Trackerless ultrasound-integrated bone cement detection using a modular minirobot in revision total hip replacement.

Medical robots are superior to freehand manipulation if an accurate, precise, and time-efficient implementation of a preplanned intervention is required. In the first part of this contribution a new modular minirobot for automatic ultrasound-based bone cement detection followed by subsequent cement milling in revision total hip replacement is presented. A minirobot integrated ultrasound module eliminates the need for external position tracking (e.g. by an optical system) as well as patient registration since the scanned contours can be directly provided within the robot's coordinate system. Further, the modular minirobot concept allows kinematics, workspace, and mechanical parameters to be easily adapted to the requirements of related or even new surgical applications. In the experimental part, the impact of ultrasound module integration on the implementation of optimized scanning strategies is investigated and evaluated in a laboratory set-up. As wave mode conversion and refraction artefacts due to angular sound incidence influence the detection accuracy, the transducer alignment can be optimized with respect to the number of degrees of freedom (DOFs) provided by the minirobot. A model-based scanning approach using two degrees of freedom (2DOFs), three degrees of freedom (3DOFs), and four degrees of freedom (4DOFs) respectively is presented. For automated scanning path calculation, a 2DOF distal-proximal prescan has been performed to estimate the principal components of the cement cavity's geometry using either a model-based or a statistical approach. In a cadaver study, the model-based approach consistently outperformed the statistical approach. The 3DOFs and 4DOFs scanning strategies yielded a significantly higher scanning accuracy if compared with the 2DOFs approach whereas the 3DOFs approach represents a trade-off between system complexity and detection accuracy.

Robot- and computer-assisted craniotomy (CRANIO): from active systems to synergistic man-machine interaction.

Computer and robot assistance in craniotomy/craniectomy procedures is intended to increase precision and efficiency of the removal of calvarial tumours, enabling the preoperative design and manufacturing of the corresponding implant. In the framework of the CRANIO project, an active robotic system was developed to automate the milling processes based on a predefined resection planning. This approach allows for a very efficient milling process, but lacks feedback of the intra-operative process to the surgeon. To better integrate the surgeon into the process, a new teleoperated synergistic architecture was designed. This enables the surgeon to realize changes during the procedure and use their human cognitive capabilities. The preoperative planning information is used as guidance for the user interacting with the system through a master-slave architecture. In this article, the CRANIO system is presented together with this new synergistic approach. Experiments have been performed to evaluate the accuracy of the system in active and synergistic modes for the bone milling procedure. The laboratory studies showed the general feasibility of the new concept for the selected medical procedure and determined the accuracy of the system. Although the integration of the surgeon partially reduces the efficiency of the milling process compared with a purely active (automatic) milling, it provides more feedback and flexibility to the user during the intra-operative procedure.

A conditional tetracycline-regulated increase in Gamma amino butyric acid production near luteinizing hormone-releasing hormone nerve terminals disrupts estrous cyclicity in the rat.

Gamma amino butyric acid (GABA) is the main inhibitory neurotransmitter controlling LH-releasing hormone (LHRH) secretion in the mammalian hypothalamus. Whether alterations in GABA homeostasis within discrete regions of the neuroendocrine brain known to be targets of GABA action, such as the median eminence, can disrupt the ability of the LHRH releasing system to maintain reproductive cyclicity is not known but amenable to experimental scrutiny. The present experiments were undertaken to examine this issue. Immortalized BAS-8.1 astroglial cells were genetically modified by infection with a regulatable retroviral vector to express the gene encoding the GABA synthesizing enzyme glutamic acid decarboxylase-67 (GAD-67) under the control of a tetracycline (tet) controlled gene expression system. In this system, expression of the gene of interest is repressed by tet and activated in the absence of the antibiotic. BAS-8.1 cells carrying this regulatory cassette, and cultured in the absence of tet ("GAD on"), expressed abundant levels of GAD-67 messenger RNA and GAD enzymatic activity, and released GABA when challenged with glutamate. All of these responses were inhibited within 24 h of exposure to tet ("GAD off"). Grafting "GAD on" cells into the median eminence of late juvenile female rats, near LHRH nerve terminals, did not affect the age at vaginal opening, but greatly disrupted subsequent estrous cyclicity. These animals exhibiting long periods of persistent estrus, interrupted by occasional days in proestrus and diestrus, suggesting the occurrence of irregular ovulatory episodes. Administration of the tetracycline analog doxycycline (DOXY) in the drinking water inhibited GAD-67synthesis and restored estrous cyclicity to a pattern indistinguishable from that of control rats grafted with native BAS-8.1 cells. Animals carrying "GAD on" cells showed a small increase in serum LH and estradiol levels, and a marked elevation in serum androstenedione, all of which were obliterated by turning GAD-67 synthesis off in the grafted cells. Morphometric analysis of the ovaries revealed that both groups grafted with GABA-producing cells had an increased incidence of large antral follicles (>500 micrometer) compared with animals grafted with native BAS-8.1 cells, but that within this category the incidence of steroidogenically more active follicles (i.e. larger than 600 micrometer) was greater in "GAD on" than in "GAD off" rats. These results indicate that a regionally discrete, temporally controlled increase in GABA availability to LHRH nerve terminals in the median eminence of the hypothalamus suffices to disrupt estrous cyclicity in the rat, and raise the possibility that similar local alterations in GABA homeostasis may contribute to the pathology of hypothalamic amenorrhea/oligomenorrhea in humans.

