Introduction
The period of human growth and development that occurs during adolescence is commonly referred to as puberty. This chapter focuses on normal pubertal changes, including sexual maturity and physical growth, as well as the underlying endocrinologic systems responsible for these processes. It is important for clinicians to understand these expected changes and the timing at which they occur.
HPG axis
The hypothalamic-pituitary-gonadal (HPG) axis is responsible for many of the physical changes that occur during puberty. A change from constant to pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus signals the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary, which in turn stimulate the production of estradiol or testosterone from the ovaries or testes, respectively ( Fig. 5.1 ). For the purposes of this chapter, individuals with ovaries will be referred to as assigned female at birth (AFAB).
AFAB pubertal changes
Estradiol, produced in the ovaries, plays an important role in pubertal changes for those AFAB. Breast development, changes in genitalia, and skeletal maturation are all influenced by estradiol and other circulating estrogens. Pubertal changes related to estrogen happen sequentially.
Thelarche, or breast budding, is typically the earliest recognizable sign of puberty in AFAB. These changes occur at a median age of 8.8 to 10 years and, as with many pubertal findings, may vary depending on race and ethnicity. Black and Hispanic youth have been noted to experience earlier initiation of puberty. Adrenarche, or onset of pubic hair development, occurs at a similar time, between the ages 8.8 and 10.5 years. Thelarche and adrenarche are followed closely by the height spurt, with an average onset at 9.5 years and peak velocity around 11.5 years. Finally, menarche occurs at 12.5 years of age on average, with height growth potential continuing for 2 to 2.5 years after menarche with a maximum gain of ∼2 inches.
SMR: Breast stages
The sexual maturity rating (SMR) scale describes different stages of pubertal development in three areas: breast, genitalia, and pubic hair. This staging is used as a common notation for clinicians and in some texts is also known as Tanner staging. Breast staging and pubic hair staging can be used in those AFAB. The SMR stages of breast development are described next ( Fig. 5.2 A):
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SMR 1 – Prepubertal. Only the papilla is elevated above the chest wall.
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SMR 2 – Breast bud. There is elevation of the breasts and papillae and increased diameter of the areolas.
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SMR 3 – The breasts and areolas continue to enlarge, but there is no separation of contour.
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SMR 4 – Mound on mound. The areolas and papillae elevate above the breasts.
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SMR 5 – Mature female breasts. The areolas have receded, and the papillae may extend slightly above the contour of the breasts.
Genital changes
External genitalia changes also occur in AFAB during puberty in response to an increase in estrogen and other hormones; however, there are not specific SMR stages to describe this. In general, the external portion of the clitoris and the labia grow and widen, and the vulva may also change in color. In adults, the color can range from light pink to red, dark brown, or black and can vary with different ethnicities. Overall, the vulval mucosa becomes less erythematous with estrogen exposure. Internally, the vagina and cervix also grow in size, and vaginal secretions are produced. This thin, white discharge is referred to as physiologic leukorrhea, and it typically precedes menarche by approximately 6 to 12 months.
HPA axis
In addition to the gonadal axis, the hypothalamus and pituitary also signal to the adrenal glands (hypothalamic-pituitary-adrenal [HPA] axis) to produce adrenal androgens (dehydroepiandrosterone [DHEA], dehydroepiandrosterone sulfate [DHEAS], and androstenedione). This process occurs in AFAB between age 6 and 8 years and is referred to as adrenarche. The primary physical manifestation of adrenarche is the growth of axillary and pubic hair, or pubarche. Onset of hair growth typically occurs after age 8 in AFAB youth.
In addition to sexual hair growth, youth experience other physical changes related to adrenal androgens. For example, DHEAS is converted in the apocrine and sebaceous glands, contributing to the development of body odor and acne, respectively.
SMR: Pubic hair stages (see Fig. 5.2 B)
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SMR 1 – Vellus hair develops over the mons pubis similar to the rest of the body. There is no sexual hair.
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Stage 2 – Sparse, long, pigmented, downy hair, which is straight or only slightly curled, appears on the labia majora or base of the phallus and scrotum.
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Stage 3 – A moderate amount of darker, coarser, and curlier sexual hair appears. The hair has spread laterally over the pubic hair.
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Stage 4 – The hair distribution is adult in type but decreased in total quantity. There is no spread to the medial surface of the thighs.
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Stage 5 – Hair is adult in quantity and type. There is spread to the medial surface of the thighs.
HPS axis
Another important aspect of puberty is linear growth and bone maturation. This is primarily driven by growth hormone (GH) via the hypothalamic-pituitary-somatotropic (HPS) axis. The hypothalamus signals to the pituitary via alternating GH-releasing hormone and somatostatin, leading to pulsatile release of GH ( Fig. 5.3 ). Influences of many other factors are involved in stimulation and inhibition of GH release. The biologic effects of GH include increases in linear growth, bone thickness, and soft tissue growth.
The pubertal growth spurt is a period of rapid growth that is mediated by GH via insulin growth factor hormones (IGF-1/somatomedin-C and IGF-2) as well as sex hormones: estradiol and testosterone.
