PubertyPubertyClinic of Reproduction and GynecologyClinic of Reproduction and Gynecology

Pomeranian Medical AcademyPomeranian Medical AcademyIwona SzydłowskaIwona Szydłowska

It is a physiological phase It is a physiological phase lasting lasting 2 to 5 years2 to 5 years,, during during which the genital organs which the genital organs

maturemature

SEXUAL MATURATIONSEXUAL MATURATION

Physical, emotional and sexual transition Physical, emotional and sexual transition from childhood to adulthoodfrom childhood to adulthood

Gradually. Sequence of Gradually. Sequence of physiological physiological changes.changes.

The first sign of pubertal development The first sign of pubertal development is usually breast growth is usually breast growth (thelarche),(thelarche), followed by appearance of pubic hair followed by appearance of pubic hair (pubarche),(pubarche), then axillary then axillary hhairair ((adrenarche)), then , then menarche.menarche.

The mean interval between breast The mean interval between breast budding and menarche is budding and menarche is 2.5 years2.5 years with with a standard deviation of about one year.a standard deviation of about one year.

ADRENARCHEADRENARCHE

Somatic changes dependent on adrenal Somatic changes dependent on adrenal

steroid hormones steroid hormones

means means increased activity of the suprarenal cortexincreased activity of the suprarenal cortex

at puberty with increased production of adrenal at puberty with increased production of adrenal

androgens which lead to appearance of androgens which lead to appearance of pubic pubic

and axillary hairand axillary hair..

GONADARCHEGONADARCHE

Somatic changes dependent on Somatic changes dependent on

gonadal sex steroid hormonesgonadal sex steroid hormones

CAUSE OF PUBERTY:CAUSE OF PUBERTY:

During childhood, the During childhood, the hypothalamus is hypothalamus is extremely sensitive to the negative extremely sensitive to the negative feedbackfeedback exerted by the small quantities exerted by the small quantities of estradiol & testosterone produced by of estradiol & testosterone produced by the child's ovaries. the child's ovaries.

As puberty approaches, As puberty approaches, the sensitivity of the sensitivity of the hypothalamus is decreasedthe hypothalamus is decreased and and subsequently, it subsequently, it increase the pulsatile increase the pulsatile GnRH secretion .GnRH secretion .

CNS-Hypothalamus-PituitaryOvary-Uterus Interaction

Neural control Chemical control

Dopamine (-)

Norepinephrine (+)

Endorphines (-)

Hypothalamus

Gn-RH

Ant. pituitary

FSH, LH

Ovaries

Uterus

ProgesteroneEstrogen

Menses

–± ?

HYPOTHALAMUS-PITUITARYOVARIAN AXIS

Necessary for the normal sexual maturation.Necessary for the normal sexual maturation.

Pulsatile secretion of gonadotropins begins Pulsatile secretion of gonadotropins begins the maturation process.the maturation process.

Important is not the amplitude of Gn pulses, Important is not the amplitude of Gn pulses, but the frequency.but the frequency.

In the late prepubertal period secretion of Gn In the late prepubertal period secretion of Gn is reinforced – subsequent pulses of GnRH is reinforced – subsequent pulses of GnRH reinforce the release of Gn.reinforce the release of Gn.

Activation of positive and negative feedback Activation of positive and negative feedback loops at puberty.loops at puberty.

The The anterior pituitaryanterior pituitary responds responds by progressive secretion of by progressive secretion of FSH and LHFSH and LH associated with associated with

increased secretion of increased secretion of growth growth hormonehormone..

The The ovariesovaries respond to the respond to the

increase Gonadotrophin increase Gonadotrophin

secretion by secretion by follicular follicular

development & estrogen development & estrogen

secretion.secretion.

EstrogenEstrogen causes development of causes development of the genital organs and the the genital organs and the appearance of the secondary appearance of the secondary sexual characters. sexual characters.

With increased estrogen secretion, With increased estrogen secretion, menarchemenarche and cyclic estrogen and cyclic estrogen secretion occurs.secretion occurs.

SECONDARY SEX SECONDARY SEX CHARACTERS INCLUDE:CHARACTERS INCLUDE:

development of the breast, development of the breast,

aappearance of pubic and ppearance of pubic and axillary hair.axillary hair.

FACTORS AFFECTING THE FACTORS AFFECTING THE INITIATION OF PUBERTAL INITIATION OF PUBERTAL

DEVELOPMENT:DEVELOPMENT:

1 - 1 - Height and weight ratioHeight and weight ratio- 48 kg- 48 kg

(nutritional factors).(nutritional factors).

