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STUDY QUESTION: What is the peripubertal outcome of recombinant human FSH (r-hFSH) treatment during minipuberty in boys with congenital hypogonadotropic hypogonadism (CHH)? SUMMARY ANSWER: Sertoli-cell response to r-hFSH, given during the minipuberty of infancy, appears insufficient to maintain Sertoli cell function throughout childhood, as evaluated by inhibin B measurements. WHAT IS KNOWN ALREADY: Severe CHH in boys can be diagnosed during the minipuberty of infancy. Combined gonadotropin treatment at that age is suggested to improve testicular endocrine function and future fertility, yet long-term evidence is lacking. STUDY DESIGN, SIZE, DURATION: In this retrospective cohort study, we describe five CHH boys treated with r-hFSH in Helsinki University Hospital or Kuopio University Hospital between 2004 and 2018. Immediate follow-up data (0.1-1.4 months after cessation of the gonadotropin therapy) was available for four boys and long-term observations (at the age of 10.0-12.8 years) was available for three boys. As a retrospective control cohort, we provide inhibin B values of eight untreated CHH boys at the age of 12.7-17.8 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Four patients had combined pituitary hormone deficiency, and one had CHARGE syndrome due to a CHD7 mutation. The patients were treated at the age of 0.7-4.2 months with r-hFSH (3.4 IU/kg-7.5 IU/kg per week in 2 or 3 s.c. doses for 3-4.5 months) combined with T (25 mg i.m. monthly for three months for the treatment of micropenis). Inhibin B was chosen as the primary outcome measure. MAIN RESULTS AND THE ROLE OF CHANCE: During the r-hFSH + T treatment, inhibin B increased from 76 ± 18 ng/l to 176 ± 80 ng/l (P = 0.04) and penile length increased by 81 ± 50% (P = 0.04). Unexpectedly, two boys with robust inhibin B responses in infancy demonstrated low inhibin B values in peripuberty: declining from 290 ng/l (4 months) to 16 ng/l (12.4 years), and from 207 ng/l (6 months) to 21 ng/l (12.8 years). All boys underwent orchiopexy at 2.0 ± 0.7 years of age. Inhibin B values in long-term follow-up, available for the three boys, did not significantly differ from the untreated CHH controls. LIMITATIONS, REASONS FOR CAUTION: Limitations of this retrospective study are the small number and heterogeneity of the patients and their treatment schemes. WIDER IMPLICATIONS OF THE FINDINGS: We describe the first long-term follow-up data on CHH boys treated with r-hFSH and T as infants. The results from this small patient series suggest that the effects of infant r-hFSH treatment may be transient, and further longitudinal studies are required to determine the efficacy of this treatment approach to optimise the fertility potential in this patient population. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Finnish foundation for Pediatric Research, the Academy of Finland and the Emil Aaltonen Foundation. The authors have no competing interests. TRIAL REGISTRATION NUMBER: Non-applicable.
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Gonadotropinas/deficiência , Hipogonadismo/tratamento farmacológico , Puberdade/efeitos dos fármacos , Células de Sertoli/efeitos dos fármacos , Adolescente , Criança , Pré-Escolar , Quimioterapia Combinada/métodos , Hormônio Foliculoestimulante Humano/administração & dosagem , Seguimentos , Gonadotropinas/sangue , Humanos , Hipogonadismo/sangue , Hipogonadismo/congênito , Hipogonadismo/diagnóstico , Lactente , Inibinas/sangue , Inibinas/metabolismo , Estudos Longitudinais , Masculino , Puberdade/sangue , Proteínas Recombinantes/administração & dosagem , Estudos Retrospectivos , Células de Sertoli/metabolismo , Índice de Gravidade de Doença , Testosterona/administração & dosagem , Resultado do TratamentoRESUMO
