Puberty and Disorders of Pubertal Development PDF

CHAPTER 32 Puberty and Disorders of Pubertal Development SARA CHURCHILL CAROLYN J. ALEXANDER CLINICAL KEYS FOR THIS CHAPTER Both genetic an...

CHAPTER 32 Puberty and Disorders of Pubertal Development SARA CHURCHILL CAROLYN J. ALEXANDER CLINICAL KEYS FOR THIS CHAPTER Both genetic and environmental factors determine the pituitary–ovarian axis. A combination of high sensitivity onset of pubertal change in young girls. Puberty may be to low levels of estradiol resulting in negative feedback delayed or may occur earlier, depending on nutrition- on gonadotropin release, and an intrinsic central nervous related factors and physical activity. Obesity causes system inhibition of gonadotropin-releasing hormone earlier onset of puberty, and excessive exercise causes secretion, keep gonadotropins at low levels. By age 11 delay. Psychological disorders and chronic isolation may years (the usual onset of pubertal development), there is also affect the normal onset of puberty. a gradual loss of the negative feedback to low levels of The Frisch hypothesis states that an invariant mean sex steroids, and pubertal development begins. weight (48 kg/106 lb) is essential for the initiation of the The usual sequence of physical signs of puberty in girls first menses (menarche). Leptin (a peptide hormone) is (1) thelarche (breast budding), (2) adrenarche and/or secreted by adipose tissue may provide the “triggering pubarche (axillary and pubic hair growth), (3) peak link” for the initiation of menarche. height velocity, (4) menarche (first menses), and (5) The female fetus has the highest lifetime number of mature sexual hair and breast growth. oocytes by mid-gestation. Brief follicular maturation and Disorders of puberty include precocious development negative feedback on gonadotropin release due to fol- and delayed puberty. Precocious puberty refers to the licular estradiol production also occurs in utero. Peak development of any sign of secondary sexual maturation serum levels of gonadotropins are seen by 3 months after at an age earlier than 8 years in girls. Failure to undergo birth and then slowly decline, reaching their nadir at age thelarche by the age of 14 years constitutes significant 4 years. Between the ages of 4 and about 10 years, the delay of pubertal development and requires evaluation. “gonadostat” is said to regulate the hypothalamic– Puberty encompasses the development of secondary puberty. It has been proposed that an invariant mean sexual characteristics and the acquisition of repro- weight of 48 kg (106 lb) is essential for the initiation ductive capability. During this transition, usually of menarche in healthy girls. Leptin, a peptide secreted between 10 and 16 years of age, a variety of physical, by adipose tissue, may be the link between weight and endocrinologic, and psychological changes accom- the initiation of menarche. Psychological factors, pany the increasing levels of circulating sex steroids. severe neurotic or psychotic disorders, and chronic iso- The onset of pubertal changes is determined pri- lation may interfere with the normal onset of puberty marily by genetic factors, including race, and is also through a mechanism similar to adult hypothalamic influenced by geographic location (girls in metropoli- amenorrhea. tan areas, at altitudes near sea level, or at latitudes In the United States and Western Europe, a decrease close to the equator tend to begin puberty at an earlier in the age of menarche (i.e., age at first menses) was age) and nutritional status (obese children have an noted between 1840 and 1970, from an estimated mean earlier onset of puberty, and those who are malnour- age of 17 years in 1840 down to a reported mean age of ished or have chronic illnesses associated with weight 13 years in 1970. This trend has plateaued since then, loss have a later onset of menses). Excessive exercise and currently the mean age of menarche is approxi- relative to the caloric intake can also delay the onset of mately 12.4 years in the United States. 