An overview of central precocious puberty (CPP) delivered at Ipsen conference 'Navigating the Central Precocious Puberty (CPP) Journal' on 18 March 202

Davies, K.

English

LSBU Research Open

An Introduction to Central Precocious Puberty Kate DaviesAssociate ProfessorPaediatric Prescribing & EndocrinologyLondon South Bank UniversityHonorary Clinical Research FellowBarts and The London NHS Trust University College Hospital London NHS TrustTRI-UK-005039Date of preparation: March 2022This virtual promotional meeting is organized and funded by Ipsen. This meeting is intended for UK healthcare professionals only. Prescribing information can be found at the end of this virtual meeting. Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in Google Play or Apple App Store. Adverse events should also be reported to Ipsen via email at pharmacovigilance.uk-ie@ipsen.com or phone on 01753 627777.DisclosuresHonoraria- Ipsen Ltd- Novo Nordisk Ltd- Springer HealthcareIntroductionKey termsNormal puberty overviewWhat does Central Precocious Puberty mean?GirlsBoysTreatmentKey terms Puberty• Development of secondary sexual characteristics• Attain reproductive capacityAdrenarche• Onset of androgen dependent changesThelarche• Onset of female breast developmentBlair, J. C. and M. O. Savage (2002). Normal and Abnormal Puberty. Comprehensive Clinical Endocrinology. G. M. Besser and M. Thorner. Michigan, Mosby.Key termsGonadarche• Activation of reproductive glands by LH and FSHMenarche• Onset of menstruationSpermarche• Development of sperm in the testesTanner stagingDavies, K. (2020). "Biological basis of child health 7: growth, development and the reproductive system." Nurs Child Young People.Normal puberty?GirlsStarting pubertal development after the age of 8 years (average is 10 years)BoysStarting pubertal development after the age of 9 years (average is 12 years)Pyra, E. & Schwarz, W. (2019) Puberty: Normal, Delayed and Precocious. Advanced Practice in Endocrinology Nursing. S. Llahana, C. Follin, C. Yedinak et al. Cham, Springer. 1: 63 - 84.Hypothalamic Pituitary Gonadal (HPG) axisImage from https://www.dsdgenetics.org/index.php?id=48.Consonant puberty: girlsBreast growthAcceleration in height velocityPubic and axillary hair growthMenarcheConsonant puberty in boysTesticular growthGrowth of penis, pubic and axillary hair growthAcceleration in height velocityVoice deepens, facial hair growthMenarche6-10ml testesAdvanced pubertyBreast stage 2-3Facial hair and shavingBoys and girls normal pubertySorensen, K., et al. (2012). "Recent secular trends in pubertal timing: implications for evaluation and diagnosis of precocious puberty." Horm Res Paediatr 77(3): 137-145Pubertal timing influencesGeneticsGeneral health of the childEnvironmental factorsGeneticsFamily historyMother – Age at menarcheFather – Delayed growth spurt - Voice breakingSiblings - pubertal milestones• FSHR• Gene that encodes the FSH receptor• Variants• Later testicular growth• Later Thelarche• MKRN3 / DLK1 / Kisspeptin• Central precocious puberty• IGFS10• Delayed pubertyGeneral health of the child- Adequate nutrition- Obesity – increased BMI- Emotional and behaviouraldifficulties- Chronic disease• Full History• Craniospinal / gonadal / abdominal irradiation• Gonadal treatment• Testicular damage• Congenital anomalies• Chromosomal disordersRaine, J. E., et al., Eds. (2011). Practical endocrinology and diabetes in children. Chichester, Wiley - Blackwell.EnvironmentPhytoestrogens- Carrots, garlic, apple, coffee, cherryPesticides, herbicides, fungicidesDDTBPA (Bisphenol A)- Baby feeding bottlesJ Clin Res Ped Endo (2011) 3:1 pp1-6What about Central Precocious Puberty?Onset of clinical signs of puberty before the age of - 8 years in girls- 9.5 years in boysCAUSES?CNS lesionsLesions of the central nervous systemCerebral malformationsTraumaRadiationPyra, E. & Schwarz, W. (2019) Puberty: Normal, Delayed and Precocious. Advanced Practice in Endocrinology Nursing. S. Llahana, C. Follin, C. Yedinak et al. Cham, Springer. 