Duplications of the functional CYP21A2 gene are primarily restricted to Q318X alleles: evidence for a founder effect.

CONTEXT: Rare haplotypes with Q318X mutations and duplicated CYP21A2 genes have been reported to occur in different populations to a varying extent. Discrimination between a normal (Q318X mutation on one of the duplicated CYP21A2 genes) and a congenital adrenal hyperplasia (CAH, Q318X mutation without duplicated functional gene) allele is of importance, particularly for prenatal diagnosis and the respective genetic counseling. Although methods to differentiate between such alleles have been published only recently, it remains unclear with which frequency Q318X mutations are associated with duplicated CYP21A2 genes and whether these haplotypes have a common ancestry. SUBJECTS AND METHODS: Human leukocyte antigen (HLA) typing has been performed in 38 unrelated individuals and in 11 family members detected to carry a Q318X mutation in the course of CYP21 genotyping using sequence, multiplex ligation-dependent probe amplification, and Southern blot analyses. RESULTS: The majority (n = 32, 84.2%) of the 38 unrelated individuals carrying the Q318X mutation had the trimodular RCCX haplotype, carrying the Q318X mutation on a duplicated CYP21A2 gene. Twenty-two individuals of these 32 (68.8%) were of the rare HLA-B*50-Cw*06 haplotype, suggesting a common ancestry of this haplotype. In five (13.2%) of the 38 subjects, the Q318X mutation was not associated with a duplicated CYP21A2 gene and thus represents a CAH allele. None of these five patients had the above mentioned HLA haplotype. CONCLUSION: The majority of individuals in whom Q318X mutations are detected carry a duplicated functional CYP21A2 gene and the rare HLA-B*50-Cw*06 haplotype.

Seismic identification of along-axis hydrothermal flow on the East Pacific Rise.

Hydrothermal circulation at the axis of mid-ocean ridges affects the chemistry of the lithosphere and overlying ocean, supports chemosynthetic biological communities and is responsible for significant heat transfer from the lithosphere to the ocean. It is commonly thought that flow in these systems is oriented across the ridge axis, with recharge occurring along off-axis faults, but the structure and scale of hydrothermal systems are usually inferred from thermal and geochemical models constrained by the geophysical setting, rather than direct observations. The presence of microearthquakes may shed light on hydrothermal pathways by revealing zones of thermal cracking where cold sea water extracts heat from hot crustal rocks, as well as regions where magmatic and tectonic stresses create fractures that increase porosity and permeability. Here we show that hypocentres beneath a well-studied hydrothermal vent field on the East Pacific Rise cluster in a vertical pipe-like zone near a small axial discontinuity, and in a band that lies directly above the axial magma chamber. The location of the shallow pipe-like cluster relative to the distribution and temperature of hydrothermal vents along this section of the ridge suggests that hydrothermal recharge may be concentrated there as a consequence of the permeability generated by tectonic fracturing. Furthermore, we interpret the band of seismicity above the magma chamber as a zone of hydrothermal cracking, which suggests that hydrothermal circulation may be strongly aligned along the ridge axis. We conclude that models that suggest that hydrothermal cells are oriented across-axis, with diffuse off-axis recharge zones, may not apply to the fast-spreading East Pacific Rise.

A sea-floor spreading event captured by seismometers.

Two-thirds of Earth's surface is formed at mid-ocean ridges, yet sea-floor spreading events are poorly understood because they occur far beneath the ocean surface. At 9 degrees 50'N on the East Pacific Rise, ocean-bottom seismometers recently recorded the microearthquake character of a mid-ocean ridge eruption, including precursory activity. A gradual ramp-up in activity rates since seismic monitoring began at this site in October 2003 suggests that eruptions may be forecast in the fast-spreading environment. The pattern culminates in an intense but brief (approximately 6-hour) inferred diking event on 22 January 2006, followed by rapid tapering to markedly decreased levels of seismicity.

Implications for prediction and hazard assessment from the 2004 Parkfield earthquake.

Obtaining high-quality measurements close to a large earthquake is not easy: one has to be in the right place at the right time with the right instruments. Such a convergence happened, for the first time, when the 28 September 2004 Parkfield, California, earthquake occurred on the San Andreas fault in the middle of a dense network of instruments designed to record it. The resulting data reveal aspects of the earthquake process never before seen. Here we show what these data, when combined with data from earlier Parkfield earthquakes, tell us about earthquake physics and earthquake prediction. The 2004 Parkfield earthquake, with its lack of obvious precursors, demonstrates that reliable short-term earthquake prediction still is not achievable. To reduce the societal impact of earthquakes now, we should focus on developing the next generation of models that can provide better predictions of the strength and location of damaging ground shaking.

