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1.
Front Endocrinol (Lausanne) ; 15: 1410122, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39175568

RESUMO

Introduction: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) or 11-hydroxylase deficiency (11OHD) is characterized by underproduction of cortisol and overproduction of adrenal androgens. These androgens lead to a variable degree of virilization of the female external genitalia in 46,XX individuals. Especially in developing countries, diagnosis is often delayed and 46,XX patients might be assigned as males. This study aims to describe the clinical and biochemical characteristics of a unique cohort of untreated male-reared 46,XX classic CAH patients from Indonesia and discusses treatment challenges. Methods: Nine untreated classic CAH patients with 46,XX genotype and 21OHD (n=6) or 11OHD (n=3), aged 3-46 years old, were included. Biometrical parameters, clinical characteristics, and biochemical measurements including glucocorticoids, renin, androgens, and the pituitary-gonadal axis were evaluated. Results: All patients had low early morning serum cortisol concentrations (median 89 nmol/L) without significant increase after ACTH stimulation. Three patients with salt wasting 21OHD reported one or more periods with seizures and/or vomiting in their past until the age of 6, but not thereafter. The remaining patients reported no severe illness or hospitalization episodes, despite their decreased capacity to produce cortisol. In the 21OHD patients, plasma renin levels were elevated compared to the reference range, and in 11OHD patients renin levels were in the low-normal range. All adult patients had serum testosterone concentrations within the normal male reference range. In 21OHD patients, serum 11-oxygenated androgens comprised 41-60% of the total serum androgen concentrations. Glucocorticoid treatment was offered to all patients, but they refused after counseling as this would reduce their endogenous androgen production and they did not report complaints of their low cortisol levels. Discussion: We describe a unique cohort of untreated classic 46,XX male CAH patients without overt clinical signs of cortisol deficiency despite their cortisol underproduction and incapacity to increase cortisol levels after ACTH stimulation. The described adolescent and adult patients produce androgen levels within or above the normal male reference range. Glucocorticoid treatment will lower these adrenal androgen concentrations. Therefore, in 46,XX CAH patients reared as males an individual treatment approach with careful counseling and clear instructions is needed.


Assuntos
Hiperplasia Suprarrenal Congênita , Hidrocortisona , Humanos , Hiperplasia Suprarrenal Congênita/genética , Hiperplasia Suprarrenal Congênita/sangue , Hiperplasia Suprarrenal Congênita/complicações , Masculino , Adulto , Pré-Escolar , Criança , Adulto Jovem , Adolescente , Pessoa de Meia-Idade , Hidrocortisona/sangue , Feminino , Indonésia/epidemiologia , Estudos de Coortes
2.
Artigo em Inglês | MEDLINE | ID: mdl-39183148

RESUMO

CONTEXT: Some patients with classic congenital adrenal hyperplasia (CAH) survive without glucocorticoid treatment. Increased precursor concentrations in these patients might lead to higher free (biological active) cortisol concentrations by influencing the cortisol-protein binding. In 21-hydroxylase deficiency (21OHD), the most common CAH form, accumulated 21-deoxycortisol (21DF) may further increase glucocorticoid activity. Both mechanisms could explain the low occurrence of symptoms in some untreated classic CAH patients. OBJECTIVE: Develop and validate an LC-MS/MS method for free cortisol and free 21DF to quantify these steroids in untreated patients with classic CAH (n=29), non-classic CAH (NCCAH, n=5), other forms of adrenal insufficiency (AI, n=3), and controls (n=11) before and 60 minutes after Synacthen® administration. RESULTS: Unstimulated total cortisol concentrations of untreated classic CAH patients (median 109 nmol/L) were lower than in untreated NCCAH patients (249 nmol/L, p=0.010) and controls (202 nmol/L, p=0.016), but free cortisol concentrations were similar. Basal free 21DF concentrations were high in 21OHD patients (median 5.32 nmol/L) and undetectable in AI patients and controls (<0.19 nmol/L). After Synacthen® administration, free 21DF concentrations increased in 21OHD patients, while free cortisol concentrations did not change. CONCLUSIONS: Free cortisol concentrations in classic CAH patients were similar to those in controls and NCCAH patients, indicating comparable cortisol availability. Additionally, 21OHD patients produce high concentrations of 21DF, possibly explaining the low occurrence of symptoms in some classic 21OHD patients. Free cortisol and 21DF levels should be considered in evaluating adrenal insufficiency in patients with CAH.