Linear growth and bone density
Linear growth during this time accelerates in puberty, with a peak height velocity (PHV) of 8.3 cm/yr, occurring between SMR 2 and 3, or age 11.5 years on average.
Final adult height for an individual can be estimated using the following mid-parental height formulas :
It is important to remember that this calculation provides an estimate and that many other factors contribute to final adult height. For this reason, it is best to present this information to patients as a target height range, equal to the mid-parental height ± 2 standard deviations (SD) (1 SD = 5 cm or 2 in).
Linear growth continues until there is closure of the growth plates, a process primarily driven by estrogen. This effect is also important for bone density, of which significant deposition is laid in childhood and adolescence. Bone density creation is completed at the latest by 30 years of age and will remain stable and eventually decrease with age.
Weight gain
Continued weight gain along the growth curve is also expected during puberty. Similar to height velocity, weight velocity also peaks during adolescence. This is in part because of the linear growth and increasing bone density described earlier. Additionally, increases in lean body mass and adipose tissue contribute to weight gain, even after the final adult height is reached. During puberty, the proportion of lean body mass vs. adipose tissue increases in assigned male at birth (AMAB) and decreases in AFAB.
Timing of pubertal onset
There are multiple factors affecting pubertal timing, including genetic and epigenetic factors as well as environmental influences. Genetics likely accounts for 50% to 80% of the onset of puberty; however, pinpointing what cascade signals these genes has yet to be fully identified.
In developed nations, younger age trends for onset of thelarche (earlier by 1 year) and menarche (earlier by 4 months) have been demonstrated in the Copenhagen Puberty Study over a 15-year time span. Although, as previously noted in this chapter, pubertal onset and menarchal age have been documented as occurring slightly earlier in African American/Black and Hispanic youth compared with Caucasian/White youth, the reality is often a matter of months difference. Between the mid-1800s and mid-1900s, average menarchal age decreased by 4 years. In the 1960s the average reported age of menarche for Black girls was 12.5 years and 12.8 years for White girls. However, in the 1970s in a Louisiana study, very little difference in menarchal age was found related to race. Between the 1970s and 1990s there were multiple small studies demonstrating a decrease in menarchal age of 0.7 years among Black girls and 0.1 years among White girls. Menarche seems to be the most notable stage in AFAB puberty and therefore has been studied more. However, it is a late occurrence in the sequence of AFAB pubertal changes, and skeletal maturation may have more to do with genetic or familial differences than menarche. Earlier age of menarche (<11 years of age) seems to be correlated with overall shorter status and higher weight (up to 5.5 kg heavier), with possible increased risk of breast cancer. Race is a social construct, and it should be noted that in available studies race may have inappropriately been used to represent other variables, including weight, environmental exposures, and stressors including but not limited to racism. Diagnosis of early or precocious puberty should not be made on the basis of someone’s racial or ethnic background, and treatments should not be withheld or offered differentially.
Physiology of pubertal onset
As outlined earlier, pulsatile GnRH secretion from the hypothalamus initiates the hormonal cascade, marking the onset of puberty. However, the events leading to the trigger of this pulse remain obscure overall.
Three neuropeptides act as activators of GnRH secretion: kisspeptin, neurokinin B, and dynorphin are produced by KNDy neurons in the arcuate nucleus of the hypothalamus and have direct projections to GnRH cell bodies. Kisspeptin pulses seem to be required for episodic LH secretion and occur simultaneously with GnRH pulses. In loss-of-function mutations of the KISS1 gene coding kisspeptin, pubertal development does not occur (idiopathic hypogonadotropic hypogonadism). Neurokinin B dysfunction also leads to delayed pubertal development when encoding TAC3 or TACR3 genes have mutations.
Inhibitors of GnRH secretion, or “silencers” of the polycomb group (PcG), repress the KISS1 gene. The decreased expression from the hypothalamus of silencer genes along with increased methylation of silencers proceeds the onset of puberty. If these processes are blocked, pubertal failure can occur. This also means that if there is dysfunction in the silencer genes at earlier ages, precocious puberty may occur. Mutations in puberty inhibition pathways and genes that have been identified include neurotransmitter gamma-aminobutyric acid (GABA) receptor, MKRN3 gene loss of function (one-third of familial precocious puberty cases), and DLK1 gene deletion.
Nongenetic influences of puberty
Delayed pubertal onset has been related to overall poor health in cases of children with chronic disease affecting nutrition and inflammation. Social and environmental stressors, including those within the family unit, have been suggested to have variable effects on pubertal timing.
Increased weight has been associated with earlier pubertal onset and progression. The leptin hormone, made in adipocytes, can affect the activity of the GnRH pulse generator, but is likely one of many influences. The theory is that leptin levels likely signal a sufficient store of metabolic fuel.
Endocrine-disrupting chemicals in the environment have also been linked to affecting the age or advancement of puberty. They are further listed in Table 5.1 .
