 vs 0.56±0.34 pg/ml, p=0.44) and SHBG (27 [19, 33] vs 30 [21, 39] nmol/L, p=0.52) were similar. Quantitative PCR data showed there was a large inter-individual variation of ACE2 expression level, up to 15-fold difference. Average ACE2 level did not differ between subnormal and normal testosterone groups (3.4 [2.7, 5.0] vs 3.9 [2.5, 5.7] arbitrary units). ACE2 expression was not related to free testosterone (r=0.11), free estradiol (r=0.18) or sex hormone binding globulin (r=0.15) on linear regression analyses (p&gt;0.30 for all). ACE2 expression was also not related to age (r= -0.15, p=0.34), BMI (r= -0.2, p=0.23) or presence of diabetes. We were not able to detect a significant expression of TMPRSS2 in MNC.
Conclusion: Our results do not support a role for testosterone or estradiol as regulators of ACE2 expression in peripheral blood MNC in males.
Bioidentical Hormone Replacement Therapy at a Hormone Clinic Causing Significant Virilization in a Post-Menopausal Women
Authors: Tsushima Yumiko , Mikhael Alexandra 
Published: May 2021

Abstract
Introduction: Bioidentical hormones (BH) are compounds that have the exact chemical and molecular composition as hormones produced in our bodies. The term typically refers to testosterone, progesterone, and androgens. Compounding pharmacies market these products as being individually tailored, safer, and more effective than modified hormones synthesized under FDA supervision. These compounded products are not subject to FDA approval for dose, purity, safety, or efficacy, which poses a risk to patients. Our case highlights the dangers of unmonitored BH replacement therapy (BHRT) use and the importance of patient education regarding these products.
Clinical Case: A 48 year-old woman presented to our clinic for evaluation of elevated testosterone levels. She underwent a total hysterectomy and bilateral oophorectomies 8 years prior for heavy menses. She was briefly placed on estradiol replacement which was discontinued due to tobacco abuse. She presented to a “hormone clinic” where she was told that her testosterone levels were low and was started on BHRT pellets. The composition of these pellets were not disclosed on the manufacturer’s website. They were to be inserted every 3 months. The patient had received two pellet insertions prior to her initial visit.
The patient reported feeling miserable with nausea, headaches, hot flashes, severe hirsutism, hair loss, severe aggression, increased libido, and clitoromegaly (the size of a ping-pong ball). Physical exam was notable for hirsutism of the upper lip, cheeks, and chin. No obvious foreign objects were identified in the buttocks. Genital exam was declined. Lab results prior to pellet insertion showed: total testosterone 6 ng/dL (N: 8-60 ng/dL), FSH 96.4 mU/ml (post-menopausal: 20-100 mU/ml) and estradiol &lt; 5 pg/mL (post-menopausal &lt; 41 pg/mL). After the initial pellet insertion: total testosterone 320 ng/dL, FSH 85.3 mU/mL, and estradiol 36.2 pg/mL. Five months after the second pellet insertion, total testosterone was 112 ng/dL, DHEAS 15.2 ug/dL (N: 35.4-256.0 ug/dL), FSH 74.9 mU/mL, and estradiol 46 pg/mL. Ultrasound of the buttocks revealed 1 ovoid hypoechoic structure in each buttock.
The patient underwent surgical removal of the pellets. Post-procedural total testosterone was &lt; 12 ng/dL (N &lt; 40 ng/dL). Her aggression and hirsutism improved, but libido became low and clitoromegaly remained unchanged.
Conclusion: The misunderstanding that BHRT is safer and more effective than synthesized, FDA-regulated hormones can lead to harmful adverse effects as seen in our patient with significant signs and symptoms of virilization. Patient education regarding the safety and efficacy of unregulated use of these compounds is crucial along with heightened physician awareness for appropriate patient guidance.