2 - Maturation of the 2 - Maturation of the hypothalamushypothalamus..

3 - Increased 3 - Increased neurotransmitter outputneurotransmitter output in in

CNS.CNS.

4 - Onset of 4 - Onset of adrenal androgenadrenal androgen activity activity..

DEPOSITION OF SC FAT:DEPOSITION OF SC FAT:

17%17% to to menstruate menstruate

& &

22%22% to to ovulateovulate

PUBERTYPUBERTY

FFive stages from childhood to full ive stages from childhood to full

maturity (P1 to P5)maturity (P1 to P5),, described by described by

Marshall and Tanner. In bothMarshall and Tanner. In both sexes, sexes,

these stages reflect the progressivethese stages reflect the progressive

modifications of the external genitalia modifications of the external genitalia

and of sexual hair. Secondary sex and of sexual hair. Secondary sex

characteristics appear at a mean characteristics appear at a mean age ofage of

10.510.5 y in y in girlsgirls and and 11.5 to 1211.5 to 12 y in y in bboysoys..

SEQUENCE AND AGE OF SEXUAL SEQUENCE AND AGE OF SEXUAL MATURATION AND HORMONES MATURATION AND HORMONES

RESPONSIBLE FOR THIS PROCESSES.RESPONSIBLE FOR THIS PROCESSES.

EventEvent Age (mean)Age (mean) HormonesHormones

Thelarche (breast Thelarche (breast budding)budding)

Pubarche (sexual hair Pubarche (sexual hair growth)growth)

Growth spurtGrowth spurt

MenarcheMenarche

Adult breast developmentAdult breast development

Adult sexual hairAdult sexual hair

10,510,5

10,610,6

12,012,0

12,712,7

13,713,7

14,714,7

EstradiolEstradiol

AndrogensAndrogens

GHGH

EstradiolEstradiol

ProgesteroneProgesterone

AndrogensAndrogens

FEMALE PUBERTAL STAGES FEMALE PUBERTAL STAGES (TANNER)(TANNER)

P1 P1 PrepubertalPrepubertalP2 P2 Early development of subareolar breast Early development of subareolar breast

bud +/-bud +/- small amounts of pubic hair and small amounts of pubic hair and axillairy hairaxillairy hair

P3P3 Increase in size of palpable breast Increase in size of palpable breast tissue tissue and areolae, and areolae, iincreased amount of ncreased amount of dark dark pubic hair andpubic hair and//of axillary hairof axillary hair

P4P4 Further increase in breast size and Further increase in breast size and areolae that protrude above breast levelareolae that protrude above breast level adult pubic hairadult pubic hair

P5P5 Adult stage, pubic hair with extension Adult stage, pubic hair with extension to to upper upper thighthigh

TANNER’S CLASSIFICATION OF TANNER’S CLASSIFICATION OF SEXUAL MATURITY: BREASTSSEXUAL MATURITY: BREASTS

Th 1- child (only papillae are elevated) Th 1- child (only papillae are elevated)

Th 2 – prepubertal (breast bud and papilla are Th 2 – prepubertal (breast bud and papilla are

elevated and a small mount is present; areola elevated and a small mount is present; areola

diameter is enlarged); age 11,2 yrs (9,0-13,3 yrs)diameter is enlarged); age 11,2 yrs (9,0-13,3 yrs)

Th 3 - early pubescent, age 12,2 yrs (10,0-14,3)Th 3 - early pubescent, age 12,2 yrs (10,0-14,3)

Th 4 - late pubescent, age 13,1 yrs (10,8-15,3)Th 4 - late pubescent, age 13,1 yrs (10,8-15,3)

Th 5 - adult mature breast (recession of areola to the Th 5 - adult mature breast (recession of areola to the

mound of breast tissue, rounding of the breast mound of breast tissue, rounding of the breast

mound, and projection of only the papilla are mound, and projection of only the papilla are

evident); age 15,3 yrs (11,9-18,8)evident); age 15,3 yrs (11,9-18,8)

TANNER’S CLASSIFICATION OF TANNER’S CLASSIFICATION OF SEXUAL MATURITY: PUBIC HAIRSEXUAL MATURITY: PUBIC HAIR

P1- prepubertal/Pre-adolescent (vellus hair only, no pubic hair)P1- prepubertal/Pre-adolescent (vellus hair only, no pubic hair)