370  CH A PTE R 32 Puberty and Disorders of Pubertal Development 371 FSH and Birth LH Number of oogonia FSH LH hCG FSH LH DHEA Androstenedione Estradiol 10 20 30 40 2 4 6 2 4 6 8 10 12 14 16 18 INTRAUTERINE WEEKS NEONATAL YEARS OF PUBERTAL DEVELOPMENT MONTHS FIGURE 32-1 Changes in the concentration of gonadotropins (LH and FSH), sex steroids (DHEA, androstenedione, and estradiol), and the number of oogonia throughout fetal life and pubertal development. DHEA, Dehydroepiandrosterone; FSH, follicle-stimulating hormone; hCG, human chorionic gonadotropin; LH, luteinizing hormone. Adapted from Speroff L, Fritz MA: Neuroendocrinology. In Speroff L, Fritz MA, editors: Clinical gynecologic endocrinology and infertility, ed 7, Baltimore, MD, 2005, Lippincott Williams & Wilkins. Endocrinologic Changes of Puberty ing adult or near-adult concentrations in the early neo- natal period. In the female infant, peak serum levels FETAL AND NEWBORN PERIOD of gonadotropins are generally seen by 3 months of The fetal hypothalamic–pituitary–gonadal axis is age, then they slowly decline until a nadir is reached capable of producing adult levels of gonadotropins by the age of 4 years. In contrast to gonadotropin and sex steroids. By 20 weeks’ gestation, levels of levels, sex steroid concentrations decrease rapidly to gonadotropins—follicle-stimulating hormone (FSH) prepubertal values within 1 week of birth and remain and luteinizing hormone (LH)—rise dramatically in low until the onset of puberty. both male and female fetuses (Figure 32-1). Late in During fetal development, the adrenal glands are gestation, a surge in levels of glucocorticoids in the large in proportion to their size in adult life (similar fetal circulation occurs. This is essential for normal to the fetal kidneys). Early in gestation, the fetal adrenal maturation of fetal lungs and critical for the develop- gland produces abundant dehydroepiandrosterone ment of the fetal thyroid, kidney, brain, and pituitary. sulfate (DHEA-S), which serves as a precursor for estro- Recently, it has been suggested that excessive exposure gen production by the placenta and is also able to of the developing fetus to glucocorticoids or exposure convert placental progesterone into cortisol. It is not at the wrong time may lead to lifelong alterations in the until about 23 weeks’ gestation that the fetal adrenal function of the hypothalamic–pituitary–adrenal axis. cortex expresses the enzyme to directly synthesize The female fetus acquires the lifetime peak number cortisol from cholesterol or pregnenolone. In the first of oocytes (in utero) by mid-gestation and also has a few months of postnatal life, the innermost part of brief period of follicular maturation and sex steroid the adrenal cortex (the fetal zone) largely regresses, production in response to elevated gonadotropin levels and there is a rapid decrease in the production of in utero. This transient increase in serum estradiol (a DHEA-S. sex steroid) acts on the fetal hypothalamic-pituitary unit, resulting in a reduction of gonadotropin secretion CHILDHOOD (a negative feedback effect), which in turn reduces The hypothalamic–pituitary–gonadal axis in the estradiol production. This indicates that the inhibitory young child is suppressed between the ages of 4 and effect of sex steroids on gonadotropin release is opera- 10 years. The hypothalamic–pituitary system regulat- tive before birth. ing gonadotropin release has been termed the gonad- In both male and female fetuses, serum estradiol ostat. Low levels of gonadotropins and sex steroids is primarily of maternal and placental origin. With during this prepubertal period are a function of two birth and the acute loss of maternal and placental mechanisms: (1) maximal sensitivity of the gonad- sex steroids, the negative feedback action on the ostat to the negative feedback effect of the low circu- hypothalamic-pituitary axis is lost, and gonadotropins lating levels of estradiol present in prepubertal are once again released from the pituitary gland, reach- children, and (2) intrinsic central nervous system 372 PAR T 4 Reproductive Endocrinology and Infertility inhibition of hypothalamic gonadotropin-releasing Serum concentrations of DHEA, DHEA-S, and andro- hormone (GnRH) secretion. These mechanisms occur stenedione rise between the ages of 8 and 11 years. independently of the presence of functional gonadal This rise in adrenal androgens induces the growth of tissue. This is clearly demonstrated in children with both axillary and pubic hair and is known as adre- gonadal dysgenesis. Agonadal children display elevated narche or pubarche. This increase in adrenal androgen gonadotropin concentrations during the first 2 to 4 production occurs independently of gonadotropin years of life, followed by a decline in circulating FSH secretion or gonadal steroid levels, and the mechanism and LH levels by 6 to 8 years of age. By 10 to 12 years of its initiation is not understood at this time. Some of age, gonadotropin concentrations spontaneously studies have suggested that the morphologic and func- rise once again, eventually achieving castration levels. tional changes in the zona reticularis are induced by This pattern of gonadotropin secretion in early child- increasing cortisol levels. In cellular studies, human hood is similar to that of children with normal gonadal fetal adrenal cells exposed to