Hypothalamic-Pituitary-Ovarian Axis

The HPO axis lies dormant before puberty, although well-developed and functional during fetal development. In the higher cortical centers, from the arcuate nucleus of the hypothalamus, gonadotropin-releasing hormone (GnRH) is synthesized and released.¹ This decapeptide is secreted in a pulsatile fashion and has a fleeting half-life of 2 to 4 minutes. Through its effect on the anterior pituitary, GnRH regulates the synthesis, storage, and release of the pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

These hormone levels approach those of an adult in the fetal circulation by midgestation. However, with increasing maternal steroid hormone production closer to term, gonadotropin levels decline. Shortly after delivery, as the maternal source of estrogen is withdrawn, gonadotropin levels are noted to increase as a result of the release from the negative feedback circuit.² The HPO feedback system is illustrated in Figure 11-1.

Figure 11-1 Neuroendocrine Control of the Hypothalamic-Pituitary Axis Sexual maturation begins with the activation of the hypothalamic-pituitary-ovarian axis. Release of central nervous system inhibitory influence results in gonadotropin-releasing hormone (GnRH) secretion, which stimulates the anterior pituitary to produce the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Ovarian steroidogenesis follows, and the feedback circuit is created. Through an undetermined pathway, the adrenal gland begins to produce androgens, primarily dehydroepiandrosterone sulfate (DHEA-S).

This sequence of events demonstrates the functional capability of the HPO axis early in development and results in follicular growth in the prepubertal ovary and an increase in circulating estradiol. This effective and exquisitely sensitive negative feedback system, often referred to as the gonadostat, develops rapidly, and in the years preceding puberty, gonadotropin levels remain low in response to suppression by low levels of circulating estrogen (10 pg/mL).

It is thought that the two primary inhibitory influences on the pulsatile release of GnRH and the downregulation of the HPO axis during childhood are the (1) intrinsic central nervous system (CNS) inhibition via γ-aminobutyric acid and the (2) negative feedback system driven by ovarian steroid hormones.^3,4 With continued maturation of the CNS after birth, a more profound internal inhibitory effect can be noted in reference to GnRH-secreting neurons. In premature infants with less developed neuronal pathways, pituitary gonadotropins are higher than in term counterparts, presumably due to a weaker inhibitory influence.⁵ The presence of a nonsteroidal regulator of these pathways is further substantiated by the ability of patients with gonadal agenesis to secrete moderate levels of gonadotropins in response to GnRH.⁶ Other potential executors of the CNS regulation of steroid hormone production have been assessed, but none have shown a definitive effect.

Onset of Puberty

The events that then lead to the onset of puberty are fairly well understood; however, the signal for the CNS to release its inhibitory influence on the hypothalamus remains a mystery. Pulsatile secretion of GnRH from the arcuate nucleus of the hypothalamus leads to gonadarche, documented by profound increases in sex steroid hormone production.¹ Early pubertal changes are temporally associated with an increase in GnRH pulse frequency, primarily during the sleep cycle.⁷ As menarche approaches, GnRH pulses increase in amplitude and can be detected throughout the day, similar to those in an adult.^8,9 Ovulatory cycles occur with the arrest of the inhibitory effect of the CNS, and regulation of the HPO axis is then managed primarily by circulating steroid hormones via functional feedback circuits.

LH and FSH are also released in a pulsatile fashion, which increases with the preceding increase in GnRH activity. In prepubertal girls, FSH responses to GnRH action are marked, whereas the response seen by LH is quite low (LH/FSH ratio < 1). Conversely, during puberty, a predominant LH response is seen and the LH/FSH ratio reverses. LH pulsatility is always dependent on GnRH secretion regardless of age, whereas there is a diminished FSH response to GnRH with the increase in ovarian activity that occurs during puberty.¹⁰ This may help explain the dichotomous maturation of the LH/FSH response.