P2 - presexual hair (sparse growth of long, slightly pigmented, P2 - presexual hair (sparse growth of long, slightly pigmented,

downy hair or only slightly curled hair, appearing along labia) - downy hair or only slightly curled hair, appearing along labia) -

age 11,7 (9,3-14,1)age 11,7 (9,3-14,1)

P3 - sexual hair (hair is darker, coarser, more curled, and P3 - sexual hair (hair is darker, coarser, more curled, and

spreads above the syphysis pubis) – age 12,4 (10,2-14,6)spreads above the syphysis pubis) – age 12,4 (10,2-14,6)

P4 - mild-escutcheon (Adult-type hair; area covered is less than P4 - mild-escutcheon (Adult-type hair; area covered is less than

that in most adults; there is no spread to the medial surface of that in most adults; there is no spread to the medial surface of

thigh) – age 13,0 (10,8-15,1)thigh) – age 13,0 (10,8-15,1)

P5 - female escutcheon (Adult-type hair with increased spread to P5 - female escutcheon (Adult-type hair with increased spread to

medial surface of thighs; distribution is as an inverse triangle) – medial surface of thighs; distribution is as an inverse triangle) –

age 13,4 ( 12,2-16,7)age 13,4 ( 12,2-16,7)

GENITAL ORGANS CHANGES:GENITAL ORGANS CHANGES:

Mons pubes, labia majora & minora:Mons pubes, labia majora & minora: increase in size. increase in size.

Vagina:Vagina:

1.1. length:length: increase, appearance of the increase, appearance of the rugaerugae

2.2. eepithelium:pithelium: thick, stratified squamous, thick, stratified squamous, containing glycogencontaining glycogen

3.3. pH:pH: acidic. acidic.

UterusUterus::

enlarge, Uterus / Cervix :2 / 1enlarge, Uterus / Cervix :2 / 1

Ovaries:Ovaries:

1.1. Increase in size, almond shapeIncrease in size, almond shape

2.2. 300 thousands primary follicle at 300 thousands primary follicle at

menarche (2 million at birth)menarche (2 million at birth)

GENITAL ORGANS CHANGES:GENITAL ORGANS CHANGES:

In In prepubertyprepuberty, the ovarian size volume , the ovarian size volume

extends from extends from 0.3 to 0.90.3 to 0.9 cmcm33. More than . More than

1.01.0 cmcm33 indicates that indicates that pubertypuberty has has

begun. During puberty, the ovarian size begun. During puberty, the ovarian size

increases rapidly to a mean increases rapidly to a mean

ppostpubertalostpubertal volume of volume of 4.0 cm4.0 cm33 (1.8 to (1.8 to

5.3 5.3 cmcm33).).

MENARCHE

During puberty, plasma E2 levels fluctuate

widely, probably reflecting successive waves

of follicular development that fail to reach the

ovulatory stage. The uterine endometrium is

affected by these changes and undergoes

cycles of proliferation and regression, until a

point is reached when substantial growth

occurs so that withdrawal of estrogen results

in the first menstruation (menarche).

OVULATIONOVULATION

Plasma progesterone remains at low Plasma progesterone remains at low levels evenlevels even if secondary sexual if secondary sexual ccharacteristics have appeared. A rise in haracteristics have appeared. A rise in progesterone after menarche is, in progesterone after menarche is, in general, indicative that ovulation has general, indicative that ovulation has occured. The first ovulation does not occured. The first ovulation does not take place until 6-9 months after take place until 6-9 months after menarche because the positive menarche because the positive feedback mechanism of estrogen is not feedback mechanism of estrogen is not developed.developed.

ADOLESCENCE :ADOLESCENCE :

Is the period of life during which the Is the period of life during which the child becomes an adult personchild becomes an adult person

i.e. the physical , sexual and i.e. the physical , sexual and psychological development are psychological development are

complete . complete .

PubertyPuberty represents the represents the first part of first part of adolescenceadolescence . .

ABNORMALITIES OF PUBERTYABNORMALITIES OF PUBERTY

1 - 1 - Precocious puberty.

2 - Delayed puberty.

3 3 - Growth problems:

during adolescence e.g. short stature during adolescence e.g. short stature or tall stature, marked obesity and or tall stature, marked obesity and menstrual disorders at puberty .menstrual disorders at puberty .

FEMALE PRECOCIOUS FEMALE PRECOCIOUS PUBERTYPUBERTY

DEFINITION:DEFINITION:

It means menarche or It means menarche or appearance of any of the appearance of any of the

secondary sexual characters secondary sexual characters

bbeforeefore the age of the age of 8 years.8 years.