3.
Eur J Endocrinol ; 2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38243909

RESUMO

OBJECTIVE: Classic androgens such as dehydroepiandrosterone, androstenedione, and testosterone are generally measured for diagnosis and treatment monitoring in children and adolescents with hyperandrogenism, as can occur in congenital adrenal hyperplasia, premature pubarche, or polycystic ovarian syndrome. However, adrenally-derived 11-oxygenated androgens also contribute to the androgen pool and should therefore be considered in clinical management. Nevertheless, paediatric reference intervals are lacking. Therefore, we developed a serum assay to establish reference intervals for four 11-oxygenated androgens in addition to four classic androgens. DESIGN: Reference interval study for serum 11-oxygenated androgens in children. METHODS: We developed and validated a sensitive LC-MS/MS assay and quantified eight serum androgens, including four 11-oxygenated androgens, in serum of 256 healthy children (aged 0-17 years old). An age-dependency for all androgens was observed, and therefore we divided the cohort based on age (prepubertal (n=133; 94 boys, 39 girls) and pubertal (n=123; 52 boys, 71 girls)) to compute reference intervals (2.5th - 97.5th percentiles). RESULTS: In the prepubertal group, there was no significant sex-difference for any of the measured androgens. In the pubertal group, androstenedione, testosterone, and dihydrotestosterone showed a significant difference between boys and girls. In contrast, adrenal androgens dehydroepiandrosterone, 11-hydroxyandrostenedione, 11-ketoandrostenedione, 11-hydroxytestosterone, and 11-ketotestosterone did not. CONCLUSIONS: We developed and validated an assay for 11-oxygenated androgens, in addition to four classic androgens and established reference intervals. This enables a comprehensive evaluation of serum androgen status in children with clinical symptoms of hyperandrogenism.

4.
Endocrinology ; 164(12)2023 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-37935047

RESUMO

Testicular adrenal rest tumors (TARTs), commonly occurring in males with congenital adrenal hyperplasia, may arise from chronic stimulation of adrenocorticotropic hormone (ACTH)-sensitive cells in the testes. It is not yet established whether the human fetal testis (HFT) is responsive to ACTH. To investigate this, we cultured HFT tissue with and without ACTH for up to 5 days, and quantified adrenal steroid hormones and expression of adrenal steroidogenic enzymes. Fetal testis and adrenal tissue produced high levels of testosterone and cortisol, respectively, indicating viability. In contrast to fetal adrenal tissues, the expression of ACTH receptor MC2R was either absent or expressed at extremely low levels in ex vivo HFT tissue and no clear response to ACTH in gene expression or steroid hormone production was observed. Altogether, this study suggests that the HFT is unresponsive to ACTH, which would indicate that a TART does not arise from fetal testicular cells chronically exposed to ACTH in utero.


Assuntos
Hiperplasia Suprarrenal Congênita , Neoplasias Testiculares , Masculino , Humanos , Testículo/patologia , Hormônio Adrenocorticotrópico/farmacologia , Hormônio Adrenocorticotrópico/metabolismo , Glândulas Suprarrenais/metabolismo , Hiperplasia Suprarrenal Congênita/metabolismo , Neoplasias Testiculares/metabolismo , Esteroides
5.
Eur J Endocrinol ; 189(4): 460-468, 2023 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-37837609

RESUMO

IMPORTANCE: Testicular adrenal rest tumors (TARTs), often found in male patients with congenital adrenal hyperplasia (CAH), are benign lesions causing testicular damage and infertility. We hypothesize that chronically elevated adrenocorticotropic hormone exposure during early life may promote TART development. OBJECTIVE: This study aimed to examine the association between commencing adequate glucocorticoid treatment early after birth and TART development. DESIGN AND PARTICIPANTS: This retrospective multicenter (n = 22) open cohort study collected longitudinal clinical and biochemical data of the first 4 years of life using the I-CAH registry and included 188 male patients (median age 13 years; interquartile range: 10-17) with 21-hydroxylase deficiency (n = 181) or 11-hydroxylase deficiency (n = 7). All patients underwent at least 1 testicular ultrasound. RESULTS: TART was detected in 72 (38%) of the patients. Prevalence varied between centers. When adjusted for CAH phenotype, a delayed CAH diagnosis of >1 year, compared with a diagnosis within 1 month of life, was associated with a 2.6 times higher risk of TART diagnosis. TART onset was not predicted by biochemical disease control or bone age advancement in the first 4 years of life, but increased height standard deviation scores at the end of the 4-year study period were associated with a 27% higher risk of TART diagnosis. CONCLUSIONS AND RELEVANCE: A delayed CAH diagnosis of >1 year vs CAH diagnosis within 1 month after birth was associated with a higher risk of TART development, which may be attributed to poor disease control in early life.


