Modulation of growth by aromatase inhibitor treatment in boys : Efficacy and safety

Without estrogen action, the fusion of the growth plates is postponed and statural growth continues for an exceptionally long time. Aromatase inhibitors, blockers of estrogen biosynthesis, have therefore emerged as a new potential option for the treatment of children with short stature. We investigated the efficacy of the aromatase inhibitor letrozole in the treatment of boys with idiopathic short stature (ISS) using a randomised, placebo-controlled, double-blind research setting. A total of 30 boys completed the two-year treatment. By decreasing estrogen-mediated central negative feedback, letrozole increased gonadotrophin and testosterone secretion in pubertal boys, whereas the pubertal increase in IGF-I was inhibited. Treatment with letrozole effectively delayed bone maturation and increased predicted adult height by 5.9 cm (P0.001), while placebo had no effect on either parameter. The effect of letrozole treatment on near-final height was studied in another population, in boys with constitutional delay of puberty, who received letrozole (n=9) or placebo (n=8) for one year, in combination with low-dose testosterone for six months during adolescence. The mean near-final height of boys randomised to receive testosterone and letrozole was significantly greater than that of boys who received testosterone and placebo (175.8 vs. 169.1 cm, P=0.04). As regards safety, treatment effects on bone health, lipid metabolism, insulin sensitivity, and body composition were monitored in boys with ISS. During treatment, no differences in bone mass accrual were evident between the treatment groups, as evaluated by dual-energy x-ray absorptiometry measurements of the lumbar spine and femoral neck. Bone turnover and cortical bone growth, however, were affected by letrozole treatment. As indicated by differences in markers of bone resorption (U-INTP) and formation (S-PINP and S-ALP), the long-term rate of bone turnover was lower in letrozole-treated boys, despite their more rapid advancement in puberty. Letrozole stimulated cortical bone growth in those who progressed in puberty: the metacarpal index (MCI), a measure of cortical bone thickness, increased more in letrozole-treated pubertal boys than in placebo-treated pubertal boys (25% vs. 9%, P=0.007). The change in MCI correlated positively with the mean testosterone-to-estradiol ratio. In post-treatment radiographic evaluation of the spine, a high rate of vertebral deformities - mild anterior wedging and mild compression deformities - were found in both placebo and letrozole groups. In pubertal boys with ISS treated with letrozole, stimulated testosterone secretion was associated with a decrease in the percentage of fat mass and in HDL-cholesterol, while LDL-cholesterol and triglycerides remained unchanged. Insulin sensitivity, as evaluated by HOMA-IR, was not significantly affected by the treatment. In summary, treatment with the aromatase inhibitor letrozole effectively delayed bone maturation and increased predicted adult height in boys with ISS. Long-term follow-up data of boys with constitutional delay of puberty, treated with letrozole for one year during adolescence, suggest that the achieved gain in predicted adult height also results in increased adult height. However, until the safety of aromatase inhibitor treatment in children and adolescents is confirmed, such treatment should be considered experimental.Estrogeenillä on tärkeä merkitys poikien kasvun säätelyssä. Estrogeenivaikutuksen puuttuessa luuston kypsyminen on hidasta, pitkien luiden kasvulevyt eivät sulkeudu murrosiän lopussa ja pituuskasvu jatkuu poikkeuksellisen kauan. Lyhyiden poikien hoitaminen aromataasi-inhibiittorilla, estrogeenisynteesin estäjällä, voi siten lisätä heidän aikuispituuttaan pitkittämällä kasvukautta. Tässä satunnaistetussa, lumekontrolloidussa ja kaksoissokotetussa kliinisessä lääketutkimuksessa selvitimme aromataasi-inhibiittorihoidon vaikutusta lyhyiden normaalin varianttien poikien (n=30) aikuispituusennusteeseen. Hypoteesimme oli, että hoito aromataasi-inhibiittori letrotsolilla kahden vuoden ajan lisää poikien aikuispituusennustetta hidastamalla luuston kypsymistä. Havaitsimme, että letrotsoli esti tehokkaasti sekä estradiolin että kasvutekijä IGF-I:n muodostumista ja kiihdytti testosteronin eritystä. Letrotsoli hidasti tehokkaasti luuston kypsymistä ja lisäsi aikuispituusennustetta 5.9 cm (P0.001); lumelääkkeellä hoidetuilla aikuispituusennuste ei hoidon aikana muuttunut. Selvitimme aromataasin eston vaikutusta aikuispituuteen mittaamalla viivästyneen murrosiän vuoksi aikaisemmin testosteroni-joudutushoidon ohella letrotsolia (n=9) tai lumelääkettä (n=8) vuoden ajan saaneiden poikien pituudet heidän lähestyessään aikuispituutta. Havaitsimme, että testosteroni-joudutushoidon yhteydessä letrotsolia saamaan satunnaistuneet pojat olivat merkitsevästi pitempiä kuin lumelääkettä saaneet (175.8 vs. 169.1 cm, P=0.04). Tutkimme aromataasi-inhibiittorihoidon turvallisuutta seuraamalla letrotsolin vaikutusta lyhyiden normaalin varianttien poikien luuston tiheyteen ja aineenvaihduntaan, rasva-aineenvaihduntaan ja insuliiniherkkyyteen. Lannerangan ja reisiluun kaulan luuston tiheys lisääntyi samalla tavalla letrotsolia ja lumelääkettä saaneilla hoidon aikana. Luuston aineenvaihdunnasta kertovien merkkiaineiden pitoisuudet olivat puolestaan matalammat letrotsolia saaneilla. Luuston kuorikerroksen paksuudesta kertova metakarpaali-indeksi kasvoi enemmän letrotsolia saaneilla kuin lumelääkettä saaneilla murrosikäisillä pojilla (25% vs. 9%, P=0.007). Metakarpaali-indeksin muutos korreloi positiivisesti testosteroni/estradioli-suhteen kanssa, viitaten siihen että hoidon aiheuttama testosteronitason nousu kiihdytti luun kuorikerroksen kasvua. Murrosikäisillä lyhyillä normaalin varianteilla pojilla letrotsoli laski HDL-kolesterolin pitoisuutta sekä rasvaprosenttia. Hoidon ei todettu merkittävästi vaikuttavan LDL-kolesteroliin, triglyserideihin tai insuliiniherkkyyteen. Yhteenvetona voidaan todeta että hoito aromataasi-inhibiittori letrotsolilla lisää merkittävästi lyhyiden normaalin varianttien poikien aikuispituusennustetta. Viivästyneen murrosiän vuoksi testosteroni-joudutushoitoa ja letrotsolia tai lumelääkettä saaneiden poikien pitkäaikaisseurannan perusteella hoito aromataasi-inhibiittorilla lisää myös aikuispituutta. Aromataasi-inhibiittorihoidon mahdolliset haittavaikutukset mm. luuston mikrorakenteeseen ja lujuuteen tulee sulkea pois tarkemmissa tutkimuksissa ennen kuin hoidon laajempaa käyttöönottoa lääketutkimusten ulkopuolella kasvavilla lapsilla tai nuorilla voi suositella