Both genetic and environmental pressures may play a role with the initiation of pubertal development. It has been suggested that appropriate weight gain and percentage of body fat are required for these events to occur.¹¹ This postulate is based on data from adolescent females who suffer from chronic illness, malnutrition, or have low body mass indices due to extreme athletic pursuits. These young girls frequently have delays in sexual maturation and often present with primary amenorrhea resulting from hypothalamic hypogonadism. Normal menstrual cycles resume with reversal of their nutritional status.¹² Whether the increase in body fat occurs as a result of these hormonal changes or whether it is a prerequisite for activation of the HPO axis was challenged by investigators who followed healthy females throughout puberty and found that body composition did not change prior to, but rather along with, the increase in GnRH secretion.¹³

Leptin, an adipocyte-derived hormone, has received much attention in recent years. Plasma concentrations correlate well with body composition and have been shown to rise throughout puberty in female patients.¹⁴ Accordingly, several investigators have attempted to establish a causal relationship between leptin and the activation of the HPO axis. specific leptin deficiencies have been shown to prevent sexual maturation, which can then be triggered by restoring normal levels.¹⁵ Nevertheless, the role of leptin in pubertal development has not been clearly elucidated.

Another molecule that may play a role in the reversal of HPO downregulation is neuropeptide Y (NPY). Circulating levels are regulated by steroid hormones as well as nutritional status, with a net influence on gonadotropin synthesis through an alteration in GnRH pulsatility and pituitary response to GnRH.¹⁶ Increased levels of NPY have been documented in females with eating disorders such as anorexia nervosa and bulimia,¹⁷ indicating another possible correlation with percentage of body fat and reproductive potential.

Characteristics of Sexual Development

The series of events that occur during puberty have been well-defined. These predictable events, which are currently utilized as the standard for sexual development and somatic growth, were initially described by Tanner and Marshall more than 30 years ago (Fig. 11-2).¹⁸ Tanner stages describe characteristic (1) breast development, (2) pubic hair distribution, and (3) growth and maturation of genitalia by dividing each into five groups. For each characteristic, Stage I describes the prepubertal state and Stage V represents adult development. These guidelines are traditionally used to determine if an adolescent female is developing in a typical fashion.

Figure 11-2 Tanner Staging. Stages of female breast and pubic hair development during puberty as described by Marshall and Tanner.

(From Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child 44:291, 1969.)

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 ages 8 and 13 in most, with a mean of 10.6 years. The transition period from Stage II to Stage V breast development may last 4.2 years.¹⁸

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; if present, 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 ages 11 and 12, with adult hair distribution by age 14. Androgen levels change without a corresponding change in corticotropin and cortisol secretion throughout life. And so, the means by which adrenal androgens are produced is not as clearly delineated and appears to occur independent of the hypothalamic-pituitary axis. Perhaps the control of adrenal androgen production is intrinsic to the gland itself by means of key regulatory enzymes.

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 (Fig. 11-3).¹⁹ Peak growth velocity (2 to 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 and environmental factors that may influence the onset of puberty. Growth charts are useful in predicting final height achievement.

Figure 11-3 Timing of events of puberty. 1969 data (purple) from a study of British schoolchildren. 1997 data (green) from a study of American schoolchildren.

(From Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child 44:291–303, 1969; and Pediatrics in Review, Vol 8, no 2. Columbus, Ohio: Ross Laboratories, 1986.)

There are conflicting reports in reference to final height and timing of the onset of puberty. Patients with a later onset had smaller gains throughout puberty; however, they were initially taller than those who had earlier onset. Final adult height among these groups was comparable.^20,21 Growth hormone through the actions of insulin-like growth factor I (IGF-I) is likely the principal factor responsible for somatic growth and final height. As low levels of sex steroid hormones rise early in puberty, there is a concomitant increase in the pulsatile secretion of growth hormone. As such, the initial growth spurt typically occurs before advanced secondary sexual characteristics appear. Higher levels of estrogens suppress the action of IGF-I, and so the same factors that promote growth can also impact final height by inducing epiphyseal closure.²²

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 to 16 years.¹⁸ The mean age of menarche for a white adolescent in the United States is approximately 12.7 years. At the time of menarche, most have achieved Tanner Stage IV breast development,¹⁸ and the interval from initial breast development to menarche is 2.3 years.¹⁸

There seems to have been a decline in the average age of menarche in the first half of the 20th century, in part due to the improvement in general health and nutrition.²³ Nonetheless, few reports have documented any further changes since the mid-20th century.