Long-term outcome after depot gonadotropin-releasing hormone agonist treatment of central precocious puberty: final height, body proportions, body composition, bone mineral density, and reproductive function.

A considerable number of patients with central precocious puberty (CPP) treated with depot GnRH agonists have reached final height (FH). The aim of this prospective, multicentric study was the evaluation of the benefits, side-effects, and long term outcome of depot GnRH agonist therapy. We investigated 50 young women (mean +/- SD age, 16.7+/-2.6 yr; range, 12.9-23.4 yr) at FH. They received depot triptorelin over a period of 4.4+/-2.1 yr (range, 1.0-9.7 yr). Target height (TH) and predicted adult height (PAH) at the start of treatment were 163.6+/-6.2 and 154.9+/-9.6 cm, respectively (P < 0.05). FH was 160.6+/-8.0 cm (FH vs. TH, P = NS; FH vs. PAH, P < 0.05). Young patients showed the highest height gain (FH minus initial PAH). Seventy-eight percent of all patients reached a FH within their TH range. Even in young patients and those with an unfavorable initial PAH below the TH range, 60% reached a FH within their individual TH range. Standardized bone mineral density and standardized bone mineral density SD score investigated by dual energy x-ray absorptiometry of the lumbar spine (L1-L4) were 1040.9+/-124.2 mg/cm2 and 0.0+/-1.0; those of the femoral neck were 902.2+/-115.4 mg/cm2 and 0.2+/-1.0, respectively. The SD score of the ratio of sitting height over lower leg length was normal (0.3+/-1.2). Body mass index SD scores at pretreatment, at the end of treatment, and at FH were not significantly different (2.0+/-2.0, 2.0+/-2.0, and 1.7+/-2.2, respectively). Menarche or remenarche started at age 12.3+/-1.4 yr (range, 9.3-15.8 yr) in all patients. In conclusion, long term depot GnRH agonist treatment of CPP girls preserved genetic height potential and improved FH significantly combined with normal body proportions. No negative effect on bone mineral density and reproductive function was seen. Treatment neither caused nor aggravated obesity.

Labour-associated expression of intercellular adhesion molecule-1 (ICAM-1) in placental endothelial cells indicates participation of immunological processes in parturition.

Inflammatory cytokines induce or upregulate de novo expression of cell adhesion molecules on endothelial and epithelial cells. In order to demonstrate inflammatory reactions within placental tissues in association with normal term as well as non-infection-induced preterm labour, the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and endothelial leucocyte adhesion molecule-1 (ELAM-1) was examined by immunohistochemical methods in both trophoblastic villi (n=123) and umbilical cord (n=61). As a result, ICAM-1 immunoreactivity was exclusively localized in the endothelial cells of the fetal vascular system, while VCAM-1 and ELAM-1 were not detected. Whereas ICAM-1 was not expressed in early pregnancy (9-12 weeks of gestation), it could be weakly detected at the end of pregnancy in cases of elective caesarean delivery in the absence of labour, and was significantly more strongly expressed in cases of vaginal delivery after spontaneous onset of normal term labour. Significantly increased immunoreactivity of ICAM-1 within umbilical cord tissues was also found in association with uncontrollable preterm labour in the absence of intrauterine infection which was excluded after histological examination of fetal membranes, umbilical cord and chorionic plate. We conclude that ICAM-1 expression in the endothelium of the fetal vascular system is associated with the presence of labour and reflects participation of immune-inflammatory reactions in labour-promoting mechanisms.