TYPES:TYPES:

1 1 - - TrueTrue precocious puberty.precocious puberty.

2 2 - - FalseFalse (pseudo-precocious (pseudo-precocious

puberty).puberty).

3 3 - - IncompleteIncomplete precocious puberty. precocious puberty.

1. TRUE (CENTRAL,CEREBRAL) 1. TRUE (CENTRAL,CEREBRAL) PRECOCIOUS PUBERTY.PRECOCIOUS PUBERTY.

It is due to increased production It is due to increased production of pituitary gonadotrophins.of pituitary gonadotrophins.

2. FALSE (PERIPHERAL) PRECOCIOUS PUBERTY

It is of peripheral origin. It is of peripheral origin.

It is It is due to secretion of sex hormonesdue to secretion of sex hormones (estrogen or androgen)(estrogen or androgen) which is not which is not dependent on pituitary gonadotrophins dependent on pituitary gonadotrophins as in case of estrogenic or androgenic as in case of estrogenic or androgenic ovarian tumors.ovarian tumors.

False precocious puberty may be False precocious puberty may be isosexual or heterosexual.isosexual or heterosexual.

A girl who feminizes early is defined as A girl who feminizes early is defined as having having isosexual precocious pubertyisosexual precocious puberty. .

A girl who virilize early is defined as A girl who virilize early is defined as having having heterosexual precocious pubertyheterosexual precocious puberty.. (female pseudohermaphrodite)(female pseudohermaphrodite)

2. FALSE (PERIPHERAL) PRECOCIOUS 2. FALSE (PERIPHERAL) PRECOCIOUS PUBERTYPUBERTY

3. INCOMPLETE PRECOCIOUS PUBERTY

In this case only one pubertal change In this case only one pubertal change as as breast developmentbreast development is present before is present before the age of 8 years without the presence the age of 8 years without the presence of any other pubertal changes and in of any other pubertal changes and in absence of increased estrogen absence of increased estrogen production. production.

The other pubertal changes occur at the The other pubertal changes occur at the

normal age.normal age.

Incomplete forms of precocious puberty Incomplete forms of precocious puberty

include include premature thelarchepremature thelarche (unilateral (unilateral

or bilateral), or bilateral), premature pubarchepremature pubarche and and

premature adrenarchepremature adrenarche with appearance with appearance

of pubic and axillary hair.of pubic and axillary hair.

3. INCOMPLETE PRECOCIOUS PUBERTY

PRECOCIOUS PUBERTYPRECOCIOUS PUBERTY - TERMS- TERMS

breast development - premature thelarche,

pubic development - premature pubarche

axillary hair development - premature adrenarche

menses - premature menarche

ETIOLOGY OF PRECOCIOUS ETIOLOGY OF PRECOCIOUS PUBERTYPUBERTY

1.Constitutional or idiopathic:1.Constitutional or idiopathic: In most cases of precocious puberty In most cases of precocious puberty (90%)(90%) no cause is found. no cause is found. For some unknown reason the For some unknown reason the hypothalamus stimulates the pituitary hypothalamus stimulates the pituitary gland to secrete its gonadotrophic gland to secrete its gonadotrophic hormones. hormones. There is normal menstruation and There is normal menstruation and ovulation. ovulation. Pregnancy can occur at young age.Pregnancy can occur at young age.

2. 2. Organic lesions of the brain:Organic lesions of the brain:

The next common cause. The next common cause.

Organic lesionsOrganic lesions affecting the midbrain, affecting the midbrain, hypothalamus, pineal body, or pituitary gland hypothalamus, pineal body, or pituitary gland may lead to premature release of pituitary may lead to premature release of pituitary gonadotrophins. gonadotrophins.

ExamplesExamples include traumatic brain injury, include traumatic brain injury, meningitis, encephalitis, brain abscess, brain meningitis, encephalitis, brain abscess, brain tumor as glioma, craniopharyngioma, and tumor as glioma, craniopharyngioma, and hamartomas.hamartomas.

3. McCune-Albright syndrome.3. McCune-Albright syndrome.

ETIOLOGY OF PRECOCIOUS ETIOLOGY OF PRECOCIOUS PUBERTYPUBERTY

McCune-Albright Syndrome:McCune-Albright Syndrome:

The disease is found more frequently in girls. The disease is found more frequently in girls. It consists of a triad of :It consists of a triad of :

1.1. Precocious puberty, Precocious puberty, 2.2. Cystic changes in bones, and Cystic changes in bones, and 3.3. Cafe-au lait patches of the skin.Cafe-au lait patches of the skin.

