Puberty: Physiology and Abnormalities, 1st ed. 2016

11. Constitutional Delayed Puberty

Peter A. Lee  and Christopher P. Houk 

(1)

Department of Pediatrics, Hershey Medical Center, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033-0850, USA

(2)

Department of Pediatrics, Georgia Regents University, 1446 Harper Street, Augusta, GA 30912, USA

Peter A. Lee (Corresponding author)

Email: plee@psu.edu

Christopher P. Houk

Email: chouk@gru.edu

Keywords

Constitutional delayed pubertyConstitutional delay of growth and pubertyDelayed pubertyHypogonadotropic hypogonadismHypergonadotropic hypogonadismFunctional delay of puberty

Definition and Age of Puberty

Puberty is the period of human growth and development when sexual maturity and fertility are established. The timing and tempo of puberty is dependent upon a host of genetic and environmental factors. The physical changes of puberty progress in a predictable sequence within an expected time related to hormone stimulation. Onset of puberty is considered when breast development becomes apparent in girls (Tanner stage 2) or when testicular growth is documented in boys (length greater than 2.5 cm or volume greater than 3–4 mL). Progression through puberty typically occurs within 2.5–3 years; generally progression to the next Tanner stage is expected within 6–12 months. Progression may differ between breast or genital staging and pubic hair stage. The age range of pubertal development varies among racial-ethnic groups, appearing earlier among African-Americans, then Hispanics , followed by Caucasian and occurring on average somewhat later in studied Asian populations. However, precise data are not available for the age of completion of puberty, and generally it is considered that puberty is delayed if physical evidence of onset (breast development or testicular enlargement) is not present by 13 years among girls or by 14 years for boys [1]. Delayed puberty is much more common in boys and is usually benign; however, pubertal delay in girls represents pathology in the majority.

The onset of pubic hair growth does not signal the onset of puberty as this may be a consequence of adrenarche, the increase of adrenal androgen secretion that begins during late childhood, and does not indicate onset of gonadal function. Further, a girl with minimal breast development and no progression of pubertal changes, particularly in those who are heavy, does not necessarily signal the onset of pubertal ovarian secretion as progression is an obligate feature of puberty. A growth spurt (Fig. 11.1) follows a nadir of growth rate just before pubertal onset. Among girls it occurs early, together with breast budding as the first signs of puberty. In boys, the growth spurt occurs in mid-to-late puberty.

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Fig. 11.1

Height velocity for age for a (A) girl and a (B) boy with normal puberty occurring at an average age and a (C) boy with CDP (based on charts developed by the National Center for Health Statistics)

Definition of Delayed Puberty

Delayed puberty represents the late onset or the delayed progression of physical puberty. Delayed puberty is defined as the onset of puberty beyond the mean age of onset by approximately 2–2.5 standard deviations (approximately 13 years in girls and 14 years in boys) [1]. Absence of menarche by age 15 is also evidence of lack of normal progression and is called primary amenorrhea.

Constitutionally delayed puberty (CDP) , as the name implies, has traditionally been considered puberty that is temporarily delayed in onset or completion and has been considered as a normal variant [2]. It is felt to occur as a result of a delay in the onset of pubertal gonadotropin stimulation of the gonads or a lag in the progression of such secretion in an individual who ultimately attains normal adult gonadotropin secretion . Those with CDP are expected to complete puberty and attain adult height by 18 years of age [3]. CDP is distinct from other categories of delayed puberty that have an identifiable underlying pathology such as:

1.     1.

2.     2.

3.     3.

When puberty is delayed, constitutional delay and the first two pathologic categories above present with low gonadotropin levels and are usually difficult to differentiate one from another, in contrast to elevated gonadotropin levels in gonadal failure. Features at initial presentation help to categorize patients presenting with delayed puberty (Table 11.1), although the category needs to be subsequently confirmed in most instances.