Cyclical Premenstrual Psychosis - Sometimes It Is Your Hormones
Authors: Rawal Malika , Folsom Lisal J 
Published: May 2021

Abstract
Background: Menstrual psychosis is a broad term used to describe a number of disorders characterized by the acute onset of psychotic symptoms with brief duration, complete resolution of symptoms between episodes, with timing related to menses. This entity was first described in the 18th century, with only 27 confirmed cases using strict diagnostic criteria. While research into causation is limited, estrogen withdrawal is thought to precipitate psychotic symptoms. We describe a case of premenstrual psychosis successfully treated with use of transdermal hormonal contraception and extended menstrual cycling. Clinical Case: A 25-year-old non-binary biologic female (they/them/theirs) with bipolar disorder, anxiety, and psychogenic non-epileptiform seizures was referred to endocrinology for evaluation of recurrent psychotic symptoms associated with menses. They endorsed stable mental health symptoms on aripiprazole except during the seven days prior to their menstrual cycle. During this time they reported persistent auditory hallucinations along with dysmenorrhea, with symptoms resolving at the onset of menses. Timing of menarche was uncertain, however they reported oligomenorrhea until beginning oral contraceptives at age nineteen, after which they developed regular monthly cycles accompanied by psychotic symptoms. Pituitary and ovarian hormone levels were unable to be assessed due to hormonal contraception. Prolactin was 8.3 ng/mL (3-30 ng/mL). In order to limit hormonal fluctuations from daily oral contraceptive pills and monthly withdrawal, the decision was made to transition to transdermal norelgestromin and ethinyl estradiol patches changed weekly, with extended cycling to allow one menstrual cycle every three months. At follow-up visit nine months later they reported resolution of auditory hallucinations on this regimen, with symptoms recurring only during extreme stress. Conclusions: While the etiology of menstrual psychosis is unclear, described treatments include a combination of neuroleptics and hormonal therapy, including estrogen, progesterone, and GnRH agonists. As symptoms did not resolve until suppression of monthly menstrual cycles, this case supports the estrogen withdrawal hypothesis. Our case adds to the literature both in that transdermal, rather than oral or injectable therapy was used, and treatment was successful in alleviating the patient’s psychotic symptoms, improving their mental health and quality of life. References: (1) Brockington, I. Menstrual Psychosis. World Psychiatry 2005;4(1):9-17. (2) Reilly, T.J., Sagnay de la Bastida, V.C., Joyce, D.W., Cullen, A.E., McGuire, P. Exacerbation of Psychosis During the Perimenstrual Phase of the Menstrual Cycle: Systematic Review and Meta-analysis. Schizophrenia Bulletin 2020;46(1):78-90.
Effect of Omalizumab for Autoimmune Progesterone Dermatitis Refractory to Bilateral Oophorectomy: A Case Report
Authors: Varghese Akshay , Paul Terri Louise , Kim Harold , Vadas Peter , Van Uum Stan , Azzola Alescia Linda 
Published: May 2021

Abstract
Background: Autoimmune progesterone dermatitis (APD) is a rare skin condition caused by sensitivity to high levels of progesterone secreted during the luteal phase of the menstrual cycle. This may be due to various pathophysiological mechanisms including a Type I and Type IV hypersensitivity reaction, and potential cross-reactivity with other endogenous steroid hormones such as 17-α-hydroxyprogesterone. We present the case of a patient with APD who had her flare-up episodes controlled using omalizumab, after a bilateral oophorectomy failed to resolve her symptoms. Clinical Case: A 34-year-old female presented to our Endocrine Clinic with marked Cushingoid features secondary to high-dose oral prednisone prescribed for APD diagnosed six years earlier. She first developed a pruritic maculopapular rash on her arms and legs just after the birth of her second child in 2009. The rash was also associated with headaches and diffuse angioedema. It presented in a cyclical fashion, beginning one to two days before the start of her menstrual cycle, and ending shortly after it was complete. The severity of symptoms increased as time went on, and flare-ups began to also include dyspnea, nausea, vomiting and abdominal pain. After three years of persistent symptoms, the diagnosis of APD was confirmed by a progesterone skin test. Her symptoms were improved with oral prednisone use, however breakthrough episodes still occurred. After multiple failed treatment modalities, she elected bilateral oophorectomy in 2018. However, her symptoms of APD persisted and she still required high-dose oral prednisone. Her condition was further complicated by vasomotor menopausal symptoms and progressive iatrogenic Cushing’s syndrome. She eventually was started on Omalizumab, which helped resolve her APD symptoms and allowed her to wean off prednisone. Vasomotor menopausal symptoms were resolved using conjugated estrogens with bazedoxifene. However, her symptoms of diffuse bony indeterminate bony pain and arthralgias which started whilst on prednisone have persisted in spite of discontinuing prednisone. Conclusion: To our knowledge, this is only the third case of APD which was successfully treated with Omalizumab and the first case where a bilateral oophorectomy failed to resolve symptoms of APD in the literature. Our case also demonstrates the complications of vasomotor menopause symptoms secondary to a bilateral oophorectomy, as well as the adverse effects of long-term glucocorticoid therapy.
