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The Smallest Kid in School: Evaluating Delayed Puberty

December 4, 2012

A recent article published on the Medscape website highlighting the diagnostic work up in a case is suspected pubertal delay.

www.medscape.com

Authors and Disclosures

Author(s)

Peter A. Lee, MD, PhD

Professor, Pennsylvania State College of Medicine, Hershey Medical Center, Hershey, Pennsylvania

Disclosure: Peter A. Lee, MD, PhD, has disclosed no relevant financial relationships.

Christopher P. Houk, MD

Associate Professor of Pediatrics, Chief, Division of Pediatric Endocrinology, Georgia Health Sciences University, Augusta, Georgia

Disclosure: Christopher P. Houk, MD, has disclosed no relevant financial relationships.

From Medscape Pediatrics

The Smallest Kid in School: Evaluating Delayed Puberty

Peter A. Lee, MD, PhD; Christopher P. Houk, MD

Posted: 08/13/2012

Pubertal Delay: Case Challenge

A 12-year-old boy was referred for an endocrinology evaluation because his primary care provider was concerned about a lack of pubertal development during a recent annual physical examination. Although the boy is currently healthy, his medical history was notable for lack of midfacial fusion, including cleft lip and palate involving the nasal structure at birth, for which he has undergone multiple surgical repairs. He was noted to be anosmic during a postoperative evaluation early in childhood.

A review of the patient’s growth chart reveals that his growth had consistently been along the 10th percentile for height for his age. As he approached the age of 12 years, the usual age of pubertal onset for boys, he continued to grow at an annual rate of 5 cm/yr.

His current height and weight were at the 25th and 10th percentiles for age, respectively. Vital signs were normal. His physical examination was normal for a prepubertal male, with good results from his surgical facial repair and small, firm testes. His testes were 1 cc. in volume bilaterally, less than 1.0 cm in length, and slightly firm; the penis was prepubertal; and there was no sexual hair.

Before this visit, there had been no laboratory assessment of pubertal delay. Laboratory testing done at this visit was notable for luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels below detectable limits. The LH level rose to a peak of 0.3 mIU/mL after gonadotropin-releasing hormone (GnRH) stimulation. Other screening tests, including a complete blood count and basic metabolic panel, were normal.

Questions answered incorrectly will be highlighted.

Results of this child’s evaluation are:

Normal for age

Consistent with a diagnosis of delayed puberty and warrant further evaluation

Consistent with a diagnosis of delayed puberty; the child should return in 6 months for a physical examination and assessment of pubertal status

What Is Delayed Puberty?

Puberty is a complex process involving the interplay of hypothalamic, pituitary, and gonadal hormones. It is the phase of growth in which secondary sexual characteristics develop and linear growth is accelerated, and it marks the transition between childhood and adulthood.

GnRH-secreting neurons migrate from the embryonic olfactory placode to the human forebrain during fetal life. A network of these neurons within the hypothalamus acts in concert to produce pulsatile GnRH release. The resulting pubertal onset increases pituitary LH and FSH release, which in turn stimulates gonadal sex-steroid production. Gonadotropins stimulate testicular or ovarian development; gonadal sex steroids then stimulate development of secondary sexual characteristics.

Defining Delay

Delayed puberty is defined as an absence of secondary sexual characteristics at an age that is greater than 2.5 standard deviations above the mean. The absolute age varies somewhat among racial/ethnic groups and is also dependent on socioeconomic conditions. In general, the upper age limit is considered to be approximately 14 years for boys and 13 years for girls.[1,2] Lack of pubertal progression after beginning at a normal time should also be considered as delayed. For boys, failure to complete puberty within 4 years indicates lack of progression; for girls, it is the failure to attain menarche 3 years after the beginning of breast development (thelarche).

There has been a secular trend toward earlier age at thelarche over recent years.[3-5] However, there is no clear evidence of a decreasing age at menarche.[3,6]

Physical Findings

The first sign of the onset of puberty in boys is an increase in testicular volume, generally accepted to be a volume greater than 4 cc, or testicular length greater than 2.5 cm. which indicates pubertal growth. In girls, thelarche is generally the first evidence of puberty. Palpation may be required to discriminate glandular breast tissue from fatty subcutaneous tissue on the chest. A disc of firm, tender, tissue immediately beneath the areolae is consistent with breast growth. Additional findings indicative of breast development are a pigmented areolae diameter greater than 1.5cm and/or a nipple diameter greater than 3 mm.

