Dunkel, Leo

Leo Dunkel

Professor of Paediatric Endocrinology

Professor Dunkel graduated in Medicine in 1981 at the University of Helsinki, Finland and completed his residency in Paediatrics and Paediatric Endocrinology at the Hospital for Children and Adolescents, University of Helsinki. After his residency, he undertook postdoctoral training in the Division of Reproductive Biology at Stanford University. He worked at the University of Kuopio, Finland, as Chair of Paediatrics in the Department of Clinical Medicine, before moving to the UK in 2011.

In 2012, Professor Dunkel was appointed, alongside Professor Marta Korbonits, as Centre Lead for Endocrinology. He has served on the Editorial Boards of the Journal of Clinical Endocrinology and Metabolism and the Journal of Paediatric Endocrinology and Metabolism. Currently, he serves on the Editorial Board of Hormone Research in Paediatrics. He is a member of the Council and Programme Organising Committee of the European Society for Paediatric Endocrinology and is also leading the clinical work package in the EU Commission COST Action on GnRH deficiency.

Summary of Research

Paediatric Endocrinology Research Group

Professor Dunkel has a long-standing interest in the area of growth and puberty. In the past 10 years, he has focused on the regulation of linear growth. These studies have yielded evidence that inhibiting the biological action of oestrogen could provide efficacious therapies for the treatment of various growth disorders. Indeed these studies, which constitute a rationale for developing a conceptually new treatment modality for growth disorders, have culminated in the first two placebo-controlled clinical trials using a third-generation aromatase inhibitor to promote growth.

His current focus is on developing novel cell models to interrogate the genetic factors underlying the regulation of growth and the timing of sexual maturation through the GnRH neuronal network (see Figures 1 and 2). To this end, his group is generating induced pluripotent stem cell (iPSC) lines to study neuronal development and GnRH-neuron differentiation in patients with disorders of sexual maturation: constitutional delay in growth and puberty (CDGP), Kallman Syndrome (KS) and hypogonadotropic hypogonadism (HH). This platform promises to act as a basis for delineating the processes of neuronal maturation, for example, by genetically manipulating candidate gene expression in patient-generated iPSC. He is also sequencing the exomes of a large, well-characterized population of CDGP patients. Comparison of the resulting sequence data with existing GWAS data on growth and timing of puberty will inform his future studies aimed at unravelling the cellular biochemistry underlying the neuroendocrine control of sexual maturation. The work is supported by the COST Action on GnRH deficiency network.

Genetics of the timing of puberty

Figure 1. Genetics of the timing of puberty. A.
The precise genetic causes of the extreme tails of normal puberty are unclear, as is whether genetic variation in the causative genes contributes to pubertal timing in the general population (outside of families with GnRH deficiency or constitutional delay of puberty, CDGP). Identifying new genes that influence the timing of puberty, both delayed and precocious, will contribute to the understanding of the biological control of human pubertal timing both in disease and in the general population. This knowledge will directly aid patients through improved diagnostic ease and efficiency and facilitate identification of gene-environmental interactions. B. CDGP pedigrees. Based on the observed inheritance pattern, we hypothesize that families with inherited CDGP are enriched for genetic variants that have high-impact on pubertal timing; and that these variants are amenable to discovery using modern molecular genetic tools. Recently, we discovered a new gene that may influence the timing of puberty and significantly delay the onset of puberty in a subset of families.


Figure 2. Genes underlying GnRH deficiency.
Our latest genetic studies indicate that a previously uncharacterised gene contributes to the early development of gonadotropin-releasing hormone (GnRH) neurones. Disturbance of GnRH neuron development had not previously been implicated in simple delayed puberty and therefore our discovery identifies the involvement of a new biological pathway in the control of pubertal timing. We also have emerging evidence that this gene may be causal in some cases of hypogonadotrophic hypogonadism, where patients have complete pubertal failure due to GnRH deficiency.

 

Members of the Group

Leonardo Guasti (Lecturer)
Ariel Poliandri (PDRA)
Duncan Miller (PDRA)
Elena Monti (PDRA)
Sasha Howard (Wellcome Trust Clinical Training Fellow)
Muriel Meso (Btlc Clinical Training Fellow)
Harsini Katugampola (Clinical Training Fellow)
Shezan Elahi (Research nurse)

Key Publications

For a full list of publist publications click here

Sankilampi, U., Saari, A., Laine, T., Miettinen, P.J., and Dunkel, L. 2013. Use of electronic health records for automated screening of growth disorders in primary care. JAMA : the Journal of the American Medical Association 310:1071-1072.