There is good evidence that African-American girls have an earlier onset of puberty compared to white girls.^24,25 This was well demonstrated by the Pediatric Research in Office Settings (PROS) study published by Herman-Giddens in 1999.²⁴ This multicenter, cross-sectional study evaluated over 17,000 female patients between ages 3 and 12.²⁴ On average, African-American females show early signs of puberty up to 1.5 years earlier than their white counterparts. By age 7, 27.2% of African-American girls and 6.7% of white 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 years in African-American girls and 9.96 years in white girls. At each consecutive stage of development, African Americans were more advanced per year than white girls. Girls of other ethnic backgrounds may also demonstrate characteristic differences in onset of pubertal maturation. However, only white and African-American girls were included in this study.

The 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 age 6 and white girls who present before age 7. Although this provocative investigation has drawn much criticism, it does invite us to reconsider the current standards (see Fig. 11-3).

History and Physical Examination

The first gynecologic encounter is an event that the patient may remember for years to come. It is paramount that she understands the confidential agreement she has made with the healthcare provider.

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 central 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.²⁷ 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 3rd percentile.²⁷

When to Initiate an Assessment

One challenge each clinician faces is when to initiate the assessment of a child suspected of having precocious puberty. Historical accounts from the 19th century report a relative later age of onset of menstruation (16 to 17 years), presumably due to malnutrition. The definition of precocious puberty has since remained stable, such that any female who presented before age 8 was observed, if not evaluated, for progression of sexual growth.¹⁸ As referred to earlier, the traditional definition was challenged by Herman-Giddens, who strongly suggested that normal pubertal development may begin as early as age 6.²⁴

Isosexual precocity is characterized by early onset of otherwise normal physiologic development. This heterogeneous disorder can be categorized into central (GnRH-dependent), peripheral (GnRH-independent), or incomplete precocious puberty. Heterosexual precocity is evidenced by excessive androgen production and virilization of a female child. Causes of precocious puberty are listed in Table 11-1.

Table 11-1 Causes of Precocious Puberty

Psychological Issues of Premature Puberty

An important goal of treatment is to reverse sexual maturation, thereby limiting psychosocial repercussions and early reproductive potential. Girls who experience early puberty are at risk of persistent difficulty during adolescence.³⁵ It is important to remember that these patients are young and naíve, and lack the psychosocial maturity often expected of them given their appearance. It is also reasonable to assume that due to early physical development, sexual activity and the potential for abuse may occur at an earlier age. It is assumed that these reasons explain why girls with precocious puberty have been found to have more emotional problems, increased antisocial behavior, and are at risk for both dropping out of school and early pregnancy. For this reason, the parents of these girls should be made aware of these potential problems so that appropriate counseling and preventive efforts can be made.³⁶

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.³⁷ The use of GnRH analogs to treat central precocious puberty was popularized more than 20 years ago and has become the gold standard of therapy. The most commonly used preparations in the United States are leuprolide, nafarelin, and goserelin. Children with precocious puberty generally require higher doses to achieve suppression, which can be monitored with serum estradiol levels and GnRH stimulation tests. To improve compliance, subcutaneous formulations are currently used. Monthly intramuscular injections are also available.

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.³⁸ The difficulty with interpreting these results came from the lack of well-designed randomized trials and a limited ability to accurately predict adult height. In the absence of a more effective system, the methodology described by Bayley and Pinneau more than 50 years ago has been maintained throughout the literature despite the potential for overestimating predicted final height.³⁹ Furthermore, children with suspected idiopathic precocious puberty were grouped together, and the investigators did not delineate which of the patients were more at risk for significantly shortened stature. This, in part, is due to our inability to properly identify such patients.

The variable presentation of central precocious puberty creates a dilemma for investigators who would otherwise design a randomized trial. Several months of simple observation are often required before progression can be documented. A few randomized series have been published that addressed the effect of GnRH agonists on final height in girls who presented with early or slowly progressive puberty.^40,41 They confirmed results from previous observational and nonrandomized reports, which documented very little effect of hypothalamic suppression on improving final height in patients presenting at a later age. Furthermore, 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 before onset of treatment.⁴² And so it may be this rate-limiting step, patients presenting beyond the window of opportunity, which limits final height. A summary of predicted and final height in patients treated for CPP is provided in Table 11-2.