In boys and girls, the presence of pubic and other sexual hair growth does not always indicate onset of puberty. Hair growth may be a consequence of adrenarche, a normal physiologic event in which the adrenal gland begins to secrete dehydroepiandrosterone and androstenedione; these relatively weak androgens stimulate the development of pubic hair (pubarche), axillary hair, and adult-type body odor. Although temporally related to puberty, adrenarche develops independently of pubertal activation of the hypothalamic-pituitary-gonadal axis.

Suspected Delayed Puberty: Making the Diagnosis

A child presenting with suspected delayed puberty requires a thorough history, including family history; a detailed physical examination, with particular attention to breast development in girls and testicular volume in boys; and selected laboratory evaluation.

Although the basic approach to pubertal delay is similar in boys and girls, key details differ.[2,7]

History

Key components of the history include:

  • Birth and developmental history;
  • General health;
  • Growth, noting any recent changes in height and weight;
  • Intense or excessive exercise;
  • Review of systems, including anosmia, general endocrine and gastrointestinal illnesses, and any therapy (including radiation or chemotherapy);
  • History of any psychiatric disease, including anorexia or alcohol or illicit drug use; and
  • Family history of pubertal timing, menarche, and infertility.

History: Clinical Pearls

  • Development of pubic/sexual hair does not necessarily mean the onset of puberty and may be due to adrenal androgen secretion.
  • In addition to pubertal delay, an unusually slow pace of pubertal development warrants evaluation to exclude abnormalities.

Physical Examination

Key components of the physical examination include:

  • Accurate measurements, including:
    • Height;
    • Weight;
    • Weight for height (body mass index);
    • Upper/lower segment ratio (or total minus sitting height ratio): a ratio less than 1 indicated prepuberty, 1 is consistent with puberty, and greater than 1 suggests hypogonadism; and
    • Arm span: an arm span exceeding height by more than 5 cm suggests delayed epiphyseal closure resulting from delay of sex-steroid exposure.
  • Growth rates before presentation may also be instructive (Figure 1); slowing of the rate of height growth often precedes the onset of puberty. Such slowing is often accentuated before the onset of puberty in boys with constitutional delay.
;

(Download PDF)

Figure 1.

Growth charts for female and male children. Left. The female chart shows the typical pattern of height and weight gain for a girl presenting with inflammatory bowel disease (dark blue arrow) and one with Turner syndrome (light blue arrow). Right. The growth pattern of the boy with hypogonadotropic hypogonadism discussed in the article, showing no deceleration of growth rate as puberty is approached (dark blue arrow), and the second growth curve of a typical patient with constitutional delay of puberty, showing growth deceleration (light blue arrow).

  • General examination should identify:
    • Midline facial defects,
    • Syndactyly;
    • Assessment of subcutaneous fat; and
    • Size of the thyroid gland.
  • Neurologic examination should include:
    • Funduscopic examination,
    • Visual acuity, and
    • Sense of smell.
  • Genital examination:
    • Boys: testicular volume or long-axis length, symmetry, and consistency should be noted.
    • Girls: inspection for color of the vaginal mucosa; pinkish mucosa suggests an estrogen effect, whereas a reddish appearance is consistent with prepuberty.
    • Both sexes: Pubertal staging of genital or breast development, genital inspection, and pubic hair should be noted.

Physical Examination: Clinical Pearls

Initial Diagnostic Testing

  • Serum LH and FSH levels need to be obtained to document or exclude a hypergonadotropic state; and
  • Radiography of the left hand and wrist is done to determine skeletal maturity (bone age) and document biological age; a significant delay suggest a deficit of factors producing normal growth and maturity.
  • A suggested algorithm for the evaluation of the child with pubertal delay is presented in Figure 2.

On the basis of these results, second-tier testing (discussed later in this article) should then be done to determine a specific diagnosis.

;

Figure 2. Algorithm for the evaluation of pubertal delay.

What Is Causing Pubertal Delay?

Circulating LH and FSH levels increase at the onset of puberty. Excessive increases occur in the presence of gonadal failure owing to lack of feedback.[8] Accordingly, excessively elevated gonadotropin levels indicate defective gonadal function, a condition that is always pathologic.

Low gonadotropin levels suggest a delay of endogenous pubertal onset and may or may not indicate a permanent defect. Hypothalamic or, less commonly, pituitary dysfunction results in the inability to secrete LH and FSH. Thus, low gonadotropin levels alone may be inadequate to differentiate a temporary pubertal delay from a permanent one.

