AM:STARs: Adolescent Medicine: State of the Art Reviews is the official publication of the AAP Section on Adolescent Health. Published 3 times per year, the journal offers adolescent medicine specialists and other primary care physicians who treat adolescent patients with state of the art information on all matters relating to adolescent health and wellness.
This issue—Adolescent Gynecology is a collaboration of experts from the AAP Section on Adolescent Health and the North American Society for Pediatric and Adolescent Gynecology and covers topics relevant to primary care providers of adolescents. Areas covered include HPV, breast disorders, pregnancy, contraception, teen sexuality and much more.
Topics in Adolescent Gynecology include:
- A Comprehensive Approach to the Spectrum of Abnormal Pubertal Development
- Adolescents, Sex, and the Media
- Breast Disorders in the Female Adolescent
- Excessive Uterine Bleeding
- Overview of Sexually Transmitted Infections in Adolescents
- Contraception for Primary Care Providers
- Fertility Preservation for Adolescent Women with Cancer
- Pregnancy in Adolescents
- Premenstrual Syndrome and Dysmenorrhea in Adolescents
- Adolescent Polycystic Ovary Syndrome
- Ovarian Cysts in Adolescents: Medical and Surgical Management
- Human Papillomavirus Disease in Adolescents: Management and Prevention
About the Author
Author: American Academy of Pediatrics Section on Adolescent Health The American Academy of Pediatrics Section on Adolescent Health (SOAH), founded in 1978, brings together both general pediatricians interested in adolescent health issues as well as adolescent medicine specialists. It provides an educational and networking forum with the goal of improving and enhancing the care of the adolescent population. The SOAH executive committee leadership works closely with the AAP Committee on Adolescence (COA) to bring policy and education together, both for providers and for the families/adolescents they serve.
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Adolescent Medicine: State Of The Art Reviews Adolescent Gynecology April 2012 ? Volume 23 ? Number 1
By Martin M. Fisher, Lara-Torre
The American Academy of PediatricsCopyright © 2012 American Academy of Pediatrics
All rights reserved.
A Comprehensive Approach to the Spectrum of Abnormal Pubertal Development
Heather Appelbaum, MD, Shilpa Malhotra, MD
Puberty is the biological transition from childhood to adulthood. The process involves the coordination of hormonal, physical, psychosocial, and cognitive systems to result in physiologic change. Although most adolescents follow a predictable path through pubertal maturation, the timing and sequence of pubertal development can be variable. The average onset of pubertal development in girls is 12 years, but genetic predisposition is influenced by environmental exposures and overall health. An insult to the hypothalamic-pituitary-ovarian (HPO) axis can lead to significant deviation of normal pubertal development. Early activation of the HPO axis results in precocious puberty, whereas impaired activation of the HPO axis causes delayed puberty. Secondary sexual development before the age of 8 years may be indicative of precocious puberty, whereas puberty is considered delayed in girls who do not have signs of development by age 13 years. There is a spectrum of aberrant pubertal development that includes incomplete precocious puberty, where girls show evidence of early partial development, and a variation of delayed puberty, which includes prolonged sexual maturation (Figure 1).
Normal puberty is initiated centrally, with ovarian function being driven by gonadotropin-releasing hormone (GnRH) from the hypothalamus and gonadotropin secretion from the pituitary gland. Activation of the GnRH pulse generator is dependent on many factors, leading to predictable events. The pulsatile release of GnRH is obligatory to sustain normal gonadotropin synthesis and secretion, which is essential for pubertal development. The initial sign of pubertal development in most girls is breast development, although some will have pubic hair as the earliest manifestation of puberty. Thelarche is the initial appearance of breast tissue. The normal age range for this event is between 8 and 13 years. Adrenarche is the activation of the adrenal glands, resulting in development of axillary and pubic hair. Pubarche is the appearance of pubic hair. Gonadarche marks the activation of the ovaries by the pituitary hormones, follicle stimulating hormone (FSH), and luteinizing hormone (LH). Menarche is the age of onset of the first menstrual period. Growth hormone and insulin-like growth factor-1 levels increase markedly during puberty in response to rising estrogen levels. Approximately 18% of overall growth occurs during pubertyand peak height velocity occurs on average 6 months before menarche. According to a recent longitudinal study, adrenarche follows the presence of breast tissue in 66% of girls and typically starts between the ages of 9 and 11 years.
