- Email: [email protected]
Delayed Puberty—Male
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Standard Operating Procedures: Pubertas Tarda/Delayed Puberty—Male jsm_2678
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Mario Maggi, MD* and Jaques Buvat, MD† *Sexual Medicine and Andrology Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy; † Centre d’Etude et de Traitement de la Pathologie de l’Appareil Reproducteur et de la Psychosomatique, Lille, France DOI: 10.1111/j.1743-6109.2012.02678.x
ABSTRACT
Introduction. Delayed puberty (DP) is a condition characterized by the lack of sexual maturation in boys (testis volume <4 mL) at a chronological age that is 2.5 standard deviations above the mean age of puberty in a normal population. Aim. To review the etiology, pathogenesis diagnosis, and the available treatments for DP in males. Methods. A systematic search of published evidence was performed using Medline (1969 to September 2011). Main Outcome Measures. The most important evidence regarding DP and the available treatment options were reviewed and discussed. Whenever possible, levels of evidence are reported. Results. The prevalence of DP in 14-year-old boys in the United States is less than 2%, almost double of same figure in females. The etiology of DP is complex including genetic, functional, or nonidentifiable defects. The correct diagnosis should include an accurate medical history and physical examination along with specific laboratory tests. In addition, bone age radiographs are frequently helpful. If a specific disorder can be identified, therapy should be targeted at that disorder. Short-term testosterone therapy can be offered to boys with constitutional DP after a variable time of expectant observation essentially dictated by the patient’s distress. Reassurance and continued observation, to ensure that the expected sexual maturation occurs, are often sufficient. In all other cases, exogenous gonadotropins, either recombinant or extracted, induce full gonadal maturation, while long-term testosterone therapy is the treatment of choice for hypergonadotropic hypogonadism or for hypothalamic or pituitary gonadotropin deficiency until fertility is attained. Conclusions. DP is a frequent condition that if not correctly diagnosed, may cause serious clinical and psychological consequences. Appropriate diagnosis and treatment provide normal pubertal development. Maggi M and Buvat J. Standard operating procedures: Pubertas Tarda/delayed puberty—Male. J Sex Med **;**:**–**. Key Words. Delayed Puberty; Male; Hypogonadism
Introduction
N
ormal male puberty—the process of physical and psychogenic development, from the adolescence to maturity—is finely regulated by neural integration of several external (environmental) and internal (genetic and neuroendocrine) permissive signals, which, in synchrony with somatic growth and maturation of sexual and social behavior, stimulate reproductive activity. Table 1 summarizes main physical and emotional changes in pubertal males. Figure 1 shows the time frame of physical changes in pubertal male. © 2012 International Society for Sexual Medicine
The pulsatile secretion of gonadotropinreleasing hormone (GnRH) by hypothalamic neurons is a key requirement for the initiation of puberty. GnRH-secreting cells originate in the nasal compartment and are associated with the vomeronasal nerve (VNN) to traverse the nasal septum and through the cribriform plate. The VNN defasciculates after entering the brain, but GnRH neurons maintain their association with a subpopulation of VNN fibers. Then, GnRH cells dissociate from their guiding fibers in order to reach their final destination in the hypothalamus. GnRH, by activating the hypothalamic–pituitary–gonadal J Sex Med **;**:**–**
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Maggi and Buvat
Table 1 Main normal physical and mood changes in pubertal males
Definition of Pubertas Tarda Pubertas tarda, delayed sexual development, or delayed puberty (DP) (ICD 10 E30 http:// apps.who.int/classifications/apps/icd/icd10online/ ?ge20.htm+e300) is commonly defined as the absence of signs of puberty (including testicular growth over 4 mL) by age 14 [1]. Medical Subject Headings defines DP (C19.391.690) as the lack of development of sexual maturation in boys at a chronological age that is 2.5 standard deviations above the mean age at onset of puberty in a normal population (http://www.nlm.nih.gov/cgi/mesh/ 2011/MB_cgi?field=uid&term=D011628). Epidemiology Less than 2% of 14-year-old boys in the United States are prepubertal [2,3] (Evidence-Based J Sex Med **;**:**–**
Genital development Pubic hair
(HPG) axis, stimulates pituitary gonadotropin (luteinizing hormone [LH] and follicle stimulating hormone [FSH]) secretion and regulates the production of gonadal steroids. At the onset of puberty in the male, the first endocrine change is the start of LH pulse increase, first only at night, and later on, assuming a day/night rhythm, accompanied by a concomitant production of testosterone. Hence, an intact HPG axis is required; any temporary or permanent disorder of its activity can alter pubertal timing.
TV
Mood changes Development of personal and sexual identity Interest more often in the opposite sex Anxiety or excitement about the changes he is going through Shy, nervousness around girls, or flirtatious with girls Abstract thinking Emergence of skills and coping strategies to overcome problems and crises Growing ability to absorb the perspectives or viewpoints of others Increased ability of introspection Establishment of a system of values Less talkative and open with parents Increasing autonomy and personal independence Greater importance of peer relationships
PVH
Physical changes Gonadarche: testicle enlargement greater than 4 mL (11.5 years [9.5–13.5]) Pubarche: hair growth in the pubic area (12 years [10–14]) Growth spurts (14 years) Growth of the penis (measured stretched) from 6.2 to 12.4 ⫾ 2.7 cm Erections or wet dreams Deepening of the voice (later stages of puberty) Appearance of facial hair Broadening of shoulder muscles, development of chest muscles Body odor Pimples or facial breakouts
Age (years)
Age (years) Figure 1 Major physical changes in pubertal boys, according to age. Bars shows standard deviation of the mean (closed circles). TV = testicular volume, PVH = peak height velocity, G = Tunner’s stages.
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Pubertas Tarda/Delayed Puberty Table 2
Causes of male delayed puberty
Systemic illness
Systemic illnesses and other reversible conditions
Cystic fibrosis Asthma Inflammatory bowel disease Celiac disease Juvenile rheumatoid arthritis Sickle cell disease Thalassemia Hemosiderosis Chronic renal disease AIDS Malignancies
Excessive energy expenditure, exercise Emotional deprivation Malnutrition Diabetes mellitus Hypothyroidism Hyperprolactinemia Endocrinopathies Growth hormone deficiency Cushing syndrome Obesity
Reversible (functional)
Constitutional delay of puberty Hypogonadotropic (secondary) hypogonadism (10%) Irreversible (permanent)
Hypogonadotropic (secondary) hypogonadism (90%) Hypergonadotropic (primary) hypogonadism (100%)
Medicine [EBM] level lb). The proportion of male boys with DP is almost double of the same figure in the opposite gender (EBM level lc) [4].