Serum intercellular adhesion molecule-1 levels and histologic chorioamnionitis.

OBJECTIVE: To compare the diagnostic value of intercellular adhesion molecule (ICAM)-1 with that of C-reactive protein (CRP) and white blood cell (WBC) count for detecting histologic chorioamnionitis in serum of women with preterm labor. METHODS: Maternal blood was collected from 97 consecutive women admitted with preterm delivery before 37 weeks' gestation, and 50 women after normal term delivery (38-41 weeks' gestation). Intercellular adhesion molecule-1, CRP, and WBC count were measured before delivery. RESULTS: Histologic chorioamnionitis was diagnosed in 48 of 97 women (48%) who delivered preterm and in none who delivered at term. Maternal serum levels of ICAM-1 (median 169 ng/mL, range 94-510 ng/mL, P <.001), CRP (median 2.8 ng/mL, range 0.5-13.2 mg/dL, P <.001) and WBC count (12.6 x 10(3)/microL, range 6.4-30.6 x 10(3)/microL, P <.02) were statistically significantly higher in women with histologic chorioamnionitis than those without it (ICAM-1 median 70 ng/mL, range 23-107 ng/mL; CRP median 0.7 mg/dL, range 0.5-6.7 mg/dL; WBC count median 10.9 x 10(3)/microL, range 4.3-22.2 x 10(3)/microL). The sensitivity and specificity of maternal serum ICAM-1 (cutoff 106 ng/mL), CRP (cutoff 1.1 mg/dL), and WBC count (cutoff 11.8 x 10(3)/microL) for diagnosing histologic chorioamnionitis were 98.0% and 93.8%, 75.5% and 71.4%, and 63.3% and 61.2%, respectively. CONCLUSION: In women with preterm labor, ICAM-1 is a more reliable indicator of histologic chorioamnionitis than CRP or WBC count.

New thoughts on female precocious puberty.

Much effort has been devoted in recent years to unravel the neuroendocrine mechanisms responsible for the initiation of mammalian puberty. The concept that has emerged is that puberty results from the unfolding of a centrally originated process involving the concerted influence of neuronal systems that utilize excitatory and inhibitory amino acids as transmitters and astroglial networks that produce growth factors able to affect LHRH secretion. We discuss the idea that an isolated alteration of each of these components may result in the precocious activation of pulsatile LHRH release, and thus lead to idiopathic sexual precocity. According to this notion, such a premature activation of LHRH neuronal function would be neither associated with structural damage of the neuroendocrine brain system, nor related to a generalized activation of the neuronal-glial mechanisms underlying the onset of puberty. On the contrary, localized activation of discrete cellular subsets functionally connected to LHRH neurons would suffice to promote an increase in LHRH release of sufficient magnitude and duration to initiate the pubertal process.

Treatment of central precocious puberty: lessons from a 15 years prospective trial. German Decapeptyl Study Group.

There is still controversy about the auxological outcome of GnRH agonist treatment in patients with CPP and about the favorable age and auxological characteristics at start of treatment for achieving a normal final height (FH) or for preserving height potential. We analyzed the FH data of 52 young women from a prospective multicentric trial which was started in 1985. The aim of this analysis was to determine factors that may predict a favorable FH or a good height gain. Chronological age (CA) was 5.2 +/- 2.1 yr (+/- SD) at start of puberty, 6.2 +/- 2.0 yr at start of triptorelin depot treatment, 11.1 +/- 1.1 yr at end of treatment, and 16.7 +/- 2.6 yr at FH evaluation. After 4.8 +/- 2.2 yr (1.1-9.9 yr) of treatment duration, FH was 160.6 +/- 8.0 cm (vs 154.9 +/- 9.6 cm of initial height prediction [PAH], p<0.05). A FH within TH range or in excess of mean TH was achieved by 78% or 41% of patients. FH was above the 3rd percentile of the normal German population in 29% of patients (63% had an initial PAH < 156 cm). The group of patients with start of puberty at age < or = 6 yr (Group 1) showed a significantly higher height gain (FH - initial PAH) and lower height deficit compared to TH than older patients (Group 2). Furthermore, the percentage of patients from Group 1 reaching TH range or mean TH showed a significant increase with GnRH agonist treatment whereas this was not the case in Group 2. Stepwise regression analysis showed that height SDS at end of treatment, age at menarche, bone age (BA) at start of treatment, and BA advancement at end of treatment were determinants of FH (r2=0.923). Initial BA advancement and treatment duration were the factors that explained 68% of the variability of height gain. Although BA advancement at initiation of treatment was negatively associated with FH it was a positive predictor of height gain. In addition, height gain correlated significantly with CA and BA at start of treatment (r= -0.430, p=0.004 and r=0.359, p=0.018). Growth after interruption of treatment had no significant predictive effect on FH. It is concluded that a higher percentage of patients below 6 yr of age at start of puberty do profit from GnRH agonist treatment with respect to achieving a normal FH. BA, BA advancement, and height SDS at treatment start are important factors for determining outcome.