Other studies have defined the average onset of breast and pubic hair development for black girls at ages 8.8 and 8.9 years, respectively. The average age of menarche reported by the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2002 was 12.34 years, with a variance from 12.06 years in black girls to 12.52 years in non-Hispanic white girls. The median length of time between the onset of development of secondary sexual characteristics and menarche is 2.6 years. Based on 17,000 healthy girls in the United States, the Pediatric Research in Office Settings (PROS) Network defined the mean age of breast development at 10 years and the mean age of pubic hair growth at 10.5 years for white girls.
The timing and duration of the pubertal process may be modified by body composition, social milieu, and environmental exposures. Critical body weight and nutritional status play a significant role in the onset of puberty. Body mass index (BMI) is an important factor in determining the age of onset of puberty, and leptin levels may play a significant role in mediating gonadotropin secretion. In fact, studies have demonstrated that providing leptin to leptin deficient mice potentiates the onset of puberty. Nutritional deficits and low BMI can delay pubertal development, whereas obesity is associated with early maturation. Insulin may be a codeterminant of pubertal tempo. Peripubertal obesity is associated with an insulin induced reduction of sex hormone binding globulin, which increases the bioavailability of sex steroids, including estradiol. Chronic illnesses, acute infections, and therapeutic modalities, including antipsychotic medications, chemotherapeutic agents, and radiation therapy, can also affect the onset and duration of the pubertal process.
Endocrine disruptors are natural or synthetic environmental chemicals or pollutants that can alter or affect the normal physiologic endocrine processes. Endocrine disruptors accumulate in the environment and are introduced into the body through water, air, foods, and plastics or can be transferred from mother to fetus via the placenta or breast milk. Endocrine disruptors exert their effects by binding to hormone receptors and affecting cell signaling pathways, resulting in suppression or activation of relevant hormonal activities. Many chemicals used in agriculture, as well as cleaning substances, cosmetic and hygienic products, dyes, plastic compounds (phthalates), and solvents, contain endocrine disruptors. These substances are stored in fat tissue, and the cumulative effect of long-term exposures may cause detrimental effects. Certain pesticides, phthalates, bisphenol A, and plant-derived phyto estrogens have been implicated in driving a recent trend toward earlier puberty in girls.
EARLY PUBERTAL DEVELOPMENT
Precocious puberty is defined as pubertal development beginning earlier than expected based on normal standards. The standards must take into consideration race and other environmental factors. Abnormal or early pubertal development is defined by children entering puberty more than 2.5 to 3.0 standard deviations earlier than the median age. Breast development and linear growth before the age of 8 years may be indicative of precocious puberty. The Lawson Wilkins Pediatric Endocrine Society (LWPES) recommends evaluation for white girls with signs of precocious development before the age of 7 and black girls before the age of 6; however, these guidelines have been disputed because the lower age may fail to identify a significant number of patients with treatable pathologic processes.
Early development of secondary sexual characteristics may be attributable to androgen or estrogen excess via centrally mediated processes influencing the HPO axis. Alternatively, hormonal activation may originate from peripheral or exogenous sources. Gonadotropin dependent precocious puberty or central precocious puberty (true precocious puberty) is caused by early maturation of the HPO axis. Gonadotropin independent precocious puberty or peripheral precocious puberty (pseudo-precocious puberty) is caused by excess sex hormones. These hormones can be secreted from the ovaries or adrenal glands, or they may originate from external inadvertent or intentional exposures (Table 1).
Nutritional status and an increase in adiposity in obese girls leads to early signs of puberty via several mechanisms. Obese girls have lower levels of sex hormone-binding globulin, which leads to greater bioavailability of circulating sex steroid hormones. Storage of estrogens and aromatization of estrogen precursors is increased in girls with a high index of fat cells. Furthermore, the permissive action of leptin on the GnRH pulse generator may lead to earlier activation of the HPO axis in obese girls.
Gonadotropin Dependent Precocious Puberty/Central Precocious Puberty/True Precocious Puberty
Early maturation ofthe HPO axis leads to accelerated linear growth for age, advanced bone age, and hormonal levels consistent with a pubertal state. The majority of girls with gonadotropin dependent precocious puberty have no identifiable cause. However, there may be an association in some cases with central nervous system injury, an intracranial disturbance, hormonal imbalance, or genetic mutations that lead to the release of gonadotropin-releasing hormones that result in early activation of the HPO axis. For example, hamartomas contain GnRH neurons that act as ectopic hypothalamic tissue, and mutations in G protein receptor complexes involving the GPR54-kisspeptin complex responsible for the initiation of normal puberty may undergo early activation. Girls exposed to high serum levels of androgens from exogenous sources, androgen secreting tumors, or poorly controlled congenital adrenal hyperplasia may have advanced maturation of the hypothalamus. Furthermore, chronic elevation of thyroid stimulating hormone (TSH) associated with hypothyroidism may result in early activation of FSH receptors due to crossreactivity. The treatment for gonadotropin dependent precocious puberty is cause specific. Treatment of the underlying disorder is paramount, but GnRH agonists can be used to delay pubertal advancement.
