Fig. 3.1
Simplified diagram of the hypothalamic–pituitary–gonadal (HPG) axes, hypothalamic–pituitary–adrenal (HPA) axes, and growth hormone (GH) axes. The hypothalamus releases gonadotropin-releasing hormone (GnRH), corticotropin-releasing hormone (CRH), and growth hormone-releasing hormone (GHRH), which stimulate the anterior pituitary gland to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH), adrenocorticotropic hormone (ACTH), and growth hormone (GH), respectively. GnRH, LH, GHRH, and GH are released in a pulsatile fashion that varies with pubertal stage. In the HPG axis, FSH stimulates the ovarian follicles to produce estrogen (from androgenic precursors produced from theca cells), inhibin, progesterone, and ova. Estrogen provides both a positive and negative feedback on GnRH. In females, a critical amount of estrogen is needed to produce a positive feedback to stimulate the LH surge that leads to ovulation. In males, FSH stimulates Sertoli cells and seminiferous tubules to produce estrogen, inhibin, and sperm. LH stimulates theca cells in females and Leydig cells in males to produce androgens. On the HPA axis, ACTH stimulates the zona reticularis of the adrenal gland to secrete dehydroandrosterone (DHEA). DHEA is then converted to dehydroandrosterone sulfate (DHEAS) via sulfotransferase (ST), and to androstenedione (A4) via 3b-hydroxysteroid dehydrogenase (3b). A4 is then converted to testosterone via 17b-hydroxysteroid dehydrogenase (17b) and estradiol via aromatase (AT). In the GH axis, GH stimulates the liver and epiphyses of bone to produce insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2)
3.5 Characteristics of Sexual Development
The predictable and ordered series of events, which have historically been referred to as the standard for sexual development and somatic growth, were initially described by Tanner and Marshall more than 30 years ago (Sexual Maturity Rating (SMR) Scale ) [29] (◘ Fig. 3.2). Although the activation of the HPO axis results in normal onset of sexual development, alternate sources of steroid hormone production may signal abnormally early development in adolescent girls. Such agents include organic pesticides, soy-based products, and shampoos containing placental extract. Investigators have suggested several possible pathways by which these agents influence development, including direct activation of the HPO axis and steroid hormone-like activity [30–32]. These publications raise the notion of endocrine-disrupting chemicals, and although there is little doubt that persistent exposure may adversely affect developmental pathways and promote disease progression, the association with pubertal development remains tentative and weakly causative from an epidemiological perspective.
Fig. 3.2
Timing of events of puberty. 1969 data from a study of British schoolchildren. 1997 data from a study of American schoolchildren. Reproduced with permission from Solnik JM, Sanfilippo JS. In: Hurd WW, Falcone T, eds. Clinical reproductive medicine and surgery. St. Louis, MO: Mosby/Elsevier; 2007; adapted from [22]
3.6 Thelarche
The first sign of development in the majority of white females is breast budding. According to Tanner and Marshall, this initial event occurs between 8 and 13 years of age in most females, with a mean of 10.6 years. The transition period from stage II to stage V breast development may last 4.2 years [29].
3.7 Adrenarche
Pubic hair growth typically occurs after thelarche, but may occur concomitantly, with the activation of the hypothalamic–pituitary axis. Although adrenarche may also present before breast development in a normally maturing female, adult hair distribution should not be detected at this early stage, as it may represent an excess of androgen production. Accordingly, breast maturation should not be so advanced in the absence of pubic hair development, a potential sign of androgen insensitivity syndrome. Adrenarche typically occurs between the ages of 11 and 12, with adult hair distribution by age 14. Androgen levels change without a corresponding change in ACTH and cortisol secretion throughout life. So the means by which adrenal androgens are produced is not as clearly delineated and appears to occur independent of the hypothalamic–pituitary axis .
3.8 Growth Spurt
The growth spurt (peak growth velocity), during which adolescents achieve approximately 20% of their adult final height, occurs with the onset of puberty [29]. Peak growth velocity (2–3 cm/year) precedes menarche and typically occurs earlier in girls than in boys. Rapid growth of the extremities occurs first, followed by a gradual lengthening within the vertebral column. The timing of the growth spurt varies according to ethnicity.
3.9 Menarche
According to Tanner, girls in the United Kingdom in 1969 had their first menses at the average age of 13.5 years, with a range of 9–16 years [29]. The mean age of menarche for a Caucasian adolescent in the USA is approximately 12.7 years. At the time of menarche, most have achieved Tanner stage IV breast development, and the interval from initial breast development to menarche on average is 2.3 years [29].