[What is the contribution of yeast genetics to tumor biology and tumor diagnosis?]. / Welchen Beitrag leistet die Hefegenetik zur Tumorbiologie und Tumordiagnostik?

This short review article discusses methods and results of oncogene research in yeast. Current knowledge of the sequence, expression and biological function of ras-homologous genes of the yeast Saccharomyces cerevisiae is presented, as well as the implications of these findings for oncogene research in mammals. We review recent examples of highly conserved eukaryotic genes involved in growth control and mitosis control, including recent work from our own laboratories.

[Visual user guidance for registration based on A-mode ultrasound]. / Visuelle Benutzerführung zur Referenzierung auf basis von A-Mode Ultraschall.

In this study we investigate the use of an A-Mode ultrasound probe tracked by a mechanical localizer system (MicroScribe 3D) for non-invasive transcutaneous palpation and registration of bone surface points. A CT of a femur-model has been scanned and subsequently processed by segmentation and 3D-reconstruction. During the ultrasound registration, a computer based assistance tool helped guiding the alignment of the ultrasound probe. Three different modes of registration have been compared. Process times for registration have been recorded and compared. The results for using an A-Mode ultrasound system demonstrate a translation RMS accuracy of 0.58 mm. Mean ultrasound registration time has been measured to 108 sec. for palpation of 10 bone surface points of distal part of femur.

Robot- and computer-assisted craniotomy: resection planning, implant modelling and robot safety.

BACKGROUND: In cases of cranial tumour, manual resection of the cancerous tissue can be very stressful and time-consuming, due to the adhesion of the subjacent dura mater. Computer-assisted planning, navigation and robotic craniotomy, with optional skull reconstruction using customized implants, are of increasing clinical interest in craniofacial and neurosurgery. METHODS: Using preoperative computed tomography (CT) images, an automatic segmentation of the tumour is performed, followed by resection planning. The skull reconstruction is performed using computer-assisted implant modeling and manufacturing. Risk analysis of the robot-guided intervention led to the development of a new hexapod robot system. RESULTS: Results from registration and robot accuracy on plastic and Anatomical skull are shown. The concept of a stand-alone safety system is presented to supervise the robot during the intervention. The entire process from preoperative CT scan to intraoperative robot assisted removal of tumourous bone is shown in laboratory and anatomical trials. CONCLUSION: The laboratory and anatomy studies conducted so far provided a substantial basis for further improvement of the system's integration in the surgical workflow and the final approval of the system for initial clinical studies.

Psychosocial aspects of patients with focal hyperhidrosis. Marked reduction of social phobia, anxiety and depression and increased quality of life after treatment with botulinum toxin A.

BACKGROUND: Primary focal hyperhidrosis (PFH) is defined as excessive sweating typically localized to specific body areas such as axillae, hands and feet. An association between PFH and anxiety as well as depressive syndromes has been suggested. OBJECTIVES: To investigate a possible association between PFH and anxiety, depression, social phobia and quality of life, and to study the effect of treatment with botulinum toxin A on these factors. METHODS: PFH was confirmed clinically and by gravimetry. To measure anxiety and depressive syndromes several German versions of standardized questionnaires were used: State-Trait Anxiety Inventory G Form X2 (STAI), Social Phobia Scale (SPS), Symptom Checklist of Derogatis (SCL-90-R), subscales 'Social Insecurity', 'Depression', 'Anxiety' and 'Phobia', and Hospital Anxiety and Depression Scale (HADS-D). Quality of life was assessed using Skindex. Two analyses were performed. The first analysis included all patients with PFH, the second analysis only patients with PFH who were treated with botulinum toxin A. In the latter group the questionnaires were repeated 2-4 weeks after treatment. RESULTS: For the total group at baseline the values for STAI, SCL-90-R, HADS-D and SPS were well within the normal range. However, in the group of patients treated with botulinum toxin A, the mean +/- SD SPS score was 17.6 +/- 15.5, i.e. above the normal range. Quality of life was impaired, with a mean +/- SD Skindex score of 24.3 +/- 5.7 at baseline. Treatment with botulinum toxin A led to a significant reduction in all investigated symptoms. CONCLUSIONS: Despite an impaired quality of life, patients with PFH in general do not show increased symptoms of anxiety, depression or social phobia. Only in the subgroup of patients treated with botulinum toxin A was the SPS increased at baseline. Treatment with botulinum toxin A led to a marked improvement in all factors investigated.