Palmert , M., Dunkel, L. 2012. Delayed puberty. New England Journal of Medicine. 366:40-50.

Saari, A., Sankilampi, U., Hannila, M.L., Saha, M.T., Makitie, O., and Dunkel, L. 2012. Screening of Turner Syndrome with Novel Auxological Criteria Facilitates Early Diagnosis. The Journal of clinical endocrinology and metabolism. 10.1210/jc.2012-1739

Kuiri-Hänninen T, Kallio S, Seuri R, Tyrväinen E, Liakka A, Tapanainen J, Sankilampi U,  Dunkel L. 2011 Postnatal Developmental Changes in the Pituitary-Ovarian Axis in Preterm and Term Infant Girls The Journal of clinical endocrinology and metabolism 96: 3432-3439. 10.1097/OGX.0b013e318254713b

Kuiri-Hanninen, T., Seuri, R., Tyrvainen, E., Turpeinen, U., Hamalainen, E., Stenman, U.H., Dunkel, L., and Sankilampi, U. 2011. Increased activity of the hypothalamic-pituitary-testicular axis in infancy results in increased androgen action in premature boys. The Journal of clinical endocrinology and metabolism 96:98-105.

Vaaralahti, K., Wehkalampi, K., Tommiska, J., Laitinen, E.M., Dunkel, L., and Raivio, T. 2011. The role of gene defects underlying isolated hypogonadotropic hypogonadism in patients with constitutional delay of growth and puberty. Fertility and sterility 95:2756-2758. 10.1016/j.fertnstert.2010.12.059

Wehkalampi, K., Hovi, P., Dunkel, L., Strang-Karlsson, S., Jarvenpaa, A.L., Eriksson, J.G., Andersson, S., and Kajantie, E. 2011. Advanced pubertal growth spurt in subjects born preterm: the Helsinki study of very low birth weight adults. The Journal of clinical endocrinology and metabolism 96:525-533. 10.1210/jc.2010-1523

Hero, M., Toiviainen-Salo, S., Wickman, S., Makitie, O., and Dunkel, L. 2010. Vertebral morphology in aromatase inhibitor-treated males with idiopathic short stature or constitutional delay of puberty. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 25:1536-1543.

Tommiska, J., Wehkalampi, K., Vaaralahti, K., Laitinen, E.M., Raivio, T., and Dunkel, L. 2010. LIN28B in constitutional delay of growth and puberty. The Journal of clinical endocrinology and metabolism 95:3063-3066.

Wehkalampi, K., Widen, E., Laine, T., Palotie, A., and Dunkel, L. 2008. Association of the timing of puberty with a chromosome 2 locus. The Journal of clinical endocrinology and metabolism 93:4833-4839. 10.1210/jc.2008-0882

Wehkalampi, K., Widen, E., Laine, T., Palotie, A., and Dunkel, L. 2008. Patterns of inheritance of constitutional delay of growth and puberty in families of adolescent girls and boys referred to specialist pediatric care. The Journal of clinical endocrinology and metabolism 93:723-728. 10.1210/jc.2007-1786

Hero, M., Norjavaara, E., and Dunkel, L. 2005. Inhibition of estrogen biosynthesis with a potent aromatase inhibitor increases predicted adult height in boys with idiopathic short stature: a randomized controlled trial. The Journal of clinical endocrinology and metabolism 90:6396-6402.

Wikstrom, A.M., Raivio, T., Hadziselimovic, F., Wikstrom, S., Tuuri, T., and Dunkel, L. 2004. Klinefelter syndrome in adolescence: onset of puberty is associated with accelerated germ cell depletion. The Journal of clinical endocrinology and metabolism 89:2263-2270.

Wickman, S., Sipila, I., Ankarberg-Lindgren, C., Norjavaara, E., and Dunkel, L. 2001. A specific aromatase inhibitor and potential increase in adult height in boys with delayed puberty: a randomised controlled trial. Lancet 357:1743-1748.

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