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Child & Adolescent Volume

6, 201X

Robb, M.D.,

CCoonnt te ennt tS Early Puberty: The Interplay cme

1 Early Puberty: The Interplay
among Obesity, Hormones,
among Obesity, Hormones, the
Brain, and the Environment
the Brain, and the Environment
Stephanie Pope, M.D., and Sarah Lytle, M.D.
4 New Research Spotlight
• Thinner Medial Temporal Cortex in Puberty has biological, social, and psychological effects on people at its onset,
Adolescents with Attention-Deficit/
Hyperactivity Disorder and the
and these effects potentially persist into adulthood. A decline in the average
Effects of Stimulants age of puberty onset has occurred, which has led to an explosion of research
in the past few decades. Initially, research focused on the social implications of
early puberty. In the past few years, research has shifted to biologic mechanisms
11 CME Post-Test leading to early puberty and early puberty’s potential physiologic consequences.
One commonly studied risk factor for early puberty is obesity. This risk factor has
been of particular interest as the obesity epidemic affects our nation’s children.
The emerging picture of early puberty on children is an example of a phe-
nomenon that can be conceptualized within the biopsychosocial model, as it
involves the interplay between genetic, physiologic, environmental, behavioral,
and social factors. The focus of this review is on the biological mechanisms for
IMPORTANT NOTICE: This publication is intended to provide
observed trends in puberty onset at younger ages, specifically obesity and the
accurate and authoritative information regarding the subject mat-
ter covered. It is sold with the understanding that the publisher is
physiology of adipose tissue. Implications of earlier menarche and adrenarche on
not engaged in rendering medical, psychological, financial, legal, or brain development, social relationships, and specific psychiatric illnesses are also
other professional services.
The recommended doses of medications cited in this newsletter are addressed. An understanding of these factors is important for those working with
not meant to serve as a guide for prescribing of medications.
adolescent patients who experience early puberty. As psychiatrists who at times
Physicians, please check the manufacturer’s product information
sheet or the PHYSICIAN’S DESK REFERENCE for further infor-
mation and contraindications.

Educational Objectives Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this
Upon completion of this activity, participants should be able to: activity should not be used by clinicians without evaluation of their patient’s conditions and possible
• Examine literature about early puberty and interplay and implications between brain development, contraindications on dangers in use, review of any applicable manufacturer’s product information,
social relationships and specific psychiatric illnesses. and comparison with recommendations of other authorities. The information presented in this activ-
• Review two medication options for treating obesity in youth. ity is not meant to serve as a guideline for patient management.
Target Audience Disclosure of Conflicts of Interest
This CME activity is intended for child and adult psychiatrists, pediatricians and other healthcare Medical Education Resources (MER) ensures balance, independence, objectivity and scientific rigor
professionals with an interest in the psychopharmacology and treatment practices for child and in all our educational programs. In accordance with this policy, MER identifies conflicts of interest
adolescent psychiatric disorders. with its instructors, planners, managers and other individuals who are in a position to control the
Physician Accreditation content of an activity. Conflicts are resolved by MER to ensure that all scientific research referred
This activity has been planned and implemented in accordance with the Essential Areas and policies to, reported or used in a CME activity conforms to the generally accepted standards of experimental
of the Accreditation Council for Continuing Medical Education through the joint providership of design, data collection and analysis. MER is committed to providing its learners with high quality
Medical Education Resources and Guilford Publications. Medical Education Resources is accredited CME activities that promote improvements or quality in healthcare and not the business interest of
by the ACCME to provide continuing medical education for physicians. a commercial interest.
Credit Designation The faculty reported the following financial relationships with commercial interests:
Medical Education Resources designates this enduring material for a maximum of 1 AMA PRA Name of Faculty: Stephanie Pope, M.D., and Sarah Lytle, M.D.
Category 1 creditTM. Physicians should only claim credit commensurate with the extent of their Reported Financial Relationship: Stephanie Pope, M.D., and Sarah Lytle, M.D. have no financial
participation in the activity. relationships to disclose.
Release Date: 3/16 Name of Planner or Manager: Julie Johnson, PharmD.
