Joan M. Mansfield
Lawrence S. Neinstein
Chapter 1 described the varied presentation of the normal physical changes of adolescence. The current chapter focuses on the adolescent whose growth and/or development falls outside the range of normal. These issues are usually of enormous concern to adolescents and their family, and the health care provider must have a clear understanding of how to evaluate and manage these problems.
Review of Normal Growth
Chapter 1 covers normal growth and development in detail. Briefly, there are three general phases of growth during childhood and adolescence. In infancy, there is a period of rapid growth. This phase is followed by a relatively steady period of growth during midchildhood, averaging 5 to 6 cm/year with a gradual decrease seen over time. A growth rate of <5 cm/year during this middle childhood phase is considered abnormal. Growth hormone (GH) and thyroid hormone are the primary hormonal determinants of growth during midchildhood. This phase is followed by the adolescent growth spurt, which is caused primarily by the hormones of puberty (estrogen and androgens). GH secretion increases significantly during the pubertal growth spurt under the influence of sex steroids. Thyroid hormone continues to be required for growth. During peak pubertal growth, growth rates increase to the range of 9 cm/year in girls and 10 cm/year in boys. As puberty progresses, estrogen results in the gradual fusion of the epiphyses with eventual termination of growth in height. In evaluating growth during adolescence, it is necessary to assess whether a teen has reached puberty, whether puberty is proceeding normally, and whether the bony epiphyses are still open to permit further growth.
Short Stature without Delayed Puberty
Adolescents who are progressing normally through puberty may present with concerns about short stature. Most of these teens have genetic or familial short stature with other major categories including chronic disease, constitutional delay of growth and development, and endocrine diseases. Girls who are short may seek medical attention for this complaint when they have just reached menarche and worry that future growth in height will be limited. Boys may present as their pubertal growth spurt slows and they are still shorter than they had hoped. Most hormonal deficiencies, chronic diseases, and malabsorptive states which slow growth will also cause at least some delay in puberty or failure to progress normally through puberty, so that these are less likely causes for the short stature in teens who have normal puberty.
Definition of Short Stature
Adult height is strongly dictated by genetic factors; therefore, evaluation of short stature must be assessed considering the heights of family members. Generally, the 3rd percentile on a cross-sectional growth chart is used as the lower limit of normal.
Criteria for Evaluation
An adolescent should be considered for an evaluation of short stature if:
A complete physical examination is the next step in the evaluation and should include:
The laboratory evaluation of short stature should include the following:
Suggestions for Diagnosis
time of expected peak linear growth velocity, when the growth of an adolescent with constitutional delay of puberty may seem to differ from the normal growth curve as other adolescents accelerate their growth velocities. Individuals with classic GH deficiency have normal body proportions and often a high-pitched voice, a tendency toward hypoglycemia, a microphallus in boys, a childlike face, soft and finely wrinkled skin, and a large prominent forehead.
FIGURE 8.1 Constitutional delay of puberty in girls 2 to 20 years of age (National Center for Health Statistics percentiles). (Adapted from National Center for Health Statistics.NCHS growth charts. www.cdc.gov/growthcharts. 2000.)
Treatment of Short Stature with Growth Hormone
Growth Hormone Deficiency
Patients with classic GH deficiency have marked benefit in statural outcome as the result of GH treatment. In addition, those with complete GH deficiency benefit from treatment (from the metabolic effects of GH) with regard to improving bone density, decreasing fat mass, and improving muscle
strength, even if epiphyseal fusion has been achieved. It appears these subjects should continue GH treatment at a markedly reduced dose, compared with that used for growth augmentation, throughout life.
Bioengineered human GH has been available since the 1980s and indications for treatment continue to expand. Patients with classical GH deficiency usually present with extreme short stature and slow growth (<4 cm/year) well before adolescence, although acquired GH deficiency, sometimes due to head trauma, may present in adolescence with slow growth and relatively delayed puberty.
FIGURE 8.2 Catch-up growth in girls 2 to 20 years of age, with prematurity or deprivation states (National Center for Health Statistics percentiles). (Adapted from National Center for Health Statistics. NCHS growth charts. www.cdc.gov/growthcharts. 2000.)
GH has been used to increase height velocity and increase final adult height in patients who do not have GH deficiency by GH stimulation tests. GH is approved for use in patients with short stature due to Turner syndrome using
a higher dose than is recommended for GH deficiency (0.05 mg/kg/day subcutaneously or 0.35 mg/kg/week for Turner syndrome). IGF-I, thyroid screens, and bone ages by x-ray are monitored during therapy. Patients with Turner syndrome should have baseline renal ultrasonography and periodic echocardiograms to screen for aortic root enlargement. Aortic dissection is a rare but potentially fatal cause of severe chest pain in patients with Turner syndrome. GH treatment should ideally be initiated early in childhood when growth rate begins to fall off. Estrogen replacement is usually delayed to age 12 to 14 or sometimes later to maximize height gain in patients with Turner syndrome. GH has also been used in Noonan syndrome.