Etiology The etiology of DP is complex since many conditions, such as genetic, functional or not identifiable defects, can delay puberty. An etiologic classification of DP is reported in Table 2 and distinguishes between reversible and irreversible defects, with the former being defined as functional, or secondary to other disorders that, when corrected, allow puberty. DP can be caused by a variety of physical conditions including malnutrition or emotional deprivation or by chronic diseases and endocrinopathies, such as diabetes or thyroid disorders (see in [5]) (EBM level lc). Irreversible defects are essentially divided in primary testis failure (hypergonadotropic hypogonadism) and secondary testis failure due to any hypothalamic–pituitary dysfunction (hypogonadotropic hypogonadism [HH]). Diagnosis of constitutional delay of puberty (CDP) is essentially a diagnosis of exclusion, when no underlying conditions can define the delay and
sexual maturation occurs spontaneously before the age of 18 years. Such patients are overall healthy; all aspects of physical maturation typically proceed normally, but a few years later than average. These boys generally have a history of delayed growth and development throughout childhood, including short stature but a relatively normal growth rate. CDP represents the extreme end of the normal spectrum of pubertal development and tends to aggregate in families, suggesting a genetic basis. Boys with CDP often seek clinical evaluation when classmates or friends undergo faster pubertal development and growth, thereby accentuating their delay. The frequency of these diagnoses has been examined in a retrospective study of 232 adolescents (158 males, 74 females) presenting to an academic center [4] (EBM level lc). In male boys, a reversible form of DP was noted in the majority of cases (83%) due to chronic diseases or other reversible conditions in 20% and to CDP in 63%. A diagnosis of permanent hypogonadism was made in 16% of cases, being hypogonadotropic in 9% and hypergonadotropic in 7%. J Sex Med **;**:**–**
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Growth and familial history
Physical examination (Tanner stage and testis volume)
Bone age and Routine exam. + testosterone test
a)Systemic Illness and other reversible conditions
b)Costitutional delay of puberty
Specific treatment
Serum gonadotropins
yes
high low d) Hypergonadotropic (primary) hypogonadism
Short-term, Low-dose testosterone
expectant observation
Long-term, testosterone
karyotype 47, XXY
46, XY
Short-term, gonadotropins
Induction of puberty
no
c) Hypogonadotropic (secondary) hypogonadism
Klinefelter S. Figure 2 Flow chart of male delayed puberty: delay in onset of secondary sexual development after 14 years. Letters in bubbles correspond to those used in Table 2.
Pathophysiology Although it is generally assumed that congenital or idiopathic HH (IHH) is caused by irreversible GnRH deficiency, i.e., requiring lifelong hormone therapy, several clinical reports have highlighted that a small percentage of male patients with IHH, including those with known gene mutations, experience reversal of the hypogonadal state (EBM level lb, see Table 2) [6–10]. These observations allow new interpretations about the pathophysiological mechanisms underlying the altered timing of GnRH neuronal activation involved in all forms of DP, i.e., constitutional, functional, or idiopathic. In particular, the reversal of congenital HH, maintained after discontinuation of therapy with testosterone in males with either absent or partial puberty [8–10], suggests a positive effect of androgens in the reactivation of GnRH neurons. Based on these clinical observations and on recent in vitro studies on human GnRH-secreting neuroblasts [11], one can hypothesize that increasing testosterone levels may stimulate hypothalamic– pituitary neural circuits leading to spontaneous resumption of pulsatile GnRH secretion, the primum movens of sexual maturation. Hence, androgen can have a positive effect on hypothaJ Sex Med **;**:**–**
lamic neurons, causing the reversal of HH as described in several human subjects [8–10].
Clinical Evaluation and Diagnosis 1. Medical history: evaluation of DP begins with a careful history, including growth and family history of pubertal timing (see Figure 2). A positive family history of DP (mother with delayed menses or father with late onset of shaving or continued growing into the early 20s) is often present, and the predicted height for the child is in the appropriate range related to the parental height. However, this finding may be nonspecific and is common in both CDP and IHH. Assessment of the patient’s growth pattern up to the time of evaluation is critical. Patients with constitutional delay have delayed growth, adrenarche, and sexual development parallel with declining growth velocity, delayed skeletal maturation, and delayed adrenal androgen maturation. A systematic review of possible associated chronic diseases needs to be covered. 2. Physical examination: the physical examination starts with determination of height and weight, which are plotted in a growth chart. The signs of puberty, including testis volume (Prader
Pubertas Tarda/Delayed Puberty orchidometer) are noted and compared with defined Tanner stages (see Figure 1). Boys with CDP have a stature that is appropriate for bone age although short for chronological age. Early signs of sexual development, often not appreciated by the patient (such as testicular growth), may allow for reassurance and avoidance of an otherwise costly and unnecessary evaluation. A testicular volume of greater than 4 mL is the earliest sign of pubertal development (EBM level lb). If present, normal spontaneous puberty can be anticipated in more than 95% of patients, and the family can be reassured. 3. Laboratory examination: bone age radiographs are frequently helpful and should be routinely performed since onset of puberty normally corresponds with a bone age range of 11–12.5 years. However, the degree of bone age delay per se is not diagnostic, even if a concomitant GH deficiency is associated with a greater bone delay. GH deficiency can be screened by an insulin growth factor-1 (IGF-1) determination. In selected cases (see Figure 2), pituitary function needs evaluation with a focus on prolactin, TSH-thyroxine, and ACTH-cortisol to exclude underlying etiologies. Magnetic resonance imaging and targeted genetic tests must be undertaken, if appropriate. Measurement of serum gonadotropins is of major significance in distinguishing between hypergonadotropic and HH (Figure 2). If gonadotropins are high, karyotyping will identify Klinefelter syndrome. If gonadotropins are low or normal at presentation ages 13–16 years, it is usually not possible to determine definitely which patients will have a permanent deficiency unless there is a concomitant finding associated with hypogonadotropinism, such as anosmia or an anatomical lesion of the hypothalamus–pituitary. At initial presentation, patients with CDP are usually characterized by HH. If there is no activity in the HPG axis by 18 years of age, IHH, which will likely persist throughout life, is the disorder. Gonadotropin response to short- or long-acting GnRH agonists have been proposed to differentiate between CDP and IHH [12]; however, the value of these assays in clinical practice needs to be further verified. Measurement of serum testosterone can predict the onset of puberty: a testosterone value greater than 0.7 nmol/L indicates the testis will be >4 mL within 12 months in 77% and within 15 months in 100% [13]. In clinical practice, if gonadotropins are low or normal, the real options are expectant observation
5 or offer a short-term (3–6 months) low-dose testosterone therapy (see Figure 2) even if none of the commercially available preparations are licensed for the induction of puberty. The latter is recommended when appearing less mature than one’s peers can lead to psychological distress [14] (EBM level lc).