Expiration Date: 3/17 Reported Financial Relationship: No financial relationships to disclose.
Estimated time to complete this activity: 1 hour Name of Educational Partner Manager: Adelaide S. Robb, M.D. (Guilford)
Disclaimer Reported Financial Relationship: Dr. Robb has disclosed that her research has been
The content and views presented in this educational activity are those of the authors and do not supported in part by the pharmaceutical industry. See page 2 for more information.
necessarily reflect those of Medical Education Resources or Guilford Publications. The authors have Media Type: Newsletter
disclosed if any discussion of published and/or investigational uses of agents that are not indicated This activity is jointly provided by Medical Education Resources and Guilford Publications.
by the FDA in their presentations. The opinions expressed in this educational activity are those
of the faculty and do not necessarily represent the views of MER or Guilford Publications. Before
prescribing any medicine, primary references and full prescribing information should be consulted.

1 • CAPN 20(6)

NY 10001-1020.D. OH to those agents (McAllister et al.. Ironshore. Halifax. SyneuRx. Overall. Inc. Halifax. 2009. a decrease in the age of pubertal onset has been noted. Adipose viduals $150.D. 2009).. Duplicate copies cannot be sent to replace issues not deliv. discussed. 1999. Dec [6]) by Guilford Publications. the aromatase enzyme within adipose tissue converts androgens to es- 7006. more avail- able to initiate puberty. another biologically active chemical.D. For girls. & Galvez. VISA. 2007). Researchers have explored factors. pharmacologic agents. has been discovered and studied in terms of how it relates to obesity. 2015 (six issues) Indi- between adipose tissue.00 ($410. exposure to infections. Ouchi et al. dollars through a U. Steppan et al.D. Pro forma estrogen leads to the sexual characteristics associated with puberty. Suite development. ic glucose production and directly acting on the hypothalamus (Combs. leaving sex steroids. M.. reti- ered because of failure to notify publisher of change of address. which can be converted to estrogen CHANGE OF ADDRESS: Please inform publisher at least six as noted above (Lueprasitsakul. M.00 ($160. and “endocrine disrupting Bruce Meltzer. The Obesity Epidemic and Earlier Puberty University Hospitals. Robb. NS Dara J. & Masuno. Johnson.S. in New trogen. New York.D. 370 Seventh Avenue. Case Medical Center Cleveland. 370 Seventh Avenue. Inc. Apr [2]. RBP-4. and estro- invoices issued upon request. Klover. Enclose mailing label with change of address. Yang et al. MSc may contribute to obesity. The association Stony Brook University School of Medicine between increasing obesity and decreasing age of puberty appears to be direct in Stony Brook. IWK Health Centre. 2012). GlaxoSmithKline. Suite 1200. leptin. Finally. Fax 212-966-6708. 2001. OH In a review of female puberty. Simply put. Greenspan. including food and water stored in those plastics and water sources exposed Cleveland. leading to higher levels of estrogens (Senn.S. New York. & Hotamisligil.” include University of Pittsburgh Medical Center diethylstilbestrol (DES). hormones. resistin. Janssen Pharmaceuticals. McVoy. Wiesbrock. Case Western Reserve University Cleveland. has received Research Support from and/or is a share- affect hormonal control of appetite and satiety (Grün & Blumberg. that NYS Psychiatric Institute. NS rect relationship while other studies do not (Biro.guilford. 