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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.

Asunto(s)

Hiperplasia Suprarrenal Congénita , Hidrocortisona , Humanos , Hiperplasia Suprarrenal Congénita/genética , Hiperplasia Suprarrenal Congénita/sangre , Hiperplasia Suprarrenal Congénita/complicaciones , Masculino , Adulto , Preescolar , Niño , Adulto Joven , Adolescente , Persona de Mediana Edad , Hidrocortisona/sangre , Femenino , Indonesia/epidemiología , Estudios de Cohortes

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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.

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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.

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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.

Asunto(s)

Hiperplasia Suprarrenal Congénita , Neoplasias Testiculares , Masculino , Humanos , Testículo/patología , Hormona Adrenocorticotrópica/farmacología , Hormona Adrenocorticotrópica/metabolismo , Glándulas Suprarrenales/metabolismo , Hiperplasia Suprarrenal Congénita/metabolismo , Neoplasias Testiculares/metabolismo , Esteroides

RESUMEN

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.

Asunto(s)

Hiperplasia Suprarrenal Congénita , Tumor de Resto Suprarrenal , Neoplasias Testiculares , Adolescente , Humanos , Masculino , Hiperplasia Suprarrenal Congénita/genética , Tumor de Resto Suprarrenal/epidemiología , Tumor de Resto Suprarrenal/etiología , Estudios de Cohortes , Neoplasias Testiculares/epidemiología , Neoplasias Testiculares/complicaciones , Niño

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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.

Asunto(s)

Aborto Espontáneo , Enfermedad Trofoblástica Gestacional , Embarazo , Femenino , Humanos , Aborto Espontáneo/epidemiología , Aborto Espontáneo/etiología , Aborto Espontáneo/psicología , Estudios Prospectivos , Ansiedad/etiología , Consejo

RESUMEN

OBJECTIVES: The objective of this study was to collect information on human Chorionic Gonadotrophin (hCG) laboratory testing and reporting in women with Gestational Trophoblastic Disease (GTD), to assess the associated challenges, and to offer perspectives on hCG testing harmonisation. DESIGN: Information was collected from laboratories by electronic survey (Survey Monkey®) using a questionnaire designed by members of the European Organisation for the Treatment of Trophoblastic Disease (EOTTD) hCG Working Party. PARTICIPANTS: The questionnaire was distributed by the EOTTD board to member laboratories and their associated scientists who work within the GTD field. SETTING: The questionnaire was distributed and accessed via an online platform. METHODS: The questionnaire consisted of 5 main sections. These included methods used for hCG testing, quality procedures, reporting of results, laboratory operational aspects, and non-GTD testing capability. In addition to reporting these survey results, examples of case scenarios which illustrate the difficulties faced by laboratories providing hCG measurement for GTD patient management were described. The benefits and challenges of using centralised versus non-centralised hCG testing were discussed alongside the utilisation of regression curves for management of GTD patients. RESULTS: Information from the survey was collated and presented for each section and showed huge variability in responses across laboratories even for those using the same hCG testing platforms. An educational example was presented, highlighting the consequence of using inappropriate hCG assays on clinical patient management (Educational Example A), along with an example of biotin interference (Educational Example B) and an example of high-dose hook effect (Educational Example C), demonstrating the importance of knowing the limitations of hCG tests. The merits of centralised versus non-centralised hCG testing and use of hCG regression curves to aid patient management were discussed. LIMITATIONS: To ensure the survey was completed by laboratories providing hCG testing for GTD management, the questionnaire was distributed by the EOTTD board. It was assumed the EOTTD board held the correct laboratory contact, and that the questionnaire was completed by a scientist with in-depth knowledge of laboratory procedures. CONCLUSIONS: The hCG survey highlighted a lack of harmonisation of hCG testing across laboratories. Healthcare professionals involved in the management of women with GTD should be aware of this limitation. Further work is needed to ensure an appropriate quality assured laboratory service is available for hCG monitoring in women with GTD.

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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.