Table 11.1

Approach to patients with delayed puberty

Girls

No or minimal breast development with no progression in previous 6 months

Boys

Prepubertal genitalia with

 

Testicular volume

<4 mL

Likely early changes in CDP

   

>4 mL

HH or CDP with no early changes

First-tier screening testing—LH, FSH (plus testosterone in males or estradiol in females), prolactin. CBC, CMP, skeletal age X-ray, olfaction testing; depending on linear growth-free T4, TSH, IGF1; karyotype based on clinical findings

 Gonadotropin levels mIU/mL (using third-generation assay)

  Random LH levelsa

  <0.3—prepubertal or hypogonadotropic levels

    CDP (delayed but essentially normal puberty)

    Functional pubertal delay (consequence of a chronic disease or condition in a patient with a potential of normally functioning hypothalamic-pituitary-gonadal axis)

     Anorexia nervosa

     Chronic cardiac, pulmonary, and renal disease

     CNS tumors (prolactinoma, craniopharyngioma

     Excessive exercise (e.g., gymnastics)

     Growth hormone deficiency

     Hypothyroidism

     Inflammatory bowel disease

     Hypercortisolism

     Malnutrition/eating disorder

     Multiple pituitary hormone deficiency

     Psychogenic or stress related

    Hypogonadotropic hypogonadism (permanent deficiency—some with anosmia)

>0.9—pubertal levels indicating normal HPG axis

  CDP

>9.0—elevated levels suggestive of gonadal failure

  Hypergonadotropic hypogonadism

   Turner syndrome

   Klinefelter syndrome

aFSH less useful but may be confirmatory, levels >12 are consistent with hypergonadotropic hypogonadism

CDP designation is typically, but is not always, synonymous with constitutional delay of growth and puberty (CDGP) . The later involves delayed maturation including statural growth delay during prepubertal years [45]. CDGP presents with short stature compared with expected height based on parents’ heights, with a commensurate delay of skeletal age and low or borderline low growth rates. Their puberty can be expected to begin when skeletal age reaches 10–11 years for girls and 11.5–12.5 years for boys. CDGP is an inclusive term including those who did not have apparent delay of maturity during childhood, while CDGP occurs during adolescence.

Etiology

Historically our view of CDP has been that it represents the far end of the normal distribution of normal pubertal development. More recently, the identification of gene modifications that are associated with both transient CDP and permanent hypogonadotropic hypogonadism has suggested that our paradigm for understanding CDP is too simple.

The currently identified genes related to reproductive function have been recently summarized [6]. Because of the complexity of genetic and physiologic factors controlling both puberty and growth, it is reasonable to presume that multiple genetic/environmental factors impact both the age of onset and rate of progression of puberty. Thus, it is reasonable to hypothesize that the expression of gene variants results in a spectrum of diagnoses related to the resurgence of the hypothalamic-pituitary-gonadal axis that heralds the onset of puberty. This spectrum in pubertal onset/progression ranges from individuals who attain a normal adult height and adult gonadal function, to those with a foreshortened adult height or subfertility, to those who felt to have HH who unexpectedly develop normal gonadal function later in adult life [7]. This occurrence of endogenous reproductive hormone secretion in individuals diagnosed with permanent HH, some of whom carry a genetic mutation associated with permanent HH, suggests a spectrum of clinical severity extending to a portion of those patients previously classified as having constitutional delayed puberty, having relatively mild alterations in genes [8].

Evidence for incomplete or disordered pubertal development in patients with CDP includes failure to reach target height [9], lower adult bone mineral density (BMD) [10], and diminished adult fertility. These findings suggest that mild alterations of genes related to gonadotropin deficiency and genes related to growth and maturation may constitute distinct but often overlapping etiologies of CDP. This hypothesis supports by the identification of gene alterations that may delay puberty eventually results in attainment of normal function [11] and other genetic changes that delay puberty but show persistence of partial HH. Families in which multiple individuals share the same genetic mutation have been reported where some individuals manifest permanent HH, while others show CDP [12]. The increased incidence of CDP in kindreds with permanent idiopathic hypogonadotropic hypogonadism (IHH) (idiopathic to distinguish from forms of known etiology such as Kallmann syndrome) is indirect evidence that genetic alterations often show a variable clinical expression of differing severity involving secretion and action of gonadotropin-releasing hormone (GnRH) secretion [2].

