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 Shortly after delivery, as the maternal source of estrogen is withdrawn, gonadotropin levels are noted to increase as a result of the release from the negative feedback circuit.² The HPO feedback system is illustrated in Figure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