Physiology, Puberty

Logen Breehl; Omar Caban

27 April 2020

Introduction
Puberty is a vital process in the development of all individuals. The series of hormonal changes
during puberty result in the physical development of sexually mature adults. In addition to sexual
maturity children also go through other physical and emotional changes such as hair growth,
voice changes, and acne. In this article the development, organ systems involved, physiological
mechanism, evaluation and testing, pathophysiology, and clinical significance of puberty will be
discussed.
Go to:

Cellular
GnRH neurons of the hypothalamus control the initiation of puberty. The pulsatile secretion of
GnRH by these neurons causes the changes of puberty. Currently, there are increasing amounts
of evidence showing that kisspeptin neurons in the arcuate nucleus release neurokinin B and
dynorphin to generate the pulsatile secretion of GnRH.[1] GnRH causes the release of LH and
FSH from the gonadotropic cells of the anterior pituitary gland. FSH and LH affect the Leydig
and Sertoli cells in the testes and the theca and granulosa cells of the ovary. The zona reticularis
of the adrenal cortex produced the hormones responsible for adrenarche and function separately
from the hypothalamic-pituitary-gonadal axis.
Go to:

Development
Puberty typically begins around 6 for African American girls and 7 years of age in white girls
but can range between 8 and 13 years of age. The first sign of puberty is linear growth, but
examiners do not usually notice this growth. The most notable and reliable first sign of puberty
in girls is breast development. Other signs of puberty include enlargement of the labia majora
and labia minora and clear to white vaginal discharge. The pubertal growth spurt occurs between
9 and 10 years old. Breast development (thelarche) typically occurs between 8 to 12 years old
with a mean age of 10 years old. Menarche follows shortly after thelarche about 2.5 years later
with a mean age of 12.5 years but can range from 9 to 15 years old.[2] Pubic hair development
usually follows along with breast development and occurs due to the production of adrenal
androgens. Production of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate
(DHEAS) by the adrenal gland increases around age 6 to 7 years and is independent of thelarche
and menarche. DHEA and DHEAS influence pubic hair development as well as axillary hair

1
development and body odor. Tanner staging is the best way to assess the stage a child may be in;
the categorization of each stage can be seen in Table 1.
Puberty in boys begins with testicular enlargement to greater than 2.5 cm in length or greater
than 4 mL in volume; this occurs between 9.5 and 14 years of age with an average of 11.5 years
of age. Pubic hair development in males is controlled by both adrenal androgens DHEA and
DHEAS as well as androgens produced by the testicles, and usually occurs between 7 and 8
years old.[2] These androgens also assist in the development of axillary and facial hair, and voice
changes. Male growth spurts typically occur between 11 and 12 years old. Other pubertal
changes seen in males include a decrease in total body fat, voice break and change, and an
increase in muscle mass. The different stages of pubertal development and what qualifies for
each stage can be seen in Table 2.
Go to:

Organ Systems Involved

The reproductive system is the main organ system involved in puberty. The changes of puberty
allow the reproductive system to become fully functional. By the end of puberty, both males and
females are fertile and able to reproduce. The endocrine system is the other major role player in
puberty. The hypothalamus, pituitary gland, adrenal glands, ovaries, and testes all produce
hormones involved in the changes of puberty. The hormones produced affect multiple systems
within the body. The specific hormones and their involvement in the process of puberty are
discussed further in the mechanism section.
Go to:

Function
The main function of puberty is to produce sexually mature adults. The hormonal changes of
puberty allow children to become reproductively viable. Puberty is also a period of increased
linear growth; a large portion of an individual’s height is achieved from the growth occurring in
puberty.
Go to:

Mechanism
The mechanism of the initiation of puberty is not entirely understood; however, it is known
that the GnRH neurons are the primary role player in the initiation of puberty. The GnRH
neurons develop in the olfactory placode and then migrate to the area of the hypothalamus during
the gestational period. Puberty begins with the pulsatile secretion of GnRH from these neurons,
other neurotransmitters, GABA and NMDA, are also linked with this process. Additionally, the
genes KISS1 and neurokinin B have recently been shown to be involved in the regulation of
GnRH release. The increased levels of GnRH increase the release of LH and FSH from the
anterior pituitary. During puberty, the negative feedback mechanism is less sensitive allowing for
higher levels of FSH and LH to circulate within the body. FSH increases estrogen production by
the ovaries in girls, and in boys triggers testicular growth and supports maturing spermatozoa.
LH initiates ovulation and creates the corpus luteum in females, and in males acts on Leydig