HH genes have been evaluated in individuals comparing kindred with IHH with or without delayed puberty versus a kindred with no family history of IHH [11]. Potential variants were for a presumed neurodevelopmental gene involved in the initial fate specification of GnRH neurons (IL17RD) and the gene for neurokinin B (TAC 3). In the kindred with IHH, in those with pubertal delay, 53 % had a variant of the IHH gene compared to 12 % of the control family. Among those with delayed puberty with no family history, 14 % had a genetic variant and 5.6 % of controls did. These results are consistent with IHH gene variants being an etiology of CDP. Normal reproductive function among adults who have previously been diagnosed with IHH has been found to be associated with genetic variants of neurokinin B (TAC3) [13] and its receptor (TACR3) [7].

The gonadotropin-releasing hormone receptor (GNRHR) gene has also been studied using molecular analysis and in vitro experiments and correlated with phenotype in 74 male and 36 female patients with normosmic hypogonadotropic hypogonadism (IHH) and in 50 with CDP [14]. The phenotypic spectrum in patients with GNRHR mutations varied from complete GnRH deficiency to partial and reversible IHH, with evidence of genotype-phenotype correlation. However, no evidence was found that mutations in GNRHR were involved in the pathogenesis of CDP.

Associations of polymorphisms in the estrogen receptor α (ESR1) with CDP have been studied using three single nucleotide polymorphisms from intron 1 of ESR1 (rs3778609, rs12665044, and rs827421) as candidates [15]. The frequency of G/G genotype at rs827421 in intron 1 of ESR1 was increased in CDGP boys (P = 0.03). This is consistent with genetic variation of ESR1 contributing to the etiologies of CDP.

To date, there is no evidence suggesting an association with CDP among loss-of-function mutations in the immunoglobulin superfamily member 1 (IGSF1) . Such mutations result in an X-linked syndrome of central hypothyroidism, normal timing of testicular growth, but delayed rise of testosterone. Although the search found three novel variants among 30 patients with an apparent X-linked form of CDP, it did not provide evidence that IGSF1 mutations are also associated with CDP [16].

Significant linkage between the pericentromeric region of chromosome 2 and CDP among Finnish families has been recently reported [17], similar to a previous report [18]. However, the variation within the linked region that predisposes to delayed puberty has not been identified.

Natural History

As noted above, CDP is often identified at the age of puberty as a continuation of a delayed growth pattern described as constitutional delay of growth and puberty (CDGP) . This may be identified earlier in childhood during evaluation of short stature. CDGP is characterized by short stature manifest early in childhood (Fig. 11.2) and borderline or low normal growth rates but without evidence of a pathologic cause of short stature. Skeletal maturity as judged by radiographic skeletal age is delayed for age and sex. It may be considered that the typical child with CDGP has a delay of “biologic age” compared with chronologic age. Whether or not delay is apparent during prepubertal years, patients with CDP have a delayed growth spurt (Fig. 11.1). This delayed growth acceleration may also not reach the maximum rate of typically puberty. Since patients continue to grow—albeit at a slow rate—until the growth spurt begins, it is often difficult to ascertain whether adult height has been compromised.

A334826_1_En_11_Fig2_HTML.gif

Fig. 11.2

Typical growth chart for a boy with CDGP showing low normal growth rates during childhood with deviation from the normal range at the typical age of puberty and later adolescent growth spurt of lesser magnitude than the average boy

A positive family history of CDP is often present among same-sex relatives, i.e., fathers or uncles of boys and mothers or grandmothers of girls. Fifty to eighty percent of patients with CDGP have a positive family history [1920]. A recent assessment of families of 492 Finnish subjects [20] with CDGP (based upon delay of pubertal growth spurt) confirmed the heritability of CDGP but found only a slightly higher prevalence in male first-degree relatives over that seen in female relatives challenging the traditional view of a marked predominance of CDGP among males. Such clustering in families suggests a pattern consistent with autosomal dominant inheritance. While the onset and progression of puberty normally vary in a population over a number of years, the inclusion of CDGP as a variant of normal growth results in a significant skewing of the normal Gaussian distribution of puberty in males.