Gonadotropin Independent Precocious Puberty/Peripheral Precocious Puberty/ Pseudo-Precocious Puberty
Precocious puberty that is independent of gonadotropin-releasing hormone is caused by exogenous hormones or excess secretion of sex hormones from the gonads or adrenal glands. Examples of gonadotropin independent precocious puberty include ovarian cysts, granulosa-cell tumors or gonadoblastomas, adrenal tumors, enzymatic defects in adrenal steroidogenesis, and exogenous exposure to estrogens or androgens. The peripheral sources of hormone excess lead to suppression of gonadotropins, rendering GnRH agonists ineffective.
Incomplete Precocious Puberty
Rarely, children present with incomplete precocious puberty. In these cases, one or more signs of puberty may exist in isolation. Isolated premature thelarche or adrenarche is usually a normal variant but may result in precocious puberty in 18-20% of girls, with early variable development of secondary sexual characteristics. In the United States, black girls may be two to three times more likely than white girls to have an early appearance of pubic hair. The hormonal basis of early adrenarche is premature activation of adrenal sources of androgens. Typically the etiology of early activation is unknown, and most cases are idiopathic. Alternatively, premature adrenarche can be a sign of congenital adrenal hyperplasia or may be indicative of an adrenal tumor. Additionally, low birth weight increases the risk of developing premature adrenarche. The mechanism by which this occurs may be mediated by the influence of prenatal malnutrition on the development of insulin resistance or by in utero effects of altered secretion of cortisol associated with low birth weight infants. More commonly, premature adrenarche is associated with obesity and may be a marker for future development of polycystic ovarian syndrome or metabolic syndrome.
According to a longitudinal study in Israel, premature thelarche is present in 43% of girls between 1 and 24 months and 15% of girls aged 2-8 years. In the same study, 51% of all cases of premature thelarche regressed, 36% persisted, and only 3% progressed. Alternatively, estrogens from any source can promote breast tissue development. Therefore, it is possible that premature thelarche with or without premature adrenarche may not reflect true activation of the HPO axis, but more likely represents the influence of peripheral sources, including aromatization of adrenal androgens or an increased bioavailability of estrogens in obese girls, with reduced sex hormone binding globulin.
Isolated premature menarche presents a diagnostic quandary. Nonmenstrual sources of vaginal bleeding must be considered including tumors, vulvovaginal infections or dermatoses, vaginal foreign bodies, or trauma. There are case reports that identify girls with normal physical findings, normal pelvic ultrasounds, and routine hormonal levels who present with cyclic or sporadic vaginal bleeding in the absence of signs of secondary sexual development. However, there is no literature that clearly defines the mechanism of this paradox.
Evaluation of Early Pubertal Development
Evaluation in girls younger than the age of 8 years who present with signs of secondary sexual characteristics is warranted (Figure 2). A detailed history and physical examination guides further testing. The history should focus on when the initial signs of pubertal development began. Family history of pubertal onset should be elicited. A history of head trauma or an intracranial insult should be assessed, along with a focused review of systems for headaches, visual changes, seizures, nausea and vomiting, or abdominal pain. A linear growth chart should be reviewed, and height velocity (cm/year) should be assessed. It is important to assess breast development not only by inspection, but careful palpation is essential to avoid confusion with adipose tissue under the nipple and areola. A fundoscopic examination for papilledema indicating increased intracranial pressure, assessment of visual fields, an appropriate abdominal examination for masses, and a thorough dermatologic examination to evaluate for cafe-au-lait spots indicative of McCune-Albright syndrome should be performed. Tanner staging for breast development should be assessed. The presence of signs of androgen excess should be identified and evidence of acanthosis nigricans suggestive of chronic insulin resistance should be documented. Examination of the external genitalia can provide useful information on hormonal status. Evidence of genital ambiguity or estrogenization of mucosal membranes can be elucidated by inspection of the external genitalia.