2010). Neuronetics.00. or E-mail news@guilford. gen levels reaching a threshold initiate menstruation. Adipose tissue can also increase insulin resistance through other physiologic mechanisms. Printed in the United States of America. BPA has been found to be associated with weight gain and Company. chemicals” (chemicals that affect the usual adipose-regulating feedback loops in UMass Memorial Medical Center Westborough. & Mooney. including estrogen and androgens. Evidence from animal models suggests that these compounds promote adipogenesis. M. steroids. humans. tissue itself influences puberty through its direct effects on hormone levels. & Longcope. increasing maternal University of Louisville age. Oct [5].D. like estrogen. more adipose tissue results in more total estrogen.. Actions of Adipose Tissue. Pittsburgh. Some of these date. M. Laurence Greenhill. but there is no direct evidence of this yet.00. Marino. PA and organotins. phthalates. Sakolsky. M. bank. Eli Lilly and & Waxman. Inc. Berg.D.D. Kato. and Takeda. tumor necrosis factor-a (TNF-a). & Rossetti. 2003). insulin resistance Visit our website at www. 2007). Lundbeck. the description of which is beyond the scope of this article. June [3]. In turn. For $395. These findings may correlate to Child & Adolescent Psychopharmacology News (ISSN 1085.D. Aug [4]. New York. 1997. Uysal. Latour. crease. Scherer. adipokines. In addition to the chemicals described above. 2005). These include sleep disruption. Rhodes Pharmaceutical. 1990).. Yamamoto. Robb. OH Research E ditor: Jess Levy. NY Normand Carrey. The physiologic effects of leptin are now understood to be more than a 2 • CAPN 20(6) .. M. Coincident with this in- Gabrielle Carlson. specifically a subset called “obesogens. 0295) is published six times per year (Feb [1]. NY 10001-1020. Pfizer higher serum levels of cholesterol (vom Saal et al. Obici.D. Adiponectin increases insulin resistance while suppressing hepat- 1200. Canada and foreign). sistance. Postmaster: Send address changes to Child & Adolescent Psycho- nol binding protein-4 (RBP-4). Ph. M. Guilford Press. Payment must be made in U.. and Adelaide Frank Biro and colleagues describe the in- creased rate of childhood obesity in recent decades. TNF-a. which increases the bioavailability of sex Guilford’s GST registration number: 137401014. Yamauchi et al.Editorial Board Editor: Adelaide S. adipose tis- sue leads to insulin resistance directly with adipokines and by cyclically binding sex hormone–binding globulin. Forest Laboratories.S. M..D. and IL-6 have also been found to increase insulin re- Copyright © 2015 Guilford Publications. 2002. weeks prior to move. Canada and foreign) and Institutions. Sakayama. Photocopying of this newsletter is not permitted. Inquire for bulk rates. in addition to excessive dietary intake. All prices quoted in U. Dr. two medication options for treating obesity are George Washington University A ssociate Editor: Molly K.. 2001. insulin resistance. perfluorooctanoic acid. and interleukin-6 (IL-6) can impact pubertal pharmacology News. dollars. York. 212-431-9800.. University Hospitals of Cleveland tics. Younger menarche is also related to the interplay SUBSCRIPTION PRICE: Volume 20. MA the endocrine system) through in vitro studies and in animal models (National Lukas Propper. NY Sarah B. Orders by MasterCard. M. Increased adipogenesis Inc.. prescribe medications that may lead to weight gain. M. Claims for lost issues cannot be honored four months after mailing Adipose tissue also secretes several chemicals called adipokines. These chemicals can be found in a variety of medicines and plas- Robert Stansbrey. Endocrine disrupting agents. Institute of Environmental Health Sciences.D. Sunovion. The relationship may be more complex in boys as some studies show a di- IWK Health Centre. Nowak. along with producing androgens and estrogen. such as adiponectin.D. this area of M. it is important to consider Children’s National Health System. M. and adipokines. is on the Advisory Board or Speaker’s Bureau. has been noted in the offspring of pregnant mice exposed to BPA (Miyawaki. or American Express can be placed by Phone at 800-365- example. change basal metabolic rate. lowers sex hormone–binding globulin. 2007).. bisphenol A (BPA). girls. Resistin. Hurst holder with the following: Actavis/Allergan.

