NFOG - Nordic Federation of Societies of Obstetrics and Gynecology

37. Stages of puberty

Take home messages

Respect modesty, psychological state, and autonomy when examining the adolescent female.
Knowledge of normal time points of pubertal stages and normal variability in pubertal development is essential.
Establishment of cyclic recruitment (activation of the hypothalamic-pituitary-gonadal axis (HPG-axis) as marked by menarche is
necessary to obtain adult secondary sex characteristics and ultimately fertility.
Pubertal development is usually evaluated using the Tanner staging system.
Precocious and delayed puberty is important to identify, diagnose, and treat.

Adolescent Gynecology

Introduction
Considerations regarding the adolescent patient are often of a benign and prophylactic nature, such as on the variability menarche,
irregular menstrual bleeding, dysmenorrhea, development of secondary sex characteristics, vaginal discharge, HPV-vaccination or
contraception. Often, the parents have taken the initiative to seek the consultation. It is imperative to respect and understand the
modesty, physiological state and autonomy of the patient. Thus, depending on the patient´s age and maturity, consultation in the
absence of the parents, but if possible with their consent, should be an option. It is important to determine if the patient has had sexual
intercourse in order to accommodate the subsequent examination and use laboratory diagnostic options in line with this. The adolescent
patient may, in addition to conditions mentioned in this chapter, present themselves with the same conditions as a more mature female.

Video (7 minutes)  on the physiology and patophysiology of puberty

The consultation and physical examination of an adolescent patient should include:

Information regarding the primary question/problem/inquiry.

Records of growth and pubertal development prior to consultation.
Tanner stage (see Figure 1).
Inspection of external genitalia.
Gynecological examination if indicated or possible (small instruments used).
Blood samples and imaging including ultrasonography on indication only. Abdominal ultrasound is often better tolerated than
vaginal ultrasound in virgo patients (but may be possible if the girl is comfortably using tampons).
Figure 1: Tanner stages (Click to enlarge)

Tanner stage 1: prepubertal. Tanner stage 2: breast buds starting, thin downy pubic hair. Tanner stage 3: breast buds extending beyond areola,
coarser & curly pubic hair, armpit hair. Tanner stage 4: fuller breast shape, areola and mammilla elevated from skin, curly & thicker pubic hair,
usually menarche at this stage. Tanner stage 5: mature breasts size, areola in skin level, protruding mammilla, adult hair quality, pubic hair
reaches thigh

The ovary during the fertile period

During the course of a normal lifespan, a woman undergoes vast physiological and phenotypical changes. Normal female development
from the fetal period, through childhood and later in puberty is essential in attaining normal fertility.

Central in the normal development of the female are the ovaries and the gametes, i.e. the oocytes which the ovaries harbor. The
primordial follicles peak in numbers at gestational week 20 (6-7 million) with a drastic decrease to less than 1 million at birth, and fewer
still as the female reaches menarche. Primordial follicles in the ovaries remain senescent (“silent/dormant”) in the fetal ovaries, but
continuously decrease in numbers (undergo atresia) from 1 million at birth to approximately 400.000 at menarche.

During folliculogenesis, the follicles go through a number of morphologically distinguishable stages before they reach ovulation, although
they cannot fully mature until cyclic recruitment is established after menarche. Folliculogenesis is governed by myriads of signaling
pathways: initial recruitment by local ovarian androgen-signaling Anti-Müllerian Hormone (AMH, produced by the granulosa cell layer of
growing follicles), the follicular extracellular matrix and the bidirectional signaling between the oocyte and the granulosa cell layer(s). As
the follicles grow in size and attain more layers of granulosa cells, the pituitary-derived gonadotropins, follicle-stimulating hormone
(FSH) and luteinizing hormone (LH), become essential in further development, selection of the dominant follicle and ovulation.

After initial activation of primordial follicles, the granulosa cells (with FSH receptors) proliferate into several layers surrounding the
oocyte. The outermost theca-cell layer (containing LH receptors) surrounds the granulosa cell basement membrane. LH stimulation
prompts the theca cells to produce testosterone that via aromatase in the granulosa cells is modified to estrogen (”two-cell-two-
gonadotropin system”). An antrum subdivides the mural granulosa cells lining from cumulus cells adjacent to the oocyte. The mid-cycle
LH surge prompts ovulation of the dominant follicle and the ovum completes meiosis I, extrusion of the first polar body and arrest at
meiosis II, in metaphase II. The remains of the follicle transform to the corpus luteum producing vast amounts of progesterone and
estrogens to support endometrial decidualization. If the oocyte is fertilized, the zygote will stimulate the corpus luteum to continue this
process via secretion of human chorionic gonadotropin (hCG). If not, the corpus luteum will undergo atresia causing a steep drop in
progesterone and estrogen levels: the signal for endometrial detachment and thus menstruation.