cortisol in high concen- function. These data suggest that an intrinsic central trations produce DHEA, whereas in human studies, nervous system regulator of GnRH release is the prin- infants treated with high-dose adrenocorticotropic cipal inhibitor of gonadotropin secretion from 4 hormone for infantile spasms have been noted to have years of age until the peripubertal period. Further- adrenal androgen production. more, after regression of the fetal zone of the adrenal Recent studies indicate that girls who undergo pre- gland (a few months after birth), very low concentra- mature pubarche are more likely than other girls to tions of adrenal androgen precursors are available, develop polycystic ovarian syndrome (PCOS) as resulting in decreased adrenal androgen production in adults (see Chapter 33). early childhood. PUBERTAL ONSET LATE PREPUBERTAL PERIOD By approximately the 11th year of life, there is a In general, androgen production and differentiation gradual loss of sensitivity by the gonadostat to the by the zona reticularis of the adrenal cortex are the negative feedback of sex steroids (Figure 32-2). As a initial endocrine changes associated with puberty. consequence, GnRH pulses (with their mirroring pulses Increase Maturation of negative feedback mechanism Increased release of GnRH Increased pituitary Relative sensitivity of responsiveness to GnRH the "gonadostat" Gonadotropins to negative sex Increased gonadal steroid feedback responsiveness to Activation of positive gonadotropins, feedback mechanism rising sex steroid levels Sleep-associated increase in LH secretion: Episodic secretion of LH Decrease FETUS INFANCY & CHILDHOOD PUBERTY ADULT FIGURE 32-2 Changes in set point of the hypothalamic-pituitary unit (gonadostat) (solid lines) and the maturation of the negative and positive feedback mechanisms from fetal life to adulthood in relation to the normal changes of puberty. This figure does not illustrate the change in the sex steroid–independent intrinsic central nervous system inhibitory mechanism that is observed from late infancy to puberty. GnRH, Gonadotropin-releasing hormone; LH, luteinizing hormone. Adapted from Styne DM, Grumbach MM: Disorders of puberty in the male and female. In Yen SSC, Jaffe RB, editors: Reproductive endocrinology: physiology, pathophysiology and clinical management, ed 2, Philadelphia, Saunders, 1991.  CH A PTE R 32 Puberty and Disorders of Pubertal Development 373 of FSH and LH) increase in amplitude and frequency. uration of the positive feedback mechanism of estra- The factors that reduce the sensitivity of the gonad- diol on LH release from the anterior pituitary gland is ostat are incompletely understood. Some studies indi- complete, and ovulatory cycles are established. cate that a rise in the concentration of leptin, a hormone produced by adipocytes (fat cells) that mediates appetite satiety, precedes and is necessary Somatic Changes of Puberty for this change. This, in turn, supports the association Physical changes of puberty involve the development between minimum weight or total body fat and the of secondary sexual characteristics and the accelera- onset of puberty. The Frisch hypothesis suggests that a tion of linear growth (gain in height). The Marshall critical body weight is necessary for pubertal onset. and Tanner classification of breast and pubic hair Further investigations support the concept that fat development is employed for descriptive and diagnos- stores might influence pubertal onset through several tic purposes (Figures 32-3 and 32-4). A useful acronym mechanisms. First, adipocytes secrete adipokines such for remembering the usual chronologic order of the as leptin. Leptin appears to serve as a signal to the stages of female pubertal development is TAPuP ME hypothalamic GnRH pulse generator that there are suf- (standing for thelarche, adrenarche, pubarche, peak ficient energy stores for fertility to commence. Studies growth velocity, and menarche). have shown that every 1-kg gain in body weight lowers the onset of menarche by 13 days and that every STAGES OF PUBERTAL DEVELOPMENT increase of 1 ng/ml in serum leptin lowers the age of The first physical sign of puberty is usually breast menarche by 1 month. Second, aromatase activity in budding (thelarche), followed by the appearance of adipocytes is dependent on fat mass, and obesity axillary or pubic hair (adrenarche/pubarche). Unilat- results in greater peripheral conversion of androstene- eral breast development is not uncommon in early dione to estrone and of testosterone to estradiol. puberty and may last up to 6 months before the devel- Last, increasing adipose tissue is related to increasing opment of the contralateral breast. Maximal growth