Dataset Information

Anti-Mullerian hormone and letrozole levels in boys with constitutional delay of growth and puberty treated with letrozole or testosterone.

ABSTRACT: STUDY QUESTION:Does treatment of constitutional delay of growth and puberty (CDGP) in boys with aromatase inhibitor letrozole (Lz) or conventional low-dose testosterone (T) have differing effects on developing seminiferous epithelium? SUMMARY ANSWER:Anti-Müllerian hormone (AMH) declined similarly in both treatment groups, and the two Sertoli cell-derived markers (AMH and inhibin B (iB)) exhibited differing responses to changes in gonadotrophin milieu. WHAT IS KNOWN ALREADY:Boys with CDGP may benefit from puberty-inducing medication. Peroral Lz activates gonadotrophin secretion, whereas intramuscular low-dose T may transiently suppress gonadotrophins and iB. STUDY DESIGN, SIZE, DURATION:Sera of 28 boys with CDGP who participated in a randomised, controlled, open-label trial at four paediatric centres in Finland between August 2013 and January 2017 were analysed. The patients were randomly assigned to receive either Lz (2.5 mg/day) (n?=?15) or T (1 mg/kg/month) (n?=?13) for 6 months. PARTICIPANTS/MATERIALS, SETTING, METHODS:The 28 patients were at least 14 years of age, showed first signs of puberty, wanted medical attention for CDGP and were evaluated at 0, 3, 6 and 12 months of visits. AMH levels were measured with an electrochemiluminescence immunoassay and Lz levels with liquid chromatography coupled with tandem mass spectrometry. MAIN RESULTS AND THE ROLE OF CHANCE:AMH levels decreased in both treatment groups during the 12-month follow-up (P?

SUBMITTER: Kohva E

PROVIDER: S-EPMC7048712 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Anti-Müllerian hormone and letrozole levels in boys with constitutional delay of growth and puberty treated with letrozole or testosterone.

Kohva E E Varimo T T Huopio H H Tenhola S S Voutilainen R R Toppari J J Miettinen P J PJ Vaaralahti K K Viinamäki J J Backman J T JT Hero M M Raivio T T

Human reproduction (Oxford, England) 20200201 2

<h4>Study question</h4>Does treatment of constitutional delay of growth and puberty (CDGP) in boys with aromatase inhibitor letrozole (Lz) or conventional low-dose testosterone (T) have differing effects on developing seminiferous epithelium?<h4>Summary answer</h4>Anti-Müllerian hormone (AMH) declined similarly in both treatment groups, and the two Sertoli cell-derived markers (AMH and inhibin B (iB)) exhibited differing responses to changes in gonadotrophin milieu.<h4>What is known already</h4> ...[more]

PMID: 31958337

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Project description:Constitutional delay of growth and puberty (CDGP) is the most common cause of pubertal delay. CDGP is defined as the proportion of the normal population who experience pubertal onset at least 2 SD later than the population mean, representing 2.3% of all adolescents. While adolescents with CDGP spontaneously enter puberty, they are at risk for short stature, decreased bone mineral density, and psychosocial problems. Genetic factors contribute heavily to the timing of puberty, but the vast majority of CDGP cases remain biologically unexplained, and there is no definitive test to distinguish CDGP from pathological absence of puberty during adolescence. Recently, we published a study identifying significant linkage between a locus at the pericentromeric region of chromosome 2 (chr 2) and CDGP in Finnish families. To investigate this region for causal variation, we sequenced chr 2 between the genomic coordinates of 79-124 Mb (genome build GRCh37) in the proband and affected parent of the 13 families contributing most to this linkage signal. One gene, DNAH6, harbored 6 protein-altering low-frequency variants (< 6% in the Finnish population) in 10 of the CDGP probands. We sequenced an additional 135 unrelated Finnish CDGP subjects and utilized the unique Sequencing Initiative Suomi (SISu) population reference exome set to show that while 5 of these variants were present in the CDGP set, they were also present in the Finnish population at similar frequencies. Additional variants in the targeted region could not be prioritized for follow-up, possibly due to gaps in sequencing coverage or lack of functional knowledge of non-genic genomic regions. Thus, despite having a well-characterized sample collection from a genetically homogeneous population with a large population-based reference sequence dataset, we were unable to pinpoint variation in the linked region predisposing delayed puberty. This study highlights the difficulties of detecting genetic variants under linkage regions for complex traits and suggests that advancements in annotation of gene function and regulatory regions of the genome will be critical for solving the genetic background of complex phenotypes like CDGP.