and therefore sexual maturation hormones such linearly with age (Nelson. extrapolate that this could lead to increased risk-taking be- haviors. with premature menarche have lower executive functioning Clearly. as of yet. apse formation (Bourgeois. Other research supports that the fact that those undergoing on-time or later puberty (Graber. Meyer. hormones decreases over time (Berenbaum & Beltz. Goldman-Rakic. sociated with earlier menarche by one month. This understanding of different neurologic The brain undergoes dramatic changes during puberty. Further research will need to be done to Overall. and the hypo. One could take this theory further and ment. 2005).. Thus. & Larsen. & Potenza. Similar studies in humans have not been com- (48 kgs) or at a critical fat mass. 2013). heightened emotional arousal.. an overview of several decades worth of literature focusing CAPN 20(6) • 3 . and later research supports pleted. Independent not proven.. called Leptin can be considered a harbinger of menarche. and pruning (Gerocs. not tabolism. & Steiner. (Xu et al. cade initiating puberty. One possible theory developed when structures. & Rakic. Svend et al. 1978). 2005. as one the “declining sensitivity hypothesis. as estrogens (Thornton. Huttenlocher & Dabholkar. Taylor. Steinberg. 1970). Veldhuis. & Pine. and psy- Neurologic Consequences of Early Puberty chopathology. the physiology of the neuroendocrine system changes to The dopaminergic pathways involved in social informa- maintain homeostasis. as this animal model demonstrated tween their developing dopamine-regulated reward sensitiv- that insulin and leptin act on POMC–containing neurons ity pathways and cognitive control (Cauffman et al. The idea was that the body had to reach a certain composition to be able to sustain cyclic The Declining Sensitivity Hypothesis and Dopamine menstruation at menarche (Frish & Revelle. Meyer esis suggested that menarche began around a specific weight et al. 1990. This theory sug- and earlier menarche.” has been supported study found an association between serum leptin. Leibenluft. tive to dopamine when sex hormones are present during tain the peptide proopiomelanocortin (POMC). In 1992. could be the of these processes. This idea is supported by findings demonstrating that girls also affect the developing brain directly. and psychiatric presentations. 2011). prefrontal cortex and the limbic system in brains of those thalamus. 2012). 1992). other chemicals. Bourgeois & Rakic. the potential effects on the dopamine pathway Paoli. The specifics of how this occurs are tion processing and reward sensitivity. It is also important to consider potential with a lag period to develop cognitive controls (Mouridsen consequences of early puberty as it relates to brain develop. including sex hormones such as estrogen. ing are rare. & Halasz. the role of leptin in obesity. adipose tissue storage. & Mantzoros. particularly as research continues to advance enter puberty earlier more sensitive to socio-emotional cues. Heist. leptin has a direct ef. are outlined below as an example. Kurz. 1994. processing between those with early puberty and those with comparable to the significant changes that occur in the on-time puberty is supported by literature noting the social prenatal and early postnatal periods. skills compared to their puberty on-time peers (Sontag-Pa- ute to the timing of puberty onset. they would have a larger gap be- of leptin and insulin. driven brain reorganization. 2010).way to regulate adipose storage. body fat.. which. 2001). including limbic unclear at this time. Longitudinal studies including increased weight leads to increased leptin levels. The Role of Leptin in Early Menarche. The Frisch hypoth. This study found that in humans each gests that the sensitivity of brain reorganization to gonadal increase of 1 ng/mL in serum leptin levels was directly as. POMC. develop ing puberty. these processes include neuronal growth (Pinos Social Implications of Early Puberty. those who enter puberty earlier in life are more sen- study also reported that for every 1 kg of body fat. and delayed puberty would need to be done to Frisch hypothesis is re-conceptualized as involving a leptin support or refute this theory. leptin. & Mas. energy me. onset of sitive to the effects of hormones and gonadal hormone- menarche was 13 days earlier (Matkovic et al.. 2008). energy balance. develop rapidly during early and mid-adolescence leptin receptors were found in the arcuate nucleus of the hy. by multiple studies (Sisk & Zehr. (Spear 2000). 2012). 1993). These developing pathways are more sensi- pothalamus in animals. As it is understood now. 2005). In a classic down regulation model. and fertility fully understood. 1978). normal. leptin limited because longitudinal studies related to puberty tim- levels decrease as caloric intake decreases (Chan. McClure. monkeys. Cheung. While evidence supporting this theory is (Biro et al. 1997. 2003). areas of the brain that are involved in link between leptin and release of pituitary peptides initiat. 1997). Ferres-Torres. Although puberty (Chambers. some of which may be dilla et al.. One theory of brain development during puberty. in individuals who have not yet started puberty and those with turn. Clifton. De. If the hypothesis is true. This theoretically could leave those who modifiable. If someone goes through puberty Another study supported the role of POMC in the interplay earlier than someone else. 2003). In mice and rhesus implications of early puberty. or one of its byproducts. specifically the prefrontal cortex. & Erik Mouridsen and Dr. undergoing early puberty are fewer than in the brains of fect on the brain. Flemming Warborg Larsen wrote Sengelaub. there are many complicated factors that contrib. The early. These hypothalamic neurons con. 1986. 1997). Dr. dendritic tree reshaping (Goldstein. on brain reorganization or pathways that are. as leptin is part of the cas. Rethelyi.. our knowledge. cognitive control. expo- threshold instead of a threshold of adipose tissue. social implications. sure to gonadal hormones at an earlier age could have effects Leptin is also involved in regulating appetite. impulsivity. This same Thus. When leptin is low. this would mean that the connections between the elucidate the links between insulin. may contribute to an earlier age of menarche. syn.