[Psychosomatic aspects of failed back syndrome: why low back pain becomes a chronic disorder]. / Zur Psychosomatik des Failed-back-Syndroms: warum Rückenschmerzen chronifizieren. Plädoyer für einen zeitgemässen Umgang mit den Lumbago-Ischialgie-Syndromen.

Low back pain (LBP) is a widespread disorder. The socioeconomic costs caused by LBP have been increasing dramatically over the past years. These high costs are mainly due to the relatively small percentage of chronic cases. Although the multitude of empirical findings available thus far offer an impressive body of knowledge about the mechanisms and factors responsible for chronification, most LBP-patients are still being treated without their psychosocial situation being taken into account. In addition to providing a discussion of the reasons underlying this imbalance along with a review of our present understanding of Failed Back Syndrome, this article also serves as an argument in favor of an interdisciplinary approach to the treatment of pain.

[Abdominal pain syndrome as the chief symptom of an anxiety and depressive disorder. Successful treatment with inpatient psychotherapy]. / Abdominelles Schmerzsyndrom als Leitsymptom einer Angst- und depressiven Störung. Erfolgreiche Behandlung durch stationäre Psychotherapie.

OBJECTIVE: Though frequently misinterpreted, gastrointestinal complaints are among the most common psychosomatic syndromes. CASE REPORT: The following report describes the case-history of a 60-year old woman, hospitalized for recurrent abdominal pain and diarrhoea. During the course of parallel internal and psychosomatic examinations an organic cause could be excluded and the psychogenesis of the complaints identified. RESULTS: Once the diagnosis of a somatoform disorder had been established the symptoms were successfully treated within the framework of in-patient psychotherapy. CONCLUSIONS: Anxiety and depressive disorder are often masked as abdominal pain. If detected, they can be successfully treated using a psychotherapeutic approach. Thus this article also points to the great importance of the availability of a psychosomatic consultation-liaison-service within general hospitals.

[Stumbling-blocks: initiating a psychosomatic pain clinic]. / Schwellenprobleme Erfahrungen beim Aufbau einer psychosomatischen Schmerzsprechstunde.

OBJECTIVE: Despite psychosocial factors playing an important role in the course of chronic pain disorder, there is a noticeable imbalance between demand and availability of psychosomatic care for these patients. This led us to establish a psychosomatic pain clinic within the framework of our outpatient clinic at the Department of Psychosomatic Medicine and Psychotherapy at the Central Institute of Mental Health, Mannheim, Germany. A recent study aimed at the evaluation of sociodemographic variables, state of chronification, symptom load and psychiatric comorbidity. Additionally we wanted to determine whether existing conditions at our hospital can be considered suitable for those patients. METHODS: During the clinic's first year we assessed 40 consecutive patients based on a psychosomatic interview as well as a set of psychometric questionnaires (BDI, STAI, SCL-90-R). To detect differences between pain patients and psychotherapy inpatients, we compared the two groups in terms of sociodemographic variables and symptom load. RESULTS: Most pain patients were in advanced states of chronification, showing extensive psychiatric comorbidity, particularly anxiety and depressive syndromes. Drug addiction was found more infrequently. Use of the before mentioned questionnaires prevented us from underestimating existing anxiety syndromes. Pain patients differed substantially from psychotherapy inpatients in terms of age, education, family status and symptom load. CONCLUSIONS: Our examination routine effectively demonstrated the special needs of chronic pain patients. As there is significant demand for psychosomatic intervention in those patients, earlier referral appears highly desirable. As pain patients differ also greatly from the remaining hospital population, specialized therapeutic concepts must be developed.