Assuntos
Hiperplasia Suprarrenal Congênita , Tumor de Resto Suprarrenal , Neoplasias Testiculares , Adolescente , Humanos , Masculino , Hiperplasia Suprarrenal Congênita/genética , Tumor de Resto Suprarrenal/epidemiologia , Tumor de Resto Suprarrenal/etiologia , Estudos de Coortes , Neoplasias Testiculares/epidemiologia , Neoplasias Testiculares/complicações , Criança
7.
Int J Gynecol Cancer ; 33(12): 1882-1889, 2023 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-37723103

RESUMO

OBJECTIVES: Pregnancy loss, occurring after miscarriage or after gestational trophoblastic disease, has a psychological impact. Besides pregnancy loss, women diagnosed with gestational trophoblastic disease have to deal with a prolonged period of follow-up and potential advice to postpone a future pregnancy. We studied the severity and course of the psychological impact after gestational trophoblastic disease and miscarriage, to identify whether women with gestational trophoblastic disease need different psychological care. METHODS: A prospective multicenter study using online questionnaires was performed. Women diagnosed with gestational trophoblastic disease or miscarriage received the following questionnaires directly after diagnosis, and after 6, 6, and 12 months: a self-report questionnaire, the Hospital Anxiety and Depression Scale (HADS), the Impact of Event Scale, and the Reproductive Concerns Scale. RESULTS: 74 women with gestational trophoblastic disease and 76 women with miscarriage were included. At baseline, the proportion of women scoring above the cut-off level for the anxiety subscale of the HADS and for the Impact of Event Scale was significantly higher for women with gestational trophoblastic disease than for women after miscarriage (43.2% vs 28.9%, p=0.02 and 87.8% vs 78.9%, p=0.03, respectively). During follow-up, the differences between both groups vanished and only the Impact of Event Scale after 12 months remained significantly different between women with gestational trophoblastic disease and women after miscarriage (62.7% vs 37.3%, p=0.005). All outcomes, except the Reproductive Concerns Scale, showed a significant decline. However, in women who scored above the cut-off level on the HADS-total or Impact of Event Scale at baseline, and women with psychological or psychiatric history, significant higher scores persisted. CONCLUSION: Although women with gestational trophoblastic disease at baseline had more anxiety and distress than women after miscarriage, no significant differences were seen using the HADS-total after 12 months. Using the HADS or Impact of Event Scale directly after pregnancy loss is helpful to identify women at risk of remaining psychological symptoms to provide them with extra psychological support.


Assuntos
Aborto Espontâneo , Doença Trofoblástica Gestacional , Gravidez , Feminino , Humanos , Aborto Espontâneo/epidemiologia , Aborto Espontâneo/etiologia , Aborto Espontâneo/psicologia , Estudos Prospectivos , Ansiedade/etiologia , Aconselhamento
8.
Cancers (Basel) ; 15(5)2023 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-36900372

RESUMO

BACKGROUND: In node-negative breast cancer (NNBC), a high risk of recurrence is determined by clinico-pathological or tumor-biological assessment. Taxanes may improve adjuvant chemotherapy. METHODS: NNBC 3-Europe, the first randomized phase-3 trial in node-negative breast cancer (BC) with tumor-biological risk assessment, recruited 4146 node-negative breast cancer patients from 2002 to 2009 in 153 centers. Risk assessment was performed by clinico-pathological factors (43%) or biomarkers (uPA/PAI-1, urokinase-type plasminogen activator/its inhibitor PAI-1). High-risk patients received six courses 5-fluorouracil (500 mg/m2), epirubicin (100 mg/m2), cyclophosphamide (500 mg/m2) (FEC), or three courses FEC followed by three courses docetaxel 100 mg/m2 (FEC-Doc). Primary endpoint was disease-free survival (DFS). RESULTS: In the intent-to-treat population, 1286 patients had received FEC-Doc, and 1255 received FEC. Median follow-up was 45 months. Tumor characteristics were equally distributed; 90.6% of tested tumors had high uPA/PAI-1-concentrations. Planned courses were given in 84.4% (FEC-Doc) and 91.5% (FEC). Five-year-DFS was 93.2% (95% C.I. 91.1-94.8) with FEC-Doc and 93.7% (91.7-95.3) with FEC. Five-year-overall survival was 97.0% (95.4-98.0) for FEC-Doc and 96.6% % (94.9-97.8) for FEC. CONCLUSIONS: With adequate adjuvant chemotherapy, even high-risk node-negative breast cancer patients have an excellent prognosis. Docetaxel did not further reduce the rate of early recurrences and led to significantly more treatment discontinuations.

9.
Clin Endocrinol (Oxf) ; 98(1): 41-48, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35514026

RESUMO

OBJECTIVE: Patients with congenital adrenal hyperplasia (CAH) in developing countries have limited access to appropriate laboratory facilities for diagnosis and follow-up. The aim of this study is to evaluate steroid measurement in hair as a diagnostic tool to identify and monitor CAH in these patients. DESIGN: A method was developed to measure steroids in hair, the stability of steroids in hair was assessed, and the concentration range in healthy volunteers was determined. Hair samples of patients, before and after starting therapy, were transported at ambient temperature to The Netherlands for analysis. PATIENTS: Twenty-two Indonesian CAH patients and 84 healthy volunteers participated. MEASUREMENTS: Cortisol, 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone in hair were measured by liquid chromatography with tandem mass spectrometry. RESULTS: Steroids in hair could be measured and remained stable (<4.9% deviation) for at least 3 weeks at 4°C and 30°C. In each of the untreated patients, hair concentrations of 17OHP (9.43-1135 pmol/g), androstenedione (36.1-432 pmol/g), and testosterone (2.85-69.2 pmol/g) were all above the upper limit of the corresponding range in healthy volunteers; 5.5 pmol/g, 13 pmol/g, and 1.8 pmol/g, respectively. After starting glucocorticoid treatment, the steroid concentrations in the hair of CAH patients decreased significantly for androstenedione (73%) and testosterone (59%) after 6 months. CONCLUSIONS: CAH could be confirmed in Indonesian patients based on the concentration of 17OHP, androstenedione, and testosterone in hair, and a treatment effect was observed. These findings open up opportunities to diagnose and/or monitor CAH in developing countries with a simple noninvasive technique.