1: 63 - 84.The most common cause?Hypothalamic Hamartoma• Congenital• Benign• Collection of neural tissueBase of third ventricleIncidence: 1: 100,000 children(Soriano-Guillen, L., & Argente, J. (2019). Central precocious puberty, functional and tumor-related. Best Pract Res Clin Endocrinol Metab, 33(3), 101262. doi:10.1016/j.beem.2019.01.003)Idiopathic CPP – no CNS lesion92% of girls- No cause in up to 2/3 of girls50% of boys- Identifiable cause more likelyHistory of familial CPP or adoption may be presentMuir, A. (2006). Precocious puberty. Pediatr Rev, 27(10), 373-381. doi:10.1542/pir.27-10-373What are the signs of CPP in girls?Breast development before 8 yrsPubic hair before 8 yrsMenarche before 10 yrsBreast development between 8 – 9yrs –Investigate if: Onset of development before 8 yrsHV >6cm/yr- Adult height prognosis below target heightRapid progression of pubertal development (from one stage to another in less than 6 months)Clinical evidence of a neurogenic aetiologyWhat are the signs of CPP in boys?Increase in testicular volume before the age of 9.5 yrsIncreased FSH productionTestosterone stimulation Pubic hair before the age of 9.5 yrsPubertal development before 10 yrs –Investigate if:HV >6cm/yr- Adult height prognosis below target heightRapid progression of pubertal developmentClinical evidence of a neurogenic aetiologyFigure adapted from  (Synovitz, L., & Chopak-Foss, J. (2013). Precocious puberty: Pathology, related risks, and support strategies. Open Journal of Preventive Medicine, 03(09), 504-509. doi:10.4236/ojpm.2013.39068)Familial CPPGeneticsMKRN3Nursing Children and Young People, March 2020Trends in pubertal developmentBoys • Not received the same attention• 1940s - Genitalia developmental trends been consistent Sorensen, K., et al. (2012). "Recent secular trends in pubertal timing: implications for evaluation and diagnosis of precocious puberty." Horm Res Paediatr 77(3): 137-145..Why?Incidence of CPP risenUnclear whyContributing factorsGeneticsEnvironmental factorsIncrease in obesity ManagementMain goal is to prevent early fusion of the epiphyseal growth platesEpiphyseal growth plateCartilaginous tissue with specific functions since growth begins until epiphysis is closed after pubertyThree different zones- The resting zone - Stem cells slowly replicate- The proliferative zone- Generate clones of chondrocytes- Replicate at high rate- Align in columns - Replication decreases as move away from epiphysis, and form- Hypertrophic zone- Cartilage attracts the blood vessels, osteoclasts, and differentiating osteoblasts, which remodel the newly formed cartilage into bone tissue.        Devesa, J., Almenglo, C., & Devesa, P. (2016). Multiple Effects of Growth Hormone in the Body: Is it Really the Hormone for Growth? Clin Med Insights Endocrinol Diabetes, 9, 47-71. doi:10.4137/CMED.S38201GnRH analoguesArtificially created moleculesSimiliar to the actual GnRH Affinity for GnRH receptors in the pituitaryglandCarel, JC et al (2009) Consensus Statement on the Use of Gonadotropin-Releasing Hormone Analogs in Children. Pediatrics April; 123 (4): e752–e762. 10.1542/peds.2008-1783Normal physiologyJones, R. & Lopez, K. (2014) Chapter 1 - Endocrinology, Brain, and Pituitary Gland, Editor(s): Richard E. Jones, Kristin H. Lopez, Human Reproductive Biology (Fourth Edition), Academic Press, Pages 3-22AGONIST• A drug that binds to a receptor• Causes activation and then cellular changesOne simulates the intended reaction, where an antagonist binds to the receptor, and stops/ slows responsesANTAGONIST• Reduces the effectof an agonist• Type of drug that blocks or dampens the biological responseHill, B & Allan, J (2021) Pharmacodynamics and pharmacokinetics in Fundamentals of Pharmacology for Nursing and Healthcare students Peate, I & Hill, B (Eds) Chapter 5, pp. 69 – 90, Wiley Blackwell, ChichesterGnRH agonistMore potent than native GnRHLonger half life than ‘native’ GnRHProduce initial stimulation of pituitary gonadotrophs ➢- Secretion of FSH and LH ➢- Expected gonadal response- Down regulation and inhibition of HPG axisSuppression of spontaneous ovulation- Ovarian stimulation – IVF - ICSI- Assisted reproductive technology- PP…?Kumar, P & Sharma, A. (2014) Gonadotrophin releasing hormone analogs: understanding advantages and limitations Journal of Human Reproductive Sciences 7;3 July – Sept pp.170 - 174GnRH antagonist‘Antagonize’ the GnRH receptorUsed for short periods to prevent the LH surge and ovulationPROMPTLY suppress pituitary gonadotrophins by GnRH receptor competition- Avoids initial stimulatory phase of the agonistsDiscontinuation- Rapid and predictable recovery of HPG axisPotential tool for ‘chemical hypophysectomy’ Jones, R. & Lopez, K. (2014) Chapter 1 - Endocrinology, Brain, and Pituitary Gland, Editor(s): Richard E. Jones, Kristin H. Lopez, Human Reproductive Biology (Fourth Edition), Academic Press, Pages 3-22Which one?     