The control of folliculogenesis (Figure 2) is thus highly complex and, as the follicles produces estrogens, deeply intertwined with the
development of the female phenotype.

Normal pubertal development

Puberty describes the period in which a cascade of endocrine events evolve the child into a sexually mature adult. The female girl attains
her secondary sexual characteristics and reproductive competence as marked by the first menstruation; menarche. Abnormalities in
female pubescence are overall rare but important to diagnose as failure to manage them correctly has vast implications for body growth,
development of secondary sex characteristics, fertility and self-depiction. Neoplasms of the CNS, adrenal glands and ovaries causing
precocious puberty are potentially fatal and thus essential to diagnose and treat.

The transition from childhood into adulthood is a complex and still not fully understood continuum of processes. The transition is
governed by the neuroendocrine system, the hypothalamic-pituitary-gonadal axis (HPG-axis, see Figure 3), as well as the adrenal glands.

Figure 2: Ovarian folliculogenesis (Click to enlarge)

1 Primordial follicles, 2 Primary follicle, 3 Secondary follicle, 4 Anthral follicle, 5 Ovulatory follicle, 6 Corpus luteum, 7 Mature corpus luteum, 8
Corpus albicans

During pregnancy, maternal estrogen and progesterone pass the placenta and enter the fetal system, suppressing the fetal pituitary
production of FSH and LH thus keeping the fetal HPG axis in senescence. After birth of the neonate the lifting of hormonal blockage or
suppression results in a dramatic post-natal flare-up of circulating gonadotropins in the newborn girl; “mini puberty”. Consecutively, high
levels of gonadotropins stimulate the ovarian follicles to start to mature and produce estrogens. Because the immature pituitary gland
and the hypothalamus are extremely sensitive to negative feedback by estrogens, secretion of FSH and LH decrease soon after.
However, initial recruitment of primordial follicles and subsequent development of the follicles will continue resulting in constant low
secretion of ovarian estrogens, enough to suppress the secretion of gonadotropins from the pituitary until the girl has reached an age of
6-8 years. This period of development is referred to as the juvenile pause.

Figure 3: Hypothalamus-pituitary-gonadal axis (Click to enlarge)

From age 6-7 and until age 13-15, a progressive increase in adrenal cortical activity results in rising levels of the androgens
dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), stimulating growth of pubic and axillary hair. This androgen-
driven step of puberty (adrenarche) seems to be independent from the re-awakening of the HPG-axis (gonadarche), although linked
somewhat in time.

The frequency and amplitude of pulsative secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus is low during the
juvenile pause but increases during sleep from age 8-9, making the pituitary more sensitive to FSH and LH while both the hypothalamus
and the pituitary gland become less sensitive to negative feedback exerted by circulating estrogens. This results in increased pituitary
gonadotropin secretion, especially FSH, prompting further ovarian follicle maturation and increased ovarian secretion of estrogens. The
increasing levels of circulating estrogens stimulate the development of the female secondary sex characteristics; development of the
internal and external genitalia, the breasts (thelarche), a redistribution of fatty tissue towards the female adult pattern and an increase in
growth hormone (GH). The concomitant growth spurt normally occurs approximately two years prior to the first menstruation
(menarche). Estrogen stimulates growth of bones but also, in high concentrations, initiates closure of the epiphyseal plates thus
eventually terminating growth in height. The development of clinically visible secondary sex characteristics (pubarche) occurs at age 8-
13. The five-step Tanner rating scale (Tanner stage 1-5, see Figure 1) for breast development, genital growth and pubic hair was
developed by Marshall and Tanner and is still widely used by clinicians for staging pubertal progression.

The gradual maturation of the HPG-axis and genitalia will culminate in the first menstrual bleeding at menarche (see Figure 4). As the
HPG-axis is yet not capable of producing the mid-cycle LH surge, the first shedding episodes of the endometrium are anovulatory and
caused by fluctuations in estrogen levels and not by corpus luteum degeneration as after the initiation of ovulation. In time, sufficient
mid-cycle LH surges will ensure ovulation, establishing the female reproductive potential.

Figure 4: The menstrual cycle (Click to enlarge)

Ages at menarche/puberty differs in populations and are influenced by ethnicity/genetics, nutritional status/environmental exposure to
endocrine disrupting compounds and psychological factors. Inthe Nordic countries menarche occurs at an average of 13 years age with
95% experiencing menarche between age 10 years and 6 months and 15 years and 6 months. The age of menarche prior to, or after this
time-span is clinically defined as precocious or delayed menarche. The physician needs to be aware of what is normal in the given
population in order to identify abnormalities.