There seems to have been a decline in the average age of menarche in the first half of the twentieth century, in part due to the improvement in general health and nutrition [33]. Nonetheless, few reports have documented any further changes since the mid-twentieth century.
There is good evidence that African-American girls have an earlier onset of puberty compared to Caucasian girls [34, 35]. This was well demonstrated by the Pediatric Research in Office Settings (PROS) study published by Herman-Giddens in 1999 [34]. This multicenter, cross-sectional study evaluated over 17,000 female patients between the ages of 3 and 12 years of age [34]. On average, African-American females show early signs of puberty up to 1.5 years earlier than their Caucasian counterparts. By 7 years of age, 27.2% of African-American girls and 6.7% of Caucasian girls showed breast or pubic hair development. Menarche was achieved almost a year earlier. The mean age for onset of breast development was 8.87 in African-American girls and 9.96 years in Caucasian girls. At each consecutive stage of development, African-Americans were more advanced per year than Caucasians. Girls of other ethnic backgrounds may also have a characteristic difference in onset of pubertal maturation. However, only Caucasian and African-American girls were included in this study.
PROS was the first large publication to address current and demographically relevant standards for assessing normal and abnormal onset of puberty. Updated guidelines have since been proposed and recommend a formal evaluation for precocious puberty be initiated in African-American girls who present before the age of 6 and Caucasians who present before the age of 7. Although this provocative investigation has drawn much criticism, it does invite us to reconsider the current standards (◘ Fig. 3.2).
3.10 Precocious Puberty
One challenge each clinician faces is when to initiate the assessment of a child suspected of having precocious puberty. Historical accounts from the nineteenth century report a relative later age of onset of menstruation (16–17 years), presumably due to malnutrition. The definition of precocious puberty since remained stable, such that any female who presented prior to 8 years of age was observed, if not evaluated, for progression of sexual characteristics [29]. As referred to earlier, the traditional definition was challenged by Herman-Giddens, who strongly suggested that normal pubertal development may begin as early as 6 years of age [34]. Causes of precocious puberty are listed in ◘ Table 3.1.
Table 3.1
Causes of precocious puberty
Central precocious puberty (GnRH dependent) |
1. Idiopathic |
2. Central nervous system tumors |
(a) Craniopharyngioma |
(b) Trauma |
(c) Infection |
(d) Primary hypothyroidism |
3. Syndromes associated with elevated gonadotropins |
(a) Silver’s syndrome (dwarf-like characteristics) |
Peripheral precocious puberty (GnRH independent) |
1. Exogenous steroid hormone exposure (estrogens) |
2. Ovarian tumors |
(a) Granulosa cell |
(b) Functional cyst |
3. Adrenal tumors |
4. McCune-Albright syndrome |
Heterosexual precocious puberty |
1. Exogenous steroid hormone exposure (androgens) |
2. Adrenal and ovarian androgen-producing tumors |
3.10.1 Effects of Precocious Puberty on Adult Height
Low levels of estrogens have been shown to promote bone growth, as is manifest by rapid growth velocity during the growth spurt. Conversely, high levels promote closure of the epiphyseal plates. Girls who present early in the course of precocious puberty are generally taller than their age-respective cohorts due to increased levels of steroids and the actions of IGF-I. This growth is premature and limited, so that the final height in untreated patients will likely be less than 155 cm [1]. As a result, by the time most adolescents achieve menarche, they have likely reached their final height. Notwithstanding the apparent risk for short stature, a significant number of untreated patients with idiopathic disease will likely attain relatively normal adult height, greater than the third percentile [1]. Some specialists in the field believe that the diagnosis of precocious puberty cannot be assigned unless symptoms are also associated with an accelerated growth spurt.
3.10.2 Central Precocious Puberty
CPP is more frequently noted among girls, with an incidence of 1:5000–1:10,000 [36]. It results from the premature activation of the hypothalamic GnRH neurons. Approximately 70–95% of such cases are idiopathic in nature; however, other potential etiologies must first be considered, since the level of urgency and need for management of individual causes will vary [37, 38]. For a full list of etiologies, see ◘ Table 3.1.