Assuntos
Hiperplasia Suprarrenal Congênita , Humanos , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Indonésia , Esteroides/uso terapêutico , Cabelo , Testosterona
10.
Front Endocrinol (Lausanne) ; 13: 1064024, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36578966

RESUMO

Congenital adrenal hyperplasia (CAH) due to 21α-hydroxylase deficiency (21OHD) or 11ß-hydroxylase deficiency (11OHD) are congenital conditions with affected adrenal steroidogenesis. Patients with classic 21OHD and 11OHD have a (nearly) complete enzyme deficiency resulting in impaired cortisol synthesis. Elevated precursor steroids are shunted into the unaffected adrenal androgen synthesis pathway leading to elevated adrenal androgen concentrations in these patients. Classic patients are treated with glucocorticoid substitution to compensate for the low cortisol levels and to decrease elevated adrenal androgens levels via negative feedback on the pituitary gland. On the contrary, non-classic CAH (NCCAH) patients have more residual enzymatic activity and do generally not suffer from clinically relevant glucocorticoid deficiency. However, these patients may develop symptoms due to elevated adrenal androgen levels, which are most often less elevated compared to classic patients. Although glucocorticoid treatment can lower adrenal androgen production, the supraphysiological dosages also may have a negative impact on the cardiovascular system and bone health. Therefore, the benefit of glucocorticoid treatment is questionable. An individualized treatment plan is desirable as patients can present with various symptoms or may be asymptomatic. In this review, we discuss the advantages and disadvantages of different treatment options used in patients with NCCAH due to 21OHD and 11OHD.


Assuntos
Hiperplasia Suprarrenal Congênita , Humanos , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Hiperplasia Suprarrenal Congênita/diagnóstico , Glucocorticoides/uso terapêutico , Glucocorticoides/metabolismo , Hidrocortisona , Androgênios , Oxigenases de Função Mista
11.
Eur J Endocrinol ; 187(5): 607-615, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36047744

RESUMO

Background: Testicular adrenal rest tumors (TART) are a common complication of unknown cellular origin in patients with congenital adrenal hyperplasia (CAH). These benign tumors have both adrenal and testicular characteristics and are hypothesized to either derive from cells of adrenal origin from the fetal adrenogonadal primordium or by atypical differentiation of adult Leydig-progenitor cells. Objective: This study aims to unravel the identity and etiology of TART. Methods: Co-expression of adrenal-specific CYP11B1 and Leydig cell-specific HSD17B3 in TART was studied using immunohistochemistry. We studied the possibility of TART being derived from atypical differentiation of adult Leydig-progenitor cells by the quantification of adrenal-specific enzyme expression upon adrenocorticotrophic hormone (ACTH)-like stimulation of ex vivo cultured platelet-derived growth factor receptor alpha-positive cells. By comparing the transcriptome of TART (n = 16) with the transcriptome of fetal adrenal (n = 13), fetal testis (n = 5), adult adrenal (n = 11), and adult testis (n = 10) tissues, we explored the identity of TART. Results: We demonstrate co-expression of adrenal-specific CYP11B1 and testis-specific HSD17B3 in TART cells, indicating the existence of a distinct TART cell exhibiting both adrenal and testicular characteristics. Ex vivo cultured adult Leydig-progenitor cells did not express the ACTH-receptor MC2R but did express CYP11B1 upon stimulation. Unsupervised clustering of transcriptome data showed that TART was most similar to adult adrenal tissue, followed by adult testis tissue, and least similar to either fetal tissue. Conclusion: Our data suggest that TART is induced - most likely via activation of a cAMP/protein kinase A-dependent receptor - from a progenitor cell into a unique mature adrenal-like cell type, sometimes exhibiting both adrenal and testicular features.