Loss of normal circadian profile of urine excretion in idiopathic restless legs syndrome.

BACKGROUND: This study was performed to elucidate preliminary observations of excessive nighttime urine excretion in idiopathic restless legs syndrome (iRLS). METHODS: Seventeen patients, with normal serum creatinine, blood urea nitrogen, and urate, and 11 healthy controls were examined. We measured excretory renal function parameters (urine volume, osmolarity, sodium, chloride, potassium, calcium, phosphate, microalbumin, aldosterone, creatinine) between 7:00 am and 10:00 pm and between 10:00 pm and 7:00 am. RESULTS: During the nighttime, volume (P=0.006), sodium (P=0.009), and chloride excretion (P=0.001) were significantly higher, and osmolarity (P=0.025) was significantly lower in patients as compared to controls. In comparing daytime to nighttime, controls showed the physiological reduced nocturnal excretion of volume (P=0.009) and chloride (P=0.023), and an increased osmolarity (P=0.026), but patients showed similar excretion rates of these parameters (all differences ns). CONCLUSIONS: These data indicate a loss of normal circadian profile of urine excretion in iRLS. The elevated nighttime excretion, with values similar to those in the daytime, hint at a possibly elevated fluid, sodium, and chloride intake during daytime.

Mutational spectrum of steroid 21-hydroxylase and the genotype-phenotype association in Middle European patients with congenital adrenal hyperplasia.

OBJECTIVE: To analyze the mutational spectrum of steroid 21-hydroxylase (CYP21) and the genotype- phenotype correlation in patients with congenital adrenal hyperplasia (CAH) registered in the Middle European Society for Pediatric Endocrinology CAH database, and to design a reliable and rational approach for CYP21 mutation detection in Middle European populations. DESIGN AND METHODS: Molecular analysis of the CYP21 gene was performed in 432 CAH patients and 298 family members. Low-resolution genotyping was performed to detect the eight most common point mutations. High-resolution genotyping, including Southern blotting and sequencing was performed to detect CYP21 gene deletions, conversions, point mutations or other sequence changes. RESULTS: CYP21 gene deletion and In2 and Ile172Asn mutation accounted for 72.7% of the affected alleles in the whole study group. A good genotype-phenotype correlation was observed, with the exception of Ile172Asn and Pro30Leu mutations. In 37% of patients low resolution genotyping could not identify the causative mutation or distinguish homozygosity from hemizygosity. Using high-resolution genotyping, the causative mutations could be identified in 341 out of 348 analyzed patients. A novel mutation Gln315Stop was found in one simple virilising CAH (SV-CAH) patient from Austria. In the remaining seven patients polymorphisms were identified as the leading sequence alteration. The presence of elevated basal and ACTH-stimulated 17-hydroxyprogesterone, premature pubarche, advanced bone age and clitoral hypertrophy directly implicated Asn493Ser polymorphism in the manifestation of nonclassical- (NC) and even SV-CAH. CONCLUSIONS: By genotyping for the most common point mutations, CYP21 gene deletion/conversion and the 8 bp deletion in exon 3, it should be possible to identify the mutation in 94-99% of the diseased alleles in any investigated Middle European population. In patients with a mild form of the disease and no detectable mutation CYP21 gene polymorphisms should be considered as a plausible disease-causing mutation.

Pineal gland abnormalities in Langerhans cell histiocytosis.

BACKGROUND: The most common types of central nervous system (CNS) disease in Langerhans cell histiocytosis (LCH) comprise involvement of the hypothalamic-pituitary region (HPR) and neurodegenerative changes in the cerebellum, basal ganglia or pons. In the review process of magnetic resonance images (MRI) from 129 LCH patients a high frequency of cysts within or large pineal glands was noted by chance. PROCEDURE: To prove whether this observation was specific for LCH or not, we compared MRI findings of the HPR in LCH patients with a control group of 55 non-LCH patients with the same age and sex distribution. RESULTS: In LCH patients, the pineal gland was significantly larger and also the number of pineal cysts was significantly higher as compared to the control group. No difference was found regarding the size or frequency of cystic changes between patients who had received chemotherapy prior to the MRI and untreated patients. In the LCH patients, we further found a significant correlation of pineal gland enlargement with involvement of the HPR, but not with neurodegenerative changes. Analysis of melatonin (the principal hormone of the pineal gland) levels in 24 hr urine in 14 LCH patients did not reveal a melatonin deficiency or overproduction in the LCH group as compared to 6 normal controls. CONCLUSIONS: The pineal gland is another site of possible CNS involvement in LCH. LCH CNS patients did not show an overt disturbance in melatonin levels. The role of the pineal gland in CNS LCH remains to be defined.

