Mednotes

L7 RDA Puberty

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tagsrda, lecture
aliasesL7 RDA Puberty

23 min read

Overview

Puberty is the attainment of secondary sexual characteristics and reproductive capability, driven by maturation of the hypothalamic-pituitary-gonadal axis. The lecture sets out the normal physiology, timing and physical staging of puberty, then works outwards to the abnormal: puberty that is too early (precocious, central or peripheral), too late or absent (delayed), and the benign normal variants that sit between. Clinical cases run through the material, opening with a girl presenting with short stature and primary amenorrhoea (Turner syndrome) and closing with cases of premature breast development, a testicular tumour causing peripheral precocity, delayed puberty, and a 4 year old with peripheral precocity, bone disease and café-au-lait patches.

Stated objectives:

  • understand the normal physiology, timing and physical changes of puberty;
  • understand normal variants;
  • general understanding of delayed and precocious puberty;
  • general understanding of the investigations and management of precocious puberty and pubertal failure or delay.

Adolescence and why puberty matters

  • Adolescence is a time of many changes: cognitive, psychosocial, and biochemical/physical.
  • There is often a mismatch between biological and social maturation. Across historical groups (hunter-gatherer, agricultural settlement, industrial revolution, mid 20th century, present day) the age of menarche has stayed relatively low and stable while psychosocial transitions into adulthood (from first sexual activity through to marriage and parenthood) have shifted progressively later, so the gap between biological and psychosocial maturity is widest at the present day.
  • Puberty is often a transition point for increased morbidity and mortality, increased depression, suicide and mental health problems, increased substance misuse, and a range of other medical issues such as type 2 diabetes.

Definitions

  • Puberty: the attainment of secondary sexual characteristics and reproductive capabilities. A complex developmental process beginning in late childhood, characterised by maturation of the hypothalamic-pituitary-gonadal (HPG) axis, appearance of secondary sexual characteristics, acceleration of growth, and ultimately the capacity for fertility.
  • Adrenarche: activation of the adrenal cortex with production of androgens. Often occurs before the onset of true puberty. Produces pubic and axillary hair, body odour, acne, and oily skin/hair.
  • Pubarche: appearance of pubic hair.
  • Thelarche: appearance of breast tissue.
  • Menarche: age of onset of the first menstrual period.

Adrenarche in more detail

  • Biochemical adrenarche can precede GnRH release, with the physical manifestations appearing later.
  • Main androgens: dehydroepiandrosterone (DHEA/S) and androstenedione.
  • Responsible for pubic and axillary hair, acne, body odour, and oily skin/hair.

Pubertal hormones and control of the axis

Hormones involved:

  • GnRH from the hypothalamus.
  • Pituitary gonadotropins (LH, FSH): pulsatile secretion stimulates secretion of the sex steroids, androgens and oestrogens.
  • Oestrogens: predominantly oestradiol, stimulating breast and reproductive system development in girls.
  • Androgens: predominantly testosterone, stimulating pubertal changes in boys.
  • In both sexes, androgens stimulate sexual hair development, skin oiliness, acne and apocrine secretion (body odour).

Control pathway, in order:

  1. Higher centres, influenced by nutrition, health, stress, seasonal factors, exercise and genetic factors.
  2. Neurotransmitters, which may be stimulatory or inhibitory (+/-).
  3. Hypothalamus.
  4. GnRH, released in pulses; at puberty the pulses increase in amplitude.
  5. Pituitary.
  6. LH and FSH, also pulsatile and also increasing in amplitude at puberty.
  7. Gonads.
  8. Oestrogen/testosterone and others.

HPG axis anatomy: GnRH neurons project to the median eminence and release GnRH, which acts on pituitary gonadotroph cells; these release LH and FSH in a pulsatile pattern; LH and FSH act on the gonad, which produces oestradiol, progesterone and testosterone; these feed back to the GnRH neurons, closing the loop.

Hormonal changes across the lifespan

Both sexes show the same three-phase pattern of gonadotropins and sex steroids: high in fetal life and early infancy, a childhood trough, then a rise through puberty into adulthood.

  • Females: oestradiol is very high in fetal life (approximately 7,500 to 30,000 pmol/L), drops sharply after infancy to a low childhood plateau, then rises through puberty to adult levels of approximately 225 to 300 pmol/L. LH and FSH follow the same fetal/infancy peak, childhood trough, pubertal rise pattern.
  • Males: testosterone peaks in fetal life, then shows a distinct secondary rise in infancy into the mid-pubertal range during the first six months of life (mini-puberty), then a childhood trough, then a rise through puberty to adult levels. LH and FSH follow a comparable pattern.