Therapy If a specific underlying disorder is identified, therapy needs to be targeted at that disorder. Patients with CDP ultimately have spontaneous puberty. Often, reassurance and continued observation to ensure that the expected sexual maturation occurs are sufficient (EBM level lb). Therapy of Functional HH Functional HH associated with chronic disease needs to treat the underlying problem first. DP, in this situation, is usually a result of malnutrition and low body weight, or excessive energy expenditure; when body weight returns to normal, puberty usually occurs spontaneously. Treatment with thyroxine will allow normal pubertal development in hypothyroid patients with DP [5], as well as for other endocrine disorders (EBM level lc). Short-Term Therapy (Testosterone) As in Figure 2, short-term testosterone therapy should be offered to boys with CDP after a period of observation, which is essentially dictated by patient’s overall distress. The availability of several new forms of testosterone, which are approved for adults with hypogonadism, provides adolescents with an opportunity to choose among different testosterone replacement therapies (TRTs). The efficacy of these preparations has not been documented fully in children with CDP. Decades of experience with short-term testosterone therapy in these situations confirm no effect on final height (EBM level la). If during the 3 to 6 months after discontinuing testosterone therapy spontaneous puberty does not ensue or the concentrations of plasma gonadotropins and plasma testosterone in boys do not increase, this treatment can be repeated. Usually, only one or two courses of testosterone therapy are necessary (EBM level lb). Testosterone (about 25% of the adult dose) is usually sufficient to achieve early virilization and growth (i.e., 3–6 months), without inducing premature closure of the epiphyses (EBM level lb). When available, testosterone can be administered orally (testosterone undecanoate tablets), transdermally, or by depot injections. The use of transdermal testosterone gel is efficacious and convenient in adult males with hypogonadism, but it is not yet J Sex Med **;**:**–**
6 U.S. Food and Drug Administration-approved in males younger than age 18 years. An oral testosterone undecanoate preparation is available in some countries and has been used clinically in adolescent boys [15], but the final levels of serum testosterone are variable and dependent on the lipid composition of the diet. The depot injections are more effective than other preparations (EBM level lb). Testosterone enanthate (50–150 mg intramuscularly) is usually employed [16,17]. A course of treatment for from 3 to 6 months can be given and the situation reassessed. The response is positive when there is good acceleration in growth and physical and emotional development. Spontaneous development often starts during a course of treatment. Patients must be reevaluated by the clinician to ensure they enter into “true” puberty. One year after testosterone treatment, boys should exhibit testicular enlargement and a serum testosterone in the pubertal range. If this is not the case, the diagnosis of hypothalamic–pituitary insufficiency or HH should be considered (EBM level lb).
Long-Term Therapy Boys with HH typically demonstrate marginal or no pubertal development with low-dose testosterone treatment, and any pubertal progress that is accomplished is lost with cessation of therapy. Hence, long-term therapy should be instituted. The goals of therapy are to mimic the normal cadence of puberty, to maintain serum testosterone levels within the normal age range, and eventually, to induce fertility if and when the patient desires. Exogenous therapy with pulsatile GnRH or gonadotropins usually restores pubertal development and fertility to these patients, whereas testosterone therapy alone will induce only the development of male sex characteristics. Episodic administration of GnRH through portable pumps elicits pulsatile LH and FSH release and gonadal stimulation, but this is not practical for the routine induction of puberty in adolescent boys. Exog-
Maggi and Buvat enous gonadotropins, either recombinant or extractive, produce full gonadal maturation, but again, this regimen is cumbersome and expensive. GnRH. GnRH infused in a pulsatile fashion is the most physiological approach for deficiencyisolated GnRH or in combination with other hypothalamic hormones deficiencies. The most effective dosage in stimulating a pulsatile secretion of gonadotropins is the intravenous administration of GnRH with an interval of 90–120 minutes; whereas subcutaneous administration causes a more flattened gonadotropin response, which may not be sufficient to stimulate the testis. This kind of therapy allows for full development of testicular function, both for spermatogenesis and steroidogenesis. When spermatogenesis has been induced, the long-term secondary sexual characteristics can be maintained by subcutaneous human chorionic gonadotropin (hCG) injections [18]. Episodic administration of GnRH through portable pumps elicits pulsatile LH and FSH release and gonadal stimulation, but it is not practical for the routine induction of puberty in adolescent boys. Gonadotropins. Exogenous gonadotropins, either recombinant or extractive, produce full gonadal maturation. The treatment with hCG is administered in a dosage of 1,250–5,000 IU in combination with 12.5–150 IU of human menopausal gonadotropin (hMG), both intramuscularly, two to three times a week. At follow-up, the, dosage of hCG and hMG must be adjusted on the basis of testosterone levels and clinical signs, respectively [18]. Gonadotropin treatment may cause minor side effects, such as gynecomastia. In addition, induction of antibodies to hCG, resulting in loss of response to the treatment, has been described [19]. This modality of therapy can be a major inconvenience in that it cumbersome and expensive. Figure 3 shows the efficacy of gonadotropins in a 17-year-old male with DP. 䉴
Figure 3 (A) Growth chart of a boy (GL) who attended his first visit on the September 2, 2009 at the age of 17 (point A). At physical exam, he showed height, weight, and sexual development consistent with diagnosis of delayed puberty, testis volume at Prader orchidometer = 3 mL, penile length = 5.3 cm. His hormonal pattern was LH = < 0.1 U/L; FSH = 0.5 U/L; total testosterone: 0.33 ng/mL. Magnetic resonance imagery failed to show any pathological sign in hypothalamic–pituitary region. Hence, congenital hypogonadotropic hypogonadism was diagnosed. GL started human chorionic gonadotropin (hCG) with a dosage of 2,000 IU and human menopausal gonodotropin (hMG) with a dosage of 75 IU, both intramuscularly three times a week. In the growth chart, points B, C, D, and E are four follow-up visits. According to hormonal measurement and physical exam, hCG and hMG were maintained at the same dosage until visit E (February 27, 2011) when GL was 19 years old, total testosterone = 26.6 ng/mL, and he reached the height, weight, testis volume (13 mL), hair distribution, and penis growth (10 cm) consistent with his age. (B) Ultrasound images of testis volume. The upper panel was assessed at the first visit (point A on the growth chart) and it shows an infantile testis (volume 2.99 mL), the lower one was assessed during a follow-up visit (point D on the growth chart), and it shows a completely developed testis (volume 7.84 mL).