FIGURE 8.3 Low height and low weight in girls 2 to 20 years of age with familial short stature, primordial short stature, with familial short stature or primordial short stature (National Center for Health Statistics percentiles). (Adapted from National Center for Health Statistics. NCHS growth charts. www.cdc.gov/growthcharts. 2000.)
Intrauterine Growth Retardation
GH is also approved by the U.S. Food and Drug Administration for use in patients with short stature due to intrauterine growth retardation, Prader-Willi syndrome, and chronic
renal failure before transplantation. GH has also been approved for treatment of children and adolescents with idiopathic short stature who are more than 2.25 SD below the mean in height and who are unlikely to catch up in height. Patients who qualify for a trial of treatment with human GH for idiopathic short stature must have open epiphyses permitting further height gain. Patients with severe short stature who desire treatment with GH should be referred to a pediatric endocrinologist.
FIGURE 8.4 Decreased height and markedly decreased weight in girls 2 to 20 years of age with chronic illness states (National Center for Health Statistics percentiles). (Adapted from National Center for Health Statistics. NCHS growth charts. www.cdc.gov/growthcharts. 2000.)
Review of Normal Development
The appearance of secondary sex characteristics is a response to rising levels of sex steroid hormones. As outlined in Chapter 1, in the normal sequence of events, the rise of adrenal androgens known as adrenarche occurs by age 8 years and is followed several years later
by an increase of hypothalamic gonadotropin-releasing hormone (GnRH) pulsations that trigger the synthesis and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary. LH and FSH stimulate gonadal production of sex steroid hormones and development of the germ cells. The absence of puberty may be the result of failure at any point along the hypothalamic-pituitary-gonadal axis. The challenge of evaluating an adolescent with delayed puberty is to differentiate between constitutional delay of puberty, a normal variation in the tempo of development, and organic diseases such as chronic illness, nutritional insufficiency, tumor, or primary endocrinopathy associated with delayed development.
FIGURE 8.5 Markedly decreased height and decreased weight in girls 2 to 20 years of age with hypopituitary states, metabolic disorders such as rickets, or hypothyroidism (National Center for Health Statistics percentiles). (Adapted from National Center for Health Statistics. NCHS growth charts. www.cdc.gov/growthcharts. 2000.)
The pattern of normal puberty is discussed in detail in Chapter 1. Readers are reminded that secondary sexual characteristics usually begin to develop between ages 8 and 13 in girls, and 9 and 14 years in boys.
FIGURE 8.6 Decreased height and increased weight in girls 2 to 20 years of age with Cushing syndrome and hypothyroidism (National Center for Health Statistics percentiles). (Adapted from National Center for Health Statistics. NCHS growth charts. www.cdc.gov/growthcharts. 2000.)
FIGURE 8.7 Markedly decreased weight in girls 2 to 20 years of age with anorexia nervosa (National Center for Health Statistics percentiles). (Adapted from National Center for Health Statistics. NCHS growth charts. www.cdc.gov/growthcharts. 2000.)
In general, two SDs above and below the mean are used to define the range of normal variability. Chapter 1 is helpful in determining guidelines for evaluation, and further guidelines are discussed subsequently.
Delayed development is defined by the absence of breast budding by age 13 in girls or the lack of testicular enlargement by age 14 in boys, both 2.5 SD beyond the average age at onset of these changes. Alterations in the chronological relationship of pubertal events are also common causes for evaluation. These include phallic enlargement in the absence of testicular enlargement in boys or the absence of menarche by age 16, or 4 years after the onset of breast development, in girls. If puberty is interrupted, there is a regression or failure to progress
in the development of secondary sexual characteristics, accompanied by a slowing in growth rate.
General Guidelines for Evaluating Puberty
A male adolescent may be considered to have delayed puberty if:
A female adolescent may be considered to have delayed maturation if:
These general guidelines must be considered in the context of the teen's family history as to growth and pubertal development, his or her previous growth pattern, and with regard to the review of systems and physical examination.
Delayed development occurs more commonly in boys than girls. Most patients who present for an evaluation of slow growth and delayed development are high school–aged boys who are concerned about their short stature, as well as their lack of muscular and secondary sexual development which puts them at a disadvantage among their peers. Most of these boys have constitutionally delayed development; however, the clinical presentation of the patient with constitutional delay may be indistinguishable from that of the patient whose pubertal delay is the result of an organic lesion.
Constitutional Delay of Puberty
Adolescents with constitutional delay of puberty have often been slow growers throughout childhood. In the absence of sex steroids of puberty, growth may slow even further to <5 cm/year as these children reach an age when puberty would normally occur. Growth velocity increases into the normal range when these teens finally enter puberty. Adolescents with constitutional delay of puberty often have a family history of delayed growth and development in relatives. Teens with constitutional delay of puberty eventually enter puberty on their own. Although they have a longer time to grow before their epiphyses close, they tend to have a less exuberant growth spurt than earlier developers so that their final height is often shorter than average.