or insulin resistance, which decreases serum levels of sex peak height velocity is usually the next stage, followed hormone binding globulin. This leads to an increased by menarche (the onset of menstrual periods). The level of bioavailable sex hormones. final somatic changes are the appearance of adult A further decrease in sensitivity of the gonadostat pubic hair distribution and adult-type breasts. In combined with the loss of intrinsic central nervous approximately 15% of normally developing girls, the system inhibition of hypothalamic GnRH release is development of pubic hair occurs before breast devel- heralded by sleep-associated increases in GnRH opment. The sequence of pubertal changes generally secretion. This nocturnal dominant pattern gradually occurs over a period of 4.5 years, with a normal range shifts into an adult-type secretory pattern, with GnRH of 1.5 to 6 years (Figure 32-5). pulses occurring every 90 to 120 minutes throughout Race plays a role in determining the age of the onset the 24-hour day. of puberty. African American girls begin puberty earlier The increase in gonadotropin release promotes than girls in other racial groups (on average between ovarian follicular maturation and sex steroid produc- the ages of 8 and 9 years), followed by Mexican Ameri- tion, which induces the development of secondary cans and whites (Table 32-1). In African American girls, sexual characteristics. By middle to late puberty, mat- thelarche and adrenarche can occur as early as 6 years TABLE 32-1 AGE AT ONSET OF PUBIC HAIR DEVELOPMENT, BREAST DEVELOPMENT, AND MENARCHE FOR THREE RACIAL/ETHNIC GROUPS OF U.S. GIRLS: NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY III, 1988-1994 Non-Hispanic White Black Mexican American Puberty Milestone (mean age*) (mean age*) (mean age*) Pubic hair† 10.5 9.5 10.3 † Breast development 10.3 9.5 9.8 Menarche† 12.7 12.1 12.2 Menarche‡ 12.7 12.3 12.5 Modified with permission from Wu T, Mendola P, Buck GM: Ethnic differences in the presence of secondary sex characteristics and menarche among US girls: the Third National Health and Nutrition Examination Survey, 1988-1994. Pediatrics 110:752–757, 2002. *Estimated with application of weights for the examination sample of the National Health and Nutrition Examination Survey III (NHANES III). † Estimated using probit model for the status quo data of the puberty measurements. ‡ Estimated using failure time model for the recalled age at menarche. 374 PAR T 4 Reproductive Endocrinology and Infertility Stage 1 Stage 2 Stage 3 Stage 4 Stage 5 FIGURE 32-3 Stages of breast development as defined by Marshall and Tanner. Stage 1, Preadolescent; elevation of papilla only. Stage 2, Breast bud stage; elevation of breast and papilla as a small mound with enlargement of the areolar region. Stage 3, Further enlarge- ment of breast and areola without separation of their contours. Stage 4, Projection of areola and papilla to form a secondary mound above the level of the breast. Stage 5, Mature stage; projection of papilla only, resulting from recession of the areola to the general contour of the breast. Adapted from Marshall WA, Tanner JM: Variations in pattern of pubertal changes in girls. Arch Dis Child 44:291, 1969.  CH A PTE R 32 Puberty and Disorders of Pubertal Development 375 Stage 1 Stage 2 Stage 3 Stage 4 Stage 5 FIGURE 32-4 Stages of female pubic hair development according to Marshall and Tanner. Stage 1, Preadolescent; absence of pubic hair. Stage 2, Sparse hair along the labia; hair downy with slight pigmentation. Stage 3, Hair spreads sparsely over the junction of the pubes; hair is darker and coarser. Stage 4, Adult-type hair; no spread to the medial surface of the thighs. Stage 5, Adult-type hair with spread to the medial thighs assuming an inverted triangle pattern. Adapted from Marshall WA, Tanner JM: Variations in pattern of pubertal changes in girls. Arch Dis Child 44:291, 1969. Adrenarche/ Peak height Mature sexual Thelarche Menarche Pubarche velocity hair and breasts 9 10 11 12 13 14 15 AGE IN YEARS FIGURE 32-5 Sequence of physical changes during pubertal development. The acronym TAPuP ME has been used as a mnemonic device for Thelarche, Adrenarche/Pubarche, Peak height velocity, and MEnarche, which precede mature sexual hair and breast development. of age, whereas in whites, they can occur as early 7 estradiol, and insulin-like growth factor 1 (formerly years of age. somatomedin C) are involved in the adolescent growth spurt. Peak height velocity occurs approximately 1 year ADOLESCENT GROWTH SPURT before the onset of menarche. There is limited linear In general, the growth spurt is seen 2 years earlier in growth after menarche, as gonadal steroid production pubertal girls than in boys. Growth hormone, accelerates fusion of the long bone epiphyses. 