Congenital adrenal hyperplasia: lessons from a multinational study.

A study group of paediatric endocrinologists was established in Austria, Czech Republic, Hungary, Slovenia and Slovakia in order to investigate various aspects in children with congenital adrenal hyperplasia (CAH). Five hundred and ninety-eight patients with CAH who were diagnosed between 1969 and 1998 were included in order to analyze the following questions. Epidemiological data: There were significantly fewer males (43%) than females (57%), and the percentage of males did not increase during the observation period. Salt wasters (SW) totalled 64.7%, whereas 35.3% had simple virilizing (SV) CAH. Diagnosis was established significantly later in boys than in girls (median of 26 vs. 13 days for SW, p < 0.0001; 1,817 vs. 1,010 days for SV, p < 0.03). Mortality in the general population was significantly lower than in CAH siblings (1.8% vs. 7.0%, p < 0.0001) or in SW children (2.2% vs. 11.3%, p < 0.0001). According to our calculation with the present clinical diagnostic criteria in Central Europe, from 40 expected CAH patients/year, 2-2.5 SW, and one female and four male SV patients will not be diagnosed. Auxological data: Growth data from 341 patients were analyzed retrospectively. Percentiles were constructed in a longitudinal/cross-sectional study and pubertal growth was described in a longitudinal analysis. Growth of SW patients was impaired in early childhood (0-3 years), but followed a normal course until puberty. In contrast, SV children had a normal growth pattern during early childhood, but were above the standard thereafter. The pubertal growth spurt was of normal magnitude in boys and girls, but started too early. Final height was reduced compared with both standard and target heights. There was no correlation between final height and age of starting treatment or the year of birth. Bone age was accelerated in both CAH types, but more so in SV patients. Molecular genetics: Three hundred and fifty-six patients were investigated for 11-14 of the most frequent mutations by direct allele-specific polymerase chain reaction (PCR) and/or PCR followed by sequence-specific oligonucleotide, single strand chain polymorphism and restriction fragment length polymorphism. In the group as a whole, we most frequently found the Intron 2 splice mutation (30.8%) or a deletion/conversion (28.5%). The Intron 2 mutation was most frequent in the Hungarian population, whereas deletions/conversions were found more frequently in Slovenians. The other mutations had a similar distribution to those seen in other populations. Genotype-phenotype correlation confirms previous reports.

Melatonin production is similar in children with monosymptomatic nocturnal enuresis or other forms of enuresis/incontinence and in controls.

PURPOSE: Monosymptomatic nocturnal enuresis is a disorder, the precise etiology and pathomechanism of which remain unknown. An elevated sleep arousal threshold leading to deep sleep, and an amplitude disturbance in circadian arginine vasopressin secretion and urine production have been suggested as possible causes of the disease. The pineal hormone melatonin is allegedly implicated in the physiological sleep mechanism and circadian system. Melatonin serum levels are high at night and low during the day. The major metabolite of melatonin, 6-hydroxy-melatonin-sulfate (aMT6s), is excreted in the urine and is a good indicator of its production. We explore whether alterations in melatonin secretion assessed by its aMT6s excretion might be implicated in the pathomechanism of monosymptomatic nocturnal enuresis. MATERIALS AND METHODS: Urine was collected for 24-hour periods from 44 children with monosymptomatic nocturnal enuresis, 10 children with other forms of enuresis/incontinence (nonmonosymptomatic nocturnal enuresis) and 25 controls, and its aMT6s concentration was estimated using a commercially available radioimmunoassay. The total amount of aMT6s excreted per day was calculated. RESULTS: We found no significant differences in the amount of aMT6s excreted in a 24-hour period among patients with or without monosymptomatic nocturnal enuresis and controls with values of 17.6 microg. (1st to 3rd percentile 10.0 to 27.8) versus 13.4 (9.1 to 19.6) versus 21.5 (13.5 to 31.4), respectively. If aMT6s excretion was related to body weight, the result did not change. CONCLUSIONS: Our data do not indicate that alterations in melatonin production might be involved in the elevation of the sleep arousal threshold associated with deep sleep in children with monosymptomatic nocturnal enuresis.