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OBJECTIVE: Gestational trophoblastic diseases (GTD) comprise a group of rare diseases originating from the trophoblast affecting women of childbearing age. Providing optimal information to patients with a rare disease is challenging because of the small number of patients and limited clinical expertise of many healthcare professionals. Both knowledge and lack of knowledge in patients may influence illness perception. We investigated whether a web-based interactive intervention influences illness perception and knowledge in women with GTD. DESIGN: This was a multicenter randomized control trial conducted at general and academic hospitals in the Netherlands, including newly diagnosed GTD patients between 2017 and 2019. METHODS: Sixty-nine patients were randomized between direct access or postponed access to an online tool on GTD and received online questionnaires about illness perception, knowledge, and anxiety. The main outcome measures were illness perception (primary outcome measure) and knowledge (secondary outcome measure). RESULTS: Patients using the online tool were satisfied with the information from the tool (92%). Although they had a higher level of knowledge compared to the control group (p = 0.006), illness perception did not change. Also, no differences in levels of anxiety, depression, or distress were observed between the groups. LIMITATIONS: Participants had access to other information sources and many searched other websites. It is unknown what kind of websites were visited and when. It is unknown if the increased knowledge levels and low levels of distress will sustain over time as no long term follow-up took place. Healthcare professionals were not interviewed on how they experienced the consultation before and after using the tool by the patients. CONCLUSIONS: The online tool did not change illness perception but was shown to be valuable for newly diagnosed GTD patients to gain knowledge. The improvement in knowledge after digital education indicates that this tool can be used as an effective method of supporting GTD patients' informational needs without causing extra distress. TWEETABLE ABSTRACT: A web-based tool for trophoblastic disease does not change illness perception of patients but is valuable to gain knowledge.

Asunto(s)

Enfermedad Trofoblástica Gestacional , Intervención basada en la Internet , Embarazo , Humanos , Femenino , Enfermedad Trofoblástica Gestacional/terapia , Enfermedad Trofoblástica Gestacional/complicaciones , Ansiedad/etiología , Evaluación de Resultado en la Atención de Salud , Encuestas y Cuestionarios

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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.

Asunto(s)

Hiperplasia Suprarrenal Congénita , Humanos , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Indonesia , Esteroides/uso terapéutico , Cabello , Testosterona

RESUMEN

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.

Asunto(s)

Hiperplasia Suprarrenal Congénita , Humanos , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Hiperplasia Suprarrenal Congénita/diagnóstico , Glucocorticoides/uso terapéutico , Glucocorticoides/metabolismo , Hidrocortisona , Andrógenos , Oxigenasas de Función Mixta

RESUMEN

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.

Asunto(s)

Hiperplasia Suprarrenal Congénita , Tumor de Resto Suprarrenal , Neoplasias Testiculares , Hiperplasia Suprarrenal Congénita/complicaciones , Tumor de Resto Suprarrenal/genética , Hormona Adrenocorticotrópica , Adulto , Proteínas Quinasas Dependientes de AMP Cíclico , Feto , Humanos , Masculino , Receptores del Factor de Crecimiento Derivado de Plaquetas , Esteroide 11-beta-Hidroxilasa , Neoplasias Testiculares/complicaciones

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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.

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Coriocarcinoma , Enfermedad Trofoblástica Gestacional , Mola Hidatiforme , Animales , Anticuerpos , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor , Cricetinae , Cricetulus , Femenino , Enfermedad Trofoblástica Gestacional/metabolismo , Enfermedad Trofoblástica Gestacional/patología , Humanos , Inmunohistoquímica , Embarazo

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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.

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Hiperplasia Suprarrenal Congénita , Androstenodiona , 17-alfa-Hidroxiprogesterona/análisis , Adolescente , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Adulto , Anciano , Andrógenos , Niño , Preescolar , Voluntarios Sanos , Humanos , Persona de Mediana Edad , Esteroides , Resultado del Tratamiento , Adulto Joven

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Enfermedad Trofoblástica Gestacional , Mola Hidatiforme , Estudios de Cohortes , Femenino , Humanos , Embarazo , Estudios Prospectivos

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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.