The cause of precocious puberty is The cause of precocious puberty is autonomous production of estrogen by the autonomous production of estrogen by the ovaries. ovaries. FSH and LH levels are lowFSH and LH levels are low. . The treatment is The treatment is testolactonetestolactone oral tablets oral tablets which inhibit ovarian steroidogenesis.which inhibit ovarian steroidogenesis.

4. Adrenal causes:4. Adrenal causes:

(a) Hyperplasia, adenoma, or carcinoma of (a) Hyperplasia, adenoma, or carcinoma of suprarenal cortex. suprarenal cortex.

Congenital adrenal hyperplasia and Cushing Congenital adrenal hyperplasia and Cushing syndromesyndrome lead to precocious puberty in the lead to precocious puberty in the male direction, i.e. heterosexual precocious male direction, i.e. heterosexual precocious

puberty; puberty;

(b) Estrogen secreting adrenal tumor which is (b) Estrogen secreting adrenal tumor which is very rare.very rare.

ETIOLOGY OF PRECOCIOUS ETIOLOGY OF PRECOCIOUS PUBERTYPUBERTY

5. Ovarian causes :5. Ovarian causes :

(a) (a) Estrogen producing tumorsEstrogen producing tumors as granulosa and as granulosa and theca cell tumor; theca cell tumor;

(b) (b) Androgen producing tumorsAndrogen producing tumors as as androblastoma; androblastoma;

(c) (c) ChoriocarcinomaChoriocarcinoma because it secretes human because it secretes human chorionic gonadotrophin (HCG) which may chorionic gonadotrophin (HCG) which may stimulate the ovaries to secrete estrogen; stimulate the ovaries to secrete estrogen;

(d) (d) Dysgerminoma Dysgerminoma if it secretes HCG.if it secretes HCG.

ETIOLOGY OF PRECOCIOUS ETIOLOGY OF PRECOCIOUS PUBERTYPUBERTY

6. 6. Juvenile hypothyroidism:Juvenile hypothyroidism:

Lack of thyroxine leads to increased production Lack of thyroxine leads to increased production of of TSHTSH and the secretion of pituitary and the secretion of pituitary gonadotrophins may also be increased.gonadotrophins may also be increased.

7. 7. Drugs:Drugs:

IIatrogenic may follow oral or local atrogenic may follow oral or local administration of estrogen. administration of estrogen.

A long course of estrogen cream used for A long course of estrogen cream used for treatment of vulvovaginitis of children may lead treatment of vulvovaginitis of children may lead to breast development or withdrawal bleeding.to breast development or withdrawal bleeding.

ETIOLOGY OF PRECOCIOUS ETIOLOGY OF PRECOCIOUS PUBERTYPUBERTY

1. History: 1. History: It excludes iatrogenic source of It excludes iatrogenic source of estrogen or androgen. estrogen or androgen.

It differentiates between isosexual and It differentiates between isosexual and heterosexual precocious puberty.heterosexual precocious puberty.

DIAGNOSIS OF PRECOCIOUS DIAGNOSIS OF PRECOCIOUS PUBERTYPUBERTY

2. Physical examination:2. Physical examination:

It diagnoses McCune-Albright It diagnoses McCune-Albright syndrome. syndrome.

Neurologic and ophthalmologic Neurologic and ophthalmologic examinations exclude organic lesions examinations exclude organic lesions of the brain.of the brain.

DIAGNOSIS OF PRECOCIOUS DIAGNOSIS OF PRECOCIOUS PUBERTYPUBERTY

3. Special investigations:3. Special investigations:

These are done according to the history These are done according to the history

and clinical findings and include:and clinical findings and include:

DIAGNOSIS OF PRECOCIOUS DIAGNOSIS OF PRECOCIOUS PUBERTYPUBERTY

a. a. X-ray examination of the hand and wristX-ray examination of the hand and wrist to determine bone age. to determine bone age.

Estrogen stimulates growth of bone but Estrogen stimulates growth of bone but causes early fusion of the epiphysis. causes early fusion of the epiphysis.

So the child is taller than her peers So the child is taller than her peers during childhood, but she is short during childhood, but she is short during adult life. during adult life.

3 .SPECIAL INVESTIGATIONS:

b. b. Hormonal assay:Hormonal assay:

including serum FSH, LH, prolactin, including serum FSH, LH, prolactin, estradiol, testosterone, 17estradiol, testosterone, 17αα--hydroxy progesterone, TSH, and human , TSH, and human chorionic gonadotrophin to diagnose chorionic gonadotrophin to diagnose Choriocarcinoma.Choriocarcinoma.

