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Physiologic Changes of the Adolescent

Greg Ozark M.D.

Ext. 55612

A few observations

• The pros and cons of clinical relevance…

• Byrne and Levy discrimination?

Objectives

• Understand pertinent embryology in its relationship to puberty development.

• Know the definitions of the terms menarche, thelarche, gonadarche, and adrenarche.

• Know the normal age ranges for puberty development in males and females.

• Know the Tanner stages of development.• Understand the menstrual cycle and the

physiology underlying it’s irregularities.

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Developmental basics: Chromosomes and Hormones

• It all starts with one X and one X or Y – (or maybe just one X, or maybe 2 or 3X and one Y, or

maybe an X and one X that doesn’t work…)

• Hormones– lots and lots of Hormones

– autocrine, paracrine influence

– positive and negative feedback (sometimes both)

– up and down regulation of receptors (sometimes both)

– pulsatile vs constant secretion

– loss of responsiveness to a hormone

– permanently, abnormally “on” receptor genes causing unopposed hormone synthesis

Developmental basics: Hypothalamus

• Hypothalamus

– Secretes GnRH.

Developmental basics: Anterior Pituitary

• Secretes gonadotropins.

• FSH (Follicular Stimulating Hormone)– Stimulates Granulosa (female) and Sertoli

Cells (male) (“support” cells).

• LH (Leutenizing Hormone)– Stimulates theca (female) and Leydig

(male) cells to secrete androgens.

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Developmental basics: Ovaries

• Ovaries: no role in the development of the female GU tract

• Follicle: oogenesis occurs between 15-28 weeks of gestation and developing follicles enter a prolonged prophase (10-45 years)

• XX needed for sexual maturation and fertility

Developmental basics: Testis

• Sertoli cells: – MIF: regression of mullerian duct (a.k.a. AMH)

– H-Y antigen

– Inhibin

– Tight Junctions (anatomy and immunoprotection)

• Leydig cells: – disappear after birth and reappear at puberty.

– Testosterone: promote growth and differentiation of the Wolfian duct.

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Abnormal Development

• Congenital Adrenal Hypoplasia– deficiency of either 21- or 11- hydroxylase

enzymes leads to increased production of 17-OH steroids (androgens)

Abnormal Development • XX with excess adrenal

androgen production (CAH)

– 21 or 11 -OH deficiency

– Increased 17 -OH progesterone

– infants exposed to adrenal androgens appear virilized.

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Abnormal Development

• XO (Turner Syndrome)– Although one X chromosome eventually becomes inactivated,

2 are needed for normal functioning ovaries to develop.

– Primary ovarian failure (i.e. no E2)

– Usually, XO, but ~40% have a structurally abnormal X or a mosaic 46XX/45XO pattern.

– Classic features:

• short stature

• webbed neck

• widely spaced nipples

• high arched palate

• congenital heart disease

• autoimmune d/0 (thyroid, addisons)

Abnormal Development

• XO (Turner Syndrome)– Classic features:

– short stature

– webbed neck

– widely spaced nipples

– high arched palate

– congenital heartdisease

– autoimmune d/0 (thyroid, addisons)

Abnormal DevelopmentTestosterone defects

• Testicular feminization (XY)

– no androgen receptors

– + testis (intra-abdominal)

– no wolffian duct structures (not responsive to testosterone)

– no mullarian structures secondarily to + AMH

– Breasts, female GU present. Minimal adrenarche.

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Abnormal DevelopmentTestosterone defects

• 5 alpha reductase deficiency XY– no mullarian

structures secondarily to AMH

– wolffian duct structures present b/c of local testosterone action

– external GU from partial to total female pattern

Physiologic Changes of the Adolescent

• Puberty– Transition from non-reproductive to

reproductive status.

– Requires intact hypothalamus, pituitary, and gonadal development and communication.

Physiologic Changes of the Adolescent: Pre-puberty

• Before ~ 10 y/o low levels of FSH and LH are present despite low levels of GnRH.

• Therefore, either the negative feedback system is inoperative or the pituitary and hypothlamus are insensitive to testosterone, inhibin, and estradiol.

• ? Role of melatonin from pineal gland. (Gradual decrease in melatonin levels from childhood to adult.)

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Physiologic Changes of the Adolescent: Pre-puberty

• Gradual onset of maturation on hypothalamus leads to increased synthesis and release of GnRH.

• As puberty approaches, pulsatile release of FSH and LH occur.

Onset of puberty

• Timing ranges from 9-17 y/o.

• Timing of development depends on: genetics, race, and nutritional status.

• Girls start puberty ~2 yrs before boys.

• Most girls start puberty between 8-10 years.

Pubertal Development:Female

• Pituitary hormone secretion stimulate ovaries and adrenal glands.

• Breast budding (thelarche) and pubic hair (adrenarche) first appear.

• Thelarche coincides with the first detectable increase in E2.

• No thelarche by 13 y/o is considered ‘delayed’.

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Pubertal Development: Female

• Menarche (first menses) usually occurs between 11-14 y/o (average in U.S. 12.5 years).