Assuntos
Hiperplasia Suprarrenal Congênita , Tumor de Resto Suprarrenal , Neoplasias Testiculares , Hiperplasia Suprarrenal Congênita/complicações , Tumor de Resto Suprarrenal/genética , Hormônio Adrenocorticotrópico , Adulto , Proteínas Quinases Dependentes de AMP Cíclico , Feto , Humanos , Masculino , Receptores do Fator de Crescimento Derivado de Plaquetas , Esteroide 11-beta-Hidroxilase , Neoplasias Testiculares/complicações
12.
Acta Obstet Gynecol Scand ; 101(9): 1007-1016, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35689468

RESUMO

INTRODUCTION: Treatment with antibodies directed against programed-cell death ligand 1 (PD-L1) is a novel therapy for patients with gestational trophoblastic disease. Assessment of PD-L1 expression in tumor tissue is commonly used to identify patients who might benefit from anti-PD-L1 treatment. Multiple antibodies are available to detect PD-L1-expressing cells, and percentages of PD-L1-expressing cells in samples of patients with gestational trophoblastic disease indicated by these antibodies differ substantially. This raises the question which PD-L1 antibody best reflects PD-L1 expression to select patients for treatment. MATERIAL AND METHODS: Seven commercially available antibodies for PD-L1 staining (E1L3N, 73-10, 22C3, CAL10, SP142, 28-8, SP263) were validated on Chinese hamster ovarian (CHO) cells transfected with PD-L1, PD-L2, wildtype CHO cells and tonsil tissue. Next, four complete hydatidiform moles and four choriocarcinomas were stained. Samples were independently assessed by two pathologists. RESULTS: All seven antibodies showed membranous staining in the PD-L1-transfected CHO cells. E1L3N and 22C3 scored the highest percentages of PD-L1-positive cells (70%-90% and 60%-70%, respectively). E1L3N stained the cytoplasm of non-transfected CHO cells and was excluded from analysis. The remaining six antibodies predominantly stained syncytiotrophoblast cells of both complete hydatidiform moles and choriocarcinomas. The percentage of PD-L1-stained trophoblast cells and staining intensity varied substantially per used PD-L1 antibody and between complete hydatidiform moles and choriocarcinomas. Agreement between pathologists was best with 22C3 (intraclass correlation coefficient 0.94-0.96). CONCLUSIONS: Based on staining results of the CHO cells, gestational trophoblastic disease samples and intraclass correlation coefficient, 22C3 seems the most suitable for adequate detection of PD-L1-expressing trophoblast cells. All antibodies detected PD-L1-expressing cells in the gestational trophoblastic disease samples, though with great variability, hampering comparison of results between studies in this rare disease and emphasizing the need for uniformity in detecting PD-L1-expressing cells.


Assuntos
Coriocarcinoma , Doença Trofoblástica Gestacional , Mola Hidatiforme , Animais , Anticorpos , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais , Cricetinae , Cricetulus , Feminino , Doença Trofoblástica Gestacional/metabolismo , Doença Trofoblástica Gestacional/patologia , Humanos , Imuno-Histoquímica , Gravidez
13.
Clin Endocrinol (Oxf) ; 97(1): 36-42, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35150157

RESUMO

OBJECTIVE: Treatment of congenital adrenal hyperplasia (CAH) patients with glucocorticoids is often challenging since there is a delicate balance between over- and undertreatment. Treatment can be monitored noninvasively by measuring salivary androstenedione (A4) and 17-hydroxyprogesterone (17-OHP). Optimal treatment monitoring requires the establishment of reference values in saliva. DESIGN: A descriptive study. PATIENTS: For this study saliva of 255 healthy paediatric and adult volunteers with an age range of 4-75 years old was used. MEASUREMENTS: We developed a sensitive liquid chromatography-tandem mass spectrometry method, assessed salivary A4 and 17-OHP stability, and measured A4 and 17-OHP concentrations in saliva collected in the morning, afternoon, and evening. RESULTS: We quantified A4 and 17-OHP concentrations in the morning, afternoon, and evening and demonstrated that there is a significant rhythm with the highest levels in the morning and decreasing levels over the day. A4 and 17-OHP concentrations display an age-dependent pattern. These steroids remain stable in saliva at ambient temperature for up to 5 days. CONCLUSIONS: Good stability of the steroids in saliva enables saliva collection by the patient at home. Since salivary A4 and 17-OHP display a diurnal rhythm and age-dependent pattern, we established reference values for both children and adults at three time points during the day. These reference values support treatment monitoring of children and adults with CAH.


Assuntos
Hiperplasia Suprarrenal Congênita , Androstenodiona , 17-alfa-Hidroxiprogesterona/análise , Adolescente , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Adulto , Idoso , Androgênios , Criança , Pré-Escolar , Voluntários Saudáveis , Humanos , Pessoa de Meia-Idade , Esteroides , Resultado do Tratamento , Adulto Jovem
14.
J Clin Endocrinol Metab ; 107(4): e1661-e1672, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-34788830