. When discussing these associations.. as adult height is indirectly related puberty are significant and can impact a patient for a life- to the time of puberty onset (Kumar.001). Phinney. Unsupportive reactions of parents and peers creatic lipases. their interac. 1961). excessive shyness. have been Evidence suggests that girls who have earlier maturation are studied for the treatment of obesity.. This is a particular concern for parents and pe- listat). 1961). Other associations with early puberty pre- stressful for boys. 2010). 2013). topiramate and naltrexone SR/bupropion SR. Drug Administration is tetrahydrolipstatin (Orlistat). (Orlistat package insert. was noted to be associated with higher rates of gastrointes- These associations only suggest linked mechanisms between tinal adverse effects (Viner. Boldrin. and pharmacotherapy. significantly less than the placebo groups (0. 2011. 1968). 2014. 2005).47–1. Vural. & Partonen. and educational and occupational A number of medications. his/ with substance abuse and eating disorders (Stice. weights in Stressors during puberty.14 ing behaviors. Christopher. and may be at a higher risk for being sexually abused (Deardoff. Thamdrup. & Orlistat.on the psychological and social implications of precocious research suggests that later onset of puberty in boys is associ- puberty and the stressors these children face (Mouridsen & ated with depressive disorders in later adolescence (Negriff Larsen. Some psychiatrists may consider obesity and its treat- 1987). only tetra- more likely to have an earlier age of first intercourse as com- hydrolipstatin and metformin have been studied in adoles- pared to same-age peers. al. Adolescence pediatric pregnancies. 1969. & Alloy. time. Toffol. Presnell. Wong. Neubert. appropriate exercise. have been both groups were higher. Gonzalez. & Hauptman. & Hamlat. her self-worth. It should be used with lifestyle modifications may contribute to negative outcomes for these children. Jensen. 2014. 1990). Such children need to adapt Although limited and requiring further study. and social effects of early tremely early puberty. Viner. Roosa. neurological. & Bearman.53 kg vs. These treatments include ther- Studies also suggest that children with earlier puberty are apy. at risk for negative relationships in school with peers and adults. In- terestingly. Stange. 1961). and kg. phentermine. phentermine/ diatric clinicians (Ehrhardt et al. The only medication treatment for obesity in Millsap. 2013). and menstruation can of puberty and eating disorders was then challenged by a lead to embarrassment. resulted in a body mass index reduction of 0. Mild to moderate gastrointestinal adverse substance use as described later. decreases fat absorption by inhibiting gastric and pan- youth’s parents. Tet- The emotional and social outcomes of early and preco. especially from the a day. At the end of the study. This changes how the child views him/herself. it is kg/m2 (95% CI 0. & Wong. 2009). Along with social stresses and neurologic changes. 2011). Luoto. some mental illnesses and pubertal changes. The psychiatric. 1–13%) (Chanoine. & Kilic. and his/her personal identity. Hayles. Hample. including tetrahydrolipstatin (or- disruption. Turk- adulthood (Money & Alexander. adherence (McDuffie et al. this suggests first to their early growth spurt and then adapt again if their that both early and delayed puberty could be associated with peers later exceed them in height. metformin. This poor adherence and high rates of dis- nen. as additional 4 • CAPN 20(6) . This can be especially eating disorders. Edgardh. and depression.83 has been studied. However. 