376 PAR T 4 Reproductive Endocrinology and Infertility BOX 32-1 BODY COMPOSITION AND BONE AGE CLASSIFICATION OF FEMALE PRECOCIOUS PUBERTY There are no significant differences in skeletal mass, lean body mass, or percentage of body fat between pre- Heterosexual Precocious Puberty pubertal boys and prepubertal girls. After attaining Virilizing neoplasm sexual maturity, girls generally have less skeletal and Ovarian lean body mass and a greater percentage of body fat Adrenal Congenital adrenal hyperplasia (adrenogenital than boys do. syndrome) Bone age correlates well with the onset of second- Exogenous androgen exposure ary sexual characteristics and menarche. Bone age is Isosexual Precocious Puberty determined by obtaining radiographs of the left (or nondominant) hand and wrist, elbow, or knee and Incomplete Isosexual Precocious Puberty comparing them with an index population. Osseous Premature thelarche maturation is particularly useful in the evaluation of Premature adrenarche Premature pubarche adolescents with delayed onset of puberty. Bone matu- ration, chronologic age, and height can also be used to Complete Isosexual Precocious Puberty predict the final adult stature based on standardized True isosexual precocious puberty nomograms. Constitutional (idiopathic) Organic brain disease Central nervous system tumors Precocious Puberty Head trauma Hydrocephalus Precocious puberty refers to the development of any Central nervous system infection (abscess, enceph- sign of secondary sexual maturation at an age 2.5 alitis, meningitis) standard deviations earlier than the expected age of Pseudoisosexual Precocious Puberty pubertal onset. In North America, these ages are 8 Ovarian neoplasm years for girls and 9 years for boys. The incidence of Adrenal neoplasm precocious puberty is 1 in 10,000 children in North Exogenous estrogen exposure America, and it is approximately five times more Advanced hypothyroidism common in girls. In 75% of cases of precocious puberty McCune-Albright syndrome in girls, the cause is idiopathic. A thorough evaluation Peutz-Jeghers syndrome to eliminate a serious disease process, and to arrest Adapted from Brenner PF: Precocious puberty in the female. In Mishell DR potential premature osseous maturation that may Jr, Davajan V, Lobo RA, editors: Infertility, contraception and reproductive affect the normal growth pattern, is mandatory. endocrinology, ed 3, Cambridge, MA, 1991, Blackwell Scientific, p 349. The early development of secondary sexual charac- teristics may promote psychosocial problems for the child and should be addressed carefully. Typically, or adrenal in origin and are exceedingly rare in child- these girls are taller than their peers as children but hood. They are diagnosed on the basis of physical and ultimately are shorter as adults, due to the premature radiologic examinations of the abdomen and are fusion of the long bone epiphyses. A classification treated by surgical removal. system for female precocious puberty is shown in Congenital adrenal hyperplasia most commonly Box 32-1. results from a defect of the adrenal enzyme Precocious puberty may be divided into two major 21-hydroxylase that leads to excessive androgen pro- subgroups: heterosexual precocious puberty (devel- duction. More severe forms of this defect cause the opment of secondary sexual characteristics opposite birth of a female with ambiguous genitalia. If untreated, those of the anticipated phenotypic sex) and isosex- progressive virilization during childhood and short ual precocious puberty (premature sexual matura- adult stature will result. The treatment of this disorder tion that is appropriate for the phenotype of the includes replacement of cortisol with a related gluco- affected individual). corticoid and surgical correction of any anatomic Investigations for females with precocious puberty abnormalities in the first few years of life. A less severe are shown in Box 32-2. form of this defect, referred to as nonclassic (late onset) adrenal hyperplasia can cause premature pubarche HETEROSEXUAL PRECOCITY and an adult disorder resembling PCOS. In females, heterosexual precocity results from viril- izing neoplasms, congenital adrenal hyperplasia, or ISOSEXUAL PRECOCIOUS PUBERTY exposure to exogenous androgens. Complete isosexual precocious puberty results in the Androgen-secreting neoplasms in females are development of the full complement of secondary either ovarian (most commonly an arrhenoblastoma) sexual characteristics and increased levels of sex  CH A PTE R 32 Puberty and Disorders of Pubertal Development 377 BOX 32-2 Pseudoisosexual Precocity LABORATORY TESTS USED SELECTIVELY TO