Timing of puberty

  • 50 to 80% of pubertal timing is genetic.
  • Males: on average 11 to 13 years (95% range 9.5 to 13.5 years); average duration 3 years.
  • Females: on average 10 to 11 years (95% range 8.5 to 13 years); menstruation follows about 2 years later.
  • There is some ethnic variation.

Sequence of physical changes

Approximate ages of onset and duration from the pubertal timeline:

  • Females: breast stage 2 around 10 to 12 years; pubic hair stage 2 around 11 to 12.5 years; peak height velocity around 11.5 to 13 years; breast stage 4 around 13 to 14.5 years; menarche around 13 to 14 years; pubic hair stage 4 around 13.5 to 15 years. Adrenarche is labelled separately below the female panel without a plotted age bar.
  • Males: testicular volume 4 mL around 10.5 to 12 years; genital stage 2 around 11 to 12.5 years; pubic hair stage 2 around 12 to 13.5 years; testicular volume 12 mL around 13.5 to 15 years; genital stage 4 around 13.5 to 15 years; peak height velocity around 13.5 to 15 years; pubic hair stage 4 around 14 to 15.5 years.

Note the sex difference in the growth spurt: peak height velocity comes early in female puberty but late in male puberty.

Tanner staging

Breast development (girls)

  • Stage 1: prepubertal.
  • Stage 2: elevation of breast and papilla.
  • Stage 3: further elevation of breast and areola, but no separation of contours.
  • Stage 4: areola and papilla form a secondary mound above the level of the breast.
  • Stage 5: areola recedes to the general contour of the breast.

Pubic hair is staged separately (stages 2 to 5). A growth velocity chart (cm/year against age, with 3rd to 97th percentile bands) shows the pubertal growth spurt as a peak around ages 11 to 13 in girls before velocity declines.

Boys: staged by testicular volume using an orchidometer (bead set numbered 4, 5, 6, 8, 9, 10, 12, 15, 20 mL) alongside genital and pubic hair stages 2 to 5. Corresponding testicular lengths:

  • 4 mL = 2.5 cm
  • 10 mL = 3.5 cm
  • 20 mL = 4.5 cm

Abnormal puberty: the two questions

Abnormalities are framed as either too early/too fast (precocious) or too late/absent (delayed).

Precocious puberty

Definition: onset before 8 years in girls, before 9 years in boys. The two main classifications are central (gonadotropin dependent) and peripheral (gonadotropin independent).

Central precocious puberty (CPP)

  • Incidence 1:5000.
  • Gonadotropin dependent: the normal sequence of puberty, but occurring early.
  • Female predominance, 10:1 F>M.
  • Idiopathic in 85% of girls; idiopathic CPP is rare in boys.
  • A CNS lesion or variation accounts for 20 to 50% of boys.
  • Aetiology in a Glasgow series of 189 patients (girls, boys): idiopathic 122, 5. Cranial irradiation: ALL 2, 0; medulloblastoma 1, 0; other tumour 1, 0; NHL 0, 0. Tumour: optic nerve glioma (NF) 6 (4 with neurofibromatosis), 5 (3 with NF); craniopharyngioma 1, 1; hypothalamic hamartoma 3, 1; germinoma 0, 1; third ventricle cyst 1, 1. Neurological disorder: learning disability with or without epilepsy 8, 4; hydrocephalus/spina bifida 11, 1; tuberculous meningitis 1, 0; cerebral palsy 5, 0. Priming: 11-hydroxylase deficiency 1, 0; simple virilising 21-hydroxylase deficiency 1, 3; oxymetholone 0, 2; testotoxicosis 0, 1.
  • The slide asks about the final consequences of CPP but does not state them [slide does not elaborate].

Peripheral precocious puberty (PPP)

  • Gonadotropin independent: signs of puberty without HPG axis activation.
  • The differential diagnosis is vast. Sources of excess sex steroid:
    • Gonads
    • Adrenal
    • HCG secreting tumours (often CNS)
    • Hypothyroidism
    • Exogenous

History

Symptoms of sex steroid production:

  • Androgen related: oily skin/hair, acne, body odour, pubic/axillary hair, increased growth, behaviour change, aggression, growth of penis, testicles or clitoris.
  • Oestrogen related: breast development or tenderness, behavioural change, vaginal discharge or blood.

Features suggesting a cause: family history, adoption, excessive weight gain, CNS symptoms (headache, visual disturbance, personality change, coordination problems), other neurological disease (hydrocephalus, cerebral palsy), cranial irradiation, bone pain or fractures, and drugs or parental drugs.