PURPOSE: α2C-Adrenoceptors share inhibitory presynaptic functions with the more abundant α2A-adrenoceptor subtype, but they also have widespread postsynaptic modulatory functions in the brain. Research on the noradrenergic system of the human brain has been hampered by the lack of suitable PET tracers targeted to the α2-adrenoceptor subtypes. METHODS: PET imaging with the specific α2C-adrenoceptor antagonist tracer [(11)C]ORM-13070 was performed twice in six healthy male subjects to investigate the test-retest reliability of tracer binding. RESULTS: The bound/free ratio of tracer uptake relative to nonspecific uptake into the cerebellum during the time interval of 5 - 30 min was most prominent in the dorsal striatum: 0.77 in the putamen and 0.58 in the caudate nucleus. Absolute test-retest variability in bound/free ratios of tracer ranged from 4.3 % in the putamen to 29 % in the hippocampus. Variability was also <10 % in the caudate nucleus and thalamus. Intraclass correlation coefficients (ICC) ranged from 0.50 in the hippocampus to 0.89 in the thalamus (ICC >0.70 was also reached in the caudate nucleus, putamen, lateral frontal cortex and parietal cortex). The pattern of [(11)C]ORM-13070 binding, as determined by PET, was in good agreement with receptor density results previously derived from post-mortem autoradiography. PET data analysis results obtained with a compartmental model fit, the simplified reference tissue model and a graphical reference tissue analysis method were convergent with the tissue ratio method. CONCLUSION: The results of this study support the use of [(11)C]ORM-13070 PET in the quantitative assessment of α2C-adrenoceptors in the human brain in vivo. Reliable assessment of specific tracer binding in the dorsal striatum is possible with the help of reference tissue ratios.
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Encéfalo/diagnóstico por imagem , Dioxanos/farmacocinética , Piperazinas/farmacocinética , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/farmacocinética , Receptores Adrenérgicos alfa 2/metabolismo , Adulto , Humanos , Masculino , Reprodutibilidade dos Testes , Distribuição TecidualRESUMO
PURPOSE: (11)C-labelled 1-[(S)-1-(2,3-dihydrobenzo[1,2]dioxin-2-yl)methyl]-4-(3-methoxy-methylpyridin-2-yl)-piperazine ((11)C-ORM-13070) is a novel PET tracer for imaging of α2C-adrenoceptors in the human brain. Brain α2C-adrenoceptors may be therapeutic targets in several neuropsychiatric disorders, including depression, schizophrenia and Alzheimer's disease. To validate the use of (11)C-ORM-13070 in humans, we investigated its radiometabolism, pharmacokinetics, whole-body distribution and radiation dose. METHODS: Radiometabolism was studied in a test-retest setting in six healthy men. After intravenous injection of (11)C-ORM-13070, blood samples were drawn over 60 min. Plasma samples were analysed by radio-HPLC for intact tracer and its radioactive metabolites. Metabolite-corrected plasma time-activity curves were used for calculation of pharmacokinetics. In a separate group of 12 healthy men, the whole-body distribution of (11)C-ORM-13070 and radiation exposure were investigated by dynamic PET/CT imaging without blood sampling. RESULTS: Two radioactive metabolites of (11)C-ORM-13070 were detected in human arterial plasma. The proportion of unchanged (11)C-ORM-13070 decreased from 81 ± 4 % of total radioactivity at 4 min after tracer injection to 23 ± 4 % at 60 min. At least one of the radioactive metabolites penetrated into red blood cells, while the parent tracer remained in plasma. The apparent elimination rate constant and corresponding half-life of unchanged (11)C-ORM-13070 in arterial plasma were 0.0117 ± 0.0056 min(-1) and 73.6 ± 35.8 min, respectively. The organs with the highest absorbed doses were the liver (12 µSv/MBq), gallbladder wall (12 µSv/MBq) and pancreas (9.1 µSv/MBq). The mean effective dose was 3.9 µSv/MBq, with a range of 3.6 - 4.2 µSv/MBq. CONCLUSION: (11)C-ORM-13070 was rapidly metabolized in human subjects after intravenous injection. The effective radiation dose of (11)C-ORM-13070 was in the same range as that of other (11)C-labelled brain receptor tracers. An injection of 500 MBq of (11)C-ORM-13070 would expose a subject to 2.0 mSv of radiation. This supports the use of (11)C-ORM-13070 in repeated PET scans, for example, in receptor occupancy trials with novel drug candidates.