EVALUATE Pseudoisosexual precocity occurs when estrogen FEMALE PRECOCIOUS PUBERTY levels are elevated and cause characteristic sexual Radiologic maturation without activation of the hypothalamic– Serial bone age (isosexual precocity) pituitary axis. In these girls, a GnRH stimulation test Magnetic resonance imaging (MRI) or computed tomog- does not induce pubertal levels of gonadotropins. raphy (CT) of the brain with optimal visualization of Causes include ovarian tumors and cysts, exogenous hypothalamic region and sella turcica (true isosexual estrogenic compound use, McCune-Albright syn- precocity) MRI, CT, or ultrasonography of abdomen, pelvis, or drome, severe prolonged hypothyroidism, and Peutz- adrenal gland (heterosexual precocity, pseudoisosexual Jeghers syndrome. Curiously, when the initial cause of precocity) pseudoisosexual precocity is eliminated, some girls go Laboratory on to develop true isosexual precocity. Some ovarian tumors can be felt on abdominal Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) examination and are usually unilateral. Other lesions Dehydroepiandrosterone sulfate, testosterone (hetero- may require radiologic or ultrasonic imaging for diag- sexual precocity) nosis. Treatment of these lesions is surgical. 17-hydroxyprogesterone, 11-deoxycortisol (suspected The McCune-Albright syndrome (polyostotic congenital adrenal hyperplasia causing heterosexual fibrous dysplasia) represents 5% of cases of female precocity) precocious puberty. This syndrome consists of sexual Thyroid function tests (thyroid-stimulating hormone, free precocity, multiple cystic bone defects that fracture thyroxine) (isosexual precocious puberty) easily, café au lait spots with irregular borders (most Gonadotropin-releasing hormone (GnRH) stimula- frequently on the face, neck, shoulders, and back), and tion test: LH measurement after 100 μg of GnRH is adrenal hypercortisolism. Hyperthyroidism and acro- given intravenously (to differentiate gonadotropin- dependent from gonadotropin-independent isosexual megaly may also occur in this syndrome. The patho- precocity) physiology involves a somatic mutation in affected postzygotic tissues that causes them to function inde- pendently of their normal stimulating hormones. Prolonged, severe hypothyroidism has been steroids. It may arise from premature activation of the hypothesized to cause pituitary gonadotropin release normal process of pubertal development involving the in response to the persistently elevated secretion hypothalamic–pituitary–gonadal axis, which is called of thyroid-releasing hormone. Concomitant elevation true isosexual precocity. Exposure to estrogen, inde- of prolactin may also occur with the development of pendent of the hypothalamic–pituitary axis (such as galactorrhea. Ovarian cysts may occasionally develop, from an estrogen-producing tumor), is called pseudo- and bone age may be retarded. This is the only form of isosexual precocity. precocious puberty associated with delayed bone age. Treatment is with thyroid replacement therapy. True Isosexual Precocity The Peutz-Jeghers syndrome has been associated In females, 75% of cases are constitutional. True iso- with a rare sex cord tumor with annular tubules, sexual precocity may be diagnosed by the administra- which may secrete estrogen. Because this syndrome of tion of exogenous GnRH (a GnRH stimulation test) gastrointestinal tract polyposis and mucocutaneous with a resultant rise in LH levels equivalent to those pigmentation has also been reported in association seen in older girls who are undergoing normal puberty. with granulosa-theca cell tumors, children with this In approximately 10% of girls with the true form of disorder should be screened for the development of precocious puberty, a central nervous system disor- gonadal neoplasms. der is the underlying cause. This includes tumors, Incomplete isosexual precocity is the early appear- obstructive lesions (hydrocephalus), granulomatous ance of a single secondary sexual characteristic. These diseases (sarcoidosis, tuberculosis), infective processes conditions include premature thelarche, the isolated (meningitis, encephalitis, or brain abscess), neurofi- appearance of breast development before the age of 4 bromatosis, and head trauma. It is postulated that years (unilateral or bilateral) that resolves spontane- these conditions interfere with the normal inhibition ously within months and that is probably secondary to of hypothalamic GnRH release. Children with preco- transient estradiol secretion; premature adrenarche, cious puberty secondary to organic brain disease the isolated appearance of axillary hair before the age often exhibit neurologic symptoms before the appear- of 7 years that is the result of premature androgen ance of premature sexual maturation. Evaluation of secretion by the adrenal gland; and premature true isosexual precocity should include MRI of the pubarche, the isolated appearance of pubic hair in head for lesions. girls before the age of 8 years. 