Quantification of urinary total luteinizing hormone immunoreactivity may improve the prediction of ovulation time

ObjectivesMost of the currently available ovulation prediction kits provide a relatively rough estimation of ovulation time with a short fertility window. This is due to their focus on the maximum probability of conception occurring one day before ovulation, with no follow-up after LH surge until ovulation nor during the subsequent days thereafter. Earlier studies have shown that urine of reproductive age women contains at least 3 different molecular forms of luteinizing hormone (LH); 1) intact LH, 2) LH beta-subunit (LH beta) and a 3) small molecular weight fragment of LH beta, LH beta core fragment (LH beta cf). The proportion of these LH forms in urine varies remarkably during the menstrual cycle, particularly in relation to the mid-cycle LH surge. In this exploratory study, we studied the potential implications of determining the periovulatory course of total LH immunoreactivity in urine (U-LH-ir) and intact LH immunoreactivity in serum (S-LH-ir) in the evaluation of the fertility window from a broader aspect with emphasis on the post-surge segment. MethodsWe determined total U-LH-ir in addition to intact S-LH-ir, follicle-stimulating hormone (FSH), progesterone, and estradiol in 32 consecutive samples collected daily from 10 women at reproductive age. Inference to the non-intact U-LH-ir levels was made by calculating the proportion of total U-LH-ir to intact S-LH-ir. ResultsTotal U-LH-ir increased along with LH surge and remained at statistically significantly higher levels than those in serum for 5 consecutive days after the surge in S-LH-ir. S-LH-ir returned to follicular phase levels immediately on the following day after the LH surge, whereas the same took 7 days for total U-LH-ir. ConclusionsThe current exploratory study provides preliminary evidence of the fact that U-LH-ir derived from degradation products of LH remains detectable at peak levels from the LH surge until ovulation and further during the early postovulatory period of fecundability. Thus, non-intact (or total) U-LH-ir appears to be a promising marker in the evaluation of the post-surge segment of the fertility window. Future studies are needed to unravel if this method can improve the prediction of ovulation time and higher rates of fecundability in both natural and assisted conception.Peer reviewe

Näyttö D-vitamiinilisien hyödystä kansantautien ehkäisyssä puuttuu

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Geenitiedon käyttö laajenee

Useita kansansairauksille altistavia geenejä pystytään jo tunnistamaan

100-vuotiaan insuliinin kahdet kasvot

Teema : insuliini

Näyttö D-vitamiinilisien hyödystä kansantautien ehkäisyssä puuttuu

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Geenitiedon käyttö laajenee

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Etiology of severe short stature below-3 SDS in a screened Finnish population