Mutational spectrum of the steroid 21-hydroxylase gene in Austria: identification of a novel missense mutation.

This study attempted an analysis of the mutational spectrum of 21-hydroxylase deficiency in 79 unrelated Austrian patients with classical and nonclassical forms of congenital adrenal hyperplasia and their respective 112 family members. Apparent large gene deletions/conversions were present in 31% of the 158 unrelated congenital adrenal hyperplasia alleles, whereas the most frequent point mutations were intron 2 splice (22.8%), I172N (15.8%), V281L (12%), and P30L (7.6%), in line with the frequencies reported for other countries. In 5 of the 12 congenital adrenal hyperplasia alleles carrying a P30L mutation the aberration is based on a single base substitution, whereas the remaining 7 represent part of a CYP21B conversion (1 allele) or CYP21B/21A hybrid gene (6 alleles), the latter characterized by a junction site before intron 2 as indicated by Southern blot, PCR, and sequence analyses. Previously described mutations were not present in 1.2% of unrelated congenital adrenal hyperplasia alleles, including one female patient presenting with severe genital virilization. Sequence analysis of the complete functional 21-hydroxylase gene revealed an as yet undescribed mutation in exon 10-Arg(426)His, which has not yet been described to represent a common pseudogene sequence. In vitro expression experiments showed the Arg(426)His mutant to exhibit only low enzyme activity toward the natural substrate 17-hydroxyprogesterone corresponding to the degree of disease manifestation in the patient in whom it was found.

Growth patterns and final height in congenital adrenal hyperplasia due to classical 21-hydroxylase deficiency. Results of a multicenter study.

BACKGROUND: Longitudinal growth and bone age (BA) development are the most important clinical parameters for monitoring adequate glucocorticoid replacement in children with congenital adrenal hyperplasia (CAH). AIM OF THE STUDY: To analyze the growth pattern of patients treated for CAH of the salt wasting (SW) and simple virilizing (SV) clinical forms; to evaluate final height as compared to reference data and individual target height; to evaluate the course of BA development. PATIENTS AND METHODS: A large database of 598 patients with CAH was created in 5 Central European countries and growth data of 341 treated patients with 21-hydroxylase deficiency were analyzed retrospectively. The patients were of Caucasian origin. Centiles were constructed in a cross-sectional manner and an additional longitudinal analysis was performed in order to evaluate the pubertal growth spurt by applying particular statistical methods (Preece-Baines model). RESULTS: The growth of SW CAH patients was impaired in infancy and early childhood (0-3 years of age), but followed normal patterns in childhood until puberty. In contrast, children with SV CAH had normal patterns of growth in infancy and early childhood and were considerably taller than healthy references during childhood. In the longitudinal study, peak height velocity in both boys and girls was normal, but it occurred at an earlier age than in the standard population. The final height of patients with CAH was reduced in comparison to both the reference and the individual target height. No correlations were found between final height and age at the start of the therapy in SV patients or between final height and year of birth. BA was advanced in both types of CAH, but more accelerated in SV patients. CONCLUSION: Characteristic growth patterns for treated SV and SW CAH children were identified, with a normal pubertal growth spurt and reduced final height being observed.

Lessons from 30 years of clinical diagnosis and treatment of congenital adrenal hyperplasia in five middle European countries.

Despite the fact that congenital adrenal hyperplasia (CAH) is one of the most common inborn endocrine disorders, some patients are not identified, or may even die, in an acute salt-losing crisis. In a retrospective study covering the last 30 yr, we examined the time elapsing before diagnosis of CAH patients, in 5 Middle European countries, and the mortality rate in diagnosed patients and their siblings during childhood; we also attempted to estimate how many patients are not diagnosed clinically each year. Basic and follow-up clinical data and the family histories of 484 patients with classical forms of CAH diagnosed between 1969 and 1998 were collected and recorded in 5 Middle European countries. The sex-ratio, time elapsing before diagnosis, and mortality among siblings and patients were calculated, and the number of undiagnosed patients was estimated. We found significantly fewer genetic males (43.0%) than females (57.0%) among 484 classic CAH patients, and the percentage of diagnosed boys did not increase with time; 64.7% of them suffered from the salt-wasting (SW) form, and 35.3% from the simple virilizing (SV) form, of the disease. The diagnosis of CAH was established significantly later in males than in females in both forms [SW: 26 vs. 13 days (median), P < 0.0001; SV: 5.0 vs. 2.8 yr, P = 0.03]. Infant mortality in the general population was significantly lower than in either siblings (1.8% vs. 7.0%; P < 0.0001) or in SW (2.29% vs. 11.3%; P < 0.0001). According to our calculations, by our current praxis of clinical ascertainment, 2-2.5 SW and up to 5 SV stay undiagnosed, out of 40 expected CAH patients per year in the countries investigated. Both clinical detection and treatment of CAH patients, at least in males, were insufficient in the five Middle European countries examined during the last 30 yr. Neonatal mass screening and/or greater awareness of the medical community are discussed as ways of improving the efficacy of CAH management. Our experience may be applicable to other countries with similar health care systems.