3.10.3 Laboratory Findings
Baseline gonadotropin levels in the pubertal range with a predominant LH response are suggestive of CPP. Random daytime levels may be of less use in early central pubertal development because the initial increase in pulsatility occurs at night. To help distinguish CPP from GnRH-independent forms of precocious puberty, a GnRH stimulation test should be performed. To accomplish this, 100 μg of GnRH (gonadorelin acetate) is administered intravenously, and gonadotropin levels are drawn at baseline and at 20, 40, and 60 min. One of the earliest signs of physiologic puberty is the nocturnal, pulsatile secretion of GnRH with a subsequent increase in serum LH. There is a corresponding rise in LH for each pulse of GnRH secreted. These same events occur with early onset, and an LH:FSH ratio >1 would be expected. Serum estradiol levels would be detected in the pubertal range as well. In order to maintain the diagnosis of CPP, androgen (DHEA, DHEA-S, testosterone) and 17-hydroxyprogesterone (17-OHP) levels should be drawn.
3.10.4 Imaging Studies
Imaging studies play a key role in the evaluation of children with precocious puberty, because a rapid increase in growth and bone age are typically seen in children with rapidly increasing levels of sex steroid hormones. Linear growth and skeletal maturation are often a more accurate assessment of pubertal development than progression of secondary sexual characteristics.
Bone age is typically evaluated by radiographic plain films of the left hand and wrist. This is a simple and noninvasive test that is well tolerated by most children. Bone age advance over chronological age is diagnostic for precocious puberty, and a disparity of greater than 2 years is more suspicious for a progressive disorder [39]. Given the higher prevalence of CNS abnormalities, especially in girls who present with particularly early onset or who have a known history of childhood seizures, neuroimaging is always indicated to rule out space-occupying lesions, malignant neoplasms, and other CNS anomalies, even in the absence of neurological complaints.
Pelvic ultrasound, however, is typically one of the easiest and most useful studies since it provides a good picture of ovarian function (developing follicles capable of producing estradiol, increased cortical volume suggestive of excess androgen production) or neoplastic processes. Ultrasound may also demonstrate subsequent steroid hormone influence on other reproductive organs. A diagnostic approach to precocious puberty is given in ◘ Fig. 3.3
Fig. 3.3
Evaluation of central, peripheral, and incomplete precocious puberty
3.10.5 Treatment
The ultimate therapeutic goal with Central Precocious Puberty is to suppress the HPO axis and return the hormonal environment to that of the prepubertal state (serum estradiol <10 pg/mL). Most important is the normalization of linear growth velocity and bone maturation. The outcome for patients with CPP can vary significantly, which further limits our ability to predict who will benefit most from therapy.
3.10.6 Hypothalamic Suppression
Initial attempts to achieve such a degree of hypothalamic suppression included the use of progestins; however, these were unsuccessful at limiting progressive changes and their use has since been abandoned [40]. The most commonly used GnRH analogs to treat CPP in the USA are leuprolide, nafarelin, and histrelin. Children with precocious puberty generally require higher doses to achieve suppression, which can be monitored with serum estradiol levels and GnRH stimulation tests. In order to improve compliance, subcutaneous formulations can be used. Early treatment protocols using long-acting GnRH agonists reported significant regression of secondary sexual characteristics and overall improvement in final height compared to nonrandomized controls [41]. A few randomized series have, however , been published that addressed the effect of GnRH agonists on final height in girls who presented with early or slowly progressive puberty [42, 43]. They confirmed results from previous observational and non-randomized reports that documented very little effect of hypothalamic suppression on improving final height in patients presenting at a later age. Children presenting with either “early puberty” or advanced “slowly progressive puberty” were likely to achieve reasonable adult height without hypothalamic suppression.
One theory that may help explain impaired growth during GnRH analog therapy in this group is early growth plate senescence related to estrogen exposure prior to onset of treatment [44]. So it may be this rate-limiting step, patients presenting beyond the window of opportunity, that limits final height.
Significant consideration should be given to promptly initiating therapy in girls presenting early with advanced bone age, as they will likely benefit most from GnRH agonist therapy [45–48]. Adan et al. suggested the following as risk factors for decreased stature and appropriate indications for therapy, especially at an earlier age of onset: (1) predicted adult height below 155 cm (may include those with a predicted height over 155 cm if the LH/FSH ratio is consistent with CPP) and (2) bone age advance over chronological age greater than 2 years [48]. Hormonal monitoring of therapy can be performed with the GnRH stimulation test at 3, 6, and 12 months after initiation, with annual follow-up thereafter.
Although the optimal time of discontinuing therapy remains unclear, many recommend that suppression stop at a bone age of 12–12.5 years. Other elements to consider include the total duration of therapy and growth velocity over the months preceding. Routine evaluation of secondary sexual characteristics, weight, and sonographic measurements of pelvic structures should be performed on an ongoing basis as well. Bone mineral density may be affected by prolonged use of GnRH agonists, so attention to bone health should not be omitted .