Precocious puberty (pubertas praecox)

Pubertas praecox, or precocious puberty, is defined as pubertal changes before the age of eight. However, there is a trend towards an
earlier start of puberty in normal girls. Therefore this age limit is not absolute. Precocious puberty is a rare condition, but untreated it will
have negative effects on psychosocial development as well as adult end height.

Precocious puberty is caused by a premature increase of systemic estrogens and/or androgens with subsequent clinically visible pubertal
signs; thelarche, adrenarche, premature excessive growth, or menarche prior to the age of eight. The etiology behind the precocious
puberty syndrome can be divided into two groups:

1. Premature activation of the HPG-axis/true precocious puberty:

In up to 80% of all cases, Precocious puberty is caused by premature gonadotropin production by the pituitary with subsequent ovarian
stimulation and estrogen production. Most often, the reason is idiopathic. Other causes are CNS tumors, CNS infections, hydrocephalus,
von Recklinghausen’s disease and brain trauma. In extreme hypothyroidism, high levels of thyroid-stimulating hormone (TSH) may
stimulate the FSH receptors.

2. Pseudo-precocious puberty:

In pseudo-precocious puberty, an ectopic focus, such as a tumor or hyperplasic benign cells, produces sex steroids (directly effect) or
hCG, (via ovarian stimulation). This stimulation thus acts independently of the hypothalamic-pituitary gonadotrophin stimulation in
inducing precocious puberty.

The most common ectopic focus is the presence of an ovarian germinal cell tumor producing estrogens. A second cause is the McCune-
Albright syndrome; a genetic mutation leading to autonomous ovarian estrogen production. This syndrome includes multiple cystic bone
lesions, café-au-lait spots, hyperthyroidism, excessive growth and Cushing’s syndrome.

Rarer etiologies include hyperplasia/tumors in the adrenal glands, liver, ingestion of unregistered medicines containing estrogens and
transient hormonally active simple ovarian cysts.

Diagnostics and findings

Physical evaluation should include:

Record of growth in relation to height and weight percentiles in the given population.
Tanner stage.
Skin examination: signs of café-au-lait spots or androgenization.
Thorough examination of the abdomen, pelvis (exclude tumor, infection, trauma*, sexual abuse*), and neurological state. Use of
ultrasound may be required.
Physiological state of the patient and her parents.
* Girls with precocious puberty are at higher risk of being exposed to sexual abuse.

Laboratory evaluation should include:

Blood assays (FSH, LH, hCG, androgens, estrogens, progesterone, TSH, free T4)
Imaging (Ultrasonography of abdomen and pelvis, x-ray for bone age, CT and MRI of the brain and possibly whole body scan).

Treatment
Referral to secondary expert care is essential. Treatment is targeted to the identified underlying cause: tumors are removed via surgery if
possible. If there is premature reactivation of the HPG axis, continuous administration of GnRH agonists will inhibit the gonadotropic cells
of the pituitary, thus halting the pubertal development. This should be continued until age 12. These patients tend to have a shorter end
height due to premature epiphyseal disc-closure owing to premature estrogen exposure. Physiological support to both patient and
parents is imperative.

Delayed puberty (Pubertas tarda)

Delayed puberty is defined as absence of pubertal development at the age of 13 years and is seen in approximately 0.5% of the female
population. As in the cases of precocious puberty there are different prevalences in different populations. Delayed puberty is caused by a
lack of sufficient systemic estrogen and/or androgen levels. The etiology behind delayed puberty can be divided into four groups:

1. Idiopathic delay
2. Hypogonadotropic hypogonadism
3. Hypergonadotropic hypogonadism
4. Eugonadism/other

1. Idiopathic delayed puberty:

In most cases delayed puberty is merely a normal pubertal development that occurs later than normal due to late reactivation of the
HPG-axis. It is important to map family history and development. Despite a corresponding later closure of the epiphyseal plates, girls
with idiopathic delayed puberty tend to have a shorter end height than normal girls.

2. Hypogonadotropic hypogonadism:
In cases with little or no production of pituitary gonadotropins (low FSH and LH), with subsequent continued ovarian senescence (low
estrogen) due to lack of stimulation, the cases are referred to as hypogonadotropic hypogonadism. Etiologies include irreversible causes:
brain tumors (craniopharyngioma, germinoma, pituitary tumors), hypopituitarism, congenital CNS defects, or CNS infections. Kallmanns
syndrome is a deficiency in GnRH production- and secretion with associated stigmata including a lack of sense of smell (anosmia),
epilepsy, midline cranio-facial defects, and renal agenesis.