Examination

Height, weight, growth velocity, blood pressure, dysmorphic features, fundi and visual fields, full systems examination, pubertal staging, and skin (for example café-au-lait spots).

Work-up of precocious breast development in a girl

The algorithm branches on three findings together: associated signs of puberty (absent versus present), height velocity (normal versus increased) and bone age (normal versus advanced).

Absent signs, normal height velocity, normal bone age leads to a prepubertal pelvic ultrasound and a GnRH test showing an FSH-dominant response (FSH > LH):

  • Chronological age under 2 years: infantile mammoplasia. Follow up growth and development.
  • Chronological age over 2 years: premature thelarche. Follow up growth and development.

From the “over 2 years” node, an LH-dominant response to GnRH (LH > FSH) instead indicates central precocious puberty:

  • Negative CNS imaging: idiopathic central precocious puberty, treated with GnRH agonist therapy.
  • Positive CNS imaging: organic central precocious puberty, treated with aetiologic therapy.

Present signs, increased height velocity, advanced bone age leads to a pubertal pelvic ultrasound and a suppressed FSH and LH response to GnRH, indicating peripheral precocious puberty. Proceed to ovarian (and adrenal) imaging:

  • With café-au-lait spots: McCune-Albright syndrome, treated with testolactone or aromatase inhibitors.
  • Otherwise: ovarian cyst or tumour, exogenous steroids, HCG-secreting tumour, or hypothyroidism, managed medically and surgically.

Warning

The precocious-breast-development algorithm carries numbered footnote markers (roughly 1 to 13) with no footnote text present on the slide, so that detail is unavailable.

Normal variants

  • Premature thelarche: isolated breast development in girls, under 2 years, with no acceleration in growth or bone age. Self-limited and not progressive.
  • Premature adrenarche: appearance of secondary sexual characteristics; may be benign or pathological. The benign form shows a lack of significant growth velocity acceleration, minimal increase in bone age, and no breast or testicular changes.

Delayed or absent puberty

Delayed puberty is likewise divided into central and peripheral causes.

  • Females: no signs by 13 years; 30% is constitutional delay of growth and development (CDGD).
  • Males: no signs by 14 years; 60% is CDGD.

Work-up of delayed or absent testicular development

Relevant history: radiotherapy or chemotherapy, cryptorchidism, torsion, orchitis, orchidopexy, anosmia; and separately chronic disease.

Absent virilization, normal height velocity

  • Markedly raised FSH and LH with low testosterone: primary testicular failure. Treat with testosterone therapy.
  • Prepubertal or low FSH and LH with low testosterone: gonadotropin deficiency. With normal T4 and prepubertal IGF-1: markedly raised prolactin indicates a prolactinoma (TRH test, CNS imaging, medical or surgical management); normal prolactin indicates isolated gonadotropin deficiency (CNS imaging, medical or surgical management with associated hormones).

Absent virilization, decreased height velocity

  • Prepubertal or low FSH and LH with low testosterone: gonadotropin deficiency. With low T4, low IGF-1 and low or raised prolactin: multiple pituitary hormone deficiency (CNS imaging, medical or gonadotropin therapy with associated hormones). With normal T4, low IGF-1 and normal prolactin: isolated GH deficiency (CNS imaging, GH therapy).

Partial or adult virilization but small testes

  • Normal height velocity with gynaecomastia, markedly raised FSH and raised LH, pubertal testosterone: constitutional or temporary delay. Possible temporary testosterone therapy.
  • Decreased height velocity, prepubertal or low FSH and LH, pubertal testosterone: primary germinal failure. Karyotype; testosterone supplementation in some patients.

Chronic disease history leads to familial delay, or to Cushing syndrome (24-hour urine free cortisol, dexamethasone test, medical or surgical management).

Delayed puberty decision tree (growth velocity and bone age)

Normal growth velocity with slight delay in bone age

  • Low weight: anorexia or chronic illness.
  • Normal weight with raised FSH/LH: hypergonadotropic hypogonadism.
  • Normal weight with prepubertal or low FSH/LH and normal prolactin: hypogonadotropic hypogonadism or constitutional delay.
  • Normal weight with raised prolactin: prolactinoma or CNS tumour.

Decreased growth velocity with mild to severe delay in bone age

  • Raised weight, normal T4 and TSH, prepubertal or low FSH/LH: Cushing.
  • Raised weight, low T4 and raised TSH, prepubertal FSH/LH: hypothyroidism.
  • Normal weight, raised FSH/LH with normal IGF-1: tumours (females only).
  • Normal weight, prepubertal or raised FSH/LH with low IGF-1, normal T4/TSH and normal prolactin: isolated GH deficiency.
  • Normal weight, low T4, normal or low TSH, low or raised prolactin: multiple pituitary hormone deficiency.