3.10.7 Recombinant Growth Hormone
Some children with precocious puberty will have early closure of their epiphyseal plates despite the use of GnRH analogs. As a result, these girls will grow up to be short adults without further intervention. The use of growth hormone as an adjunct to GnRH agonists in girls with precocious puberty has been evaluated by several observational and randomized series and has been found to improve final height prognosis [49]. Although the use of growth hormone in certain patients is frequently prescribed among pediatric endocrinologists, the studies evaluating efficacy are troubled by obstacles quite similar to those seen with the analysis of GnRH agonists on final height. It is important to be aware that growth hormone has not yet been approved by the U.S. Food and Drug Administration for treatment of girls with short stature as a result of precocious puberty
3.10.8 GnRH-Independent Precocious Puberty
When precocious puberty occurs independent of pituitary gonadotropins, the source of estrogen production must be established. One common source is surreptitious ingestion of exogenous hormones, such as those found in oral contraceptive pills or anabolic steroids. Other less common sources include primary hypothyroidism. However, the most common origin of GnRH-independent estrogen production is frequently the ovary itself.
3.10.9 Autonomous Ovarian Estrogen Production
Ovarian tumors are uncommon but important childhood neoplasms that present with precocious puberty in approximately 10% of cases [50]. Granulosa cell tumors are the most common estrogen-producing neoplasms detected. However, other tumors, such as thecal cell tumors, gonadoblastomas, teratomas, cystadenomas, and ovarian cancers, may be responsible. Intra-abdominal masses are often palpable, but imaging with sonography or magnetic resonance imaging may help characterize the tumor, and surgical exploration is generally warranted.
Laboratory criteria that help distinguish these processes from a central source include low baseline gonadotropin levels and a prepubertal response to the GnRH stimulation test. Similar to CPP, estradiol levels will be high and bone age advanced (see ◘ Fig. 3.2). Treatment is based on surgical extirpation of the source, which results in regression of pubertal changes.
3.10.10 McCune-Albright Syndrome
McCune-Albright syndrome, also known as polyostotic fibrous dysplasia, is a genetic disease affecting the bones and pigmentation of the skin. The hallmark of McCune-Albright syndrome in girls is precocious puberty, and this condition accounts for approximately 5% of all girls with precocious puberty. These patients have estrogen-producing ovarian follicular cysts that develop independent of gonadal hormone stimulation, a condition termed autonomous follicle development.
Children with this rare disorder also have fibrous dysplasia in their bones, which leads to fractures, deformities, and X-ray abnormalities. Facial bone deformities may result in appropriate concerns for cosmesis. In addition, these children have cafe-au-lait spots, which are light tan birthmarks. McCune-Albright syndrome is often associated with several other endocrinopathies, including hyperthyroidism, acromegaly, pituitary adenomas, and adrenal hyperplasia [51].
3.10.11 Treatment
In contrast to girls with CPP, girls with McCune-Albright syndrome exhibit a lack of GnRH pulsatility, gonadotropin levels are low, and estradiol is produced from autonomous follicle development. Treatment protocols for McCune-Albright syndrome are aimed at inhibiting peripheral estradiol production with aromatase inhibitors or blocking the effects at the receptor level with selective estrogen receptor modulators (SERMs).
Aromatase inhibitors offer several theoretical benefits for the treatment of McCune-Albright syndrome. Unfortunately, results from studies evaluating testolactone have been inconclusive [52–54].
It has been suggested that continuous estrogen exposure from a peripheral source may secondarily induce the HPO axis, such that a central component may occur simultaneously [55]. These findings help to explain the lack of therapeutic benefit of aromatase inhibitors in certain patients with McCune-Albright syndrome. Evaluation and management of these complicated patients should then be based on algorithms used for CPP.
The SERM, tamoxifen, was studied in a prospective, multicenter trial, for the 12-month treatment of 25 girls with McCune-Albright syndrome. This treatment decreased the incidence of vaginal bleeding and also decreased bone velocity and bone maturation [56]. Other causes of precocious puberty can be found in ◘ Table 3.1.
3.10.12 Premature Thelarche
Early breast development in the absence of other signs of sexual maturity is typically a benign, self-limited event. Initial laboratory evaluation will reveal prepubertal gonadotropin levels and normal bone age. GnRH stimulation will result in a predominant FSH response. Continued observation is nonetheless mandatory, and breast development, which may be unilateral or bilateral, will likely regress, but may persist until normal onset of puberty.
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