3. SPECIAL 3. SPECIAL INVESTIGATIONS:INVESTIGATIONS:

c.c. Ultrasonography Ultrasonography

to diagnose ovarian or adrenal tumor. to diagnose ovarian or adrenal tumor.

d. d. CT or MRICT or MRI : :

to diagnose an organic lesion of the to diagnose an organic lesion of the brain, or adrenal tumor.brain, or adrenal tumor.

3. SPECIAL INVESTIGATIONS:3. SPECIAL INVESTIGATIONS:

Hypothyroidism Hypothyroidism retards bone retards bone ageage and is the only condition and is the only condition

of precocious puberty in of precocious puberty in which bone age is retardedwhich bone age is retarded

is diagnosed after excluding is diagnosed after excluding

all other causes.all other causes.

IDIOPATHIC PRECOCIOUSIDIOPATHIC PRECOCIOUS PUBERTYPUBERTY::

TREATMENT OF PRECOCIOUS TREATMENT OF PRECOCIOUS PUBERTYPUBERTY

Objectives:Objectives:

1.1. Arrest maturation until normal pubertal Arrest maturation until normal pubertal age. age.

2.2. Attenuate & diminish established Attenuate & diminish established precocious characteristics.precocious characteristics.

3.3. Maximize adult height.Maximize adult height.

4.4. Avoid abuse, reduce emotional & social Avoid abuse, reduce emotional & social problemsproblems

1.1. Treatment of the causeTreatment of the cause, e.g., thyroxin , e.g., thyroxin for hypothyroidism, removal of ovarian for hypothyroidism, removal of ovarian and adrenal tumors.and adrenal tumors.

2.2. Incomplete formsIncomplete forms of precocious puberty of precocious puberty do not require treatment, as estrogen do not require treatment, as estrogen production is not increased.production is not increased.

TREATMENT OF PRECOCIOUS TREATMENT OF PRECOCIOUS PUBERTYPUBERTY

McCune-Albright syndromeMcCune-Albright syndrome

IIs treated with s treated with testolactonetestolactone oral tablets. oral tablets.

The drug inhibits the formation of The drug inhibits the formation of

estrogen from its precursors, so reduces estrogen from its precursors, so reduces

estrogen level. estrogen level.

The dose is The dose is 20 mg/kg20 mg/kg body weight in body weight in 4 4

divided dosesdivided doses and increased to and increased to 40 mg/kg40 mg/kg

body weight during a body weight during a 3 week3 week interval. interval.

IDIOPATHIC TYPEIDIOPATHIC TYPEis treated by explanation and reassurance is treated by explanation and reassurance

and by giving one of the following drugs and by giving one of the following drugs which inhibit the secretion of which inhibit the secretion of

gonadotrophins:gonadotrophins:(a)(a) Gonadotrophin releasing hormone analoguesGonadotrophin releasing hormone analogues

which are given as daily nasal spray, which are given as daily nasal spray, intramuscular, or subcutaneous injections every intramuscular, or subcutaneous injections every 4 weeks. 4 weeks.

(b)(b) Medroxyprogesterone acetate tabletsMedroxyprogesterone acetate tablets (Provera (Provera tablets) or intramuscular injection (Depo-tablets) or intramuscular injection (Depo-Provera); Provera);

(c) (c) DanazolDanazol capsules; capsules; (d) (d) Cyproterone acetateCyproterone acetate tablets (Androcur). tablets (Androcur).

Treatment is given till the age Treatment is given till the age

of 12 years of 12 years (mean age of (mean age of

pubertal development).pubertal development).

IDIOPATHIC TYPEIDIOPATHIC TYPE

Gonadotrophin releasing hormone Gonadotrophin releasing hormone analoguesanalogues

Drug of choice because it achieves all objectives:Drug of choice because it achieves all objectives:1.1. It acts by binding to the anterior pituitary receptors It acts by binding to the anterior pituitary receptors

causing down-regulation & desensitization of the causing down-regulation & desensitization of the pituitary. pituitary.

2.2. Regression of symptoms occurs in the first yearRegression of symptoms occurs in the first year

3.3. Delayed epiphyseal fusion; treatment more effective if Delayed epiphyseal fusion; treatment more effective if begun before bone age >12 yrs. begun before bone age >12 yrs.