Classifying Pubertal Delay

Pubertal delay may be classified on the basis of gonadotropin levels:

Temporary hypogonadotropism. Low gonadotropin levels, with temporary delay resulting from physiologic or constitutional delay (Table 1).

Table 1. Conditions Associated With Temporary Hypogonadotropism

Significant underweight
Chronic disease: inflammatory disease, hypercortisolism, malnutrition/eating disorder, excessive exercise (eg, gymnastics); psychogenic or stress-related; hypothyroidism, prolactinoma, brain tumor (eg, craniopharyngioma); alcohol use/abuse
Testicular volume greater than prepubertal
Growth acceleration and breast budding in girls
Recent history of weight gain, consistent with hyperprolactinemia rather than hypothyroidism
Previous onset of puberty followed by cessation of progression
Family history of delayed adolescent growth and puberty

Constitutional delay is the most common cause of pubertal delay in both boys and girls. Approximately 40% of these children have a family history of delayed puberty. Constitutional delay is much more common in males, accounting for about 80% of cases.[9] In girls, that percentage decreases to only 30%.[10] Significant delay is associated with skeletal age delay.

Unless there is early evidence of the onset of puberty, such as early growth acceleration among girls or early testicular growth among boys, it can be very difficult initially to distinguish constitutional delay from permanent hypothalamic hypogonadism. Systemic diseases and other chronic conditions may also result in delayed puberty, because nutritional delay and other deficits result in immature or impaired GnRH release.

Permanent hypogonadotropism. Low gonadotropins because of a permanent defect (hypogonadotropic hypogonadism) (Table 2).

Table 2. Conditions Associated With Permanent Hypogonadotropism

Midline facial developmental defect
Anosmia/hyposmia
Known pituitary hormone deficiencies or isolated defect in gonadotropin production
Among males: cryptorchidism or diminished penis size
History of radiation therapy or chemotherapy involving the central nervous system
Genetic defects

Approximately 33% of cases of idiopathic hypogonadotropic hypogonadism have a genetic cause and are familial; the remainder are sporadic. Isolated defects in gonadotropin production may result from defects in the synthesis or function of GnRH receptors or GnRH posttranslational processing, both of which lead to decreased release of gonadotropins.

Kallmann syndrome is the most common cause of permanent hypogonadotropism, occurring in approximately 1 in 10,000 males and 1 in 50,000 females. Mutations in the KAL1 (Xp22.3) and KzAL2 (8p12) genes result in autosomal dominant forms.

Kallmann syndrome results from failure of differentiation or migration of the GnRH-releasing neurons and may be associated with facial midline defects and a tendency to mirror-image movements (synkinesia). It may also be associated with inability (anosmia) or reduced ability (hyposmia) to smell.

Many hypothalamic (GnRH) and pituitary (LH and FSH) synthesis and secretory defects result in hypogonadotropic hypogonadism. Damage to the hypothalamus, pituitary, or surrounding areas from hemochromatosis may lead to the condition. Hypogonadotropic hypogonadism may result from HIV infection; craniopharyngioma; prolactinomas (with or without galactorrhea); other central nervous system tumors; head trauma, surgery, infections, infiltrative diseases; midline central nervous system defects, including septo-optic dysplasia; and autoimmune pituitary hypophysitis.

The condition may coexist with other anterior pituitary hormone deficiencies (growth hormone, thyroid-stimulating hormone, and adrenocorticotropic hormone) or may represent an isolated pituitary deficiency. When hypogonadotropic hypogonadism is verified, other pituitary functions should be assessed.

Other conditions associated with permanent hypogonadotropism include:

  • PROP-1 gene abnormalities: a transcription factor involved in pituitary development, this abnormality is most frequently associated with other pituitary hormone insufficiencies;
  • DAX-1 gene (Xp21) mutation: impairs a nuclear receptor protein involved in steroidogenesis and reproductive development leading to congenital X-linked adrenal hypoplasia;
  • Leptin deficiency: associated with early-onset obesity and delayed puberty;
  • FSH (FSH-beta or beta subunit) gene mutation: characterized by undetectable FSH and elevated LH level; and
  • Kisspeptin receptor/GPR54 mutation: involved in stimulation of GnRH secretion and GnRH receptor mutations (4p13.1).