Need for Screening Triglyceride Levels in Women on Oral Contraceptives
Authors: Yau Alice , Idowu Abidemi , Elayaperumal Pramma , Gryguc-Saxanoff Agnieszka , Martinez Jose , Bahtiyar Gul , Rodriguez Giovanna 
Published: May 2021

Abstract
Introduction: Oral contraceptive pills (OCPs) are the most used form of reversible contraceptives by women. Major risks are cardiovascular but OCPs also cause secondary hypertriglyceridemia (HTG) through effects of estrogen, which decreases hepatic triglyceride lipase and lipoprotein lipase activity. This causes increased triglycerides, cholesterol and free fatty acids,1 which then in turn can lead to life-threatening acute pancreatitis.
Case Description: A 23-year-old morbidly obese (BMI 38.2 mg/kg2) female presented with severe epigastric pain, nausea and vomiting. She had a history of mild intermittent asthma, recently diagnosed pre-diabetes and recently started on OCPs. Initial labs were consistent with diabetic ketoacidosis with glucose 528 mg/dL (65-115 mg/dL), anion gap 21 mEq/L (5-15 mEq), and beta-hydroxybutyrate 2.00 mmol/L (0.02-0.27 mmol/L); and acute pancreatitis with triglyceride 4,425 mg/dL (30-200 mg/dL) and lipase &gt;600 U/L (8-78 UL), confirmed on imaging.
She rapidly deteriorated, developing acute hypoxemic respiratory distress requiring intubation and distributive shock requiring three vasopressors. She progressed into multi-organ failure with acute respiratory distress syndrome, ischemic liver and acute renal failure despite insulin drip, colloidal fluid resuscitation, continuous veno-venous hemofiltration and high positive end-exploratory pressures. She developed rhabdomyolysis, followed by abdominal compartment syndrome requiring decompressive laparotomy that resulted in large volume blood loss and retroperitoneal necrosis needing multiple laparotomies. Ultimately, she became non-responsive off sedation, attributed to malignant cerebral edema that progressed to brain herniation.
While HTG was likely the cause of her pancreatitis, she had normal triglyceride levels on prior routine lab work while not on OCPs.
Discussion: Severe acute pancreatitis is a life-threatening complication of HTG which may be precipitated by use of OCPs. We believe that there is a need for more research in this field and even propose periodic monitoring of HTG in women taking OCPs given the severity of the consequences. While there are currently no guidelines for monitoring lipid levels in women on OCP, appropriate clinical awareness of physicians prescribing OCPs to patients may prevent fatal outcomes.
References: 1. Stumpf, M., Kluthcovsky, A., Okamoto, J., Schrut, G., Cajoeiro, P., Chacra, A. and Bizeli, R. (2018). Acute pancreatitis secondary to oral contraceptive-induced hypertriglyceridemia: a case report. Gynecological Endocrinology, 34(11), pp.930-932.