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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.