Melatonin and adolescent idiopathic scoliosis.

Scoliosis seen in the chicken after pinealectomy resembles adolescent idiopathic scoliosis in man. It has been suggested that in both species, deficiency of the pineal hormone, melatonin, is responsible for this phenomenon. In nine patients with adolescent idiopathic scoliosis and in ten age- and gender-matched controls, the circadian levels of serum melatonin and the excretion of urinary 6-hydroxy-melatonin-sulphate, the principal metabolite of melatonin, were determined. There were no statistically significant differences in the secretion of serum melatonin or the excretion of urinary 6-hydroxy-melatonin-sulphate between the patients and the control group. The hypothesis of melatonin deficiency as a causative factor in the aetiology of adolescent idiopathic scoliosis cannot be supported by our data.

Measurement of urinary melatonin: a useful tool for monitoring serum melatonin after its oral administration.

The relevance of measuring urinary melatonin (MLT) for human pineal research is sometimes questioned, and the relationship among serum levels of MLT, urinary excretion of the unmetabolized hormone, and excretion of MLTs main metabolite, 6-hydroxymelatonin sulfate (aMT6s), is still uncertain. We applied a well established RIA for measuring MLT in serum to urine samples, characterized its criteria of performance in this body fluid, and used it for human studies. In 16 adolescents, the endogenous overnight MLT secretion, expressed as the area under the concentration time curve, correlated significantly with the amounts of urinary aMT6s (r = 0.86; P < 0.0001) and urinary MLT (r = 0.70; P = 0.0027) excreted during a 16-h observation period. Oral administration of 3 mg exogenous MLT in 17 healthy volunteers resulted in peak MLT serum levels differing 28-fold among subjects (940-27,240 pg/ mL; range). In this study urinary MLT, but not aMT6s, excretion was associated with blood MLT concentrations (r = 0.76; P = 0.0004 vs. r = 0.02; P = 0.93, respectively). Thus, endogenous MLT production can be assessed accurately by measuring either aMT6s or MLT excretion. After oral application of MLT, however, only measurement of MLT excretion is a reliable marker of serum concentrations. Determination of MLT in urine may prove to be a useful tool for drug monitoring after oral administration of the pineal hormone.

Treatment of nephrogenic diabetes insipidus with hydrochlorothiazide and amiloride.

Nephrogenic diabetes insipidus (NDI) is characterised by the inability of the kidney to concentrate urine in response to arginine vasopressin. The consequences are severe polyuria and polydipsia, often associated with hypertonic dehydration. Intracerebral calcification, seizures, psychosomatic retardation, hydronephrosis, and hydroureters are its sequelae. In this study, four children with NDI were treated with 3 mg/kg/day hydrochlorothiazide and 0.3 mg/kg/day amiloride orally three times a day for up to five years. While undergoing treatment, none of the patients had signs of dehydration or electrolyte imbalance, all showed normal body growth, and there was no evidence of cerebral calcification or seizures. All but one had normal psychomotor development and normal sonography of the urinary tract. However, normal fluid balance was not attainable (fluid intake, 3.8-7.7 l/m2/day; urine output, 2.2-7.4 l/m2/day). The treatment was well tolerated and no side effects could be detected. Prolonged treatment with hydrochlorothiazide/amiloride appears to be more effective and better tolerated than just hydrochlorothiazide. Its efficacy appears to be similar to that of hydrochlorothiazide/indomethacin but without their severe side effects.

Improved extraction procedure and RIA for determination of arginine8-vasopressin in plasma: role of premeasurement sample treatment and reference values in children.