Reversible causes include a range of chronic diseases (juvenile diabetes, hypothyroidism, malabsorption, anorexia, extreme exercise,
leukemia, kidney failure and prolactinomas).

3. Hypergonadotropic hypogonadism:
If hypothalamic-pituitary function is normal, but gonadal function compromised, FSH and LH can rise to post-menopausal levels without
sufficient ovarian response (low estrogen). The most common cause is gonadal dysgenesis seen in Turner syndrome patients (45X/45X0)
which is present in 1/3.000 girls. A normal karyotype may be seen in patients presenting themselves with gonadal dysgenesis and
premature/primary ovarian insufficiency (POI) or failure (POF). Single gene defects such as FOXO3A contribute to the development of POI.
Destruction of the ovaries by chemotherapy, infections, surgery, radiation or torsion can cause primary ovarian insufficiency and thus
hypergonadotropic hypogonadism.

4. Eugonadism/other:
Anatomical reasons for absent menarche include Müllerian agenesis with uterine malformations (Mayer-Rokitansky-Küster-Hauser
syndrome, MRKP), a vaginal septum and imperforate hymen. Further, in androgen insensitivity syndrome (Morris’ syndrome) a defect in
the androgen receptor causes genetic boys (XY) to have a female phenotype due to estrogen actions. As these patients have no uterus,
the condition may not be recognized until menarche does not occur.

Diagnostics and findings

Physical evaluation should include:

Record of growth in relation to height and weight percentiles in the given population as well as the familial pattern.
Medical history/examination in order to identify chronic illness.
Tanner staging.
Thorough examination of the abdomen, pelvis, and neurological state.
Gynecological examination to identify anatomical abnormalities.
Psychological state of the patient and her parents.

Laboratory evaluation should include:

Blood assays (FSH, LH, androgens, estrogen, prolactin, TSH, free T4, as well as IGF-1, IGFBP3, and IGFBP-2 to differentiate
between delayed puberty and growth hormone deficiency).
Genetic evaluation (karyotype/ChIP-array).
Imaging (Ultrasonography of abdomen and pelvis, x-ray for bone age, CT and MRI of the brain and possibly whole body).
If a chronic illness is suspected, diagnostics should be targeted at this.

Treatment
Treatment will be initiated by secondary care and depends on the cause of the delayed puberty. Clear familial idiopathic delayed
puberty, needs no intervention. Low-dose estrogens for 1-2 years stimulates the development of secondary sex characteristics, which
may improve the patient’s self-depiction (self-esteem) and social life. Later, sequential estrogen-progesterone treatment can mimic a
menstrual cycle. At some point, the treatment should be discontinued for a while in order to test if the HPG-axis has been reactivated,
thus eliminating the need for further intervention.

Tumors are removed via surgery if possible. Chronic illness should be treated according to relevant guidelines. Hormone supplementation
should be given in cases of specific hormone deficiency such as in hypothyroidism and growth hormone deficiency.

In hypergonadotropic hypogonadism, hormone therapy is initiated to stimulate and maintain development of secondary sex
characteristics. Treatment should continue to at least the average age of menopause to avoid consequences of estrogen deficiency
(osteoporosis, vaginal atrophy). Egg donation may be the sole option for these patients to become pregnant later in life.

As in cases of precocious puberty, psychological support to both the patient and her parents is imperative in all cases of delayed puberty.

Keywords: Delayed puberty (pubertas tarda), folliculogenesis, menarche, precocial puberty (pubertas precox), puberty.
Test yourself
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References

Literature
Speroff´s Clinical Gynecologic Endocrinology and Infertility. Ninth Edition. Hugh S. Taylor, Lubina Pal, Emre U. Seli. Wolters Kluwer, 2019.

“Gynækologi”. Fourth edition. Bent Ottesen, Ole Mogensen, Axel Forman. Munksgaard Denmark.

“Variations in the pattern of pubertal changes in girls”. Marshall, W.A.J.M. Tanner. Arch Dis Child, 1969. 44(235): p. 291-303.

Emans, Laufer, Goldstein´s pediatric and adolescent gynecology. Emans SJ, Laufer MR. ISBN/ISSN 9781608316489

Authors
Emil Hagen Ernst, MD, PhD, Denmark.

Elina Holopainen , MD, PhD, Finland.

Marie Bixo , MD, professor, Sweden.

Last edited 29.08.2020

Published by:
NFOG - Nordic Federation of Societies of Obstetrics and Gynecology
Ole Mogensen Department of Obstetrics and Gynecology - Aarhus University Hospital
8200 Århus N

Telephone: +45 30 71 45 62
[email protected]