Objective: To describe the etiology of severe short stature in the Helsinki University Hospital district covering a population of 1.2 million that is subject to frequent growth monitoring and screening rules during childhood. Design: Retrospective cohort study. Design: Retrospective cohort study. Methods: We identified all subjects born 1990 or later with a height SD score Results: A pathological cause for short stature was diagnosed in 76% of the girls and 71% of the boys (P= NS). Syndromes were the most numerous pathological cause (n = 160; 20%), followed by organ disorders (n = 127; 16%), growth hormone deficiency (GHD, n = 94; 12%), SGA without catch-up growth (n = 73; 9%), and skeletal dysplasias (n = 57; 7%). Idiopathic short stature (ISS) was diagnosed in 210 (27%) subjects. The probability of growth-related pathology, particularly of a syndrome or skeletal dysplasia, increased with the shorter height SD score and the greater deviation from the target height. Sitting height to height SDS was increased in subjects with ISS, GHD, and SGA (all P <0.01). Conclusions: HeightPeer reviewe

Onset and progression of puberty in Klinefelter syndrome

Objective: Klinefelter syndrome (KS) (47,XXY and variants, KS) is the most common sex chromosome disorder in humans. However, little is known about the onset and progression of puberty in patients with KS. In this study, we describe the onset and progression of puberty in a large series of boys with KS in a single tertiary centre. Design and Patients: Retrospective data (Tanner stages, testicular length, testosterone supplementation, levels of luteinizing hormone [LH] and testosterone) before possible testosterone treatment on 72 KS patients with 47,XXY karyotype were reviewed, and G (n = 59 patients) and P (n = 56 patients) stages were plotted on puberty nomograms. Measurements and Results: One boy had a delayed onset of puberty, as he was at the G1 stage at the age of 13.8 years (-2.2 SDs). No observations of delay were made of boys at Stage G2. The progression of G stages was within normal limits in the majority of patients; only few boys were late at G3 (4.1%; 1 out of 24) and G4 (7.4%; 2 out of 27). Testosterone supplementation was started at the average age of 15.5 years to 35 boys (47%), 2 of whom were over 18 years old. LH level was on average 18.2 IU/L (SD: 6.3 IU/L) and testosterone 9.1 nmol/L (SD: 3.1 nmol/L) when testosterone supplementation was started. Conclusions: Our results suggest that puberty starts within the normal age limits in boys with KS, and testosterone supplementation is not needed for the initial pubertal progression in the majority of patients.Peer reviewe

The aetiology of extreme tall stature in a screened Finnish paediatric population

Publisher Copyright: © 2021 The AuthorsBackground: Extremely tall children (defined as height SDS (HSDS) ≥+3) are frequently referred to specialized healthcare for diagnostic work-up. However, no systematic studies focusing on such children currently exist. We investigated the aetiology, clinical features, and auxological clues indicative of syndromic tall stature in extremely tall children subject to population-wide growth monitoring and screening rules. Methods: Subjects with HSDS ≥+3 after three years of age born between 1990 and 2010 were identified from the Helsinki University Hospital district growth database. We comprehensively reviewed their medical records up to December 2020 and recorded underlying diagnoses, auxological data, and clinical features. Findings: We identified 424 subjects (214 girls and 210 boys) who fulfilled the inclusion criteria. Underlying growth disorder was diagnosed in 61 (14%) patients, in 36 (17%) girls and 25 (12%) boys, respectively (P=0•15). Secondary causes were diagnosed in 42 (10%) patients and the two most frequent secondary diagnoses, premature adrenarche, and central precocious puberty were more frequent in girls. Primary disorder, mainly Marfan or Sotos syndrome, was diagnosed in 19 (4%) patients. Molecular genetic studies were used as a part of diagnostic work-up in 120 subjects. However, array CGH or next-generation sequencing studies were seldom used. Idiopathic tall stature (ITS) was diagnosed in 363 (86%) subjects, and it was considered familial in two-thirds. Dysmorphic features or a neurodevelopmental disorder were recorded in 104 (29%) children with ITS. The probability of a monogenic primary growth disorder increased with the degree of tall stature and deviation from target height. Interpretation: A considerable proportion of extremely tall children have an underlying primary or secondary growth disorder, and their risk is associated with auxological parameters. Clinical features related to syndromic tall stature were surprisingly frequent in subjects with ITS, supporting the view that syndromic growth disorders with mild phenotypes may be underdiagnosed in extremely tall children. Our results lend support to comprehensive diagnostic work-up of extremely tall children. Funding: Päivikki and Sakari Sohlberg Foundation, Foundation for Pediatric Research, and Helsinki University Hospital research grants.Peer reviewe