We optimized an RIA for measurement of arginine8-vasopressin (AVP) in plasma by use of 100-mg Isolute C18 columns for extraction, addition of a preincubation step, and use of maximal dilution of a commercially available antiserum. The detection limit was 0.06 ng/L when 0.5 mL of acidified plasma was extracted. The within- and between-run CVs (n = 16) at physiological concentrations were 5.8-10. 2% and 6.5-11.7%, respectively. Prolonged storage of blood at 25 degreesC, but not at 4 degreesC, led to a significant increase in measured plasma AVP concentrations. When plasma samples were prepared at several centrifugation speeds, plasma AVP was significantly correlated with the platelet count (r = 0.899; P <0. 001). This emphasizes the need for careful sample preparation to avoid contamination of plasma with platelet-bound AVP. Basal plasma AVP in 203 children and adolescents (105 males and 98 females; ages, 1 day to 18 years) averaged 1.1 +/- 0.6 ng/L. There was no significant difference between males and females and no correlation with age. In 16 healthy adult controls, plasma AVP averaged 1.0 +/- 0.5 ng/L.

Hyperprolactinemia, a tool in treatment control of tetrahydrobiopterin deficiency: endocrine studies in an affected girl.

Severe tetrahydrobiopterin (BH4) deficiency is a naturally occurring model of cerebral catecholamine and serotonin shortage. Examination of the stimulated release and physiologic secretion pattern of several hormones in affected individuals permits certain conclusions concerning the involvement of these neurotransmitters in hormone regulation. Treatment, moreover, permits the ranking of the quality of the therapeutic regimens in use according to the degree of hormonal alteration. The 24-h secretion pattern of prolactin, GH, cortisol, and melatonin and the stimulated release of prolactin, GH, TSH, and gonadotropins were studied in an affected girl. Severe hyperprolactinemia with disruption of the pulsatile and circadian secretion pattern was the prevailing feature. The GH physiologic secretion pattern was not affected, but its stimulation was impaired. Melatonin displayed a normal circadian secretion pattern; the rhythm, however, was advanced by several hours. Conventional treatment of BH4 deficiency, i.e. BH4, 5-hydroxytryptophan, and L-DOPA/carbidopa (the last named given in three doses per day), suppresses prolactin levels merely for a few hours. L-DOPA/carbidopa given at shorter intervals or, even better, as a slow release preparation, is more effective in suppressing prolactin levels. Our data indicate immense hyperprolactinemia but few other hormonal disturbances in severe BH4 deficiency. Prolactin secretion may serve as an extremely sensitive marker for the hypothalamic dopamine content under different therapeutic regimens. Treatment with an L-DOPA/carbidopa slow release preparation produces virtually normal prolactin levels.

Age-related changes in melatonin levels in humans and its potential consequences for sleep disorders.

Prior to three months of age there is little melatonin (MLT) secretion in humans. MLT production then commences, becomes circadian, and reaches its highest nocturnal blood levels between the ages of one to three years. During the remainder of childhood, nocturnal peak levels drop progressively by 80%. In adults, these levels show an additional drop of some 10%, mainly during senescence. The large drop in serum MLT during childhood is probably the result of the increase in size of the human body, despite a constant MLT production after infancy. The additional decline of MLT with higher age may be due to a yet unidentified physiological mechanism accompanying senescence. The biological significance of these MLT alterations remains unknown. Since the discovery of MLT, an immediate sedative action of this hormone has been known. A number of recent studies have demonstrated that MLT indeed exerts a sleep-promoting action by accelerating sleep initiation, improving sleep maintenance, and marginally altering sleep architecture. The potential of MLT in the treatment of insomnia is being explored, and the results are promising. Although in most of these studies pharmacological dosages of MLT have been used, preliminary data suggest that similar effects can also be achieved by physiological hormone concentrations. The latter observation raises the question of whether MLT might be involved in the physiological control of sleep.

[Melatonin in the human--an overview]. / Melatonin beim Menschen--ein Uberblick.

Over the past two decades, the pineal gland with its major hormone, melatonin, has been shown to control the seasonal changes in a wide variety of species. Nevertheless, its place in human physiology is unclear at present. Melatonin is a hormone secreted during the dark period of the day. On comparing different age groups, serum melatonin concentrations are at a peak during early childhood, decline steadily until puberty, remain stable and, finally, decrease in elderly people. Melatonin appears to have a physiologic role as a nocturnal sleep inducer in man, but it might also have a certain effect on the human circadian rhythms, the reproductive and the immune system. Patients suffering from pineal tumors, disturbed sexual maturation or a phase shift in their circadian rhythms may also show altered serum melatonin levels. Exogenous melatonin shows a direct sedative-hypnotic action, with no serious toxic or side effects even after ingestion of large doses. Melatonin may gain importance as a natural hypnotic substance in the near future.