Functional Causes of Delayed Puberty
GnRH secretion, can be inhibited centrally by
Eating disorders associated with self-imposed restriction of caloric intake can delay or interrupt the progression of puberty. Anorexia nervosa most often develops in girls in early to middle adolescence, who have already entered puberty. Young adolescent boys or girls who are dieting because of fear of obesity may present with the complaint of delayed development. Crohn disease or celiac disease may also present with delayed development and poor growth as the major symptoms. Since adolescence is normally a period of rapid growth and weight gain, failure to gain or small amounts of weight loss may be manifestations of significant nutritional insufficiency. Poor growth and delayed puberty are common in cystic fibrosis, thalassemia major, renal tubular acidosis, renal failure, cyanotic congenital heart disease, sickle cell anemia, systemic lupus erythematosus, acquired immune deficiency syndrome, or very poorly controlled asthma or type 1 diabetes. Patients who are on stimulants such as methylphenidate (Ritalin) for treatment of attention deficit disorder may have decreased appetite because of the medication and slower growth rates as a result of nutritional insufficiency.
Hypothyroidism may present in an adolescent with slowing of height velocity (height dropping percentiles on the growth chart) whose weight is well preserved for height or who is mildly overweight, sometimes with delayed or interrupted pubertal development. The classic signs include dull dry skin, perhaps with scalp hair loss, decrease in pulse rate and blood pressure, constipation, and cold intolerance. A goiter is not always present. Autoimmune thyroiditis is the most common cause of hypothyroidism in teens. There may be a family history of hypothyroidism or autoimmune issues.
Cushing syndrome (endogenous glucocorticoid overproduction) or chronic exposure to high doses of glucocorticoids for medical treatment causes excessive weight gain, slowing of height velocity, and may interrupt or delay puberty or, if endogenous sex steroid production is also increased, may present with precocious puberty without a growth spurt.
Hypothalamic Causes of Delayed Puberty
The ability of the hypothalamus to secrete GnRH may be damaged by:
Pituitary Causes of Delayed Puberty
Puberty may not begin or may fail to proceed if the pituitary cannot respond to GnRH stimulation with LH and FSH production. This may be due to:
If the gonads are unable to respond to LH and FSH, puberty will not proceed.
The causes of gonadal failure with abnormal karyotype include:
The causes of gonadal failure with normal karyotype include:
Syndromes Associated with Pubertal Delay
There are several syndromes that are characterized by extreme obesity, short stature, and delayed puberty. These include the following:
Another congenital syndrome is congenital absence of the uterus and upper vagina (Mayer-Rokintansky-Kuster-Hauser syndrome). This is associated with normal puberty, but absent menses.
Work-Up of Delayed Puberty
Most adolescents with delayed maturation have constitutional delay of puberty. However, this diagnosis is made by excluding other causes. Following is a discussion of the evaluation of the adolescent with delayed puberty, including criteria for a provisional diagnosis of constitutional delay of puberty. A detailed history and physical examination will help focus and minimize the laboratory testing needed to evaluate an adolescent with delayed development.
A complete physical examination is indicated for the adolescent with delayed puberty, but the following areas are of particular importance:
Laboratory evaluation should be focused according to the clinical impression (see clue to diagnosis). In the patient who is underweight for height, studies would include screening tests for chronic disease or malabsorptive states such as celiac disease.
The most useful initial examination in delayed puberty and slow growth is often an x-ray of the left hand and wrist for a bone age assessment. This information can be used to assess how much height growth potential remains in the patient with short stature and delayed development. A predicted adult height can be obtained using the Bayley-Pinneau tables in the Atlas of Skeletal Maturation by Gruelich and Pyle (or see Table 1.5).
Bone age may also be used in conjunction with height age and chronological age to give clues about a diagnosis as indicated below. Height age is determined by locating the corresponding age at which the patient's height would be equal to the 50th percentile. See Table 8.1.
Routine Laboratory Tests
Initial laboratory studies to be considered in the adolescent with delayed puberty include a CBC count, erythrocyte sedimentation rate (useful as a screening test for chronic illness such as inflammatory bowel disease) electrolytes, blood urea nitrogen, creatinine, glucose, calcium, phosphorus, albumin, liver enzymes and urinalysis.
Evaluation for Celiac Disease
Evaluation for celiac disease (antitissue transglutaminase and total IgA, or celiac panel) should be considered. More extensive testing for inflammatory bowel disease includes an upper gastrointestinal tract series with small bowel follow through and barium enema.
Central Imaging Studies
If there is a suspicion of a CNS tumor, cranial magnetic imaging with contrast is the best way to evaluate the hypothalamus and pituitary. A computed tomography (CT) scan is a less sensitive alternative.
Hormonal tests to be considered include thyroid function tests (adjusted T4, TSH), prolactin, LH and FSH, dehydroepiandrosterone sulfate, testosterone or estradiol, and IGF-I and IGFBP-3.