The numerous changes within the neural systems that regulate GnRH synthesis and puberty are impacted by metabolic factors related to body size and composition [21] and psychological, social, and other unknown factors. The relationship of obesity and puberty onset is unclear. When delayed puberty occurs in obese boys, the association of linear growth pattern is not that typically found in CDGP and tends to show a greater height for age, less delay of bone age, as well as taller stature for bone age [22]. Predicted heights are greater than midparental height in contrast to normal-weight boys with delayed puberty who typically have predicted adult heights within or below midparental height ranges. Hence, the relatively taller stature among obese boys is not associated with foreshortened adult height suggesting a different etiology of delayed puberty than the “typical” CDGP [23].

The diagnostic category of familial short stature (FSS) should be considered when assessing CDGP since findings also include diminishing height for age, slow growth rates, and skeletal age delay. While FSS involves adult family members with stature below the normal range, findings overlap at presentation of FSS and CDGP [24]. Among patients presenting with CDGP, 40 % have been reported to have short family members suggesting familial short stature [25]. Such is not surprising since both are descriptive categories with multiple etiologies related to numerous factors including multiple genes.

Physical Observations

A common clinical criterion for the diagnosis of CDP among boys is the lack of evidence of the physical onset of puberty by age 14 years. The first evidence is an increase in testicular volume (greater than 4 mL. or a long axis greater than 2.5–3 cm.) in boys. Among girls, the first physical evidence is the onset of breast development (clear evidence of growth of mammary tissue); delay is commonly diagnosed if not present by 13 years of age. Onset should be followed by the timely attainment of pubertal milestones, including accelerated growth rates typical of sex. Growth rates for stage of puberty are informative, including the period of deceleration of growth rate in late childhood, since with CDP there may be a prolongation of this interval of slow growth rate. Upper-lower body proportions with relatively longer limbs, a finding characteristic of hypogonadal individuals, have been noted in CDGP ; this suggests a prolonged duration of the childhood growth phase. In boys with CDP, the duration of the interval between the onset of puberty and the pubertal growth spurt is shortened as the duration of growth acceleration leading to an attenuation of the peak growth velocity. Those who have a height deficit early in childhood, typically described as CDGP, have a less favorable adult height prognosis than those who develop this deficit late in childhood [26].

Estimation of testicular volume when a boy presents with the complaint of delayed puberty is crucial. Testicular growth, as the first physical evidence of the onset of puberty in boys, is often evident at the time of presentation with the complaint of delayed puberty. Evidence of testicular growth suggests CDP rather than hypogonadism because this is an indication that puberty has begun. Among those with testicular volume at presentation of greater than 4 mL, at least 95 % have been found to have CDP, while among those with volume <4 mL, the likelihood of HH is much greater (40 % of series presenting with delayed puberty; all have been shown to have HH) [27].

A pubertal nomogram has recently been published for Danish boys classifying CDP using a puberty nomogram (genital stage < −2 SD for age) rather than the classical criteria (genital stage 1 at ≥ 14 years) [28]. In this study, results from 287 boys found that 78 (27 %) had delayed pubertal onset according to the classical criteria, whereas 173 (60 %) had impaired pubertal progression according to the puberty nomogram. These results suggest the CDP may be more even frequent when rates of progression are considered or that standards for progression are too narrow.