RESUMO

CONTEXT: Hydrocortisone treatment of young patients with 21-hydroxylase deficiency (21OHD) is given thrice daily, but there is debate about the optimal timing of the highest hydrocortisone dose, either mimicking the physiological diurnal rhythm (morning), or optimally suppressing androgen activity (evening). OBJECTIVE: We aimed to compare 2 standard hydrocortisone timing strategies, either highest dosage in the morning or evening, with respect to hormonal status throughout the day, nocturnal blood pressure (BP), and sleep and activity scores. METHODS: This 6-week crossover study included 39 patients (aged 4-19 years) with 21OHD. Patients were treated for 3 weeks with the highest hydrocortisone dose in the morning, followed by 3 weeks with the highest dose in the evening (n = 21), or vice versa (n = 18). Androstenedione (A4) and 17-hydroxyprogesterone (17OHP) levels were quantified in saliva collected at 5 am; 7 am; 3 pm; and 11 pm during the last 2 days of each treatment period. The main outcome measure was comparison of saliva 17OHP and A4 levels between the 2 treatment strategies. RESULTS: Administration of the highest dose in the evening resulted in significantly lower 17OHP levels at 5 am, whereas the highest dose in the morning resulted in significantly lower 17OHP and A4 levels in the afternoon. The 2 treatment dose regimens were comparable with respect to averaged daily hormone levels, nocturnal BP, and activity and sleep scores. CONCLUSION: No clear benefit for either treatment schedule was established. Given the variation in individual responses, we recommend individually optimizing dose distribution and monitoring disease control at multiple time points.


Assuntos
Hiperplasia Suprarrenal Congênita , Hidrocortisona , 17-alfa-Hidroxiprogesterona , Adolescente , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Androgênios/uso terapêutico , Criança , Pré-Escolar , Estudos Cross-Over , Feminino , Humanos , Masculino , Adulto Jovem
15.
J Clin Endocrinol Metab ; 107(1): e272-e280, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34390337

RESUMO

CONTEXT: Testicular adrenal rest tumors (TART) are a common complication in males with classic 21-hydroxylase deficiency (21OHD). TART are likely to contribute to the androgen excess in 21OHD patients, but a direct quantification of steroidogenesis from these tumors has not been yet done. OBJECTIVE: We aimed to define the production of 11-oxygenated 19-carbon (11oxC19) steroids by TART. METHODS: Using liquid chromatography-tandem mass spectrometry, steroids were measured in left (n = 7) and right (n = 4) spermatic vein and simultaneously drawn peripheral blood (n = 7) samples from 7 men with 21OHD and TART. For comparison, we also measured the peripheral steroid concentrations in 5 adrenalectomized patients and 12 age- and BMI-matched controls. Additionally, steroids were quantified in TART cell- and adrenal cell-conditioned medium, with and without adrenocorticotropic hormone (ACTH) stimulation. RESULTS: Compared with peripheral blood from 21OHD patients with TART, the spermatic vein samples displayed the highest gradient for 11ß-hydroxytestosterone (11OHT; 96-fold) of the 11oxC19 steroids, followed by 11-ketotestosterone (47-fold) and 11ß-hydroxyandrostenedione (11OHA4; 29-fold), suggesting production of these steroids in TART. TART cells produced higher levels of testosterone and lower levels of A4 and 11OHA4 after ACTH stimulation compared with adrenal cells, indicating ACTH-induced production of testosterone in TART. CONCLUSION: In patients with 21OHD, TART produce 11oxC19 steroids, but in different proportions than the adrenals. The very high ratio of 11OHT in spermatic vs peripheral vein blood suggests the 11-hydroxylation of testosterone by TART, and the in vitro results indicate that this metabolism is ACTH-sensitive.


Assuntos
Glândulas Suprarrenais/metabolismo , Hiperplasia Suprarrenal Congênita/sangue , Tumor de Resto Suprarrenal/sangue , Neoplasias Testiculares/sangue , Testículo/patologia , Glândulas Suprarrenais/patologia , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/genética , Hiperplasia Suprarrenal Congênita/patologia , Tumor de Resto Suprarrenal/genética , Tumor de Resto Suprarrenal/patologia , Tumor de Resto Suprarrenal/cirurgia , Adulto , Androstenodiona/análogos & derivados , Androstenodiona/sangue , Androstenodiona/metabolismo , Estudos de Casos e Controles , Humanos , Hidroxitestosteronas/sangue , Hidroxitestosteronas/metabolismo , Masculino , Pessoa de Meia-Idade , Esteroide 21-Hidroxilase/genética , Neoplasias Testiculares/genética , Neoplasias Testiculares/patologia , Neoplasias Testiculares/cirurgia , Testículo/metabolismo , Testículo/cirurgia , Testosterona/análogos & derivados , Testosterona/sangue , Testosterona/metabolismo , Adulto Jovem
16.
Gynecol Oncol ; 163(3): 531-537, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34602288

RESUMO

BACKGROUND: Clinicians are unable to provide individualized counseling regarding risk of progression for patients with a complete hydatidiform mole (CHM). We developed nomograms enabling early prediction of post-molar gestational trophoblastic neoplasia (GTN) and resistance to methotrexate (MTX) based on a single serum human chorion gonadotropin (hCG) measurement. METHODS: We generated two nomograms with logistic regression: to predict post-molar GTN, and MTX resistance. For patients with high probability to progress to post-molar GTN or MTX resistance, we determined hCG cut-offs at 97.5% specificity to select patients for additional- or adjustments in current treatment. RESULTS: The nomograms had a good to excellent ability to distinguish either between patients with uneventful hCG regression versus progression to post molar GTN, or between patients cured by MTX versus patients in whom resistance would occur. At 97.5% specificity, we identified 66% (95%CI 56-75) of the 149 patients who would progress to post-molar GTN, four weeks after initial curettage. For patients treated with MTX, we identified 55% (95%CI 23-83) of the 43 patients who would become resistant, preceding their third course at 97.5% specificity. CONCLUSION: The nomograms and cut-off levels can be used to assist in counseling for patients diagnosed with CHM.