Permanent hypergonadotropism. Elevated gonadotropin levels because of gonadal failure (hypergonadotropic hypogonadism) (Table 3).

Table 3. Conditions Associated With Permanent Hypergonadotropism

Radiation therapy or chemotherapy involving the pelvis
Prior surgery or trauma involving the pelvis or gonads
Small, firm or nonpalpable testes
Unusual causes: galactosemia, gonadal dysgenesis (XX or XY), androgen insensitivity (androgen receptor defect in 46,XY), and autoimmune gonadal failure
Klinefelter syndrome usually does not present with delayed onset of puberty, although completion of puberty may not occur and testicular volume is diminished
Turner syndrome (indicated by short stature and typical facies, among other features)

Hypergonadotropic hypogonadism is always pathologic and is generally permanent. It can occur as a result of radiation injury when the total dose exceeds 6 Gy, an absorbed ionizing radiation dose that is associated with permanent ovarian failure. Several chemotherapeutic agents, including cyclophosphamide, busulfan, procarbazine, and etoposide, also may lead to the condition; in this situation, however, some recovery may occur.

Other causes include:

  • Premature gonadal failure in Klinefelter syndrome, Turner syndrome, or other forms of gonadal dysgenesis;
  • Autoimmune disease;
  • Galactosemia (GALT enzyme gene [9p13]);
  • Mutations in gonadotropin (FSH-beta gene) and gonadotropin receptor genes;
  • Abdominopelvic trauma;
  • Infectious disease (mumps, shigella, malaria, varicella); and
  • Androgen receptor defects in phenotypic females.

Autoimmune polyglandular syndromes (APS) are constellations of multiple endocrine gland insufficiencies. The components of type 1 APS include autoimmune adrenal insufficiency (Addison disease), hypoparathyroidism, and mucocutaneous candidiasis; more than one half of affected girls will also experience ovarian failure.

The most common form of APS is type 2, also known as Schmidt syndrome. Features of this syndrome include Addison disease; autoimmune thyroid disease; type 1 diabetes mellitus; and, less commonly, hypogonadism. Approximately 10% of girls with type 2 APS also have ovarian failure.

Several conditions, including HIV infection, autoimmunity, Präder-Willi syndrome, and Noonan syndrome, may be associated with both hypo- and hypergonadotropic hypogonadism.

Second-Tier Testing

Second-tier testing, if indicated, is initiated after gonadotropin status and other results of first-tier testing are known. This stage of the diagnostic evaluation should be based on history and physical findings and LH/FSH levels.

Elevated gonadotropinlevels. A karyotype and iron studies should be considered. In girls, ovarian antibodies and pelvic/abdominal ultrasonography should be considered. In girls with type 1 APS, the presence of side-chain cleavage enzyme autoantibodies is a predictor of future ovarian failure.

Low gonadotropin levels. Additional tests should include complete blood count, complete metabolic panel, prolactin levels, immunoglobulin F1, TSH, free thyroxine, bone age radiography, and GnRH/GnRH analogue stimulation testing to assess pubertal gonadotropin response. Onset of puberty can be documented by a significant increase gonadotropin levels, generally with LH levels peaking at about 8-10 mIU/mL; lower peaks suggest an immature system or a deficiency. Central nervous system MRI should be obtained if an intracranial mass is suspected.

In girls with either low or high gonadotropin levels, pelvic/abdominal ultrasonography should be obtained to visualize ovarian and uterine size and symmetry. In addition, determination of endometrial stripe (a measure of the thickness of the endometrial lining) provides an indication of amount of pubertal hormone stimulation.

Single measurements of estradiol and testosterone are relatively unhelpful for diagnosis, whereas numerous measurements over time may be helpful. The adrenal androgen dehydroepiandrosterone sulfate is a good marker of adrenarche and can be helpful in documenting adrenarche.

When hyperprolactinemia is identified and hypothyroidism has been eliminated as a secondary cause, pituitary MRI should be performed.

Management

Regardless of the cause of pubertal delay, prompt medical assessment and treatment is important because timely therapy is associated with better quality of life. When there is constitutional delay in normal growth and development, treatment is temporary and normal adult gonadal function is expected. When the delay is associated with permanent dysfunction, however, hormone substitution is lifelong and the potential for fertility must be assessed.

When Is Sex-Steroid Therapy Needed?