[Motivation for in-patient psychotherapy among patients of a psychosomatic pain clinic]. / Motivation zur stationären Psychotherapie bei Patienten einer Psychosomatischen Schmerzsprechstunde.

OBJECTIVE: For a number of pain patients inpatient psychotherapy is an adequate treatment. Many of these patients are lacking in motivation, though. The present study aimed at identifying factors associated with acceptance or rejection of inpatient psychotherapy. METHODS: 63 patients of a psychosomatic pain clinic underwent a multimodal assessment based on a psychosomatic interview as well as a set of psychodiagnostic questionnaires regarding sociodemographic factors, symptomatology (pain intensity, BSS, SCL-90-R, BDI), state of chronification, psychological defense mechanisms (DSQ) and biographic traumatisation (risk index). RESULTS: 71% of the patients were recommended in-patient psychotherapy. Among those, 63% accepted the recommendation, 27% rejected it. Among the patients who accepted in-patient psychotherapy, the extent of total psychological impairment as well as severity of depression and anxiety were more severe and the state of chronification tended to be less marked than in the rejecting group. Referring to sociodemographic variables, pain intensity,physical impairment and severity of biographic traumatisation,no significant difference between the groups could be shown. CONCLUSIONS: In our highly selected population the extent of psychiatric comorbidity and the state of chronification determined motivation for in-patient psychotherapy. Further studies should focus on unselected pain patients and on differences in motivation between various forms of psychotherapy.

Efficacy of the subcutaneous reformulated triptorelin depot in children with central precocious puberty.

The efficacy, safety and acceptance of newly formulated triptorelin s.c. (Decapeptyl Depot, DDsc) was compared to triptorelin i.m. (DDim) in seven children with central precocious puberty (CPP) in a prospective study. Both formulations were given for 6 months consecutively. During both treatment periods suppression of basal and gonadotropin-releasing hormone (GnRH)-stimulated levels of luteinizing hormone and follicle-stimulating hormone, suppression of sex steroids, arrest of the maturation of gonads and uterus, and slowing of bone maturation were achieved. The height standard deviation score for bone age increased significantly during DDsc treatment (-1.33+/-0.90 to 1.07+/-0.92, p < 0.05). The ratio bone age/chronological age decreased significantly during both treatment periods (1.25+/-0.24 to 1.20+/-0.23,p < 0.05, and 1.20+/-0.23 to 1.16+/-0.22, p < 0.05). With the injection of DDsc in the abdominal wall, a palpable, non-irritating resistance which gradually decreased in size occurred in one patient. With injection into the thigh no indurations were seen. No allergic reactions were encountered. Five of the patients considered DDsc therapy as more pleasant and described a definite decrease in fear of injections. All parents considered DDsc treatment as equal or better than DDim in respect to the suppression of their child' s puberty. It was concluded that DDsc is equipotent to DDim in the treatment of CPP. For the majority of patients DDsc was more acceptable than DDim. The thigh is recommended for the subcutaneous application of DD.

Serum leptin levels in patients with progressive central precocious puberty.

Leptin is a metabolic signal that may be involved in signaling adequacy of energy metabolism for the onset of reproductive function. The aim of this study was to investigate the relationship between leptin serum levels and pubertal development in girls with progressive central precocious puberty (CPP). We investigated longitudinally 14 girls with CPP before and during treatment with depot leuprorelin acetate. Mean (+/-SEM) chronological age and bone age at start of therapy were 6.0+/-0.6 y and 9.5+/-0.7 y, respectively. Leptin was determined by RIA. Girls with CPP showed no significant difference in leptin levels at pretreatment and after 1 and 2 y of treatment compared with healthy girls of the same body mass index (BMI). Mean leptin SD score adjusted for BMI was 0.31+/-0.4, 0.24+/-0.2, and 0.49+/-0.3, respectively (not significant). In a stepwise regression analysis model with BMI, bone age, chronological age, basal and stimulated LH, estradiol, dehydroepiandrosterone, androstenedione, and clinical pubertal signs, BMI was the only parameter that showed a significant correlation with leptin (p = 0.006). In conclusion, these data suggest that serum leptin levels are not significantly elevated at the onset of CPP compared with normal girls. Treatment with depot gonadotropin releasing hormone agonist seems to have no influence on leptin concentrations. As in normal girls, serum leptin levels in girls with CPP are mainly determined by BMI. Thus, we have no evidence that alterations of leptin are related to premature onset of puberty.