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Encéfalo/diagnóstico por imagem , Dioxanos/farmacocinética , Piperazinas/farmacocinética , Tomografia por Emissão de Pósitrons , Doses de Radiação , Compostos Radiofarmacêuticos/farmacocinética , Receptores Adrenérgicos alfa 2/metabolismo , Adulto , Humanos , Ligantes , Masculino , Ligação Proteica , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/sangue , Distribuição TecidualRESUMO
This article addresses the differences between girls and boys in the disclosure of sexual violence. The dataset combines data from the Finnish Child Victim Survey (FCVS) of 2008 (N = 13,459) and 2013 (N = 11,364), focusing on victims of sexual violence, ages 11 to 17 years, from the perspectives of disclosure and gender. Frequency and percentage analysis, cross tabulation, and a Chi-square test were used in the analysis. In the FCVS for both years, around 85% of the victims were girls. In almost two-thirds of the cases, the offender was a relative, friend, or some other known person, while in more than one-third of the cases, the offender was unknown to the victim. The second most common case was that the victim knew the offender, who was not, however, a friend. Sexual violence was found to be, in many ways, gendered. Most of the victims were girls, and most of the offenders were men. There was also a gender difference in the disclosure of experiences. Twenty-one percent of the girls and 45% of the boys reported that they had not told anyone about their experiences. Irrespective of the type of offender, the victims most often (63%) told a peer about their experiences, while 23% told parents, and only 10% told authorities. Moreover, victims reported shame and fear, distrust toward adults, and disbelief that disclosure would be helpful as reasons for not disclosing their experiences. To address this problem, raising awareness of the phenomenon, promoting an atmosphere that supports disclosing experiences of sexual violence, and improving readiness to address them are required.
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Vítimas de Crime , Delitos Sexuais , Humanos , Masculino , Feminino , Adolescente , Criança , Delitos Sexuais/psicologia , Vítimas de Crime/psicologia , Vítimas de Crime/estatística & dados numéricos , Finlândia , Fatores Sexuais , Revelação , Abuso Sexual na Infância/psicologiaRESUMO
This study aims to estimate direct health-related costs for victims of intimate partner violence (IPV) using nationwide linked data based on police reports and two healthcare registers in Finland from 2015 to 2020 (N = 21,073). We used a unique register dataset to identify IPV victims from the data based on police reports and estimated the attributable costs by applying econometric models to individual-level data. We used exact matching to create a reference group who had not been exposed to IPV. The mean, unadjusted, attributable healthcare cost for victims of IPV was 6,910 per individual over the 5-year period after being first identified as a victim. When adjusting for gender, age, education, occupation, and mental-health- and pregnancy-related diagnoses, the mean attributable health-related cost for the 5 years was 3,280. The annual attributable costs of the victims were consistently higher than those for nonvictims during the entire study period. Thus, our results suggest that the adverse health consequences of IPV persist and are associated with excess health service use for 5 years after exposure to IPV. Most victims of IPV were women, but men were also exposed to IPV, although the estimates were statistically significant only for female victims. Victims of IPV were over-represented among individuals outside the labor force and lower among those who were educated. The total healthcare costs of victims of IPV varied according to the socioeconomic factors. This study highlights the need for using linked register data to understand the characteristics of IPV and to assess its healthcare costs. The study results suggest that there is a significant socioeconomic gradient in victimization, which could also be useful to address future IPV prevention and resource allocation.
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Vítimas de Crime , Violência por Parceiro Íntimo , Masculino , Gravidez , Humanos , Feminino , Pré-Escolar , Polícia , Saúde Mental , Custos de Cuidados de SaúdeRESUMO
BACKGROUND: The research on adverse childhood experiences (ACEs) has deepened our understanding of the long-lasting and cumulative effects of childhood adversities. However, the instruments measuring ACEs have several shortcomings, including limited item coverage, collapsing of items and response options, simplistic scoring, and inadequate psychometric assessments. OBJECTIVE: To design and conduct preliminarily psychometric testing for a brief new self-report instrument-the THL Adverse Childhood Experiences questionnaire (ACE-THL)-with a comprehensive set of clearly formulated items and appropriate response options. METHODS: A previously published process model was applied to develop the ACE-THL questionnaire, which was validated by cognitive interviews (N = 20). Interviewers and interviewees completed the questionnaire separately for a cross-informant comparison. In a separate survey panel validation, the respondents filled out the ACE-THL twice, two weeks apart (N = 513, with 426 in the follow-up). Interview data were used to improve item clarity, and test-retest reliability and structural validity were assessed with repeated survey data. RESULTS: The final 14-item questionnaire, including 12 ACE items and two items measuring protective experiences, was highly acceptable to the respondents. In the factor analysis of the quantitative data, a sufficiently single-dimensional construct was found, remaining stable in retesting two weeks later. The internal consistency (omega) of the a priori one-dimensional model was 0.89 and 0.90 at baseline and follow-up, respectively. The high test-retest reliability (mean score rank order correlation 0.93) of the ACE-THL indicated that the probed perceptions of childhood experiences are stable. CONCLUSION: Based on the initial validation, the 14-item ACE-THL questionnaire is a reliable and valid instrument to measure adverse childhood experiences, as well as protective experiences.