Laboratory Assessment

A reasonable approach to the boy presenting with pubertal delay would include determination of a random, preferably morning, testosterone level paired with an LH level. FSH often adds little additional information, except when abnormally high levels, indicative of gonadal failure, are noted. Anti-Müllerian hormone (AMH) and inhibin B levels are higher among boys with CDP than HH. Values > 100 pmol/L and >35 pg/mL suggest CDP [2930]. While CDP among girls has not been studied extensively, a similar approach is appropriate, substituting a sensitive estradiol assay for testosterone. In addition, screening to rule out a functional cause of pubertal delay should be done based on history and physical findings. A skeletal age determination is also pertinent to determine biologic delay and estimate growth potential. Care for the patient with a tentative diagnosis of CDP involves follow-up to determine endogenous HPG axis function.

Virtually all presenting with the complaint of delayed puberty who have basal morning serum concentration of testosterone (T) of >1.7 nmol/L (48 ng/dL) have CDP, while if T is <1.7, 45 % had CDP with the rest having HH [26].

Over recent decades there have been reports of different endocrine tests to differentiate CDGP from HH at the time of presentation. A meta-analysis of publications concluded that basal and GnRH analog stimulated gonadotropin levels have limited diagnostic specificity because of overlap of values for these two diagnoses during adolescence [31]. Stimulation tests with GnRH agonists or hCG may have better discrimination, but they involve prolonged protocols, while an inhibin B level may provide good differentiation. A summary of differentiation criteria is discussed below comparing criteria for CDP vs. those of HH with some specificity and sensitivity data:

1.     1.

2.     2.

3.     3.

4.     4.

5.     5.

6.     6.

7.     7.

8.     8.

Because there is overlap of the prepubertal hypothalamic-pituitary-gonadal function in those with normal versus compromised hypothalamic-pituitary function, none of these tests clearly distinguish between CDP and HH. This may in part be explained by the current recent understanding that some instances of CDP may represent a partial gonadotropin deficiency in spite of later evidence of functioning HPG axis, albeit at a borderline or lower level.

Treatment

Short-term treatment of females with estrogen and males with testosterone may be diagnostic as well as therapeutic since not only should physical changes of puberty be stimulated, but also reassessment after a period of therapy may indicate that endogenous pubertal hormone secretion has begun. While there are more data for males, because of the higher frequency of CDP among boys, similar therapy among girls for whom other causes of pubertal delay have been ruled out is reasonable. It is pertinent that dosages of estrogen are low so that pubertal changes and particularly skeletal maturity is not stimulated to mature at a faster rate than concomitant statural growth. For CDP, treatment is given for short intervals, commonly of 3–6 months duration, followed by interruptions for at least 6–8 weeks so endogenous hormonal secretion, and testicular enlargement in males, can be assessed.

For girls, estrogen therapy is given using the lowest available dosages orally or transdermally. Some forms of patches can be cut and are used by some. Ethinyl estradiol should be avoided. For boys, treatment commonly involves depot T for several months. While it can be argued that the topical (transdermal) forms of testosterone therapy can be prescribed to more closely mimic the gradual rise of levels found in spontaneous puberty, such have generally not been popular among boys and offer no long-term advantage for those with CDP. However, adjusting dosages for those who require long-term therapy is a general practice. Depot testosterone injections are practical and effective, with the goal of therapy being to induce physical changes of puberty and accelerated growth without inappropriate advance of skeletal age. Overall, as long as initial dosages are low to moderate, results are satisfactory. Typically it is unnecessary to monitor T levels during therapy, but if levels are measured, it is important to realize that levels rise progressively over the first 5–7 days after injection and decline thereafter. A reasonable initial dosage would be 25–50 mg every month for the patient who has very low circulating testosterone levels (<30 ng/dL, 1 nmol/L), while 50–75 mg can be used for those whose pretreatment testosterone levels are somewhat higher. If a second course is needed, the dosage can be increased to 100–150 mg every 4 weeks. Since this therapy is a diagnostic and therapeutic trial, there is no need to develop a long-term plan with gradual increases of dosage unless there is evidence of permanent hypogonadism.