In the early stages (Tanner stage 2) of puberty, breast budding and vaginal maturation in girls and penile and testicular enlargement in boys are more sensitive indicators of pubertal neuroendocrine-gonadal function than a single daytime measurement of gonadotropin (LH and FSH) levels, estradiol or testosterone. LH, FSH, and testosterone or estradiol may be in the prepubertal range on a daytime sample even though these hormones are actively being secreted at night. Testosterone or estradiol levels may be valuable in following the patient whose puberty is not progressing normally by clinical assessment of growth and secondary sexual development.
GH is secreted primarily during sleep, so daytime levels are expected to be low. IGF-I and IGFBP-3 are used to assess GH sufficiency. IGF-I levels should be compared with normals for bone age rather than chronological age since the levels increase during puberty. IGF-I levels are low in patients with nutritional insufficiency. Patients with delayed puberty and slow growth often have temporarily decreased GH secretion simply due to pubertal delay which increases to normal as puberty begins. If GH deficiency is suspected, the patient should be referred to a pediatric endocrinologist for GH stimulation testing. Patients with constitutional delay of puberty who are prepubertal may appear GH deficient on GH stimulation testing unless primed with estrogen before the test.
LH and FSH determinations are only useful if they are elevated since these hormones are secreted primarily during sleep in the early phases of puberty. Early to midpubertal levels (Tanner breast stage 2) are indistinguishable from prepubertal levels, usually with a very low LH and FSH higher than LH. Elevated LH and FSH levels are suggestive
of primary gonadal failure. If LH and FSH levels are elevated, further laboratory evaluation would include blood karyotyping in search of a chromosomal abnormality such as 45,X. Patients with gonadal dysgenesis who have Y chromosomal material present should have their gonads removed surgically because of an increased risk for gonadoblastoma. If the chromosomes are normal in the patient with gonadal failure, antiovarian antibodies may be obtained to look for autoimmune gonadal damage. Pelvic ultrasonography may be used to visualize the uterus and ovaries, but should be interpreted with caution since the prepubertal uterus is small and may be missed on ultrasonography. A vaginal ultrasonography is usually postponed until adulthood.
If the initial prolactin level is elevated, it should be repeated without a breast examination on the day of the testing, and ideally in a fasting state. Patients with significantly elevated prolactin levels should have a cranial magnetic resonance imaging (MRI) with contrast.
Neuroendocrine Pharmacological Testing
If there is a question of multiple pituitary hormone defects, the patient may be referred to an endocrinologist for pharmacological and physiological tests of neuroendocrine function. A GnRH stimulation test with gonadorelin (Factrel), 2.5 µg/kg intravenously, maximum 100 µg, has been used in the past to assess pituitary LH and FSH response in the evaluation of delayed puberty. If the patient has central puberty, there will be a large increase in LH during the 2 hours after GnRH is given (sample can be drawn at 45 minutes). Since GnRH is currently not commercially available, GnRH analog stimulation tests are substituted (leuprolide acetate 500 µg).
Constitutional Delay of Puberty
The chief diagnostic challenge in the patient with pubertal delay is to distinguish between constitutional delay and true GnRH deficiency. About 90% to 95% of delayed puberty is constitutional delay of puberty. No single test reliably separates patients with constitutional delay from those with idiopathic hypogonadotropic hypogonadism.
This diagnosis is made by excluding the other causes, as discussed. However, using the guidelines in Table 8.2, one can confidently make a provisional diagnosis.
Clues to Other Diagnoses
The presence of midline facial defects, anosmia, cryptorchidism, or microphallus strongly suggests idiopathic hypogonadotropic hypogonadism; however the diagnosis cannot be firmly established until the patient reaches the age of 18 years and is still prepubertal. Genes for hypothalamic hypogonadism have been identified, as have some genes for familial pubertal delay.
Turner syndrome usually have some of the following characteristics:
Savendahl and Davenport (2000) recommend a karyotype in all girls with unexplained short stature, delayed puberty, webbed neck, lymphedema, or coarctation of the aorta. Karyotype should also be considered for girls with a height below the 5th percentile and two or more features of Turner syndrome, such as high palate, nail dysplasia, short fourth metacarpal, and strabismus.
. Abnormal findings on review of systems or physical examination
Management of Delayed Puberty
Before age 14 years in girls and age 16 years in boys, if there is no evidence of an underlying disease or neurological abnormality and the initial evaluation reveals normal prepubertal hormone levels, the adolescent can be seen at 6-month intervals for measurements of growth, assessment of pubertal status by physical examination, and reassurance if progression of secondary sexual development is evident. After the first signs of testicular or beast enlargement are observed, follow-up at regular intervals is desirable to reassure the patient and parents that puberty is progressing. Since the testes begin to enlarge in males before increased testosterone production and increased growth velocity occur, support and guidance in dealing with the frustrations of delayed puberty are important, even after there is evidence that secondary sexual development has begun.