If the delay in onset or progression of puberty[11] has been verified and adequately assessed, it is usually appropriate to begin sex-steroid therapy to stimulate pubertal changes, even when a final diagnosis is not yet possible. An exception may be when the delay is associated with malnutrition as a result of systemic disease or psychiatric illness.

When an underlying condition, such as hypothyroidism, is present, primary therapy is directed toward it. In some instances, the underlying conditions, such as those associated with malnutrition, may resolve slowly. In these situations, sex-steroid therapy can be tried before the condition is resolved, in an attempt to stimulate pubertal progression. In patients with short stature as a result of Turner syndrome, growth hormone deficiency, or another underlying cause, height at assessment and growth hormone treatment must be considered before initiation of sex-steroid therapy.

Steroid Therapy in Constitutional Delay

Treatment will stimulate the development of pubertal changes and accelerated linear growth and help the child to catch up with his or her peers. This goal is appropriate for both psychosocial and physical reasons, including attainment of adult body composition and build, sexual maturity, and adult bone density. Therapy is discontinued after 4-6 months to determine whether endogenous hormone secretion has occurred. If present, this confirms the diagnosis of constitutional delay, and further hormone therapy is unnecessary.

If endogenous gonadal sex-steroid secretion is not apparent, therapy can be restarted with care and continued until an underlying diagnosis is confirmed.

Dosing Considerations

Boys. Testosterone therapy in boys stimulates physical changes of puberty. Such therapy causes full pubertal development, with the exception of testicular growth. The initial dosage is low, with gradual upward titration over 2-3 years. If depot injectable forms are used, the dosage can begin at 50-75 mg every 4 weeks. Dosages are increased at intervals of approximately 6 months, usually by increasing the frequency of injections. The full replacement dose is typically 100 mg given at 1- to 2-week intervals. Transdermal forms of testosterone can also be used; again, the dose is gradually increased to full replacement over 2-3 years.

If permanent hypogonadism is present, long-term GnRH or gonadotropin therapy is needed when fertility is desired.

Girls. Induction of puberty in girls begins with the lowest available estradiol dosage. If ongoing therapy is needed, dosages are gradually increased to full replacement over 2-3 years. The lowest available dosage may be a transdermal form, such as a patch that can be cut to deliver daily estradiol doses of 25 µg or less.

The lowest dose of conjugated estrogens is 0.3 mg, which can initially be given daily or every other day. A cyclical progestational agent is added when breakthrough bleeding occurs or after 18 months of estrogen therapy. The progesterone may be given for 10 days at the end of a 21-day estrogen cycle, followed by 1 week of no medication.

Estrogen dosing should be sufficient to allow for bone mass accrual. For long-term sex-steroid replacement therapy, oral contraceptives that combine estrogen and progesterone may be used.

Discontinuing Therapy

As noted previously, unless it is clear that the defect is permanent, initial therapy should be stopped after 4-6 months. Baseline hormones, including LH, FSH, testosterone in boys, and estradiol in girls, can be measured 4-8 weeks after discontinuation of treatment to assess for evidence of endogenous pubertal hormone secretion.

Fertility Issues

Once the patient has been exposed to adequate sex-steroid stimulation, physical maturity occurs, resulting in an adult individual with potential sexual function. It is important for patients to realize that their underlying condition is not apparent to others, even in physically intimate situations. Boys will have normal adult male sexual responses even though testicular volume will remain low. In both males and females, further therapy is needed if biological fertility is desired.

The potential for fertility is based on the presence of gonads containing germ cells. Depending on gonadal status, various assisted fertility techniques can be attempted; these range from gonadotropin hormonal stimulation to sophisticated techniques, such as intratesticular sperm retrieval and intracytoplasmic sperm injection into ova.

GnRH, recombinant FSH and LH, or human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG) can be used to stimulate ovulation and spermatogenesis. Patients with Turner syndrome require specific considerations depending on the manifestations of the syndrome.[12]

Educating the Child and Family

The patient and, as appropriate, his or her parents should be informed of the reasons for assessment and therapy throughout the process. It is important for patients to understand the extent to which their physical development will normalize. In most instances, the patient will be physically — including sexually — similar to any other adult within a few years, with a capacity for normal sexual function. For patients who, even with appropriate therapy, are biologically unable to attain fertility, the potential for fertility may be dependent on assisted techniques or donated germ cells.

Back to the Case

The boy with small testes, prepubertal genitalia, midline facial defects, and anosmia discussed earlier was diagnosed with hypogonadotropic hypogonadism. He responded well to testosterone replacement therapy and reached full male maturation, except for small testes.