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Experiências Adversas da Infância , Humanos , Reprodutibilidade dos Testes , Inquéritos e Questionários , AutorrelatoRESUMO
Background: Childhood-onset combined pituitary hormone deficiency (CPHD) has a wide spectrum of etiologies and genetic causes for congenital disease. We aimed to describe the clinical spectrum and genetic etiologies of CPHD in a single tertiary center and estimate the population-level incidence of congenital CPHD. Methods: The retrospective clinical cohort comprised 124 CPHD patients (48 with congenital CPHD) treated at the Helsinki University Hospital (HUH) Children's Hospital between 1985 and 2018. Clinical data were collected from the patient charts. Whole exome sequencing was performed in 21 patients with congenital CPHD of unknown etiology. Findings: The majority (61%;76/124) of the patients had acquired CPHD, most frequently due to craniopharyngiomas and gliomas. The estimated incidence of congenital CPHD was 1/16 000 (95%CI, 1/11 000-1/24 000). The clinical presentation of congenital CPHD in infancy included prolonged/severe neonatal hypoglycaemia, prolonged jaundice, and/or micropenis/bilateral cryptorchidism in 23 (66%) patients; despite these clinical cues, only 76% of them were referred to endocrine investigations during the first year of life. The median delay between the first violation of the growth screening rules and the initiation of GH Rx treatment among all congenital CPHD patients was 2·2 years, interquartile range 1·2-3·7 years. Seven patients harbored pathogenic variants in PROP1, SOX3, TBC1D32, OTX2, and SOX2, and one patient carried a likely pathogenic variant in SHH (c.676G>A, p.(Ala226Thr)). Interpretation: Our study suggests that congenital CPHD can occur in 1/16 000 children, and that patients frequently exhibit neonatal cues of hypopituitarism and early height growth deflection. These results need to be corroborated in future studies and might inform clinical practice. Funding: Päivikki and Sakari Sohlberg Foundation, Biomedicum Helsinki Foundation, and Emil Aaltonen Foundation research grants.
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Background-Intimate partner violence (IPV) has both direct and longer-term effects on children's well-being. Much of the research thus far has relied on caregiver reports of IPV and clinical samples of children. By contrast, minimal research has examined violence between parents from the perspective of children using nationwide samples. Objective-This study explored the frequency of IPV witnessed by children and gender variations regarding the victims, perpetrators, and witnesses. Methods-The data were derived from a sample of 11,364 children from the Finnish Child Victim Survey 2013. The children were between 11 and 17 years old and were enrolled in the Finnish school system. The main methods of analysis included crosstabulation and the chi-square test. Results-The results indicate that children witnessed more IPV against their mother (4.9%) than their father (3.5%). Girls reported having witnessed more violence against both their mother (7.0%) and father (5.1%) than boys did (mothers 2.7%, fathers 1.8%). Girls' reports of IPV against both parents were twice or more than twice as common as boys' reports. Conclusions-The above differences might result from gendered expectations and boys' and girls' different relationships to violence, as well as differences in the recognition and interpretation of violent incidents. Therefore, practitioners should adopt a gender-sensitive approach as a precondition and practice for working with children in social and health care.