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8 Testosterone. Long-term testosterone therapy is the treatment of choice for hypothalamic or pituitary gonadotropin deficiency, unless fertility is desired. For hypergonadotropic hypogonadism, testosterone replacement is the only option. Typically, testosterone enanthate 50–100 mg is given every 4 weeks and escalated gradually every 6 months to 100–150 mg/month before changing to a triweekly 250 mg dose after 3–4 years [20]. A recent experience with long-lasting injectable preparation of testosterone undecanoate has been recently published [21]. A teenage boy is less likely to apply a patch or a gel daily for poor compliance. If a transdermal preparation is used, the starting dose had to be approximately one-third of the daily adult dose for the first year, gradually increased by one third daily every year to an adult daily dose by the third year. This is preferably self-applied at bedtime and avoiding potential cross-contamination [20]. New testosterone gel preparations, applied onto the forearms, have been approved for adults but not yet for adolescents. Low-dose replacement therapy is appropriate until the pubertal growth spurt. Once adequate virilization is induced and final expected adult height achieved, any form of TRT can be used. Side effects of TRT in adolescent boys are similar to those in adults. Polycythemia, as evidenced by a raised hematocrit (>55%), necessitates a prompt reduction in testosterone dose by about 25%. Gynecomastia occurs in up to a third of patients on gonadotropins or testosterone and usually (although not invariably) occurs with supraphysiological replacement. Gynecomastia results from excessive peripheral aromatization of testosterone in adipose tissue, especially in the breast. The risk and severity of gynecomastia can be reversed by adjusting the dose of testosterone or hCG as appropriate [20]. Conclusions
DP is a relatively frequent condition, which if not properly diagnosed can cause negative clinical and psychological consequences. Adolescents not only lack secondary sexual characteristics but are usually shorter. This situation can reduce selfesteem and quality of life. For example, a previously active teenage boy may stop participating in sports because he is uncomfortable undressing in front of his teammates. Fortunately, appropriate diagnosis and treatment can prevent these sequelae and provide normal pubertal development in the majority of cases. J Sex Med **;**:**–**
Maggi and Buvat Corresponding Author: Mario Maggi, MD, Sexual Medicine and Andrology Unit, Department of Clinical Physiopathology, University of Florence, Viale Pieraccini, 6, Florence 50139, Italy. Tel: +39 0554271415; Fax: +39 0554271413; E-mail: [email protected]fi.it Conflict of Interest: None. References 1 Grumbach MM, Styne DM. Puberty: Ontogeny, neuroendocrinology, phisiology and disorders. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, eds. Williams Textbook of Endocrinology. 10th edition. Philadelphia: Saunders; 2003: 1033. 2 Roche AF, Wellens R, Attie KM, Siervogel RM. The timing of sexual maturation in a group of US white youths. J Pediatr Endocrinol Metab 1995;8:11–8. 3 Harlan WR, Grillo GP, Cornoni-Huntley J, Leaverton PE. Secondary sex characteristics of boys 12 to 17 years of age: The U.S. Health Examination Survey. J Pediatr 1979;95:293–7. 4 Sedlmeyer IL, Palmert MR. Delayed puberty: Analysis of a large case series from an academic center. J Clin Endocrinol Metab 2002;87:1613–20. 5 Pozo J, Argente J. Delayed puberty in chronic illness. Best Pract Res Clin Endocrinol Metab 2002;16:73–90. 6 Bauman A. Markedly delayed puberty or Kallmann’s syndrome variant. J Androl 1986;7:224–7. 7 Quinton R, Cheow HK, Tymms DJ, Bouloux PM, Wu FC, Jacobs HS. Kallmann’s syndrome: Is it always for life? Clin Endocrinol 1999;50:481–5. 8 Pitteloud N, Acierno JS Jr, Meysing AU, Dwyer AA, Hayes FJ, Crowley WF Jr. Reversible Kallmann syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 gene. J Clin Endocrinol Metab 2005;90:1317–22. 9 Raivio T, Falardeau J, Dwyer A, Quinton R, Hayes FJ, Hughes VA, Cole LW, Pearce SH, Lee H, Boepple P, Crowley WF Jr, Pitteloud N. Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med 2007;357:863–73. 10 Ribeiro RS, Vieira TC, Abucham J. Reversible Kallmann syndrome: Report of the first case with a KAL1 mutation and literature review. Eur J Endocrinol 2007;156:285–90. 11 Morelli A, Fibbi B, Marini M, Silvestrini E, De Vita G, Chavalmane AK, Vignozzi L, Filippi S, Forti G, Vannelli GB, Maggi M. Dihydrotestosterone and leptin regulate gonadotropinreleasing hormone (GnRH) expression and secretion in human GnRH-secreting neuroblasts. J Sex Med 2009;6: 397–407. 12 Ghai K, Cara JF, Rosenfield RL. Gonadotropin releasing hormone agonist (nafarelin) test to differentiate gonadotropin deficiency from constitutionally delayed puberty in teen-age boys—A clinical research center study. J Clin Endocrinol Metab 1995;80:2980–6. 13 Wu FC, Brown DC, Butler GE, Stirling HF, Kelnar CJ. Early morning plasma testosterone is an accurate predictor of imminent pubertal development in prepubertal boys. J Clin Endocrinol Metab 1993;76:26–31. 14 Arrigo T, Cisternino M, Luca De F, Saggese G, Messina MF, Pasquino AM, De Sanctis V. Final height outcome in both untreated and testosterone-treated boys with constitutional delay of growth and puberty. J Pediatr Endocrinol Metab 1996;9:511–7. 15 Butler GE, Sellar RE, Walker RF, Hendry M, Kelnar CJ, Wu FC. Oral testosterone undecanoate in the management of delayed puberty in boys: Pharmacokinetics and effects on sexual maturation and growth. J Clin Endocrinol Metab 1992;75:37–44.
Pubertas Tarda/Delayed Puberty 16 Rosenfeld RG, Northcraft GB, Hintz RL. A prospective, randomized trial of testosterone treatment of constitutional short stature in adolescent males. Pediatrics 1982;69:681–7. 17 Richman RA, Kirsch LR. Testosterone treatment in adolescent boys with constitutional delay in growth and development. N Engl J Med 1988;319:1563–7. 18 Delemarre EM, Felius B, Delemarre-van de Waal HA. Inducing puberty. Eur J Endocrinol 2008;159(suppl 1):S9–15. 19 Thau RB, Goldstein M, Yamamoto Y, Burrow GN, Phillips D, Bardin CW. Failure of gonadotropin therapy secondary to
9 chorionic gonadotropin-induced antibodies. J Clin Endocrinol Metab 1988;66:862–7. 20 Han TS, Bouloux PM. What is the optimal therapy for young males with hypogonadotropic hypogonadism? Clin Endocrinol 2010;72:731–7. 21 Giagulli VA, Triggiani V, Carbone MD, Corona G, Tafaro E, Licchelli B, Guastamacchia E. The role of long-acting parenteral testosterone undecanoate compound in the induction of secondary sexual characteristics in males with hypogonadotropic hypogonadism. J Sex Med 2011;8:3471–8.