Warning

Both delayed-puberty algorithms are dense multi-branch flowcharts with unexplained footnote numbers and asterisks against the FSH/LH labels, with no footnote text on the slides. Some fine connector routing was reconstructed as faithfully as legible.

Primary amenorrhoea with abnormal genital anatomy

Start with history, examination, bone age and a chronic disease panel, then split on breast development.

Breasts absent or immature, assess weight and height:

  • Underweight: eating disorder or athletic amenorrhoea.
  • Not underweight, high FSH: primary ovarian failure.
  • Not underweight, prepubertal LH: constitutional delay of puberty or gonadotropin deficiency.
  • Chronic nonreproductive disorder: work up accordingly.

Breasts mature, assess external genitalia:

  • Normal genitalia, positive beta-hCG: pregnancy.
  • Normal genitalia, negative beta-hCG, high testosterone with sparse pubic hair: androgen resistance.
  • Normal genitalia, negative beta-hCG, high testosterone with pubic hair normal or greater: hyperandrogenism pathway.
  • Normal genitalia, negative beta-hCG, normal testosterone: pelvic ultrasound. Uterus absent means Rokitansky syndrome; uterus enlarged means imperforate hymen; uterus normal means follow the secondary amenorrhoea pathway.
  • Abnormal external genitalia: vaginal aplasia or intersex.

Menstrual and pubertal variants

  • Pubertal arrest: puberty starts then stops.
  • Delayed menarche: first period after 15 years.
  • Primary amenorrhoea: no period.
  • Secondary amenorrhoea: cessation of established periods.
  • Oligomenorrhoea: infrequent periods, 6 or fewer per year.

Gynaecomastia in males

  • Occurs in up to 50% of males during puberty, peaking at 14 years. Fat can mimic it. Usually mild and transient.
  • Evaluate if prepubertal, greater than 5 cm, or showing no regression.
  • Possible causes: hypogonadism (for example Klinefelter syndrome, partial androgen insensitivity syndrome), tumours, other endocrine disease such as hyperthyroidism, chronic illness, and drugs.

Cases

Opening case: Miss T, 15 years 9 months

Referral with long-standing short stature, concern about primary amenorrhoea (early breast development at 12 to 13 years with little progression since), and hirsutism and acne over face, chest and back.

  • Growth: actual height plotted near the -3SD line (around 140 cm) at age 15 to 16, against a target height of roughly 175 to 180 cm, so markedly short relative to both population norms and her genetic target.
  • Examination: well in self, short 4th metacarpal, increased carrying angle (cubitus valgus). Puberty: Tanner stage 2 breasts (2/5), pubic hair Tanner 3, normal vaginal opening.
  • Investigations: FSH 71.6 IU/L (very high), LH 23.9 IU/L (very high), prolactin 279 mIU/L (reference 50 to 550), 17-beta oestradiol under 44 pmol/L. Genetics: 20/30 cells with 45 chromosomes and loss of one X, 10/30 cells with 46,XX.
  • Diagnosis: Turner syndrome with a mosaic karyotype, associated primary ovarian insufficiency and associated short stature.

The pattern to recognise is very high gonadotropins with low oestradiol, that is hypergonadotropic hypogonadism, meaning gonadal (ovarian) failure rather than a central cause.

Case 1

A 10 month old girl, otherwise well, with no change in growth velocity. The slide asks for the likely diagnosis but does not print an answer [slide does not elaborate]. On the precocious-breast-development algorithm, absent other pubertal signs with normal height velocity and normal bone age under 2 years of age routes to infantile mammoplasia with follow-up of growth and development.

Case 2

A 7 year old male with 1 year of increased height velocity (up 2 shoe sizes, now one head taller than classmates, increased musculature), pubertal changes noticed in the last month (possible large phallus, increased erections, pubic hair, acne, body odour), and 1 month of scrotal pain.

  • Growth chart: about 103 to 105 cm at age 4 and about 135 to 137 cm at age 7, both above the percentile curves and diverging upwards over time.
  • Examination: Tanner stage 4. Right testis normal feeling at 3 to 4 mL; left testis abnormal, very firm, 12 mL. No palpable nodes. The asymmetry is the key finding.
  • Investigations: bone age 11 years at chronological age 7 (bone age is the key investigation for skeletal maturity); FSH and LH very low; normal hCG and alpha-fetoprotein; high testosterone at 15; testicular ultrasound the next day showed only a small rim of normal tissue with mostly tumour and no cyst (making teratoma less likely).
  • Suppressed gonadotropins with high testosterone is the gonadotropin-independent (peripheral) pattern, with the sex steroid coming from the gonad. The slide poses the diagnosis as a question and does not print the answer.