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Violência por Parceiro Íntimo , Caracteres Sexuais , Adolescente , Criança , Feminino , Finlândia/epidemiologia , Humanos , Masculino , Prevalência , ViolênciaRESUMO
CONTEXT: Congenital pituitary hormone deficiencies with syndromic phenotypes and/or familial occurrence suggest genetic hypopituitarism; however, in many such patients the underlying molecular basis of the disease remains unknown. OBJECTIVE: To describe patients with syndromic hypopituitarism due to biallelic loss-of-function variants in TBC1D32, a gene implicated in Sonic Hedgehog (Shh) signaling. SETTING: Referral center. PATIENTS: A Finnish family of 2 siblings with panhypopituitarism, absent anterior pituitary, and mild craniofacial dysmorphism, and a Pakistani family with a proband with growth hormone deficiency, anterior pituitary hypoplasia, and developmental delay. INTERVENTIONS: The patients were investigated by whole genome sequencing. Expression profiling of TBC1D32 in human fetal brain was performed through in situ hybridization. Stable and dynamic protein-protein interaction partners of TBC1D32 were investigated in HEK cells followed by mass spectrometry analyses. MAIN OUTCOME MEASURES: Genetic and phenotypic features of patients with biallelic loss-of-function mutations in TBC1D32. RESULTS: The Finnish patients harboured compound heterozygous loss-of-function variants (c.1165_1166dup p.(Gln390Phefs*32) and c.2151del p.(Lys717Asnfs*29)) in TBC1D32; the Pakistani proband carried a known pathogenic homozygous TBC1D32 splice-site variant c.1372â +â 1Gâ >â A p.(Arg411_Gly458del), as did a fetus with a cleft lip and partial intestinal malrotation from a terminated pregnancy within the same pedigree. TBC1D32 was expressed in the developing hypothalamus, Rathke's pouch, and areas of the hindbrain. TBC1D32 interacted with proteins implicated in cilium assembly, Shh signaling, and brain development. CONCLUSIONS: Biallelic TBC1D32 variants underlie syndromic hypopituitarism, and the underlying mechanism may be via disrupted Shh signaling.
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Proteínas Adaptadoras de Transdução de Sinal/genética , Biomarcadores/análise , Hipopituitarismo/etiologia , Mutação , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Hipopituitarismo/patologia , Lactente , Recém-Nascido , Masculino , Linhagem , Fenótipo , Prognóstico , Transdução de SinaisRESUMO
The initiation and maintenance of reproductive capacity in humans is dependent on pulsatile secretion of the hypothalamic hormone GnRH. Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder that results from the failure of the normal episodic GnRH secretion, leading to delayed puberty and infertility. CHH can be associated with an absent sense of smell, also termed Kallmann syndrome, or with other anomalies. CHH is characterized by rich genetic heterogeneity, with mutations in >30 genes identified to date acting either alone or in combination. CHH can be challenging to diagnose, particularly in early adolescence where the clinical picture mirrors that of constitutional delay of growth and puberty. Timely diagnosis and treatment will induce puberty, leading to improved sexual, bone, metabolic, and psychological health. In most cases, patients require lifelong treatment, yet a notable portion of male patients (â¼10% to 20%) exhibit a spontaneous recovery of their reproductive function. Finally, fertility can be induced with pulsatile GnRH treatment or gonadotropin regimens in most patients. In summary, this review is a comprehensive synthesis of the current literature available regarding the diagnosis, patient management, and genetic foundations of CHH relative to normal reproductive development.
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Hormônio Liberador de Gonadotropina , Gonadotropinas/administração & dosagem , Hipogonadismo , Adolescente , Adulto , Feminino , Hormônio Liberador de Gonadotropina/administração & dosagem , Hormônio Liberador de Gonadotropina/deficiência , Hormônio Liberador de Gonadotropina/metabolismo , Humanos , Hipogonadismo/congênito , Hipogonadismo/diagnóstico , Hipogonadismo/tratamento farmacológico , Hipogonadismo/metabolismo , Lactente , Recém-Nascido , MasculinoRESUMO
PURPOSE: The increasing interest in professional judgement and decision making is often separate from the discourse about "risk," and the time-honored focus on assessment. METHOD: The need to develop research in and across these topics was recognized in the founding of a Decisions, Assessment, and Risk Special Interest Group (DARSIG) by the European Social Work Research Association in 2014. RESULTS: The Group's interests include cognitive judgements; decision processes with clients, families, other professionals and courts; assessment tools and processes; the assessment, communication, and management of risk; and legal, ethical, and emotional aspects of these. This article outlines the founding and scope of DARSIG; gives an overview of decision making, assessment, and risk for practice; illustrates connections between these; and highlights future research directions. DISCUSSION: Professional knowledge about decision making, assessment, and risk complements knowledge about effectiveness of interventions. CONCLUSION: DARSIG promises to be a useful mechanism for the purpose.