4.4. Maintain E2 at <10 pg/mL. Maintain E2 at <10 pg/mL.

5.5. Children require higher doses than adults for Children require higher doses than adults for suppression. suppression.

6.6. Adrenarche will continue. Adrenarche will continue.

DELAYED PUBERTYDELAYED PUBERTY

Secondary Sexual Characters Secondary Sexual Characters do not develop by the age of do not develop by the age of

14 y14 yrsrs or or

no menstruation till age of no menstruation till age of 16y16yrsrs

It is either :It is either :• Delayed onset:Delayed onset: Breast bud does not Breast bud does not

appear till 13 years or menarche does appear till 13 years or menarche does not occur till 16 years. not occur till 16 years.

oorr• Delayed progreession:Delayed progreession: Menarche does Menarche does

not occur within 5 years after breast not occur within 5 years after breast bud. bud.

DELAYED PUBERTYDELAYED PUBERTY

ETIOLOGY OF DELAYED PUBERTYETIOLOGY OF DELAYED PUBERTY

1 - Constitutional1 - Constitutional with +ve family history, short stature & normal with +ve family history, short stature & normal fertility.fertility.

2 - Hypergonadotropic hypogonadism2 - Hypergonadotropic hypogonadism (FSH > 40) (FSH > 40) = ovarian causes of Iry amenorrhea = primary = ovarian causes of Iry amenorrhea = primary ovarian failure & 2ry ovarian failure (if occurs ovarian failure & 2ry ovarian failure (if occurs before puberty).before puberty).

3 - Hypogonadtropic hypogonadism =3 - Hypogonadtropic hypogonadism = hypothalamic & pituitary causes of Iry hypothalamic & pituitary causes of Iry amenorrhea e.g. Kallman's syndrome, amenorrhea e.g. Kallman's syndrome, Anorexia nervosa.Anorexia nervosa.

4 - Normogonadtropic hypogonadism4 - Normogonadtropic hypogonadism = end = end organ defects = uterine causesorgan defects = uterine causes (Mullerian (Mullerian agenesis and testicular feminizationagenesis and testicular feminization syndrome), imperforate hymen (c/o = delayed syndrome), imperforate hymen (c/o = delayed menarche + normal other aspects of puberty), menarche + normal other aspects of puberty), PCOD and Virilizing ovarian adrenal tumors.PCOD and Virilizing ovarian adrenal tumors.

5 - General causes of amenorrhea5 - General causes of amenorrhea (endocrinal or (endocrinal or non-endocrinal especially malnutrition) if non-endocrinal especially malnutrition) if occurred before puberty &occurred before puberty &↓↓GH & steroid GH & steroid synthesis defects .synthesis defects .

ETIOLOGY OF DELAYED PUBERTYETIOLOGY OF DELAYED PUBERTY

INVESTIGATIONS OF DELAYED INVESTIGATIONS OF DELAYED PUBERTYPUBERTY

History :History :

1 - Family 1 - Family historyhistory, nutritional history, any , nutritional history, any systemic diseases (e.g. history of systemic diseases (e.g. history of endocrinal disturbanceendocrinal disturbancess).).

2 - 2 - Clinical pictureClinical picture of space occupying of space occupying lesion in the ovary, adrenal, pituitary & lesion in the ovary, adrenal, pituitary & hypothalamus.hypothalamus.

3 - Periodic pain and +ve 2ry sexual 3 - Periodic pain and +ve 2ry sexual

characteristics in imperforate hymen .characteristics in imperforate hymen .

Examination :Examination :(A) (A) Body measurementBody measurement for causes of amenorrhea for causes of amenorrhea

+ + ↑↑ or or ↓↓ weight, short or tall stature, proportions weight, short or tall stature, proportions (upper/lower segment ratio & arm span/height (upper/lower segment ratio & arm span/height ratio).ratio).

(B) (B) Tanner stagingTanner staging of breast, pubic & axillary hair of breast, pubic & axillary hair if present.if present.

(C) (C) Clinical pictureClinical picture of Turner, Mullerian agenesis & of Turner, Mullerian agenesis & imperforate hymen.imperforate hymen.

(D) (D) Neurological examinationNeurological examination for smell sense for smell sense (Kallman's syndrome), visual field & other (Kallman's syndrome), visual field & other cranial nerve lesions .cranial nerve lesions .

INVESTIGATIONS OF DELAYED INVESTIGATIONS OF DELAYED PUBERTYPUBERTY

SPECIAL INVESTIGATIONS:SPECIAL INVESTIGATIONS:

1 - FSH & LH assay1 - FSH & LH assay important to important to differentiate level of the lesion & differentiate level of the lesion & progesterone assay in 17 OH deficiency.progesterone assay in 17 OH deficiency.