2003). Trepanier et al. the when combined with behavioral support in people less than link between early versus later puberty and mental illness 20 years old. but the medicated group gained linked to anxiety. Thamdrup. the opposite may be true for boys. Jen- Psychiatric Consequences of Early Puberty sen. 2014). One study randomized 539 This is especially true for girls who do not receive the usual patients between 12 and 16 years old to tetrahydrolipstatin support from peers (Ehrhardt et al. Teasing be.. 3. a prospective study using a structured inter- tions with other children and adults may differ (Alley. Sonis et associated with eating disorders (Martino & Lester. alterations in learning and cognition. usually dosed 120 mg by mouth three times cious puberty are related to support. no matter the timing. The use of tetrahydrolipstatin important to remember that correlation is not causation. sented in the literature include anxiety symptoms and cata- and early puberty is related to shortened average height in strophizing benign anxiety sensations (Akca. 2000.. and a less positive later study that found that puberty later than expected was view of one’s own body (Money & Walker. This indirect association between age cause of height. This is congruent with previously noted studies finding An association between early puberty in girls and depres. 2011). Concerns have been raised that these children with Pharmacologic Treatment Options for Obesity in negative relationships are at risk for earlier sexual contact. depression. Olsen. A systematic review and meta-analysis of placebo control trials of tetrahydrolipstatin. are more likely to become preg- cents. Thamdrup. This can be worse for those undergoing ex. gastrointestinal adverse effects limiting their use and poor sive disorders has been well established (Galvao et al.119). nutrition. p < 0. Hsia. Hsia. rahydrolipstatin. lorcaserin. 1992). risk-taking and novelty-seek. 1984. 1984. Sigurjonsdottir & oglu. Abramson. Tomsic.. view with 496 girls found early menarche to be associated 1983). nant at an earlier age. ment a part of their practice. & Chansoria. 1971. Mehta. breast development. Kopo. events were higher in the medicated groups versus the pla- cebo groups (9–50% vs. earlier growth spurts and earlier presentation of secondary While also supporting a link between early puberty in girls sex characteristics compared to their peers. or placebo for 54 weeks. As children with precocious puberty undergo & Susman. 1985. 2014. & adolescents at least 12 years old approved by the Food and Cundick. as height is a highly regarded physical trait. 2005.

2006).P. systems.2). Understanding how early puberty may Cottingham. Sort- and lifestyle modifications in obese adults patients suffering er. Krakoff. double-blind. Shulman. reward Ward. son.D.. the prefrontal cortex and the limbic system. 2015).M.. A 16-week. atric mechanisms. decreased hunger ratings. In considering treatment supporting the use of metformin in adults suffering obesity. & Kilic. E. be well tolerated in both studies. References Adeyemo. 289-294. E-mail: Stephanie.. over 6 months long. referral to a weight loss bo-controlled trial included a 48-week follow-up period of program and working closely with the patient’s pediatrician adolescents between 13 and 18 years old. C. J. increase in z scores for weight and body mass index. 78-96.. Ohio. Anxiety sensitivity: Changes 183-200. in the metformin group (2000 mg/day) had decreased body Both orlistat and metformin are also reasonable options to mass indexes (0. the authors reported that insulin sensitivity decreased Metformin. and Metabolism. Goldman-Rakic. Alley. of metformin use in children Conclusion less than 19 years old and found that body mass index was Puberty is an important time in brain development. the brain is also sensitive to hormonal changes. Child Bourgeois. Bourgeois. M. who received placebo continued to gain weight and had an Pope@UHhospitals.83–2. Stephanie Pope.. Growth-produced changes Journal of Pediatric and Adolescent Gynecology. randomized. J. McDuffie. 2010).M. L.Lytle@UHhospitals... The adolescents as well as a nutritionist are also important considerations. Brady. Kinra.. Barton. Claus.M. with es in the placebo group (0. metformin for treatment of weight gain associated with an- Further research could help elucidate what these long-term tipsychotic medication use. Studies have focused on the use of metformin in those who received metformin (Klein. In addition.. Diabetes. clini- PCOS. file. The children in the metformin-treated group had lower ca- recent studies have demonstrated that the biologic implica- loric intake at meals even after adjusting for individual body tions of early puberty may have long-term effects on brain mass.comfort due to gastrointestinal effects has led some prescrib. 