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Tomada de Decisões , Julgamento , Serviço Social/organização & administração , Cognição , Europa (Continente) , Humanos , Conhecimento , Papel Profissional , Fatores de RiscoRESUMO
Biallelic, partial loss-of-function mutations in GNRHR cause a wide spectrum of reproductive phenotypes from constitutional delay of growth and puberty to complete congenital hypogonadotropic hypogonadism. We studied the frequency of GNRHR, FGFR1, TAC3, and TACR3 mutations in nine adolescent and young adult females with clinical cues consistent with partial gonadotropin deficiency (stalled puberty, unexplained secondary amenorrhea), and describe phenotypic features and molecular genetic findings of monozygotic twin brothers with stalled puberty. Two girls out of nine (22%, 95%CI 6-55%) carried biallelic mutations in GNRHR. The girl with compound heterozygous c.317A>G p.(Gln106Arg) and c.924_926delCTT p.(Phe309del) GNRHR mutations displayed incomplete puberty and clinical signs of hypoestrogenism. The patient carrying a homozygous c.785G>A p.(Arg262Gln) mutation presented with signs of hypoestrogenism and unexplained secondary amenorrhea. None of the patients exhibited mutations in FGFR1, TAC3, or TACR3. The twin brothers, compound heterozygous for GNRHR mutations c.317A>G p.(Gln106Arg) and c.785G>A p.(Arg262Gln), presented with stalled puberty and were discordant for weight, and the heavier of them had lower testosterone levels. These results suggest that genetic testing of the GNRHR gene should be offered to adolescent females with low-normal gonadotropins and unexplained stalled puberty or menstrual dysfunction. In male patients with partial gonadotropin deficiency, excess adipose tissue may suppress hypothalamic-pituitary-gonadal axis.
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Gonadotropinas/deficiência , Mutação , Receptores LHRH/genética , Adolescente , Adulto , Feminino , Humanos , Masculino , Adulto JovemRESUMO
INTRODUCTION: We describe the etiology, MRI findings, and growth patterns in girls who had presented with signs of precocious puberty (PP), i.e., premature breast development or early menarche. Special attention was paid to the diagnostic findings in 6- to 8-year-olds. MATERIALS AND METHODS: We reviewed the medical records of 149 girls (aged 0.7-10.3 years) who had been evaluated for PP in the Helsinki University Hospital between 2001 and 2014. RESULTS: In 6- to 8-year-old girls, PP was most frequently caused by idiopathic gonadotropin-releasing hormone (GnRH)-dependent PP (60%) and premature thelarche (PT; 39%). The former subgroup grew faster (8.7 ± 2.0 cm/year, n = 58) than the girls with PT (7.0 ± 1.1 cm/year, n = 32) (P < 0.001), and the best discrimination for GnRH-dependent PP was achieved with a growth velocity cut-off value of 7.0 cm/year (sensitivity 92% and specificity 58%) [area under the curve 0.82, 95% confidence interval (CI) 0.73-0.91, P < 0.001]. Among asymptomatic and previously healthy 6- to 8-year-old girls with GnRH-dependent PP, one (1.7%, 95% CI 0.3-9.7%) had a pathological brain MRI finding requiring surgical intervention (craniopharyngioma). In girls younger than 3 years, the most frequent cause of breast development was PT, and, in 3- to 6-year-olds, GnRH-dependent PP. CONCLUSION: In 6- to 8-year-old girls, analysis of growth velocity is helpful in differentiating between PT and GnRH-dependent PP. Although the frequency of clinically relevant intracranial findings in previously healthy, asymptomatic 6- to 8-year-old girls was low, they can present without any signs or symptoms, which favors routine MRI imaging also in this age group.