If the evaluation reveals primary gonadal failure, cyclic estrogen and progestin therapy in girls or testosterone therapy in boys will be necessary. Adolescents with hypogonadotropic hypogonadism or hypopituitarism will also need estrogen or testosterone replacement, often with replacement of other hormones as well. Short courses of estrogen or testosterone can also to be used to initiate development in constitutional delay of puberty if there is no sign of development by age 14 in girls or 15 in boys.
Treatment for Girls
In girls, there are several regimens for replacing estrogen and progesterone. If growth is desired, estrogen is begun at a low dose, since height velocity is greater at low estrogen doses, and higher doses cause more rapid epiphyseal closure. The three phases of estrogen replacement are:
Induction of Breast Development
In the first phase, a number of low dose estrogen preparations have been used: estrogen regimens include conjugated estrogens (Premarin) 0.3 mg tablet or less (1/2 tablet) daily by mouth, 0.3 mg estrone sulfate (Estratab), or 0.5 mg micronized estradiol (Estrace) for the first 6 to 12 months of treatment or until linear growth slows. Although lower doses of ethinyl estradiol (10 µg) and transdermal estradiol (5–10 µg) have been used in research studies to induce puberty, the lowest dose estradiol transdermal patch available is 25 µg and the lowest dose of ethinyl estradiol available is 20 µg.
Induction of Menses
In the second phase, the daily dose of estrogen is increased to 0.625 mg conjugated estrogens, 1.0 mg micronized estradiol, 20 µg ethinyl estradiol, or a 50 µg transdermal estradiol patch. After 2 to 3 months, a progestin such as (medroxyprogesterone [Provera] 5–10 mg or norethindrone 0.7–1 mg) or micronized progesterone 200 mg is added initially 5 days each month.
Long-term Estrogen Replacement
In the third phase, 10 mg of medroxyprogesterone or other progestin is given 12 to 14 days a month to decrease the risk of endometrial hyperplasia. Estrogen regimens for long-term replacement include conjugated estrogens 0.625 mg, ethinyl estradiol 20 µg, esterified estrogens 0.625 mg, micronized estradiol 1.0 mg, or transdermal estradiol 50 to 100 µg. Once growth is essentially complete, estrogen can also be replaced as a 20 to 35 µg oral contraceptive pill, or combined estrogen–progestin transdermal patch.
Oral estrogens pass first through the liver which could theoretically increase side effects. Transdermal alternatives include estradiol patches (Vivelle dot, Climera, Alora, and Estraderm) which are changed once or twice a week depending on the preparation. An oral progestin (medroxyprogesterone 10 mg or micronized progesterone 200 mg) is added for 12 to 14 days each month. One transdermal regimen is Vivelle dot (0.05 mg) for 2 weeks each month followed by Combipatch 0.05 mg estradiol/0.14 mg norethindrone acetate for 2 weeks.
Many patients with delayed puberty have decreased bone density for age. The optimal dose of estrogen replacement for increasing bone density in adolescents remains to be established, but it is probably higher than in menopausal women. A bone density by dual-energy x-ray absorptiometry (DXA) of the hip and spine at baseline and every 2 years is commonly carried out in adolescents on estrogen or testosterone replacement. Bone density is compared with age-matched norms. The importance of
appropriate calcium (1,300 mg/day) intake by diet or supplements and at least 400 IU vitamin D to support bone calcification should be stressed on each visit. The timing of initiation of sex steroid therapy to achieve maximum height depends on the patient's chronological and skeletal age, and current height velocity.
Treatment for Boys
In boys with constitutional delay of puberty, 3 to 6 month courses of testosterone 1% gel 2.5 to 5 gm daily or intramuscular testosterone enanthate 25 to 50 mg every 2 to 4 weeks can be used to initiate secondary sexual development. Intramuscular hCG is used less commonly. Exposure to testosterone or hCG may speed the onset of the patient's own puberty. Since sex steroids cause fusion of epiphyses, care must be taken in the timing and monitoring of these therapies so that final height is not compromised. These patients should therefore be referred to an endocrinologist for treatment. The timing of such an intervention must take into account such complex issues as psychosocial stress, self-image, and school performance which appear to be more affected by pubertal delay than by short stature alone. Males with gonadal failure, hypopituitarism, or hypothalamic hypogonadism are maintained on long-term testosterone replacement using testosterone gel. They should receive dietary adequate calcium and vitamin D and should have DXA scans for spinal and hip bone density measurements since they are at risk for a low bone mass. In both males and females whose delayed puberty is due to abnormalities in hypothalamic GnRH secretion that do not correct with time, fertility can be achieved using a small pump to deliver pulses of GnRH intravenously or subcutaneously for weeks or months. Some GnRH-deficient males will achieve spermatogenesis with hCG alone or in combination with FSH. Ovulation can be induced by FSH and hCG in GnRH-deficient females.