Significant consideration should then be given to promptly initiating therapy in girls presenting early with advanced bone age, because they will likely benefit most from GnRH agonist therapy.^43–46 The question still remains as to what criteria should be used to determine maximum therapeutic benefit. Adan and colleagues 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 central precocious puberty) and (2) bone age advanced over chronological age by more than 2 years.⁴⁶ 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 to 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, and so attention to bone health should not be omitted.

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. Since the 1980s, recombinant human growth hormone (somatropin) has been available to treat patients with growth hormone deficiency and other conditions associated with poor growth. 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.⁴⁷ Early initiation of therapy in patients with central precocious puberty may further enhance the response.

The long-term effects of prolonged therapy with growth hormone, outside of bone growth, are unknown. Although the use of growth hormone in certain patients has become extremely popular 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: patient compliance, dosing, and the inability to monitor efficacy. Care should then be prescribed when administering growth hormone in patients whose final height is expected to be within normal adult range, and a thorough discussion with the child’s parents should precede such therapies. 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.

Autonomous Ovarian Estrogen Production

Ovarian tumors are uncommon but important childhood neoplasms that present with precocious puberty in approximately 10% of cases.⁴⁸ 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 sonography or magnetic resonance imaging (MRI) 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. As with central precocious puberty, estradiol levels will be high and bone age advanced (see Fig. 11-4). Treatment is based on surgical extirpation of the source, which results in regression of pubertal changes.

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 cases with with precocious puberty. These patients have estrogen-producing ovarian follicular cysts that develop independent of gonadal hormone stimulation, a condition termed autonomous follicle development. Menstrual periods usually begin in early childhood, long before the appearance of breast buds or pubic hair 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 cause cosmetic problems. In addition, these children have café-au-lait spots, which are light tan birth marks. McCune-Albright syndrome is often associated with several other endocrinopathies, including hyperthyroidism, acromegaly, pituitary adenomas, and adrenal hyperplasia.⁴⁹

McCune-Albright syndrome is caused by a postzygotic somatic mutation in the GNAS-1 gene that is sporadic rather than inherited. The GNAS-1 gene encodes for the Gsα (guanine-nucleotide binding) protein. The substitution of arginine into histidine or cysteine results in continuous overactivity of the adenylate cyclase system and unregulated productivity from affected tissues. The abnormalities associated with this syndrome are related to this overactivity.

McCune-Albright syndrome results in mosaicism, such that the abnormal gene is present in only a fraction of the patient’s cells. The timing of the mutation determines which organ systems are affected and the severity of the presentation, thus explaining the heterogeneity of these syndromes. In a recent, large collaborative study, investigators were able to identify the Gsα mutation in 43% of patients presenting with at least one sign of McCune-Albright syndrome and in 33% of those presenting with isolated signs of gonadotropin-independent precocious puberty.⁵⁰

Other Causes

Other causes of GnRH-independent precocious puberty include adrenal disorders such as congenital adrenal hyperplasia (see Table 11-1). Patients present with heterosexual development, and androgen levels, including 17OH-progesterone, will be elevated. Corticosteroid therapy is the treatment of choice. Primary hypothyroidism, albeit uncommon, may result in ovarian cyst development, resulting in high estradiol levels. This has been hypothesized to be the result of cross-reactivity of high levels of thyroid-stimulating hormone (TSH) with FSH at the level of the ovarian receptors.⁵⁶

Premature Adrenarche and Polycystic Ovary Syndrome

There is evidence to suggest that girls with premature adrenarche may be at risk for developing polycystic ovary syndrome (PCOS). Known outcomes of this syndrome include obesity, dyslipidemia, hyperinsulinemia, hirsutism, and infertility. A recent randomized trial evaluating the effectiveness of metformin therapy in adolescents with a history of precocious pubarche and low birth weight noted significant reversal in dyslipidemia, excess truncal fat, increased levels of IGF-I, and insulin insensitivity compared to controls. Early therapy aimed at improving insulin resistance and reducing percentage of body fat may improve cardiovascular risk later in life.⁵⁸

Hypergonadotropic Hypogonadism

Hypergonadotropic hypogonadism, often referred to as ovarian failure, is the single most common etiology of pubertal delay. The essential condition required to make this diagnosis is elevated gonadotropins, both FSH and LH.