Case 3

A 14 year old female with shorter stature and no signs of puberty; the slide asks for thoughts and gives no answer. The following slide is an unlabelled clinical photograph of a person standing against a grid-lined measurement backdrop with the eyes masked, with no caption or diagnostic label, so its specific relevance cannot be determined [slide does not elaborate].

Case 4

A 4 year old female with 1 month of right hip pain, breast development since 18 months of age, and per-vaginal bleeding for 9 months. Initial presentation was to the emergency department with query right hip pain or fracture.

  • GnRH (LHRH) stimulation test: FSH 0.3, 0.5, 1.0, 2.3 and LH under 0.1, 0.3, 0.7, 1.1 across the four hourly samples, that is a blunted prepubertal gonadotropin response, while oestradiol was high at 419 (flagged H) and 316 (flagged H).
  • A subsequent image-only slide shows a large irregular-bordered brown (café-au-lait) patch on the chest/neck with visible early breast development, an X-ray of the lower leg showing bowing/deformity of the tibia and fibula, and three further irregular-bordered pigmented patches labelled B, C and D.

Warning

The café-au-lait and bone slide carries no caption or diagnostic label. It plausibly relates to the McCune-Albright content on the precocious-puberty algorithm, but that association is not stated on the slide itself.

Self-test

  1. Define puberty and list the four features that characterise it.
  2. Distinguish adrenarche, pubarche, thelarche and menarche.
  3. Which adrenal androgens drive adrenarche, and which physical features do they produce?
  4. Describe the control pathway of puberty from higher centres down to the gonads.
  5. What changes about GnRH and gonadotropin secretion at the onset of puberty?
  6. Describe the pattern of FSH, LH and sex steroid levels from fetal life to adulthood, and name the feature unique to male infancy.
  7. What proportion of pubertal timing is genetic, and what are the average ages and 95% ranges of pubertal onset in each sex?
  8. Distinguish the timing of peak height velocity in girls from that in boys.
  9. Describe Tanner breast stages 1 to 5.
  10. What testicular lengths correspond to volumes of 4 mL, 10 mL and 20 mL?
  11. State the age cut-offs defining precocious puberty in each sex, and the two main classifications.
  12. Distinguish central from peripheral precocious puberty by mechanism, and list the sources of excess sex steroid in the peripheral form.
  13. Give the incidence, sex ratio and proportion that is idiopathic for central precocious puberty in each sex.
  14. A girl presents with isolated breast development, absent other pubertal signs, normal height velocity and normal bone age, and a GnRH test showing FSH greater than LH. Predict the diagnosis if she is 14 months old, and if she is 4 years old.
  15. In a girl with precocious breast development, what pattern of GnRH response distinguishes central from peripheral precocious puberty, and how does the treatment differ?
  16. Distinguish premature thelarche from benign premature adrenarche.
  17. At what ages is puberty considered delayed in each sex, and what proportion of each is constitutional delay of growth and development?
  18. A boy has absent virilization, normal height velocity, markedly raised FSH and LH and low testosterone. Explain the diagnosis and treatment, and predict how the picture would differ in gonadotropin deficiency.
  19. In a girl with primary amenorrhoea and mature breasts, normal external genitalia, negative beta-hCG and normal testosterone, what does pelvic ultrasound distinguish?
  20. Distinguish delayed menarche, primary amenorrhoea, secondary amenorrhoea and oligomenorrhoea.
  21. How common is pubertal gynaecomastia, when does it peak, and what three features should prompt evaluation?
  22. A 15 year old girl has short stature, primary amenorrhoea, arrested breast development, a short 4th metacarpal and increased carrying angle, FSH 71.6 and LH 23.9 with oestradiol under 44. Explain the biochemical pattern and give the diagnosis.
  23. A 7 year old boy has accelerated growth, Tanner stage 4, one small soft testis and one very firm 12 mL testis, bone age 11 years, very low FSH/LH and high testosterone. Explain what the gonadotropin and testosterone pattern indicates and where the sex steroid is coming from.
  24. Integrative: two children present with signs of puberty far too early. Explain how you would use height velocity, bone age, pelvic or gonadal imaging and the GnRH stimulation test together to place each on the central versus peripheral pathway, and say what the skin examination adds.

Answers

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