• Average age of menarche has changed in U.S. from 14.5 yrs in 1900 to 12.5 yrs in 1990.

• No menarche ~2.5 years after thelarche or after 16 y/o is considered abnormal. (Especially with Tanner 4-5 breasts.)

• Timing of menarche can be affected by exercise, body fat stores, and light exposure.

Pubertal Development: Male

• Onset of puberty at 10-11 yrs.

• Complete (i.e. full sexual functioning) by 15-17 yrs.

• Normal variability: onset as early as 9 yrs. and completion as late as 20 yrs.

• Pituitary hormone secretion stimulates testes and adrenal glands.

• The first and most important sign is the enlargement of the testis (Increased FSH production.). This correlates with increased volume of the seminiferous tubules.

Pubertal Development: Male

• After the increased FSH, LH increases, Leydig cells re-appear, and testosterone synthesis is stimulated.

• Once testosterone synthesis has been initiated, primary and secondary sexual characteristics can occur. (Fig52-16, p 985 Berne & Levy)

• At approximately 13 yrs., spermatogenesis begins.

• Also, scrotal skin darkening, larynx enlargement, testes enlargement, penis enlargement, body hair, and facial hair appears.

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Pubertal Development: Male

• Secondary sexual characteristics– scrotal skin

darkening

– larynx enlargement

– testes enlargement

– penis enlargement

– body hair appears.

– facial hair appears.

Growth spurts• Girls may grow 5-8

cm and gain 5-6 kg/yr between ages 10-13.

• Girls start their growth spurt 2 years before boys.

• Boys grow 10-13 cm and gain 5-6 kg/yr between 12.5-15 years old.

• Males may grow into their early 20’s.

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Tanner stages: Female Breast

• 1) Appearance typical of children.

• 2) Breast button stage; areola increases in diameter and pigmentation; breast and nipple are elevated.

• 3) More growth. Similar in appearance to adult except smaller.

• 4) Areola and nipple continue to grow. Nipple forms a secondary mound.

• 5) Adult appearance. Areola not separated from the plane of the rest of the breast tissue.

Tanner stages: Female Pubic Hair

• 1) Appearance typical of children.

• 2) Scant, fine, smooth, light colored hair on labia majora.

• 3) Coarse. Increased in quantity; spread to pubis.

• 4) Similar quality; extension limited to pubis.

• 5) Adult distribution (triangular form).

Tanner stages: Male GU

• 1) Appearance typical of children.

• 2) Increase of > 3 ml in volume(> 2.5 cm long diameter); increased size of the scrotum; pigmentation of scrotal skin.

• 3) Increased length of penis; small increase in diameter; increased size of the scrotum.

• 4) Increase in length and diameter of the penis; development of glans penis; further pigmentation and growth of the scrotum.

• 5) Adult

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Tanner stages:Male Pubic Hair

• 1) Appearance typical of children.

• 2) Scant, long, light colored, slightly curly at the base of the penis and scrotum.

• 3) Curly, coarse, darker, increase quantity extending to the pubis.

• 4) Abundant, adult characteristics, but still limited to the pubis.

• 5) Adult, rhomboidal distribution.

Tanner Stages of Development

• Relevance of differentiation

• Gaps of > 2 stages in different areas is abnormal.

Clinical Correlates:Precocious Puberty

• Definition: The appearance of physical signs of sexual development in keeping with the phenotypic gender of the child prior to the earliest accepted age of sexual maturation.

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Precocious Puberty

• So what are the accepted ages of puberty?

• For girls,

– breast development (thelarche) before 6-7 yrs in Caucasian and before 5-6 yrs in African-American girls is precocious.

– Menses tends to occur younger in AA girls (mean 12.2 yrs v.s. 12.9 yrs.)

• For boys, sexual development before 9 y/o is considered precocious.

• Abnormal : <6 for girls, < 9 for boys

Precocious Puberty:Why the concern?

• Indication of underlying disease.

• Premature skeletal maturation leads to short adult stature.

• Psychosocial issues.

Precocious Puberty:Causes

• 50% have true central precocious puberty. That is, the normal ‘restraint’ on the HPG axis by higher centers is removed.

• Infectious, neoplastic, traumatic insults to the CNS cause this “release of control”.

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Other (extra-HPG) causes of precocious puberty include :

• hCG secreting germinomas of the hypothalamus, pineal, or mediastinum stimulate Leydig cells.

• Testotoxicosis & McCune-Albright Syndrome.

• ovarian cysts and tumors.

• Congenital Adrenal Hyperplasia (21- or 11- beta-hydroxylase deficiencies).

• Adrenal tumors.

• Hypothyroidism

• testicular germ cell tumors

Precocious Puberty:Clinical Evaluation

• History and Physical. (BP, abdominal mass, GU exam, visual field deficits, acromegally).

• Growth charts (determine changes in growth velocity).

• Siblings with ambiguous genitalia. FHx precocious puberty

• Tanner stages.

– Gaps of > 2 stages in different areas are abnormal.