378 PAR T 4 Reproductive Endocrinology and Infertility In general, premature thelarche and premature BOX 32-3 adrenarche are associated with appropriate sexual RADIOLOGIC AND LABORATORY TESTS USED TO maturation, though they may be associated with the EVALUATE FEMALE DELAYED PUBERTY development of nonclassic adrenal hyperplasia and perhaps PCOS. Therapy for these conditions is not Radiologic required. Both conditions are more common in girls Magnetic resonance imaging or computed tomography than in boys. It is not possible to diagnose an incom- of the brain with optimal visualization of hypotha- plete form of sexual precocity on the basis of a single lamic region and sella turcica (hypogonadotropic hypogonadism) evaluation, and interval examinations of bone age are necessary to rule out true precocious puberty. Laboratory Follicle-stimulating hormone TREATMENT OF TRUE ISOSEXUAL Karyotype (delayed puberty, ambiguous genitalia) PRECOCIOUS PUBERTY Progesterone (delayed puberty secondary to 17-hydroxylase [P450c17] deficiency) Approximately 75% of cases of precocious puberty in Prolactin (hypogonadotropic hypogonadism) girls prove to have a constitutional or idiopathic cause, and these patients are candidates for GnRH agonist therapy (e.g., leuprolide acetate). These girls require treatment to prevent further sex steroid release and accelerated epiphyseal fusion. Less than 50% of girls with idiopathic precocity will attain an adult States begin pubertal maturation by the age of 13 years. height of 5 feet if the condition is left untreated. If thelarche does not occur by age 14 years, an evalu- GnRH agonists are the most effective therapy for ation is required. A physiologic delay in the onset of idiopathic precocity. Long-term GnRH agonist treat- puberty occurs in only 10% of girls with delayed ment suppresses pituitary release of LH and FSH, puberty, and exclusion of other diagnoses is necessary. resulting in decline of gonadotropin levels to prepu- Physiologic delay in puberty tends to be familial. A bertal concentrations and arrest of gonadal sex steroid careful history must be taken, with special attention to secretion. Clinically, normal gonadotropin release, sex the patient’s past general health, height, dietary habits, steroid production, and pubertal maturation will and exercise patterns. Details about the pubertal devel- resume 3 to 12 months after discontinuation of GnRH opment of the patient’s siblings and parents should be agonist therapy. obtained. Box 32-3 lists tests that should be performed The final adult stature of girls with GnRH- to evaluate girls with delayed puberty. dependent causes of precocious puberty is strongly In general, the causes of delayed onset of puberty influenced by their chronologic age at diagnosis and can be subdivided into two categories: hypogonado- initiation of treatment. When GnRH agonist treatment tropic hypogonadism and hypergonadotropic hypo- is initiated before the chronologic age of 6 years, the gonadism. Disorders resulting in hypogonadotropic final adult height is increased by 2-4%. In contrast, hypogonadism that may cause primary or secondary the final adult height is usually not affected when the amenorrhea are discussed in Chapter 33. Of note, chronologic age at diagnosis and treatment is greater anorexia nervosa, which can result in hypogonado- than 6 years. Many studies have reported good long- tropic hypogonadism and delayed puberty, can affect term reproductive outcomes in GnRH-dependent pre- 0.5-1.0% of young women. It is important to recognize cocious puberty after treatment with GnRH agonists this disorder in the evaluation of these patients. Chro- and have shown no differences between regularity mosomal abnormalities or injury to the ovaries by of menstrual cycles, pregnancy rates, and live births surgery, chemotherapy, or radiation may cause compared to a normal population. However, a few hypergonadotropic hypogonadism. When the studies have suggested a higher prevalence (32% vs. patient’s abnormal karyotype includes the presence of 10%) of PCOS. a Y chromosome or the SRY gene in the sex-determining The majority of children with sexual precocity have region, gonadectomy is recommended to prevent few significant behavioral problems, but emotional potential malignant neoplastic transformation. support is important for these children. Behavioral A growing list of single-gene disorders resulting in expectations by family members and teachers should delayed or absent female puberty is being docu- be based on the child’s chronologic age, which deter- mented in the literature. mines psychosocial development, and not on the Turner syndrome affects approximately 1 in 2500 presence of secondary sexual characteristics. live-born females and is characterized by loss or structural anomalies of an X chromosome. Its clinical features vary, and multiple organ systems may be Delayed Puberty affected. Often these patients present with hypergo- Although there is wide variation in normal pubertal nadotropic hypogonadism and clinical features such development, the vast majority of girls in the United as short stature and infertility.  