J Sex Med **;**:**–**
Standard Operating Procedures: Pubertas Tarda/Delayed Puberty—Male jsm_2678
1..9
Mario Maggi, MD* and Jaques Buvat, MD† *Sexual Medicine and Andrology Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy; † Centre d’Etude et de Traitement de la Pathologie de l’Appareil Reproducteur et de la Psychosomatique, Lille, France DOI: 10.1111/j.1743-6109.2012.02678.x
ABSTRACT
Introduction. Delayed puberty (DP) is a condition characterized by the lack of sexual maturation in boys (testis volume <4 mL) at a chronological age that is 2.5 standard deviations above the mean age of puberty in a normal population. Aim. To review the etiology, pathogenesis diagnosis, and the available treatments for DP in males. Methods. A systematic search of published evidence was performed using Medline (1969 to September 2011). Main Outcome Measures. The most important evidence regarding DP and the available treatment options were reviewed and discussed. Whenever possible, levels of evidence are reported. Results. The prevalence of DP in 14-year-old boys in the United States is less than 2%, almost double of same figure in females. The etiology of DP is complex including genetic, functional, or nonidentifiable defects. The correct diagnosis should include an accurate medical history and physical examination along with specific laboratory tests. In addition, bone age radiographs are frequently helpful. If a specific disorder can be identified, therapy should be targeted at that disorder. Short-term testosterone therapy can be offered to boys with constitutional DP after a variable time of expectant observation essentially dictated by the patient’s distress. Reassurance and continued observation, to ensure that the expected sexual maturation occurs, are often sufficient. In all other cases, exogenous gonadotropins, either recombinant or extracted, induce full gonadal maturation, while long-term testosterone therapy is the treatment of choice for hypergonadotropic hypogonadism or for hypothalamic or pituitary gonadotropin deficiency until fertility is attained. Conclusions. DP is a frequent condition that if not correctly diagnosed, may cause serious clinical and psychological consequences. Appropriate diagnosis and treatment provide normal pubertal development. Maggi M and Buvat J. Standard operating procedures: Pubertas Tarda/delayed puberty—Male. J Sex Med **;**:**–**. Key Words. Delayed Puberty; Male; Hypogonadism
Introduction
N
ormal male puberty—the process of physical and psychogenic development, from the adolescence to maturity—is finely regulated by neural integration of several external (environmental) and internal (genetic and neuroendocrine) permissive signals, which, in synchrony with somatic growth and maturation of sexual and social behavior, stimulate reproductive activity. Table 1 summarizes main physical and emotional changes in pubertal males. Figure 1 shows the time frame of physical changes in pubertal male. © 2012 International Society for Sexual Medicine
The pulsatile secretion of gonadotropinreleasing hormone (GnRH) by hypothalamic neurons is a key requirement for the initiation of puberty. GnRH-secreting cells originate in the nasal compartment and are associated with the vomeronasal nerve (VNN) to traverse the nasal septum and through the cribriform plate. The VNN defasciculates after entering the brain, but GnRH neurons maintain their association with a subpopulation of VNN fibers. Then, GnRH cells dissociate from their guiding fibers in order to reach their final destination in the hypothalamus. GnRH, by activating the hypothalamic–pituitary–gonadal J Sex Med **;**:**–**
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Table 1 Main normal physical and mood changes in pubertal males
Definition of Pubertas Tarda Pubertas tarda, delayed sexual development, or delayed puberty (DP) (ICD 10 E30 http:// apps.who.int/classifications/apps/icd/icd10online/ ?ge20.htm+e300) is commonly defined as the absence of signs of puberty (including testicular growth over 4 mL) by age 14 [1]. Medical Subject Headings defines DP (C19.391.690) as the lack of development of sexual maturation in boys at a chronological age that is 2.5 standard deviations above the mean age at onset of puberty in a normal population (http://www.nlm.nih.gov/cgi/mesh/ 2011/MB_cgi?field=uid&term=D011628). Epidemiology Less than 2% of 14-year-old boys in the United States are prepubertal [2,3] (Evidence-Based J Sex Med **;**:**–**
Genital development Pubic hair
(HPG) axis, stimulates pituitary gonadotropin (luteinizing hormone [LH] and follicle stimulating hormone [FSH]) secretion and regulates the production of gonadal steroids. At the onset of puberty in the male, the first endocrine change is the start of LH pulse increase, first only at night, and later on, assuming a day/night rhythm, accompanied by a concomitant production of testosterone. Hence, an intact HPG axis is required; any temporary or permanent disorder of its activity can alter pubertal timing.
TV
Mood changes Development of personal and sexual identity Interest more often in the opposite sex Anxiety or excitement about the changes he is going through Shy, nervousness around girls, or flirtatious with girls Abstract thinking Emergence of skills and coping strategies to overcome problems and crises Growing ability to absorb the perspectives or viewpoints of others Increased ability of introspection Establishment of a system of values Less talkative and open with parents Increasing autonomy and personal independence Greater importance of peer relationships
PVH
Physical changes Gonadarche: testicle enlargement greater than 4 mL (11.5 years [9.5–13.5]) Pubarche: hair growth in the pubic area (12 years [10–14]) Growth spurts (14 years) Growth of the penis (measured stretched) from 6.2 to 12.4 ⫾ 2.7 cm Erections or wet dreams Deepening of the voice (later stages of puberty) Appearance of facial hair Broadening of shoulder muscles, development of chest muscles Body odor Pimples or facial breakouts
Age (years)
Age (years) Figure 1 Major physical changes in pubertal boys, according to age. Bars shows standard deviation of the mean (closed circles). TV = testicular volume, PVH = peak height velocity, G = Tunner’s stages.
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Pubertas Tarda/Delayed Puberty Table 2
Causes of male delayed puberty
Systemic illness
Systemic illnesses and other reversible conditions
Cystic fibrosis Asthma Inflammatory bowel disease Celiac disease Juvenile rheumatoid arthritis Sickle cell disease Thalassemia Hemosiderosis Chronic renal disease AIDS Malignancies
Excessive energy expenditure, exercise Emotional deprivation Malnutrition Diabetes mellitus Hypothyroidism Hyperprolactinemia Endocrinopathies Growth hormone deficiency Cushing syndrome Obesity
Reversible (functional)
Constitutional delay of puberty Hypogonadotropic (secondary) hypogonadism (10%) Irreversible (permanent)
Hypogonadotropic (secondary) hypogonadism (90%) Hypergonadotropic (primary) hypogonadism (100%)
Medicine [EBM] level lb). The proportion of male boys with DP is almost double of the same figure in the opposite gender (EBM level lc) [4].