Asunto(s)

Hiperplasia Suprarrenal Congénita , Hidrocortisona , 17-alfa-Hidroxiprogesterona , Adolescente , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Andrógenos/uso terapéutico , Niño , Preescolar , Estudios Cruzados , Femenino , Humanos , Masculino , Adulto Joven

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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.

Asunto(s)

Glándulas Suprarrenales/metabolismo , Hiperplasia Suprarrenal Congénita/sangre , Tumor de Resto Suprarrenal/sangre , Neoplasias Testiculares/sangre , Testículo/patología , Glándulas Suprarrenales/patología , Hiperplasia Suprarrenal Congénita/complicaciones , Hiperplasia Suprarrenal Congénita/genética , Hiperplasia Suprarrenal Congénita/patología , Tumor de Resto Suprarrenal/genética , Tumor de Resto Suprarrenal/patología , Tumor de Resto Suprarrenal/cirugía , Adulto , Androstenodiona/análogos & derivados , Androstenodiona/sangre , Androstenodiona/metabolismo , Estudios de Casos y Controles , Humanos , Hidroxitestosteronas/sangre , Hidroxitestosteronas/metabolismo , Masculino , Persona de Mediana Edad , Esteroide 21-Hidroxilasa/genética , Neoplasias Testiculares/genética , Neoplasias Testiculares/patología , Neoplasias Testiculares/cirugía , Testículo/metabolismo , Testículo/cirugía , Testosterona/análogos & derivados , Testosterona/sangre , Testosterona/metabolismo , Adulto Joven

RESUMEN

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.

Asunto(s)

Gonadotropina Coriónica/sangre , Enfermedad Trofoblástica Gestacional/sangre , Enfermedad Trofoblástica Gestacional/tratamiento farmacológico , Mola Hidatiforme/sangre , Mola Hidatiforme/tratamiento farmacológico , Metotrexato/uso terapéutico , Adulto , Antimetabolitos Antineoplásicos/uso terapéutico , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Femenino , Humanos , Mola Hidatiforme/patología , Modelos Logísticos , Metotrexato/farmacología , Nomogramas , Medicina de Precisión , Valor Predictivo de las Pruebas , Embarazo , Medición de Riesgo

RESUMEN

BACKGROUND: Plasma-free normetanephrine and metanephrine (metanephrines) are the recommended biomarkers for testing of pheochromocytoma and paraganglioma (PPGL). This study evaluated the status of harmonization of liquid chromatography-tandem mass spectrometry-based measurements of plasma metanephrines and methoxytyramine and clinical interpretation of test results. METHODS: 125 plasma samples from patients tested for PPGLs were analyzed in 12 laboratories. Analytical performance was also assessed from results of a proficiency-testing program. Agreement of test results from different laboratories was assessed by Passing-Bablok regression and Bland-Altman analysis. Agreement in clinical test interpretation based on laboratory specific reference intervals was also examined. RESULTS: Comparisons of analytical test results by regression analysis revealed strong correlations for normetanephrine and metanephrine (R ≥ 0.95) with mean slopes of 1.013 (range 0.975-1.078), and 1.019 (range 0.963-1.081), and intercepts of -0.584 (-53.736 to 54.790) and -3.194 (-17.152 to 5.933), respectively. The mean bias between methods was 1.2% (-11.6% to 16.0%) for metanephrine and 0.1% (-18.0% to 9.5%) for normetanephrine. Measurements of 3-methoxytyramine revealed suboptimal agreement between laboratories with biases ranging from -32.2% to 64.0%. Interrater agreement in test interpretation was >94% for metanephrine and >84% for normetanephrine; improvements in interrater agreement were observed with use of harmonized reference intervals, including age-specific cut-offs for normetanephrine. CONCLUSIONS: Analytical methods for metanephrines are well harmonized between laboratories. However, the 16% disagreement in test interpretation for normetanephrine suggests use of suboptimal method-dependent reference intervals for clinical decision-making for this metabolite. Improved analytical methods and reference interval harmonization are particularly required for 3-methoxytyramine.

Asunto(s)

Neoplasias de las Glándulas Suprarrenales , Metanefrina , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Cromatografía Liquida , Dopamina/análogos & derivados , Humanos , Normetanefrina , Espectrometría de Masas en Tándem