2009). in body shape and size as determinants of 25(5). M. L. The question In addition. & Barton. Norman. Steinberg. Biro..R. In addi- ers to consider metformin for off-label use. This difference was noted in metformin reported to have a more tolerable side effect pro- weeks 12–24 in the follow-up period (Wilson et al. double-blind.F. Obesity. Effects of metformin on energy Berenbaum. 363-370.D. Cottingham. K.T.... A.P. of the macaque monkey from fetal to adult with puberty and cardiovascular variables. & Galvez... stage. Banich. University Hos- viation] for both weight and body mass index). O. risperidone. 19 individuals between the ages of 10–18 years received Nevertheless. S. (2014). synaptic density in the primary visual cortex E. mones. J. place. Puberty in girls of the 21st century. 2801- Pediatrics International..42 kg/m2 (95% CI 0. & Viner. Frontiers in Neuroendocrinology. E. M. Changes of Akca. T.P.P. S. and increased ratings of full- development. including fewer neural connections between ness after a meal (Adeymo et al. (1983). 15 individuals had sig- strates the interplay between biologic. & Reede. the literature about early puberty demon- metformin 500 mg three times a day.. contributing to obesity). (1993). Aside from the literature Medication (Park. White. During One study specifically looked at eating habits and weight this time. In an open-label study in which effects may be and whether or not they attenuate with age. tion. during decreased by 1. (2015). options for individuals with obesity or weight social. S. & Morrison.9) compared to increased body mass index.. Sarah. et Development. Graham. and both have been shown to be effective. affect individuals is important for clinicians as they engage placebo-controlled trial with 29 individuals ages 10–17 with them on topics such as reproductive health and poten- whose weight had increased by more than 10% during less tial mental health implications of early menarche. the weight of those who received metformin was stabilized (leading to a reduc- tion in z scores [age-corrected changes in the standard de. 54(1).S. in managing weight gain. 241-248. and psychi- nificant decreases in weight and body mass index (Morrison. J. Hutchin.A.. M. (2011). & Beltz. 32(2). Another study included a systematic review of double-blind trials. Journal of Neuroscience.A. some studies have specifically looked cians may consider using an alternative psychotropic agent at obesity in children.. Cerebral Cortex. 2011). & Rakic. Calis. M.A. or tion. P.. there are two studies that examined the use of remains if these consequences attenuate with age or not. 49-54.. In this study.. perceived age and adult caregiving. Cleveland. 2002). 48-week. changes in 100 obese children treated with metformin 1000 Although psychosocial consequences of early puberty as mg taken twice daily compared to placebo over 6 months. and Sarah Lytle. (1994). F. 2820. P. Cauffman. intake and satiety in obese children. Greenspan. Synaptogenesis in the prefrontal al. 17(4). while those pitals Case Medical Center. it is important that clinicians be aware of medications quetiapine was done to assess the effectiveness of metformin that are sometimes used to address obesity in youth.. 57(1). S. 13(7). T. and impulsivity undergo rapid growth. described above have been a particular focus for decades. differentiation of human behavior: Effects 4(1). P. Kozlosky. Turkoglu. (if the psychotropic medication being used is thought to be A multicenter. of prenatal and pubertal organizational hor.. consider. Sexual cortex of rhesus monkeys. & Rakic. E. In addi- than one year of treatment with olanzapine.R. Vural.Z. which neurological pathways involved in reasoning. (2012). Metformin was reported to from polycystic ovary syndrome (PCOS) (Moran. M. & continued on page 10 CAPN 20(6) • 5 . and diabetes.

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