Project description:Aims/hypothesisGiven its role in ovarian follicle development, circulating anti-Müllerian hormone (AMH) is considered to be a marker of reproductive ageing. Although accelerated reproductive ageing has been associated with a higher risk of type 2 diabetes, research on the relationship between AMH and type 2 diabetes risk is scarce. Therefore, we aimed to investigate whether age-specific AMH levels and age-related AMH trajectories are associated with type 2 diabetes risk in women.MethodsWe measured AMH in repeated plasma samples from 3293 female participants (12,460 samples in total), aged 20-59 years at recruitment, from the Doetinchem Cohort Study, a longitudinal study with follow-up visits every 5 years. We calculated age-specific AMH tertiles at baseline to account for the strong AMH-age correlation. Cox proportional hazards models adjusted for confounders were used to assess the association between baseline age-specific AMH tertiles and incident type 2 diabetes. We applied linear mixed models to compare age-related AMH trajectories for women who developed type 2 diabetes with trajectories for women who did not develop diabetes.ResultsDuring a median follow-up of 20 years, 163 women developed type 2 diabetes. Lower baseline age-specific AMH levels were associated with a higher type 2 diabetes risk (HRT2vsT3 1.24 [95% CI 0.81, 1.92]; HRT1vsT3 1.62 [95% CI 1.06, 2.48]; ptrend?=?0.02). These findings seem to be supported by predicted AMH trajectories, which suggested that plasma AMH levels were lower at younger ages in women who developed type 2 diabetes compared with women who did not. The trajectories also suggested that AMH levels declined at a slower rate in women who developed type 2 diabetes, although differences in trajectories were not statistically significant.Conclusions/interpretationWe observed that lower age-specific AMH levels were associated with a higher risk of type 2 diabetes in women. Longitudinal analyses did not show clear evidence of differing AMH trajectories between women who developed type 2 diabetes compared with women who did not, possibly because these analyses were underpowered. Further research is needed to investigate whether AMH is part of the biological mechanism explaining the association between reproductive ageing and type 2 diabetes. Graphical abstract.

Project description:BackgroundPreviously, we reported a model for assessing ovarian reserves using 4 predictors: anti-Müllerian hormone (AMH) level, antral follicle count (AFC), follicle-stimulating hormone (FSH) level, and female age. This model is referred as the AAFA (anti-Müllerian hormone level-antral follicle count-follicle-stimulating hormone level-age) model.ObjectiveThis study aims to explore the possibility of establishing a model for predicting ovarian reserves using only 3 factors: AMH level, FSH level, and age. The proposed model is referred to as the AFA (anti-Müllerian hormone level-follicle-stimulating hormone level-age) model.MethodsOocytes from ovarian cycles stimulated by gonadotropin-releasing hormone antagonist were collected retrospectively at our reproductive center. Poor ovarian response (<5 oocytes retrieved) was defined as an outcome variable. The AFA model was built using a multivariable logistic regression analysis on data from 2017; data from 2018 were used to validate the performance of AFA model. Measurements of the area under the curve (AUC), sensitivity, specificity, positive predictive value, and negative predicative value were used to evaluate the performance of the model. To rank the ovarian reserves of the whole population, we ranked the subgroups according to the predicted probability of poor ovarian response and further divided the 60 subgroups into 4 clusters, A-D, according to cut-off values consistent with the AAFA model.ResultsThe AUCs of the AFA and AAFA models were similar for the same validation set, with values of 0.853 (95% CI 0.841-0.865) and 0.850 (95% CI 0.838-0.862), respectively. We further ranked the ovarian reserves according to their predicted probability of poor ovarian response, which was calculated using our AFA model. The actual incidences of poor ovarian response in groups from A-D in the AFA model were 0.037 (95% CI 0.029-0.046), 0.128 (95% CI 0.099-0.165), 0.294 (95% CI 0.250-0.341), and 0.624 (95% CI 0.577-0.669), respectively. The order of ovarian reserve from adequate to poor followed the order from A to D. The clinical pregnancy rate, live-birth rate, and specific differences in groups A-D were similar when predicted using the AFA and AAFA models.ConclusionsThis AFA model for assessing the true ovarian reserve was more convenient, cost-effective, and objective than our original AAFA model.

Dataset Information

Anti-Mullerian hormone and letrozole levels in boys with constitutional delay of growth and puberty treated with letrozole or testosterone.

Publications

Anti-Müllerian hormone and letrozole levels in boys with constitutional delay of growth and puberty treated with letrozole or testosterone.

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