His teenage years were difficult and were complicated by his social situation, which included placement as a foster child. Shortly after he was begun on testosterone therapy, a foster parent accused him of sexual abuse of her prepubertal daughter, on the assumption that this low-dose replacement therapy stimulated uncontrollable sexual acting out. The boy was subsequently adopted and provided with opportunities to share his life experiences in support groups with positive feedback.

No mutation, including on KAL1 and KAL2 testing, was found to explain his diagnosis. Because of a keen desire to eventually have a child, he was given a combination of hCG/hMG for several months during his teen years, which resulted in some testicular growth but without seminal sperm. Further attempts to achieve fertility were deferred until he was ready to attempt paternity.

He later met and married a healthy woman who had 2 children. For several years, he and his wife attempted to have a child through use of prolonged treatment including GnRH pulsatile therapy. After numerous years without success, it was concluded that he would be biologically unable to father a child. He and his wife then decided to use donated sperm and now have a healthy 4-year-old daughter.

From the time of his diagnosis onward, the patient accepted his situation and made a commendable effort to have a good quality of life, regardless of the problems his situation has presented.

Summary

Delayed puberty is failure to begin pubertal development by age 14 years in boys or breast development by age 13 years or menarche by age 15 years in girls. Although constitutional growth delay is the most common etiology in both boys and girls, careful assessment is needed, particularly in girls, to identify children with temporal pubertal delay who have such underlying conditions as hypergonadotropic hypogonadism and permanent hypogonadotropic hypogonadism.

Regardless of the cause of delayed puberty, therapy with sex steroids results in physical maturity. However, potential fertility using current assisted fertility techniques depends largely on the presence of germ cells in the gonads. As illustrated by the case report, a severely affected hypogonadotropic patient can have a satisfying, well-adjusted adult life.

[ CLOSE WINDOW ]

References

  1. Houk CP, Lee PA. Early, precocious, and delayed female pubertal development. In Lavin N, ed. Manual of Endocrinology and Metabolism. 4th ed. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins; 2009:244-263.
  2. Reiter EO, Lee PA. Delayed puberty. In Lee PA, ed. Adolescent Medicine: State of the Art Reviews. Philadelphia: Hanley and Belfus, Inc.; 2002:101-118.
  3. Euling SY, Herman-Giddens ME, Lee PA, et al. Examination of US puberty-timing data from 1940 to 1994 for secular trends: panel findings. Pediatrics. 2008;121:S172-S191. Abstract
  4. Biro FM, Galvez MP, Greenspan LC, et al. Pubertal assessment method and baseline characteristics in a mixed longitudinal study of girls. Pediatrics. 2010;126:e583-e590. Abstract
  5. Aksglaede L, Sorensen K, Petersen JH, Skakkeback NE, Juul A. Recent decline in age at breast development: the Copenhagen Puberty Study. Pediatrics. 2009;123:e932-939. Abstract
  6. Chumlea WC, Schubert CM, Roche AF, et al. Age at menarche and racial comparisons in US girls. Pediatrics. 2003;111:110-113. Abstract
  7. Houk C, Lee P. Delayed puberty. In Hilliard PJ, ed. Obstetrics and Gynecology Clinical Consult. Philadelphia: Lippincott Williams & Wilkins; 2008:36-37.
  8. Palmert MR, Dunkel L. Clinical practice. Delayed puberty. N Engl J Med. 2012;366:443-453. Abstract
  9. Maggi M, Buvat J. Standard operating procedures: pubertas tarda/delayed puberty-male. J Sex Med. 2012 Feb 29. [Epub ahead of print].
  10. Sedlmeyer IL, Palmert MR. Delayed puberty: analysis of a large series from an academic center. J Clin Endocrinol Metab. 2002;87:1613-1620. Abstract
  11. Crowley WF, Pitteloud N. Diagnosis and treatment of delayed puberty. January 24, 2012. http://www.uptodate.com/contents/diagnosis-and-treatment-of-delayed-puberty?source=search_result&search=Diagnosis+and+treatment+of+delayed+puberty&selectedTitle=1~41 Accessed July 23, 2012.
  12. Reindollar RH. Turner syndrome: contemporary thoughts and reproductive issues. Semin Reprod Med. 2011;29:342-352. Abstract

Medscape Pediatrics © 2012 WebMD, LLC

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