Treatment of Specific Conditions
Treatment is begun with levothyroxine (see Chapter 9 for hypothyroidism). Thyroid function tests are repeated in 6 weeks and the dose is adjusted to maintain the TSH concentration in the midnormal range. The final dose is usually 75 to 100 µg in females and 100 to 125 µg in males. Noncompliance with medication is often the underlying issue in teens whose TSH is elevated despite receiving unusually high doses of thyroid replacement. A 7-day pill package and adult supervision of doses may be helpful. Once the dose is established, thyroid tests are repeated at 6-month intervals. Catch-up growth is expected when thyroid hormone replacement is initiated, but patients who have been untreated for several years will lose some adult height.
Turner Syndrome and Gonadal Dysgenesis
Short stature associated with Turner syndrome can be treated with human growth hormone (hGH). The U.S. Food and Drug Administration and other worldwide regulatory agencies have approved the use of hGH for statural improvement in Turner syndrome. The hGH therapy should be started before the adolescent years and before beginning estrogen therapy for feminization. The dose used is approximately double that used for subjects with classic GH deficiency. Data from the National Cooperative Growth Study from Genentech has shown GH to be effective in improving the final height of girls with Turner syndrome and that GH is safe for these patients (Blethen et al., 1996). Oxandrolone (0.075 to 0.25 mg/kg/day) or fluoxymesterone (2.0 mg/day) can be added to GH therapy to improve the growth response. If this is done, it is usually begun after 2 to 3 years of GH therapy alone, before feminization, for a limited time, and with great caution because androgens have the following disadvantages:
Anabolic steroids as the sole therapy for this syndrome are no longer recommended. Secondary sexual characteristics in females are achieved through the use of increasing doses of conjugated estrogens as discussed above. Chernausek et al. (2000) evaluated the timing of estrogen replacement in girls with Turner syndrome with regards to final height outcome. Patients in whom estrogen treatment was delayed until the age of 15 years gained an average of 8.4 cm over their projected height. Those who started estrogen at 12 years of age gained only 5.1 cm. They found that growth was stimulated for 2 years after beginning estrogen replacement therapy and that the timing of estrogen therapy is important for final height. This indicates that for some girls, particularly those who are shortest and in whom GH has not been given for more than 2 years, delaying estrogen therapy may be indicated to improve height outcome.
If there is a Y chromosome present on the initial study done to diagnose Turner syndrome, no further chromosomal analysis is required to anticipate that the patient will require gonadectomy. However, Y chromosomal material, rather than a full Y chromosome, may be present in girls who are virilized, either at birth or with puberty not as the result of androgen therapy. They should have fluorescent in situ hybridization (FISH) for the Y chromosome to ensure that no Y chromosomal material has been translocated. The presence of any Y material is an indication for gonadectomy, to prevent potential malignant neoplasias. Surgery should be followed by hormonal replacement therapy during and after puberty.
Treatment of pubertal delay caused by chronic illness necessitates treating the underlying disorder. For example, enzyme replacement in cystic fibrosis, gluten-free diet in celiac disease, corrective surgery for congenital heart disease, and hyperalimentation in inflammatory bowel disease usually result in catch-up growth and maturity. Medications such as steroids or antimetabolites can inhibit growth. Catch-up growth can be observed after discontinuation of treatment with these drugs. In some cases, the disease process is irreversible, such as in sickle cell anemia. The pubertal delay in sickle cell anemia is thought to be hypogonadism, possibly caused by a zinc deficiency. Zinc has been used with some early experimental success in alleviating this problem. In patients with chronic renal failure, there may be some growth after improved nutrition and hemodialysis
or transplantation. However, many patients with chronic renal failure remain short. Recent studies suggest that GH can be administered to subjects with chronic renal failure before transplantation to improve height, without causing deterioration of underlying renal function (Fine et al., 1994). HIV infected children who have poor growth and body wasting may benefit from the anabolic effects of short-term GH administration; however, long-term use of such agents remains under investigation (Mulligan et al., 1993).
Young adolescents are preoccupied with their physical appearance. Any variation from the normal timing of sexual development is a major source of embarrassment to them and evokes feelings of personal inadequacy. A review of a patient's progress on the growth pubertal growth and growth chart can help reassure him or her that growth is proceeding in a pattern that is appropriate. For patients who have a permanent defect in reproductive function, counseling and support from both the primary health provider and medical specialist can be helpful in enabling the patient to establish a positive self-image of himself or herself as a capable adult. Further counseling by a mental health professional may be necessary. Questions about fertility should be answered as they arise, with emphasis on the patient's ability to function normally as a marriage partner and parent of adopted children. With current technology, pregnancies are possible using in vitro fertilization with donor eggs in patients with ovarian failure.
Excessive Growth: Tall Stature
Tall stature is seldom a complaint in males, but is occasionally a source of concern in adolescent females. This is less common than in the past since the role models of athletes and fashion models have made tall stature more socially acceptable in women now than in the past. Most commonly, tall stature is genetic and one or both parents are also tall.