Etiology The etiology of DP is complex since many conditions, such as genetic, functional or not identifiable defects, can delay puberty. An etiologic classification of DP is reported in Table 2 and distinguishes between reversible and irreversible defects, with the former being defined as functional, or secondary to other disorders that, when corrected, allow puberty. DP can be caused by a variety of physical conditions including malnutrition or emotional deprivation or by chronic diseases and endocrinopathies, such as diabetes or thyroid disorders (see in [5]) (EBM level lc). Irreversible defects are essentially divided in primary testis failure (hypergonadotropic hypogonadism) and secondary testis failure due to any hypothalamic–pituitary dysfunction (hypogonadotropic hypogonadism [HH]). Diagnosis of constitutional delay of puberty (CDP) is essentially a diagnosis of exclusion, when no underlying conditions can define the delay and
sexual maturation occurs spontaneously before the age of 18 years. Such patients are overall healthy; all aspects of physical maturation typically proceed normally, but a few years later than average. These boys generally have a history of delayed growth and development throughout childhood, including short stature but a relatively normal growth rate. CDP represents the extreme end of the normal spectrum of pubertal development and tends to aggregate in families, suggesting a genetic basis. Boys with CDP often seek clinical evaluation when classmates or friends undergo faster pubertal development and growth, thereby accentuating their delay. The frequency of these diagnoses has been examined in a retrospective study of 232 adolescents (158 males, 74 females) presenting to an academic center [4] (EBM level lc). In male boys, a reversible form of DP was noted in the majority of cases (83%) due to chronic diseases or other reversible conditions in 20% and to CDP in 63%. A diagnosis of permanent hypogonadism was made in 16% of cases, being hypogonadotropic in 9% and hypergonadotropic in 7%. J Sex Med **;**:**–**
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Maggi and Buvat
Growth and familial history
Physical examination (Tanner stage and testis volume)
Bone age and Routine exam. + testosterone test
a)Systemic Illness and other reversible conditions
b)Costitutional delay of puberty
Specific treatment
Serum gonadotropins
yes
high low d) Hypergonadotropic (primary) hypogonadism
Short-term, Low-dose testosterone
expectant observation
Long-term, testosterone
karyotype 47, XXY
46, XY
Short-term, gonadotropins
Induction of puberty
no
c) Hypogonadotropic (secondary) hypogonadism
Klinefelter S. Figure 2 Flow chart of male delayed puberty: delay in onset of secondary sexual development after 14 years. Letters in bubbles correspond to those used in Table 2.
Pathophysiology Although it is generally assumed that congenital or idiopathic HH (IHH) is caused by irreversible GnRH deficiency, i.e., requiring lifelong hormone therapy, several clinical reports have highlighted that a small percentage of male patients with IHH, including those with known gene mutations, experience reversal of the hypogonadal state (EBM level lb, see Table 2) [6–10]. These observations allow new interpretations about the pathophysiological mechanisms underlying the altered timing of GnRH neuronal activation involved in all forms of DP, i.e., constitutional, functional, or idiopathic. In particular, the reversal of congenital HH, maintained after discontinuation of therapy with testosterone in males with either absent or partial puberty [8–10], suggests a positive effect of androgens in the reactivation of GnRH neurons. Based on these clinical observations and on recent in vitro studies on human GnRH-secreting neuroblasts [11], one can hypothesize that increasing testosterone levels may stimulate hypothalamic– pituitary neural circuits leading to spontaneous resumption of pulsatile GnRH secretion, the primum movens of sexual maturation. Hence, androgen can have a positive effect on hypothaJ Sex Med **;**:**–**
lamic neurons, causing the reversal of HH as described in several human subjects [8–10].
Clinical Evaluation and Diagnosis 1. Medical history: evaluation of DP begins with a careful history, including growth and family history of pubertal timing (see Figure 2). A positive family history of DP (mother with delayed menses or father with late onset of shaving or continued growing into the early 20s) is often present, and the predicted height for the child is in the appropriate range related to the parental height. However, this finding may be nonspecific and is common in both CDP and IHH. Assessment of the patient’s growth pattern up to the time of evaluation is critical. Patients with constitutional delay have delayed growth, adrenarche, and sexual development parallel with declining growth velocity, delayed skeletal maturation, and delayed adrenal androgen maturation. A systematic review of possible associated chronic diseases needs to be covered. 2. Physical examination: the physical examination starts with determination of height and weight, which are plotted in a growth chart. The signs of puberty, including testis volume (Prader
Pubertas Tarda/Delayed Puberty orchidometer) are noted and compared with defined Tanner stages (see Figure 1). Boys with CDP have a stature that is appropriate for bone age although short for chronological age. Early signs of sexual development, often not appreciated by the patient (such as testicular growth), may allow for reassurance and avoidance of an otherwise costly and unnecessary evaluation. A testicular volume of greater than 4 mL is the earliest sign of pubertal development (EBM level lb). If present, normal spontaneous puberty can be anticipated in more than 95% of patients, and the family can be reassured. 3. Laboratory examination: bone age radiographs are frequently helpful and should be routinely performed since onset of puberty normally corresponds with a bone age range of 11–12.5 years. However, the degree of bone age delay per se is not diagnostic, even if a concomitant GH deficiency is associated with a greater bone delay. GH deficiency can be screened by an insulin growth factor-1 (IGF-1) determination. In selected cases (see Figure 2), pituitary function needs evaluation with a focus on prolactin, TSH-thyroxine, and ACTH-cortisol to exclude underlying etiologies. Magnetic resonance imaging and targeted genetic tests must be undertaken, if appropriate. Measurement of serum gonadotropins is of major significance in distinguishing between hypergonadotropic and HH (Figure 2). If gonadotropins are high, karyotyping will identify Klinefelter syndrome. If gonadotropins are low or normal at presentation ages 13–16 years, it is usually not possible to determine definitely which patients will have a permanent deficiency unless there is a concomitant finding associated with hypogonadotropinism, such as anosmia or an anatomical lesion of the hypothalamus–pituitary. At initial presentation, patients with CDP are usually characterized by HH. If there is no activity in the HPG axis by 18 years of age, IHH, which will likely persist throughout life, is the disorder. Gonadotropin response to short- or long-acting GnRH agonists have been proposed to differentiate between CDP and IHH [12]; however, the value of these assays in clinical practice needs to be further verified. Measurement of serum testosterone can predict the onset of puberty: a testosterone value greater than 0.7 nmol/L indicates the testis will be >4 mL within 12 months in 77% and within 15 months in 100% [13]. In clinical practice, if gonadotropins are low or normal, the real options are expectant observation
5 or offer a short-term (3–6 months) low-dose testosterone therapy (see Figure 2) even if none of the commercially available preparations are licensed for the induction of puberty. The latter is recommended when appearing less mature than one’s peers can lead to psychological distress [14] (EBM level lc).