Turner’s syndrome is the most commonly (1:2000 liveborn females) diagnosed condition within this subset. Karyotype may reveal 45,X or a mosaic, which may occur in up to 40% to50% of patients with gonadal dysgenesis. DNA analysis is crucial because the presence of the Y chromosome places patients at risk for gonadal neoplasia such as gonadoblastoma and dysgerminoma.

Several forms of primary and secondary ovarian failure with normal sex chromosomes also exist. Pure gonadal dysgenesis, Swyer syndrome, typically presents with delayed puberty. Chemotherapy and/or radiation therapy may result in gonadal dysfunction and delayed development in an otherwise genetically and phenotypically normal female.

Other causes of ovarian failure include autoimmune oophoritis, galactosemia, gonadotropin-resistant ovary syndrome, steroidogenesis enzyme deficiency, infection, or gonadotropin receptor gene mutation. Autoimmune disorders associated with hypergonadotropic hypogonadism include Hashimoto’s thyroiditis and Addison’s disease. Patients with 17α-hydroxylase deficiency present with adrenal insufficiency, hypertension, and lack of sex steroids, including androgens. Although rare, patients with gonadotropin-resistant ovary syndrome will have normal appearing ovaries with multiple primordial follicles that do not respond to endogenous or exogenous gonadotropins.

Hypogonadotropic Hypogonadism

Hypogonadotropic hypogonadism is diagnosed when the gonadotropins are not elevated in girls with delayed puberty. This condition results from a failure of the HPO axis and deficiency of GnRH. The most common cause of this is constitutional delay.

The diagnosis of constitutional (or physiologic) delayed puberty is one of exclusion. Bone age and height age (age at which height is at the 50th percentile on growth charts) are delayed, unlike hypothyroidism, where bone age is delayed more than height age. Unfortunately, the only way to discern constitutional delay from idiopathic hypogonadotropic hypogonadism is by longitudinal observation.

Central etiologies of hypogonadotropic hypogonadism include brain tumors, Kallmann syndrome, hypothyroidism, and chronic disease states (Crohn’s disase, Cushing’s disease, anorexia nervosa, or malnutrition). Pituitary causes are also possible, such as a tumor or gonadotropin insufficiency.

Primary Amenorrhea with Otherwise Normal Sexual Development

Genetically normal patients with a normally functioning HPO axis who present with primary amenorrhea typically have anomalies of the genital outflow tract, such as imperforate hymen or vaginal septum (Table 11-3). The classic presentation is cyclic abdominal pain with a tender midline pelvic mass on rectal examination (see Chapters 12, 14, and 16).

Table 11-3 Causes of Primary Amenorrhea

Data from Timmreck LS, Reindollar RH. Contemporary issues in primary amenorrhea. Obstet Gynecol Clin North Am 30:287-302, 2003

One of the most common causes of primary amenorrhea in these patients is Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. This condition is characterized by a blind vaginal pouch in an otherwise normally sexually developed adolescent and results from the failure of development of the müllerian (paramesonephric) duct system in genotypic females.

Androgen insensitivity syndrome is another common cause of primary amenorrhea. Previously termed testicular feminization, this condition is the result of an abnormal androgen receptor. This maternal X-linked recessive disease occurs in individuals with XY genotypes and normal but partially or completely undescended testicles that produce testosterone (see Chapter 16). Because of the abnormal androgen receptors, high levels of circulating testosterone result in appropriately timed puberty in females who appear phenotypically normal. A harbinger is sparse or absent pubic hair.

Primary amenorrhea or delayed menarche is frequently associated with hyperandrogenemia, secondary to either PCOS or adult-onset congenital adrenal hyperplasia. These patients have otherwise normal puberty but will also present with signs of excess androgen ranging from hirsutism and acne to virilization.

Evaluation

A complete evaluation should be undertaken for any adolescent who meets the standard criteria for delayed puberty or primary amenorrhea:

Both physical and psychosocial concerns of these patients and their parents must be considered.

History

Extensive neonatal and family history, including ages of pubertal development and attainment of final height extending to members beyond the nuclear family, is helpful. History pertinent to information of prior exposure to exogenous steroid hormones or chemotherapy must also be elicited. Review of systems to evaluate for chronic illnesses and pattern of exercise and diet may uncover the diagnosis.