While the impact of short-term androgen in boys on inducing maturation of hypothalamic-pituitary axis is unclear [37], if endogenous testosterone 6 weeks later is within the pubertal range, interval maturation of the axis is suggested. During the same interval, testicular volume increase also confirms progression of endogenous secretion [38], since testosterone without gonadotropins (particularly FSH) has minimal impact on testicular growth. Some CDP patients require repeated short-term treatment courses before there is evidence of maturation of the HPG axis [39]. Ongoing monitoring is important.

Since eventual endogenous secretion is expected with CDP (as with the boy with early increase in testicular volume), the option of interval hormonal therapy should be discussed with the patient and parents. It should be made clear that normal but late development is expected, and the therapy is to avoid further delay in physical pubertal changes and growth. Because there is long-term experience with such therapy without long-term negative effects, it is reasonable to explain the presumed diagnosis to the patient and parents and give them treatment options to begin the changes, rather than wait until they happen. In the majority of such situations, patients chose therapy in order to begin growth and maturation.

Treatment is considered because delay may be prolonged with psychosocial problems, as well as a shorter adult height than target (sex-corrected midparental ) heights and decreased BMD, and perhaps affect fertility. The psychosocial problems may involve feelings of incompetence, vulnerability, poor self-esteem, less participation in athletic activities, social isolation, impaired academic performance, substance abuse, and disruptive behavior [40].

If there is severe short stature or evidence of partial hypogonadism, other therapeutic regimens may be considered. Treatments that have been used include oxandrolone (which has primarily been used for the prepubertal-aged boys with short stature in an attempt to increase growth rate without inappropriate skeletal age advance), aromatase inhibitors (used concomitantly with testosterone therapy or alone for the older adolescent boys in an attempt to delay epiphyseal closure by lowering estradiol levels allowing for more time for growth), dihydrotestosterone levels (to stimulate pubertal changes since this is a substrate that is not aromatized to estradiol, so there is diminished stimulation of skeletal maturation), and growth hormone (GH) (used in an attempt to increase adult height, sometimes begun in the short prepubertal boy at the usual age of puberty before testosterone therapy ).

It is, in fact, difficult to differentiate patients with CDP from those with mild GH deficiency based upon responses to GH stimulation testing . Because of the high variability seen in GH stimulation testing in normal patients and because patients presenting with CDP and mild GH deficiency frequently later demonstrate normal responses to GH stimulation after puberty, the diagnosis of mild GH deficiency in patients with CDP should be questioned. When GH stimulation testing is undertaken in pubertal aged children with CDP, it has been suggested that sex steroid priming be undertaken to improve the validity of testing by giving 25 mg testosterone 7–10 days before testing in boys or by using 1.25 mg of conjugated estrogen once daily for 3 days in girls. However, recent evidence fails to show that this method provides better evidence for the diagnosis of GH deficiency [41]. It is generally felt that consideration of GH therapy should be considered only for those patients whose heights are below −2.5 SD for age with predicted adult heights (based upon skeletal age) and height less than the normal adult range. If GH testing in such patients is consistent with GH deficiency, GH therapy can be initiated before or concomitant with sex steroid therapy with careful monitoring.

Summary

Constitutional delayed puberty continues to be a diagnosis of exclusion, requiring sufficient time for endogenous pubertal physiology to manifest itself. While traditionally viewed as a variant of normal growth, developing evidence suggests that a portion of this population may not achieve normal postpubertal status. Such evidence includes foreshortened adult height, diminished BMD, and adult reproductive function that may be less than the general population. While the later is difficult to document because of the wide range of variation of sexual function and fertility among adults, careful assessment suggests mild hypogonadism and subfertility in some patients previously diagnosed with CDP. Molecular genetic studies suggest that this may be related to genetic defects resulting in later or slower onset of puberty with outcome function at or below the range of normal. In the meantime, while further information is being learned, the diagnosis and treatment of these patients continues unchanged. This involves temporary androgen therapy as desired until onset of endogenous physiologic function with further assessment only if hormone levels are inadequate or infertility is apparent.

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