Assuntos
Gonadotropina Coriônica/sangue , Doença Trofoblástica Gestacional/sangue , Doença Trofoblástica Gestacional/tratamento farmacológico , Mola Hidatiforme/sangue , Mola Hidatiforme/tratamento farmacológico , Metotrexato/uso terapêutico , Adulto , Antimetabólitos Antineoplásicos/uso terapêutico , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Mola Hidatiforme/patologia , Modelos Logísticos , Metotrexato/farmacologia , Nomogramas , Medicina de Precisão , Valor Preditivo dos Testes , Gravidez , Medição de Risco
17.
Front Endocrinol (Lausanne) ; 12: 626646, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815285

RESUMO

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is a disorder of adrenal steroid biosynthesis, leading to hypocortisolism, hypoaldosteronism, and hyperandrogenism. Impaired quality of life (QoL) has been demonstrated in women with CAH, but data on men with CAH are scarce. We hypothesized that disease severity and poor treatment control are inversely associated with QoL. In this study, 109 men (16-68 years) with 21OHD were included. The WHOQOL-BREF questionnaire was used to measure self-reported QoL domain scores on a 0-100 scale, where higher scores reflect better QoL. QoL domain scores were compared to published data on healthy and chronically ill reference populations from France, Germany, the Netherlands, and the United Kingdom. Differences in QoL scores among groups of disease severity and treatment control were tested within the study population. Overall, the men with CAH in this study appeared to rate their QoL as good. Median domain scores were 78.6 (IQR: 67.9-85.7) for physical health, 79.2 (IQR: 66.7-87.5) for psychological health, 75.0 (IQR: 58.3-83.3) for social relationships, and 81.3 (IQR: 71.9-90.6) for environment. In general, these scores were similar to WHOQOL-BREF domain scores in healthy references and higher compared to chronically ill reference populations. The domain scores did not differ among genotype groups, but patients with undertreatment or increased 17-hydroxyprogestrone concentrations scored higher on several QoL domains (p<0.05). Patients treated with dexamethasone or prednisone scored higher on the physical health, psychological health, and social relationships domains, but not on the environmental domain. In conclusion, QoL domain scores appeared to be comparable to healthy reference populations and higher compared to patients with a chronic illness. QoL was not influenced by genotype, but undertreatment and use of dexamethasone or prednisone were associated with higher QoL.


Assuntos
Hiperplasia Suprarrenal Congênita/psicologia , Saúde Mental , Qualidade de Vida/psicologia , Hiperplasia Suprarrenal Congênita/diagnóstico , Adulto , Humanos , Masculino , Autorrelato , Índice de Gravidade de Doença , Inquéritos e Questionários , Adulto Jovem
18.
Psychoneuroendocrinology ; 124: 105081, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33340878

RESUMO

BACKGROUND: Learned placebo effects induced by pharmacological conditioning affect immune and endocrine outcomes and may offer new possibilities for clinical applications. Whether or not cortisol is subject to this type of associative learning processes, and whether conditioning may affect responses to stress, is currently unclear. METHOD: A randomized placebo-controlled trial was conducted in 48 healthy young women. During acquisition, participants received a pill containing either 100 mg hydrocortisone (unconditioned stimulus) or placebo, paired with a gustatory conditioned stimulus on three consecutive days. During evocation, all participants received placebo paired with the conditioned stimulus, again on three consecutive days. During the third evocation trial, participants underwent a psychosocial stress task. The main outcome parameter salivary cortisol and secondary outcome parameters salivary alpha-amylase, self-reported positive affect and tension, heart rate, and skin conductance level were measured at several time points. RESULTS: Significant baseline group differences on cortisol were found at several time points, which complicate the interpretation of group differences. During the first evocation session, the conditioned group showed a moderately smaller cumulative decrease in salivary cortisol from baseline than the placebo control group. No significant differences were found between the groups on cortisol during the second and third evocation or in response to stress, nor on other outcome measures. CONCLUSION: Although the results provide potential further indications for effects of conditioning on cortisol, baseline differences make it impossible to draw clear conclusions. No indications for possible effects of conditioning on the cortisol stress response or autonomous or affective responses to stress were found.