Therapy If a specific underlying disorder is identified, therapy needs to be targeted at that disorder. Patients with CDP ultimately have spontaneous puberty. Often, reassurance and continued observation to ensure that the expected sexual maturation occurs are sufficient (EBM level lb). Therapy of Functional HH Functional HH associated with chronic disease needs to treat the underlying problem first. DP, in this situation, is usually a result of malnutrition and low body weight, or excessive energy expenditure; when body weight returns to normal, puberty usually occurs spontaneously. Treatment with thyroxine will allow normal pubertal development in hypothyroid patients with DP [5], as well as for other endocrine disorders (EBM level lc). Short-Term Therapy (Testosterone) As in Figure 2, short-term testosterone therapy should be offered to boys with CDP after a period of observation, which is essentially dictated by patient’s overall distress. The availability of several new forms of testosterone, which are approved for adults with hypogonadism, provides adolescents with an opportunity to choose among different testosterone replacement therapies (TRTs). The efficacy of these preparations has not been documented fully in children with CDP. Decades of experience with short-term testosterone therapy in these situations confirm no effect on final height (EBM level la). If during the 3 to 6 months after discontinuing testosterone therapy spontaneous puberty does not ensue or the concentrations of plasma gonadotropins and plasma testosterone in boys do not increase, this treatment can be repeated. Usually, only one or two courses of testosterone therapy are necessary (EBM level lb). Testosterone (about 25% of the adult dose) is usually sufficient to achieve early virilization and growth (i.e., 3–6 months), without inducing premature closure of the epiphyses (EBM level lb). When available, testosterone can be administered orally (testosterone undecanoate tablets), transdermally, or by depot injections. The use of transdermal testosterone gel is efficacious and convenient in adult males with hypogonadism, but it is not yet J Sex Med **;**:**–**
6 U.S. Food and Drug Administration-approved in males younger than age 18 years. An oral testosterone undecanoate preparation is available in some countries and has been used clinically in adolescent boys [15], but the final levels of serum testosterone are variable and dependent on the lipid composition of the diet. The depot injections are more effective than other preparations (EBM level lb). Testosterone enanthate (50–150 mg intramuscularly) is usually employed [16,17]. A course of treatment for from 3 to 6 months can be given and the situation reassessed. The response is positive when there is good acceleration in growth and physical and emotional development. Spontaneous development often starts during a course of treatment. Patients must be reevaluated by the clinician to ensure they enter into “true” puberty. One year after testosterone treatment, boys should exhibit testicular enlargement and a serum testosterone in the pubertal range. If this is not the case, the diagnosis of hypothalamic–pituitary insufficiency or HH should be considered (EBM level lb).
Long-Term Therapy Boys with HH typically demonstrate marginal or no pubertal development with low-dose testosterone treatment, and any pubertal progress that is accomplished is lost with cessation of therapy. Hence, long-term therapy should be instituted. The goals of therapy are to mimic the normal cadence of puberty, to maintain serum testosterone levels within the normal age range, and eventually, to induce fertility if and when the patient desires. Exogenous therapy with pulsatile GnRH or gonadotropins usually restores pubertal development and fertility to these patients, whereas testosterone therapy alone will induce only the development of male sex characteristics. Episodic administration of GnRH through portable pumps elicits pulsatile LH and FSH release and gonadal stimulation, but this is not practical for the routine induction of puberty in adolescent boys. Exog-
Maggi and Buvat enous gonadotropins, either recombinant or extractive, produce full gonadal maturation, but again, this regimen is cumbersome and expensive. GnRH. GnRH infused in a pulsatile fashion is the most physiological approach for deficiencyisolated GnRH or in combination with other hypothalamic hormones deficiencies. The most effective dosage in stimulating a pulsatile secretion of gonadotropins is the intravenous administration of GnRH with an interval of 90–120 minutes; whereas subcutaneous administration causes a more flattened gonadotropin response, which may not be sufficient to stimulate the testis. This kind of therapy allows for full development of testicular function, both for spermatogenesis and steroidogenesis. When spermatogenesis has been induced, the long-term secondary sexual characteristics can be maintained by subcutaneous human chorionic gonadotropin (hCG) injections [18]. Episodic administration of GnRH through portable pumps elicits pulsatile LH and FSH release and gonadal stimulation, but it is not practical for the routine induction of puberty in adolescent boys. Gonadotropins. Exogenous gonadotropins, either recombinant or extractive, produce full gonadal maturation. The treatment with hCG is administered in a dosage of 1,250–5,000 IU in combination with 12.5–150 IU of human menopausal gonadotropin (hMG), both intramuscularly, two to three times a week. At follow-up, the, dosage of hCG and hMG must be adjusted on the basis of testosterone levels and clinical signs, respectively [18]. Gonadotropin treatment may cause minor side effects, such as gynecomastia. In addition, induction of antibodies to hCG, resulting in loss of response to the treatment, has been described [19]. This modality of therapy can be a major inconvenience in that it cumbersome and expensive. Figure 3 shows the efficacy of gonadotropins in a 17-year-old male with DP. 䉴
Figure 3 (A) Growth chart of a boy (GL) who attended his first visit on the September 2, 2009 at the age of 17 (point A). At physical exam, he showed height, weight, and sexual development consistent with diagnosis of delayed puberty, testis volume at Prader orchidometer = 3 mL, penile length = 5.3 cm. His hormonal pattern was LH = < 0.1 U/L; FSH = 0.5 U/L; total testosterone: 0.33 ng/mL. Magnetic resonance imagery failed to show any pathological sign in hypothalamic–pituitary region. Hence, congenital hypogonadotropic hypogonadism was diagnosed. GL started human chorionic gonadotropin (hCG) with a dosage of 2,000 IU and human menopausal gonodotropin (hMG) with a dosage of 75 IU, both intramuscularly three times a week. In the growth chart, points B, C, D, and E are four follow-up visits. According to hormonal measurement and physical exam, hCG and hMG were maintained at the same dosage until visit E (February 27, 2011) when GL was 19 years old, total testosterone = 26.6 ng/mL, and he reached the height, weight, testis volume (13 mL), hair distribution, and penis growth (10 cm) consistent with his age. (B) Ultrasound images of testis volume. The upper panel was assessed at the first visit (point A on the growth chart) and it shows an infantile testis (volume 2.99 mL), the lower one was assessed during a follow-up visit (point D on the growth chart), and it shows a completely developed testis (volume 7.84 mL).