CH A PTE R 32 Puberty and Disorders of Pubertal Development 379 roids, resulting in deficient or absent pubertal develop- ment. The accumulation of progesterone before the block leads to excessive synthesis of the mineralocor- ticoid 11-deoxycorticosterone, which generally causes hypertension and hypokalemia. Mutations of leptin and leptin receptor gene are associated with retarded pubertal development and childhood morbid obesity. Mutations in the steroidogenic acute regulatory (StAR) gene result in complete loss of adrenal steroido- genesis and delayed puberty, which is called congeni- tal lipoid adrenal hyperplasia. The StAR protein is necessary for the transportation of cholesterol from the outer mitochondrial membrane to the inner mito- chondrial membrane, which is the rate-limiting step in steroidogenesis. Adolescents who present with permanent hypoes- trogenism require estrogen therapy to complete the development of secondary sexual characteristics. Hormone therapy with estrogen plus a progestin or with a low-dose oral contraceptive after establishment of secondary sexual characteristics is required to avoid menopausal symptoms and to prevent osteoporosis. To further optimize gradual bone mineral deposition, 1500 mg of elemental calcium and 400 mg of vitamin D daily are recommended. This should be combined with regular weight-bearing exercises. FIGURE 32-6 Kallmann syndrome is a genetic condition that Polycystic Ovarian Syndrome results in hypogonadotropic hypogonadism caused by a defect in gonadotropin-releasing hormone (GnRH) production and release and Puberty from the hypothalamus. Because the area in the hypothalamus where GnRH is produced is near the olfactory center, the sense of PCOS is the leading cause of female anovulatory smell is usually affected, resulting in anosmia. infertility and is characterized by ovulatory dysfunc- tion and hyperandrogenism. It is associated with obesity, insulin resistance, and metabolic dysfunc- tion (see Chapter 33). During the transition from adrenarche/pubarche (adrenal androgen production Kallmann syndrome (Figure 32-6) presents with dominance) to menarche, a relatively similar imbal- hypogonadotropic hypogonadism and anosmia/ ance of hormones leads to irregular menses, polycystic hyposmia. It may result from a mutation of the KAL ovaries, and a relative androgen excess. Because of gene on the X chromosome or from autosomal muta- these similar clinical findings, the diagnosis of PCOS in tions that prevent the embryologic migration of GnRH the adolescent population remains controversial. neurons into the hypothalamus. Individuals with this Recently, it has been suggested that adolescents syndrome may have other anomalies of midline struc- with congenital virilization, premature pubarche, or tures of the head. One in 50,000 females is affected. central precocious puberty are at higher risk of devel- Mutations of the GnRH receptor gene in females oping PCOS. There is growing support for using a have resulted in low gonadotropin levels with primary modified Rotterdam system to make a diagnosis of amenorrhea or delayed puberty. PCOS in adolescents. This requires the presence of all Mutations of the FSH β-subunit gene and the FSH three of the following criteria (rather than the standard receptor gene have been associated with primary two of three criteria): oligo-ovulation or anovulation, amenorrhea and varying degrees of incomplete devel- hyperandrogenism, and polycystic ovaries visualized opment of secondary sexual characteristics. by pelvic ultrasonography. Adolescent PCOS is associ- Females with aromatase deficiency present at ated with metabolic syndrome and sleep disorders, puberty with progressive virilization, absence of thelar- and treatment should include lifestyle modification. che, and primary amenorrhea. Other treatments commonly used to treat PCOS in an 17-Hydroxylase (P450c17) deficiency interferes older population have not been studied thoroughly in with production of the androgenic and estrogenic ste- adolescents.