Physical Examination

Physician examination and height and weight plotted on a growth chart should be completed as well as blood pressure, thyroid examination, Tanner staging, and abdominal examination. A complete neurologic evaluation, including assessing the ability to smell, should also be performed.

Patients with hypergonadotropic hypogonadism often present short in stature. Patients with Turner’s syndrome (45,XO), the most common presentation of hypergonadotropic hypogonadism, may present during infancy with lymphedema or during childhood with typical features such as short stature, webbed neck, and shortened fourth metacarpals. Cardiovascular anomalies and renal abnormalities, such as coarctation of the aorta, bicuspid aortic valves, and horseshoe kidney, can be determined with imaging studies.

Patients with mixed gonadal dysgenesis (mosaic XY/XO) may present phenotypically similar to those with Turner’s syndrome; however, virilization or ambiguous genitalia may also be evident in the presence of the Y chromosome. Patients with 46,XX complete gonadal dysgenesis are normal to tall in stature and are commonly phenotypically female. Sexual infantilism with lack of müllerian structures and 46,XY karyotype is consistent with Swyer syndrome.

Hypogonadotropic hypogonadism can be seen in adolescents who are extremely athletic or malnourished. Minimal body fat from either cause is associated with reversible hypothalamic dysfunction. Patients with CNS tumors may present with persistent headaches or visual field defects. Marked centripetal obesity and moon facies are typical of Cushing’s syndrome. Anosmia along with hypothalamic hypogonadism is consistent with the diagnosis of Kallmann’s syndrome (isolated GnRH deficiency). A patient with a prolactinoma may present with hyperprolactinemia and galactorrhea.

Adolescents with primary amenorrhea who have normal development of other secondary sexual characteristics are usually of normal stature. Pelvic or recto-abdominal examination is performed in these patients to exclude anatomic abnormalities of the reproductive tract. Examples include vaginal septum and the blind vaginal pouch associated with MRKH and androgen insensitivity syndrome.

Laboratory Evaluation

Initial assessment of the adolescent presenting with delayed sexual development should include a complete blood count, as well as TSH, thyrotropin, FSH, LH, and prolactin levels. A chemistry panel will be helpful if chronic illness is suspected. If FSH and LH are normal or low, a GnRH stimulation test will be useful.

If FSH and LH are elevated indicating ovarian failure, a karyotype should be obtained. Regardless of gonadotropin levels, a karyotype should be considered in short girls with delayed puberty, because many adolescents with chromosomal abnormalities will not have classic clinical features of disorders such as Turner’s syndrome.

Imaging

Bone age is defined as the age consistent with the degree of bone ossification of a child and is determined by taking an x-ray of the left wrist and hand. Bone age more strongly correlates with sexual development than chronological age. This measurement will be normal to delayed in most patients with delayed puberty arising from a pathologic cause. Stature, consequently, will be decreased in patients with hypergonadotropic hypogonadism with the exception of pure gonadal dysgenesis (46,XX).

If gonadotropin levels are low with delayed puberty, a central cause must be determined. Likewise, an elevated prolactin level suggests a pituitary or hypothalamic problem. In these cases, MRI scan of the brain and pituitary gland is indicated to exclude abnormality of the hypothalamic-pituitary axis such as pituitary or hypothalamic tumors.

Adolescents with primary amenorrhea but otherwise normal sexual development require pelvic ultrasound to evaluate the internal reproductive organs and detect the presence of a fluid collection consistent with hematocolpos related to a vaginal septum. Abdominal and pelvic MRI is helpful in evaluating for renal or skeletal anomalies in patients with vaginal agenesis.

Treatment of Delayed Puberty

Psychological Implications

The ability to establish open channels of communication is extremely important in treating patients with delayed puberty. Patients and their parents should be educated about their condition and encouraged to ask questions. Addressing future issues such as treatment of infertility and prevention of osteoporosis early in the course of treatment may allow for gradual acceptance. Referral to support groups often proves beneficial because teens can discuss their concerns with those who have experienced the same problem.

Girls with delayed puberty inevitably feel different and underdeveloped from their peers, which may result in social isolation and pathologic dependency on their parents. The role of the clinician, therefore, must expand beyond the medical scope of the specific problem and consider the long-term sequelae of the problem at hand.