2
cells in the testes to increase testosterone production. The Increased production of adrenal
androgens leading to the development of acne, axillary hair, body odor, and pubic hair is also
taking place during the onset of puberty. The linear growth seen in puberty is a result of pulsatile
increases in growth hormone (GH) secretion, which is secreted by the pituitary gland. Increases
in insulin-like growth factor 1 are also present. Estrogen increases the rates of GH secretion and
is involved in growth plate acceleration and fusion. Testosterone increases insulin-like growth
factor 1 levels and bursts of GH secretion.[3]
Go to:

Related Testing
The first-line assessment for any child experiencing issues with pubertal development is a
thorough history and physical exam. The history will allow the healthcare practitioner to gain
insight as to if there is any possibility of a genetic cause. The history will also provide vital
information about the child’s growth pattern and development to date. In addition, it may also
point out clues to other causes of pubertal disorders such as poor nutrition, underlying disease,
excessive exercise, or the use of exogenous steroids. The physical exam should include an
examination of the genitalia and the breasts in girls to determine tanner staging. Tanner staging is
a standard system used to categorize the different stages of pubertal development a child has
achieved. For boys, Tanner staging includes testes and penile growth, pubic hair distribution, and
linear growth. In girls, Tanner staging includes breast development, pubic hair distribution, and
linear growth. In addition to tanner categorizations examination of the optic fundus and
determining if the sense of smell is intact can be helpful. Standardized growth charts tracking the
child’s growth over time are also helpful in determining if a child is developing appropriately.
[4] Skin lesions noted on the physical exam can also point toward certain causes of abnormal
puberty such as McCune-Albright Syndrome. An x-ray of the left wrist is commonly used to
determine bone age and whether the child’s bone maturation is more advanced than their age,
suggesting they might be going through premature puberty. In addition to an x-ray of the left
wrist, central nervous system (CNS) imaging may be performed if there are signs of CNS
involvement. Measurement of hormone levels may also be helpful in the presence of abnormal
puberty. Levels of estradiol, testosterone, FSH, and LH can be measured looking for pubertal or
prepubertal levels. A GnRH stimulation test is also helpful to determine a central or peripheral
cause. The test involves the administration of 100 micrograms of GnRH after overnight fasting
and observing the levels of FSH, LH, estradiol, and testosterone at 15, 30, 45, and 60 minutes
post-injection. The stimulation test will cause activation of the hypothalamic-pituitary-gonadal
axis in central causes resulting in increased levels of the hormones, a peripheral cause will not
increase hormone levels.[2] Additional testing that may be done includes, thyroid hormone levels
(TSH, T3, T4), blood glucose levels, a complete blood count, liver enzymes, and an erythrocyte
sedimentation rate. Another type of testing that can be done is a karyotype which will show the
child’s chromosomal pattern and is helpful if there is a suspicion of Turner or Klinefelter’s
syndrome. Although there are many other factors that could be evaluated after a history and
physical the testing should be tailored individually for each child’s presentation and towards the
most likely cause of their abnormal puberty.
Go to:

3
Pathophysiology
The pathophysiology of puberty can be broken down into 3 main categories premature puberty,
delayed puberty, and contrasexual development.
Premature Puberty
Precocious puberty or early development of secondary sexual characteristics is defined as
pubertal development before age 6 in African American girls and before 7 years in all other girls;
however, an age of anything younger than 8 years is also used. Precocious puberty is defined in
boys as the development of secondary sexual characteristics before age nine. Many of the causes
of early pubertal development are shared however there are some causes of early puberty unique
to each of the sexes.[5]
The causes of precocious puberty shared by either gender include benign premature adrenarche,
central nervous system and pituitary lesions, constitutional and idiopathic precocious puberty,
McCune-Albright syndrome, and exogenous sex hormones.
 Premature adrenarche correlates with the premature presence of pubic or axillary hair and
possibly increased sebaceous gland activity without other signs of puberty present,
usually before 6 years of age. This is usually an isolated abnormality, and most children
go on to develop the other signs of puberty at a normal age. Plasma DHEAS is usually
elevated to pubertal levels. Other sex hormones such as FSH, LH, estradiol, and
testosterone are typically at levels found in children before puberty. Other studies such as
a GnRH stimulation test will show prepubertal results, and an ACTH stimulation test may
be used to exclude congenital adrenal hyperplasia which can have similar presenting
symptoms.[2]
 CNS and pituitary lesions will typically present with normal stages of puberty but
occurring prematurely. Children may have a bone age greater than their chronological
age. Additionally, these lesions may come with other problems such as visual field
defects. If a central nervous system lesion or a pituitary lesion is suspected, an MRI of the
brain can determine the presence of a lesion in these areas.
 Constitutional/idiopathic precocious puberty tend to present more often in females but
can occur in both boys and girls. Precocious or premature puberty is considered
idiopathic when a child has no familial links to premature development and there is no
other cause that can be found for the premature development of puberty. Constitutional
precocious puberty can be linked to a familial tendency toward early development.
Children with these disorders will respond to a GnRH stimulation test with pubertal
levels of sex hormones as well as FSH and LH. These children may have a bone age that
is much higher than their chronological age. Additionally, all other causes of premature
puberty must be ruled out such as CNS pathology and elevated adrenal hormones.[2]
 McCune-Albright syndrome is associated with cafe-au-lait spots, polyostotic fibrous
dysplasia, and precocious puberty. McCune-Albright syndrome is also associated with
other endocrine disorders. The cafe-au-lait spots can be large and have been described as
resembling the coast of Maine.

4
  Exogenous sex hormones in substances such as oral contraceptives and anabolic steroids
can cause secondary sexual characteristics to develop. These causes can usually be ruled
in or out as a cause rather quickly by running a urinalysis. The metabolites of exogenous
hormones can be found in the urine. Additionally, children who have an exogenous
hormone source and are not undergoing natural puberty will lack pubic hair. Girls may
have darkened areolae, and boys will have small testicles of a prepubertal child.[2]
Causes of premature puberty unique to males include gonadotropin secreting tumors, benign
gynecomastia of adolescence, and familial gynecomastia.
 Gonadotropin secreting tumors are tumors that typically secrete hCG like components
that can have a similar function in signaling to LH resulting in an incomplete type
of premature puberty in boys. Girls, however, need FSH to increase estrogen production
in the ovaries and thus, will not have premature development due to this type of tumor
alone. Examples of tumors that might produce hCG are hepatomas, teratomas, and
germinomas of the pineal gland.[2]
 Benign gynecomastia of adolescence is gynecomastia in boys in mid to late puberty is
very common. The breasts will often be tender. If the history and physical examination
fall within normal limits reassurance and monitoring is all that is necessary, the
gynecomastia will usually resolve on its own.[2]
 Familial gynecomastia appears during puberty and has a genetic link usually either x-
linked recessive or sex-linked dominant. Some boys may need cosmetic surgery;
however, most will not require further evaluation unless there is a suspicion of
hypogonadism.[2]
The causes of the signs of premature puberty unique to females include premature menarche, and
premature thelarche.
 Menarche typically occurs two-and-a-half years after breast development begins with an
average age of first menses being 12.5, any menses occurring before the onset of breast
development, without any other signs of puberty, or in a child under the age of 8 is
concerning for premature menarche.[4] Premature menarche is not entirely understood;
however, it is thought to be due to transient activity by the ovaries. Premature menarche
can also be the result of exogenous estrogens. Girls with premature menarche are usually
just monitored frequently to ensure there are no signs of underlying pathology.
 Premature thelarche is the development of breast tissue in either or both breasts without
other signs of puberty present or before 8 years of age.[2] The breast tissue does not form
that of a mature breast. DHEAS is elevated to stage 2 pubertal levels. Premature thelarche
usually can be left to resolve on its own, and biopsying this tissue is not recommended it
could completely alter the tissue and its future development if done.
Delayed Puberty
Delayed puberty is the lack of physical evidence of puberty by 2 to 2.5 standard deviations above
the mean age for the initiation of puberty. In boys, this is considered a period longer than four
years between the first signs of testicular enlargement and the end of puberty, or the absence of
testicular growth by 14 years old. Delayed puberty in girls is considered the absence of breast