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8 Testosterone. Long-term testosterone therapy is the treatment of choice for hypothalamic or pituitary gonadotropin deficiency, unless fertility is desired. For hypergonadotropic hypogonadism, testosterone replacement is the only option. Typically, testosterone enanthate 50–100 mg is given every 4 weeks and escalated gradually every 6 months to 100–150 mg/month before changing to a triweekly 250 mg dose after 3–4 years [20]. A recent experience with long-lasting injectable preparation of testosterone undecanoate has been recently published [21]. A teenage boy is less likely to apply a patch or a gel daily for poor compliance. If a transdermal preparation is used, the starting dose had to be approximately one-third of the daily adult dose for the first year, gradually increased by one third daily every year to an adult daily dose by the third year. This is preferably self-applied at bedtime and avoiding potential cross-contamination [20]. New testosterone gel preparations, applied onto the forearms, have been approved for adults but not yet for adolescents. Low-dose replacement therapy is appropriate until the pubertal growth spurt. Once adequate virilization is induced and final expected adult height achieved, any form of TRT can be used. Side effects of TRT in adolescent boys are similar to those in adults. Polycythemia, as evidenced by a raised hematocrit (>55%), necessitates a prompt reduction in testosterone dose by about 25%. Gynecomastia occurs in up to a third of patients on gonadotropins or testosterone and usually (although not invariably) occurs with supraphysiological replacement. Gynecomastia results from excessive peripheral aromatization of testosterone in adipose tissue, especially in the breast. The risk and severity of gynecomastia can be reversed by adjusting the dose of testosterone or hCG as appropriate [20]. Conclusions
DP is a relatively frequent condition, which if not properly diagnosed can cause negative clinical and psychological consequences. Adolescents not only lack secondary sexual characteristics but are usually shorter. This situation can reduce selfesteem and quality of life. For example, a previously active teenage boy may stop participating in sports because he is uncomfortable undressing in front of his teammates. Fortunately, appropriate diagnosis and treatment can prevent these sequelae and provide normal pubertal development in the majority of cases. J Sex Med **;**:**–**
Maggi and Buvat Corresponding Author: Mario Maggi, MD, Sexual Medicine and Andrology Unit, Department of Clinical Physiopathology, University of Florence, Viale Pieraccini, 6, Florence 50139, Italy. Tel: +39 0554271415; Fax: +39 0554271413; E-mail: [email protected]fi.it Conflict of Interest: None. References 1 Grumbach MM, Styne DM. Puberty: Ontogeny, neuroendocrinology, phisiology and disorders. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, eds. Williams Textbook of Endocrinology. 10th edition. Philadelphia: Saunders; 2003: 1033. 2 Roche AF, Wellens R, Attie KM, Siervogel RM. The timing of sexual maturation in a group of US white youths. J Pediatr Endocrinol Metab 1995;8:11–8. 3 Harlan WR, Grillo GP, Cornoni-Huntley J, Leaverton PE. Secondary sex characteristics of boys 12 to 17 years of age: The U.S. Health Examination Survey. J Pediatr 1979;95:293–7. 4 Sedlmeyer IL, Palmert MR. Delayed puberty: Analysis of a large case series from an academic center. J Clin Endocrinol Metab 2002;87:1613–20. 5 Pozo J, Argente J. Delayed puberty in chronic illness. Best Pract Res Clin Endocrinol Metab 2002;16:73–90. 6 Bauman A. Markedly delayed puberty or Kallmann’s syndrome variant. J Androl 1986;7:224–7. 7 Quinton R, Cheow HK, Tymms DJ, Bouloux PM, Wu FC, Jacobs HS. Kallmann’s syndrome: Is it always for life? Clin Endocrinol 1999;50:481–5. 8 Pitteloud N, Acierno JS Jr, Meysing AU, Dwyer AA, Hayes FJ, Crowley WF Jr. Reversible Kallmann syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 gene. J Clin Endocrinol Metab 2005;90:1317–22. 9 Raivio T, Falardeau J, Dwyer A, Quinton R, Hayes FJ, Hughes VA, Cole LW, Pearce SH, Lee H, Boepple P, Crowley WF Jr, Pitteloud N. Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med 2007;357:863–73. 10 Ribeiro RS, Vieira TC, Abucham J. Reversible Kallmann syndrome: Report of the first case with a KAL1 mutation and literature review. Eur J Endocrinol 2007;156:285–90. 11 Morelli A, Fibbi B, Marini M, Silvestrini E, De Vita G, Chavalmane AK, Vignozzi L, Filippi S, Forti G, Vannelli GB, Maggi M. Dihydrotestosterone and leptin regulate gonadotropinreleasing hormone (GnRH) expression and secretion in human GnRH-secreting neuroblasts. J Sex Med 2009;6: 397–407. 12 Ghai K, Cara JF, Rosenfield RL. Gonadotropin releasing hormone agonist (nafarelin) test to differentiate gonadotropin deficiency from constitutionally delayed puberty in teen-age boys—A clinical research center study. J Clin Endocrinol Metab 1995;80:2980–6. 13 Wu FC, Brown DC, Butler GE, Stirling HF, Kelnar CJ. Early morning plasma testosterone is an accurate predictor of imminent pubertal development in prepubertal boys. J Clin Endocrinol Metab 1993;76:26–31. 14 Arrigo T, Cisternino M, Luca De F, Saggese G, Messina MF, Pasquino AM, De Sanctis V. Final height outcome in both untreated and testosterone-treated boys with constitutional delay of growth and puberty. J Pediatr Endocrinol Metab 1996;9:511–7. 15 Butler GE, Sellar RE, Walker RF, Hendry M, Kelnar CJ, Wu FC. Oral testosterone undecanoate in the management of delayed puberty in boys: Pharmacokinetics and effects on sexual maturation and growth. J Clin Endocrinol Metab 1992;75:37–44.
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9 chorionic gonadotropin-induced antibodies. J Clin Endocrinol Metab 1988;66:862–7. 20 Han TS, Bouloux PM. What is the optimal therapy for young males with hypogonadotropic hypogonadism? Clin Endocrinol 2010;72:731–7. 21 Giagulli VA, Triggiani V, Carbone MD, Corona G, Tafaro E, Licchelli B, Guastamacchia E. The role of long-acting parenteral testosterone undecanoate compound in the induction of secondary sexual characteristics in males with hypogonadotropic hypogonadism. J Sex Med 2011;8:3471–8.
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