Assessment of skeletal maturation is indicated if there are early secondary sexual findings on examination. An x-ray of the nondominant hand indicates bone age, and results can be compared with chronological age. Advanced bone age in the presence of secondary sexual characteristic development requires further evaluation with hormonal testing.
Baseline LH and FSH levels should be measured. High basal levels of LH exceeding 5 mIU/mL are indicative of gonadotropin dependent precocious puberty. Girls with low baseline levels of gonadotropins should undergo a GnRH agonist stimulation test by administering a single dose of leuprolide acetate 20 mcg/kg. Peak levels of LH above 5 mIU/mL after 1 to 3 hours are suggestive of gonadotropin dependent precocious puberty, whereas gonadotropin levels do not increase following GnRH stimulation in gonadotropin independent precocious puberty.
Girls with elevated basal or stimulated levels of LH indicative of gonadotropin dependent precocious puberty require brain imaging. Magnetic resonance imaging (MRI) is useful to determine a hypothalamic lesion.
Alternatively, if gonadotropin independent precocious puberty is suspected, a pelvic and abdominal ultrasound to assess for ovarian or adrenal tumors should be performed, along with hormonal testing that includes testosterone, estradiol, dehydroepiandrosterone sulfate (DHEAS), and 17-hydroxyprogesterone. The reliability of androgen laboratory testing is improved with the availability of standardized tests using tandem mass spectrometry and liquid chromatography assays. Thyroid function should be assessed if there is clinical evidence of hypothyroidism.
Treatment of Early Pubertal Development
Treatment is dictated by the etiology and the rate of sexual maturation. Therapy should be directed to the underlying pathology. In cases where there is an unidentifiable cause for early maturation, treatment is dependent on the estimated adult height. Treatment should be offered to prevent early fusion of the epiphyseal plates to avoid unnecessary short stature and should not be based on the perceived psychosocial consequences of early puberty. Palmert et al found that some girls with slowly progressive central precocious puberty achieve a normal adult height without treatment. However, girls with a compromised height prediction can benefit from the use of a GnRH agonist to slow growth velocity and delay epiphyseal fusion to attain slow but progressive increases in height. If the predicted adult height based on measurements of height velocity is greater than 150 cm, a more conservative approach is warranted. Studies suggest that the benefit of treatment with a GnRH agonist is greatest for girls who have the onset of central precocious puberty before 6 years of age. Treatment is less effective in children with substantially advanced bone age.
GnRH agonists, when administered chronically, blunt the natural pulsatile secretion of GnRH from the hypothalamus and thus inhibit pituitary production of gonadotropins. Treatment is continued until 10 to 11 years of age. GnRH treatment is safe, and menstrual cycles resume on an average of16 months from the end of treatment. Bone mineral density may be decreased during treatment, but it normalizes without any long-term effect on peak bone mass. Furthermore, there are no reports in the literature of compromise to reproductive function or increase in the rate of infertility following GnRH therapy
Excerpted from Adolescent Medicine: State Of The Art Reviews Adolescent Gynecology April 2012 ? Volume 23 ? Number 1 by Martin M. Fisher, Lara-Torre. Copyright © 2012 American Academy of Pediatrics. Excerpted by permission of The American Academy of Pediatrics.
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Table of Contents
Preface Martin M. Fisher Eduardo Lara-Torre xv
A Comprehensive Approach to the Spectrum of Abnormal Pubertal Development Heather Appelbaum Shilpa Malhotra 1
Adolescents, Sex, and the Media Victor C. Strasburger 15
Breast Disorders in the Female Adolescent Nirupama K. De Silva 34
Excessive Uterine Bleeding Hina J. Talib Susan M. Coupey 53
Overview of Sexually Transmitted Infections in Adolescents Fareeda Haamid Cynthia Holland-Hall 73
Contraception for Primary Care Providers Shon Patrick Rowan Jean Someshwar Pamela Murray 95
Fertility Preservation for Adolescent Women with Cancer Jonathan D. Fish 111
Pregnancy in Adolescents Amanda Y. Black Nathalie A. Fleming Ellen S. Rome 123
Premenstrual Syndrome and Dysmenorrhea in Adolescents Lisa M. Allen Alexandra C. Nevin Lam 139
Adolescent Polycystic Ovary Syndrome Ellen Lancon Connor 164
Ovarian Cysts in Adolescents: Medical and Surgical Management Yolanda A. Kirkham Sari Kives 178
Human Papillomavirus Disease in Adolescents: Management and Prevention Lea E. Widdice 192