5
growth by 13 years old or more than four years between thelarche and menarche. The causes of
delayed puberty include hypogonadotropic hypogonadism, hypopituitarism, constitutional delay,
chromosomal abnormalities, and hypothalamic dysfunction due to secondary causes.[6]
 Hypergonadotropic hypogonadism is the failure of the gonads to produce sex hormones.
FSH and LH will be elevated because there is no negative feedback on the hypothalamic-
pituitary-gonadal axis. There can be many causes of gonadal failure including genetics
and physical trauma. In boys, Noonan syndrome and myotonic dystrophy have been
known to cause gonadal failure. Additionally, there have been cases of LH beta receptor
mutations reported in boys resulting in a lack of a gonadal response. Trauma to the testes
by testicular torsion or cryptorchidism is also a cause of gonadal failure in boys. In
females, autoimmune ovarian failure is a possible cause, and the child will likely have
signs or symptoms of other autoimmune conditions. Interestingly, half of the girls with
galactosemia have been shown to develop ovarian failure probably due to toxic
metabolites.[6]
 Hypopituitarism is a lack of release of hormones from the pituitary gland. Delayed
puberty is not the only sign of hypopituitarism other endocrine dysfunctions such as
hypothyroidism, bone growth, and adrenal insufficiency may also be present. Kallmann
syndrome is a specific disorder falling under hypopituitarism where neurons in the
developing brain fail to migrate resulting in the absence of a sense of smell or anosmia
and a lack of gonadotropin-releasing hormone cells in the hypothalamus.[4]
 Constitutional delay of puberty happens to children who have had normal development
up until that point. These children then begin to fall to the bottom of the growth curve,
and their growth significantly slows down. These children will have prepubertal levels of
FSH, LH, estradiol, and testosterone on a GnRH stimulation test. Eventually, puberty will
spontaneously occur resulting in the progression of development in these children. [6]
 Chromosomal abnormalities are a cause of delayed puberty shared by both males and
females however different abnormalities are found as the cause in each sex. For girls,
Turner syndrome is a common cause of ovarian failure where there is a problem with one
of the X chromosomes. These girls will often be 45 X or 45 X/46 XX. Along with
ovarian failure, Turner syndrome has a great deal of other identifying characteristics
including but not limited to a webbed neck, short stature or delayed growth, coarctation
of the aorta, a shield chest, and widely spaced nipples. Although there are many
possible physical signs of Turner syndrome, sometimes these females are not identified
until there is an absence of menses or a fertility problem. This is because some of these
girls with Turner syndrome will show the development of pubic hair and breast
development. For boys, one of the most common disorders is Klinefelter syndrome,
which can have a multitude of chromosomal patterns including 48, XXXY, 48, XXYY,
and 49 XXXYY. Klinefelter syndrome typically presents with small testes,
gynecomastia, tall stature, and with long legs and short arms. This disorder will cause
puberty to not come to completion rather than a complete delay.[4]
 In addition to the above causes of delayed puberty pubertal delay can also be seen in
multiple different illnesses where hypothalamic dysfunction can occur. Some examples
are hypothyroidism, cystic fibrosis, sickle cell disease, celiac disease, and diabetes

6
 mellitus to name a few.[6] Additionally, poor nutrition and the use of long-term
glucocorticoids has been linked to delayed puberty.
Contrasexual Development
Contrasexual development occurs when male or female children develop physical features of the
opposite gender. This condition tends to be more common in girls and is commonly caused by
polycystic ovaries and increased responses by the adrenal gland. Girls will have a male like
distribution of hair and may develop hirsutism. Girls can also develop clitoromegaly and lose
contour of the breast mass. The possible causes include Cushing syndrome, acromegaly,
exogenous androgens, adrenal tumor, ovarian tumor, and hyperprolactinemia. Although
contrasexual development is less common in boys, the cause is typically estrogen-secreting
tumors.[2]
Go to:

Clinical Significance
Puberty is an extremely significant process and a part of all children’s development into
functional adults. During this time children begin to gain the capacity for reproduction, which is
essential to discuss with children as they progress through puberty. Discussion of sexual
practices is an important aspect of well-child visits and is pertinent to identify children that may
be having unsafe or high-risk sexual encounters. The discussion of the sexuality by pediatricians
or other medical caregivers with young teens as they progress into adulthood provides a chance
for them to speak to someone under confidentiality and ask specific questions to understand
better their sexuality as well as what is considered safe sexual practices.[7] Puberty also
coincides with a child’s psychosocial development. Children who may be early or behind in
attaining the milestones of puberty in comparison to their peers are at a much higher risk of
emotional distress and low self-esteem. The ability to monitor the progression of puberty in the
pediatric population is vital as it is essential to their reproductive development but also because
of the many physical and psychological risks children face during this time in their development.

7
8