– Breast buds v.s. sub-q fat.

– Appearance of vaginal mucosa.

– Increased volume of testis.

– Increased length of phallus.

Precocious Puberty:Lab Evaluation

• Radiographs– Bone age. (Advanced skeletal maturation

means more long-standing disease.)

– Brain MRI

• Labs– Depends on suspicion, but may include

hCG; GnRH; FSH; LH; Estradiol; Testosterone; DHEA, 17OHP; TSH.

– May require basal or stimulation testing.

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The Menstrual

Cycle• 3 Stages

– Follicular

– Ovulation

– Luteal

Follicular Phase

• Pulsatile GnRH release from hypothalamus.

• Increased FSH & LH from pituitary.

• Ovarian follicle growth.

• Ovarian Estrogen (E2) production.

• Endometrial thickening.

Ovulation

• As E2

increases, POSITIVEfeedback to the hypothalamus and pituitary cause LH surge, and follicle is released.

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Luteal Phase

• Corpus luteum makes progesterone and E2.

• Progesterone (pro-gestational) prepares the uterus for implantation of egg.

– Decreased endometrial thickening.

– Spiral artery differentiation.

Without fertilization,

• Implantation does not occur

• No hCG is made.

• Luteum regresses.

• Progesterone & E2 decrease.

• Menses.

Menstrual Cycle:Normal

• Menarche (first menses) occurs ~ 12.7 yrs.

• Cycles occur every 21-35 days.

• Most cycles last 3-7 days.

• Most women experience 30-40 cc blood loss with each menses.

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Menstrual Cycle:Abnormal

• Menorrhagia: normal intervals; increased flow.

• Metrorrhagia: irregular intervals; normal flow.

• Menometrorrhagia: irregular intervals, increased flow.

• Polymenorrhea: intervals between menses <21 days.

• Oligomenorrhea: intervals between menses >35 days.

• 0.5% cycles and < 21 days apart.

• ~1% cycles are > 35 days apart

• Adolescents have an immature HPO axis. So, regular cycles may not occur initially after menarche.

• 55-80% of cycles are anovulatory during the first 2 years after menarche.

• 10-20% of cycles are anovulatory during the first 5 years after menarche.

• What’s the physiology?

Menstruation Without Ovulation:

Example 1

• Most adolescents have a NEGATIVE feedback of E2 on HPO axis.

• Increased E2 at mid-cycle causes DECREASED LH & FSH.

• No ovulation occurs.

• Decreased E2 levels.

• Withdrawal bleeding occurs.

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Menstruation Without Ovulation:

Example 2• No E2 decrease (no

negative feedback).

• Unopposed E2 stimulation of endometrium outgrows blood supply and is sloughed.

• Metrorrhagia.

Clinical Correlates:Amenorrhea

• secondary amenorrhea: – the absence of 3 consecutive menstrual

cycles following the establishment of regular cyclic menstrual periodsof 6 months of amenorrhea.

• primary amenorrhea: – no menses by 16 y/o or 2.5 yrs after

thelarche (esp. given advanced Tanner staged breasts)

Causes of Primary Amenorrhea

• Amenorrhea with normal puberty

• Amenorrhea with abnormal puberty– hypergonadotropic hypogonadism

– hypogonadotropic hypogonadism

• GU tract abnormalities

• Hyperandrogenic anouvlatory syndrome (PCOD)

• Work-up: – physical exam

– TSH,FSH, LH, E2,

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Amenorrhea: with normal puberty

• Pregnancy

• Late onset ovarian failure

• Stress, eating d/o, exercise

Amenorrhea with abnormal puberty

• Hypergonadotropic hypogonadism

• Low E2, Increased FSH & LH (no negative feedback)

• Causes:

• Turner’s Syndrome (XO)

• Gonadal dysgenesis

• ovarian failure

–Radiation

–Chemotherapy

Amenorrhea with abnormal puberty

• Hypogonadotropic hypogonadism

• Low E2 and Low FSH, LH

• No signal from the top.

• Causes:

– Kallaman syndrome

– congenital hypopituitariasm

– stress, competitive athletes, poor nutrition

– drugs

– pituitary infiltration or infarction

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Amenorrhea:GU tract abnormalities

• Uterine synechiae

• Imperforate hymen

• Mullerian tract abnormalities– no upper vagina, cervix, uterus, fallopian

tubes

• Testicular feminization– no response to testosterone (no

receptors).

– MIF works, but no ovarian E2 is present.

• CAH with labial fusion

Review...

• Timing of development. (e.g. thelarche before menarche)

• Menarche (first menses) usually occurs between 11-14 y/o (average in U.S. 12.5 years).

• No pubertal development by age 13 warrants investigation.

Review...

• Tanner basics.

• A > two Tanner stage difference is abnormal.

• First signs of pubertal development:

– male: increase in testicular volume.(>3)

– female: breast buds.

• Puberty is considered ‘precocious’ if:

– < 6 y/o in females

– < 9 y/o in males

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Review...

• Normal cycles depend upon POSITIVEfeedback.