Assuntos
Condicionamento Clássico , Hidrocortisona , Feminino , Frequência Cardíaca , Humanos , Aprendizagem , Efeito Placebo
19.
Gynecol Oncol ; 160(2): 450-456, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33213898

RESUMO

OBJECTIVE: In 15% of patients with complete hydatidiform mole (CHM), disease progresses to post-molar gestational trophoblastic neoplasia (GTN) after curettage. Tumor infiltrating lymphocytes (TILs) are essential in overcoming disease in many tumors. Infiltrating lymphocyte composition and density may influence trophoblast regression and development of post-molar GTN. We analyzed immune cell composition and density in curettaged endometrium of patients with CHM which spontaneously regressed, and of patients with CHM which progressed to post-molar GTN. METHODS: Sixteen patients with CHM and spontaneous regression, and 16 patients with CHM which progressed to post-molar GTN were selected. Immune cell composition and density of natural killer (NK) cells, natural killer T (NKT)-like cells, Cytotoxic T cells, T-Regulatory and T-Helper cells, were determined by multiplex immunohistochemistry (mIHC). RESULTS: Curettaged endometrium of patients with CHM and spontaneous regression contained a slightly higher number of immune cells compared to patients with CHM which progressed to post-molar GTN. NKT-like cell density was significantly higher in patients with spontaneous regression compared to patients with CHM which progressed to post-molar GTN (483 ± 296 vs.295 ± 143 (mean ± SD), p = 0.03) respectively. NKT-like cell density in the spontaneous regression group was split in 'high' and 'low' (i.e. above and below the median number of NKT-like cells). In patients with high NKT-like cell density, hCG normalized earlier than in patients with low NKT-like cell density (9.5 weeks, (range 3.7-14) vs. 12.9 weeks, (range 8.6-17.9), p = 0.05). CONCLUSION: A high number of NKT-like cells in the endometrium of CHMs may contribute to spontaneous regression of molar trophoblast cells.


Assuntos
Endométrio/patologia , Mola Hidatiforme/imunologia , Linfócitos do Interstício Tumoral/imunologia , Células T Matadoras Naturais/imunologia , Neoplasias Uterinas/imunologia , Adulto , Gonadotropina Coriônica/sangue , Curetagem , Progressão da Doença , Endométrio/citologia , Endométrio/imunologia , Endométrio/cirurgia , Feminino , Citometria de Fluxo , Seguimentos , Idade Gestacional , Humanos , Mola Hidatiforme/sangue , Mola Hidatiforme/patologia , Mola Hidatiforme/cirurgia , Imunofenotipagem , Pessoa de Meia-Idade , Gravidez , Estudos Retrospectivos , Neoplasias Uterinas/sangue , Neoplasias Uterinas/patologia , Neoplasias Uterinas/cirurgia , Adulto Jovem
20.
J Cancer Res Clin Oncol ; 146(7): 1725-1735, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32394054

RESUMO

OBJECTIVE: The plasminogen activator system (PAS) and vascular endothelial growth factor (VEGF) are important in the carcinogenesis and play a key role in cancer invasion and mediating metastasis of carcinomas. The aim of the study was to evaluate the correlation of serum levels of VEGF and components of the PAS with clinicopathological risk factors and outcome in patients with endometrial cancer (EC). METHODS: Preoperative blood was collected from 173 patients treated for EC between 1999 and 2009. Serum concentrations of VEGF, urokinase plasminogen activator (uPA) tissue plasminogen activator (tPA), plasminogen activator inhibitor type-1 (PAI-1) and -2 (PAI-2) were assessed by enzyme-linked immunosorbent assays (ELISA). RESULTS: Serum levels of VEGF and components of the PAS were significantly associated with stage of the disease, tumor histology, tumor grade, myometrial invasion (MI), presence of lymphovascular space invasion (LVSI) and lymph node metastases (LNM). Preoperative serum levels of PAI-1 and -2 and tPA were higher in patients who experienced a recurrence than in patients who remained disease free (p < 0.01). PAI-1 and -2 and tPA were significantly independent prognostic factors for DFS with a HR of 3.85 (95% CI 1.84-8.07), 3.90 (95% CI 1.75-8.66) and 2.53 (95% CI 1.16-5.55), respectively. PAI-1 and tPA turned out to be independent prognostic factors for OS, with a HR of 2.09 (95% CI 1.08-4.05) and 2.16 (95% CI 1.06-4.44), respectively. CONCLUSION: Serum levels of VEGF and components of the PAS at primary diagnosis were associated with well-known clinicopathological risk factors such as; FIGO stage, tumor histology, tumor grade, MI, LVSI and LNM. High concentrations of PAI-1 and-2 and tPA are independent factors for poor prognosis in patients with endometrial cancer.


Assuntos
Neoplasias do Endométrio/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Idoso , Biomarcadores Tumorais , Transformação Celular Neoplásica , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/etiologia , Neoplasias do Endométrio/mortalidade , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Modelos Moleculares , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Ativador de Plasminogênio Tecidual/sangue , Ativador de Plasminogênio Tecidual/metabolismo , Fator A de Crescimento do Endotélio Vascular/sangue
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