GnRH AGONISTDaily injections of agonists- Desensitizing effectsNow have longer lasting antagonist analogues- Block the LH surge- Therefore longer desensitizationKumar, P & Sharma, A. (2014) Gonadotrophin releasing hormone analogs: understanding advantages and limitations Journal of Human Reproductive Sciences 7;3 July – Sept pp.170 - 174GnRHa Starting dose, per dayLeuprorelin 3.75 mg every month or 11.25 mg every 3 monthsTriptorelin 11.25 mg every 3 months22.5mg SR every 6 months. https://www.medicines.org.uk/emc/product/5906/smpchttps://www.medicines.org.uk/emc/product/780/smpchttps://www.medicines.org.uk/emc/product/4650/smpchttps://www.medicines.org.uk/emc/product/4651/smpcConclusionCPP- Differences in boys and girls- Causes- Presenting signs and symptomsManagement- Pathophysiology- GnRH analogueskate.davies@lsbu.ac.uk@LSBU_PrescribeReferences• Blair, J. C. and M. O. Savage (2002). Normal and Abnormal Puberty. Comprehensive Clinical Endocrinology. G. M. Besser and M. Thorner. Michigan, Mosby.• Carel, JC et al (2009) Consensus Statement on the Use of Gonadotropin-Releasing Hormone Analogs in Children. Pediatrics April; 123 (4): e752–e762. 10.1542/peds.2008-1783• Carel, JC (2019)• Davies, K & Dwyer, A. (2019). Genetic competencies for effective pediatricendocrine nursing practice. Journal of Pediatric nursing.• Davies, K. & Meimaridou, I. (2020) Biological basis of child health 1: Understanding the cell and genetics. Nursing Children and Young People. doi: 10.7748/ncyp.2020.e1047. Published online: 09 March 2020• Davies, K. (2020). "Biological basis of child health 7: growth, development and the reproductive system." Nurs Child Young People.References• Devesa, J., Almenglo, C., & Devesa, P. (2016). Multiple Effects of Growth Hormone in the Body: Is it Really the Hormone for Growth? Clin Med Insights Endocrinol Diabetes, 9, 47-71. doi:10.4137/CMED.S38201• Hill, B & Allan, J (2021) Pharmacodynamics and pharmacokinetics in Fundamentals of Pharmacology for Nursing and Healthcare students Peate, I & Hill, B (Eds) Chapter 5, pp. 69 – 90, Wiley Blackwell, Chichester• Jones, R. & Lopez, K. (2014) Chapter 1 - Endocrinology, Brain, and Pituitary Gland, Editor(s): Richard E. Jones, Kristin H. Lopez, Human Reproductive Biology (Fourth Edition), Academic Press, Pages 3-22• Kim, S. H., et al. (2015). "A Significant Increase in the Incidence of Central Precocious Puberty among Korean Girls from 2004 to 2010." PLoS ONE 10(11): e0141844.• Kumar, P & Sharma, A. (2014) Gonadotrophin releasing hormone analogs: understanding advantages and limitations Journal of Human Reproductive Sciences 7;3 July – Sept pp.170 - 174• Leger, J. & Carel, JC (2016) Precocious Puberty Chapter 10: Puberty: Physiology and Abnormalities Kumanov, P. & Agarwal, A (Eds) Springer, Switzerland• Muir, A. (2006). Precocious puberty. Pediatr Rev, 27(10), 373-381. doi:10.1542/pir.27-10-373References• Ozen, S. and S. Darcan (2011). "Effects of environmental endocrine disruptors on pubertal development." J Clin Res Pediatr Endocrinol 3(1): 1-6.• Pyra, E. & Schwarz, W. (2019) Puberty: Normal, Delayed and Precocious. Advanced Practice in Endocrinology Nursing. S. Llahana, C. Follin, C. Yedinak et al. Cham, Springer. 1: 63 - 84.• Raine, J. E., et al., Eds. (2011). Practical endocrinology and diabetes in children. Chichester, Wiley - Blackwell.• Rosen, D. S. (2004). "Physiologic growth and development during adolescence." Pediatrics in Review 25(6): 194 - 200• Sorensen, K., et al. (2012). "Recent secular trends in pubertal timing: implications for evaluation and diagnosis of precocious puberty." Horm Res Paediatr 77(3): 137-145..• Soriano-Guillen, L., & Argente, J. (2019). Central precocious puberty, functional and tumor-related. Best Pract Res Clin Endocrinol Metab, 33(3), 101262. doi:10.1016/j.beem.2019.01.003• Synovitz, L., & Chopak-Foss, J. (2013). Precocious puberty: Pathology, related risks, and support strategies. Open Journal of Preventive Medicine, 03(09), 504-509. doi:10.4236/ojpm.2013.39068• Zhu, J., et al. (2018). "Genetics of pubertal timing." Curr Opin Pediatr 30(4): 532-540.

An Introduction to Central Precocious Puberty

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An Introduction to Central Precocious Puberty

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