Obese girls tend to be taller than average, perhaps due to higher levels of insulin. Many genetically tall girls who are above the 95th percentile for height in the early adolescent period are experiencing an early pubertal growth spurt, but will have a final adult height in the normal range. Review of the growth chart and a bone age are useful. If growth rate is excessive, evaluation might include thyroid function tests looking for hyperthyroidism, and an IGF-I, IGFBP-3, and random GH to exclude GH excess. If GH is low, acromegaly is unlikely. Elevated GH may be a random pulse and should be repeated. IGF-I is elevated in acromegaly. Marfan syndrome is usually diagnosed clinically. The phenotype is characterized by tall stature, lean body habitus and elongated extremities. A slit lamp examination by an opthamologist may detect lens dislocation in 50% of patients. Echocardiogram may reveal a dilated aortic root. The syndrome is caused by a gene abnormality causing deficient fibrillin production.
In the past, high doses of estrogen were used to limit height gain in girls whose predicted height would be more than 6 ft (183) cm. Estrogen affects growth by suppressing IGF-I and accelerating epiphyseal fusion. This is seldom done currently since female tall stature has become more socially acceptable. High-dose estrogen treatment in girls is associated with side effects which include nausea, breast soreness, hypertension, and, rarely, blood clots.
The treatment of boys has been studied less extensively. Theoretically, administration of high-dose testosterone could accelerate epiphyseal fusion, but concerns of this therapy would include edema, acne, weight gain and a decrease in testicular volume. Therefore, tall stature in boys is typically not treated.
In boys, development before age 9 years or 2.5 SD earlier than average is considered precocious. Early development in boys is rare. There are 10 times as many girls with precocious puberty as boys. There is currently a controversy over the definition of precocious puberty in North American girls. In girls, the cut off has traditionally been 8 years or 2.5 SD below the average of breast development. However, a 1997 study by Herman-Giddens (Herman-Giddens et al., 1997) of 17,000 American girls found a mean age of breast development of just below 10 years in Caucasian girls and 9 years in African-American girls; 15% of African-American girls having the appearance of breast development by 7 to 8 years and 5% of Caucasian girls having breast development by 7 to 8 years. Pubic hair was present in 3% of Caucasian girls and 18% of African-American girls by age 7 to 8 years. This has led to a revision of the definition of precocious puberty by the Lawson Wilkins Pediatric Endocrine Society as the presence of breast or pubic hair before age 7 in Caucasian and before age 6 years in African-American girls. Since then, numerous reports have pointed out that cases of true pathology such as CNS tumors may be missed by excluding 7- to 8-year-old
girls from evaluation. Girls who have both pubic hair and breast development at ages 7 to 8, should have at least a bone age for height prediction, a review of growth and history, and consideration of further testing. Girls with rapid progression or unusual progression of puberty, a predicted height below 150 cm or -2 SD below target midparental height, those with neurological symptoms, or girls who are having psychological difficulty due to early puberty should be referred for further evaluation and consideration of possible suppression of puberty with GnRH analog therapy. Puberty is normally held back in humans during childhood by inhibitory connections to the hypothalamus which suppress GnRH pulsations. If these inhibitory connections are damaged, GnRH pulse amplitude increases, and central puberty ensues. There is often a family history of early puberty in girls with precocious puberty; some studies suggest an autosomal dominant pattern with variable penetrance.
The vast majority of girls with central precocious puberty have idiopathic precocious puberty. Boys are much more likely to have a specific lesion causing their precocity.
Central causes of precocious puberty include the following:
Gonadotropin-independent causes of precocity in girls include the following:
In boys, in addition to the central causes listed above, precocious puberty can be caused by androgen exposure, congenital adrenal hyperplasia, gonadal and adrenal tumors secreting androgens, and familial activating mutations of the LH receptor.
Incomplete Forms of Precocious Puberty
Premature thelarche occurs often in female infants and toddlers. Self-limited breast budding which is also transient occurs in girls aged 6 and above. There is no sustained growth spurt or bone age advancement in these girls. Breast budding may appear and recede several times before sustained puberty ensues.
Benign premature adrenarche presents with underarm odor, and pubic and/or axillary hair development usually at ages 6 to 8 years. Bone age is often slightly advanced (1 year) and adrenal androgens are in the pubertal range. Twenty percent of the girls with benign premature adrenarche will go on to have polycystic ovary syndrome as teens. Patients with a history of intrauterine growth retardation followed by excessive weight gain and insulin resistance in childhood may present with premature adrenarche. They are at increased risk for polycystic ovary syndrome and sometimes glucose intolerance as teens. Virilization in girls is rare and can be due to an androgen secreting adrenal or ovarian tumor, topical androgen exposure, or congenital adrenal hyperplasia. Symptoms of virilization include rapid growth and bone age advancement, deepening of the voice, clitoromegaly or muscular development. A thorough evaluation is required.
Evaluation of Precocious Puberty
History includes a review of family history of endocrine or pubertal disorders, timing of puberty in family members, use of estrogen or androgen containing gels by family members, and heights of family members. The patient's past history should be reviewed for evidence of predisposing medical conditions. The growth chart should be obtained.
The physical examination includes careful measurement of height and weight, vital signs, examination of the skin for large irregular café au lait spots suggestive of McCune-Albright syndrome, examination of the fundi, assessment for thyroid enlargement, abdominal examination, Tanner staging (measurement of breast or testicular and phallic dimensions, and pubic hair staging). The vaginal introitus can be examined for signs of estrogen effect on the labia minora and presence of leukorrhea in the frog-leg position. Internal examination is not necessary unless unexplained vaginal bleeding is present in which case an experienced observer can often visualize the vagina and cervix in the knee chest position without instrumentation. In boys, the testicular examination should focus on any testicular asymmetry or masses, or phallic enlargement without testicular enlargement suggesting a source of androgens outside of the testes, such as congenital adrenal hyperplasia.
A bone age x-ray of the left hand and wrist is useful. If the bone age is 2 years advanced, more evaluation is usually indicated (Fig. 8.8). A baseline prediction of adult height can be made using the average charts from the Bayley-Pinneau table at the back of the Gruelich and Pyle Atlas of Skeletal maturation (see Chapter 1 for details).
Laboratory evaluation might include an LH, FSH, estradiol, DHEAS, and TSH in girls, and in boys, a testosterone and 8 a.m. 17 OH progesterone and DHEAS, hCG, LH, and FSH. The LH and FSH will be in the prepubertal range (LH less than FSH) in the early stages of central puberty. By the time breast or gonadal development is in Tanner SMR stage 3, LH and FSH are often in the pubertal range. To confirm central puberty, it is sometimes necessary to do a GnRH or GnRH analog stimulation test (GnRH itself has recently been unavailable) using 500 µg leuprolide acetate and obtaining an LH, FSH, and estradiol or testosterone 45 minutes to 2 hours after the injection. If estradiol is markedly elevated (more than 100 pg/mL) and LH and FSH are suppressed, an ovarian cyst or more
rarely tumor is suspected. A pelvic ultrasonography can be done in girls if an ovarian cyst or tumor is thought to be the cause of the precocity. In boys, a hCG test should be done to rule out a hCG-producing tumor that could be causing testosterone production. A cranial MRI with contrast should be done to rule out CNS lesion in all boys with central precocious puberty, in all girls younger than 6 years, and should be considered in girls between 6 and 8 years of age depending on the clinical history. An adrenocorticotropic hormone (ACTH) stimulation test may be needed if congenital adrenal hyperplasia is suspected as a cause of androgen excess.
FIGURE 8.8 Flow sheet for evaluation of isosexual precocious puberty. hCG, human chorionic gonadotropin; CT, computed tomography; MRI, magnetic resonance imaging. (Adapted from Brenner PE. Precocious puberty in the female. In: Mishell DR, Davajan VC, eds. Reproductive endocrinology, infertility, and contraception. Philadelphia: FA Davis Co, 1979.)
Treatment of Precocious Puberty
If the evaluation has not revealed a specific treatable cause of precocious puberty and the child has central precocious puberty, GnRH analog treatment should be considered. Most girls in the 7 to 9 year range do not require treatment for suppression of puberty.
Many girls in this age range have a slow intermittent progression of their puberty and reach a final height which is not short. Early developers take longer on average to reach menarche than later developers. Often parents are most worried about how they will handle menses in a grade school child, and can be reassured that menarche is not imminent in most cases and that menses can be suppressed if necessary using GnRH analog therapy. Untreated girls should be followed up at 6 month to 1 year intervals. If the child has an initial predicted adult height below 62 in. (157 cm), bone age may need to be repeated in 6 months to 1 year because the predicted height can decline with rapid bone age advancement, and therapy may be required to preserve height potential. Depot leuprolide at an initial dose of 0.3 mg/kg can be given q28 days intramuscularly. LH, FSH, and estradiol in girls or testosterone in boys can be obtained 45 minutes to 2 hours after the depot leuprolide to document adequate suppression of puberty on therapy after 2 to 3 months of treatment. Partial suppression of puberty has been achieved in girls with gonadotropin
independent puberty (McCune-Albright syndrome) with the aromatase inhibitor testolactone. Similar regimens with antiandrogens and testolactone have been used in boys with familial LH-activating mutations.
For Teenagers and Parents
http://www.magicfoundation.org. Magic Foundation with information about growth disorders and brochures about many disorders.
http://www.hgfound.org. Human Growth Foundation Web site with information and support for children and adults with growth disorders.
http://www.keepkidshealthy.com/welcome/conditions/delayed puberty.html. Information from keepkidshealthy on delayed puberty.
http://www.turner-syndrome-us.org/. Information about Turner syndrome.
http://www.humatrope.com. Information from Eli Lilly about synthetic GH.
http://www.novonordisk.com/. Facts from novo on GH deficiency and treatment.
http://www.toosoon.com. Information from Lupron Association on precocious puberty.
For Health Professionals
http://humatrope.com. Information from Lilly on GH.
http://www.aafp.org/afp/990700ap/209.html. Review article from the American Academy of Family Physicians on Evaluation of Growth Disorders.
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