2 - Chromosomal study2 - Chromosomal study if short stature or if short stature or hypergonadotropic type.hypergonadotropic type.

3 - Radiological bone age3 - Radiological bone age study & study & radiologic study for pituitary adenomaradiologic study for pituitary adenoma..

AMENORRHEAAMENORRHEA

DEFINITIONSDEFINITIONS

Primary amenorrhea

Failure of menarche to occur when expected in relation to the onset of pubertal development.

No menarche by age 16 years with signs of pubertal development.

No onset of pubertal development by age 14 years.

PATHOPHYSIOLOGY OF PATHOPHYSIOLOGY OF AMENORRHEAAMENORRHEA

Inadequate hormonal stimulation of the Inadequate hormonal stimulation of the endomeriumendomerium “Anovulatory amenorrhea”“Anovulatory amenorrhea”

- Euestrogenic - Euestrogenic - Hypoestrogenic- Hypoestrogenic

Inability of endometrium to respond to Inability of endometrium to respond to hormoneshormones “Ovulatory amenorrhea”“Ovulatory amenorrhea”

- Uterine absence - Utero-vaginal agenesis - Uterine absence - Utero-vaginal agenesis - XY-Females (e.g T.F.S)- XY-Females (e.g T.F.S) - Damaged endometrium (e.g Asherman’s - Damaged endometrium (e.g Asherman’s

syndrome)syndrome)

EUESTROGENIC ANOVULATORYEUESTROGENIC ANOVULATORYAMENORRHEAAMENORRHEA

Normal androgensNormal androgensHypothalamic-pituitary Hypothalamic-pituitary dysfunction (stress, dysfunction (stress, weight loss or gain, weight loss or gain, exercise)exercise)HyperprolactinemiaHyperprolactinemiaFeminizing ovarian Feminizing ovarian tumourtumourNon-gonadal endocrine Non-gonadal endocrine disease (thyroid, adrenal)disease (thyroid, adrenal)Systemic illnessSystemic illness

High androgensHigh androgensPCOSPCOS

Musculinizing ovarian Musculinizing ovarian tumourtumour

Cushing’s syndromeCushing’s syndrome

Congenital adrenal Congenital adrenal hyperplasia (late hyperplasia (late onset)onset)

HYPOESTROGENIC ANOVULATORYHYPOESTROGENIC ANOVULATORYAMENORRHEAAMENORRHEA

Normal androgensNormal androgens- - Hypothalamic-pituitary Hypothalamic-pituitary

failurefailure - Severe dysfunction- Severe dysfunction - Neoplastic,destructive,- Neoplastic,destructive, infiltrative, infectious &infiltrative, infectious & trumatic conditionstrumatic conditions involving hypothalamus or involving hypothalamus or

pituitarypituitary-- Ovarian failure Ovarian failure - Gonadal dysgenesis- Gonadal dysgenesis - Premature ovarian failure- Premature ovarian failure - Enzyme defect- Enzyme defect - Resistant ovaries- Resistant ovaries - Radiotherapy, - Radiotherapy,

chemotherapychemotherapy

High androgensHigh androgens- Musculinizing ovarian - Musculinizing ovarian

tumourtumour- Cushing’s syndrome- Cushing’s syndrome- Congenital adrenal - Congenital adrenal

hyperplasia (late onset)hyperplasia (late onset)

DIAGNOSIS

HISTORY

PHYSICAL EXAMINATION

ULTRASOUND

EXAMINATION

CRYPTOMENORRHEAOutflow obstruction to menstrual blood

Imperforate hymen Transverse Vaginal septum with functioning

uterus Isolated Vaginal agenesis with functioning

uterus Isolated Cervical agenesis with functioning

uterus- Intermittent abdominal pain- Possible difficulty with micturition- Possible lower abdominal swelling

IMPERFORATE HYMEN

Once cryptomenorrhea are excluded:

The patient is a bioassay for Endocrine abnormalities

Four categories of patients are identified 1. Amenorrhea with absent or poor

secondary sex characters

2. Amenorrhea with normal 2ry sex characters

3. Amenorrhea with signs of androgen excess

4. Amenorrhea with absent uterus and vagina

FSH Serum level

Low / normal

High

Hypogonadotropichypogonadim

Gonadal dysgenesis

AMENORRHEAAMENORRHEAAbsent or poor secondary sex CharacteristicsAbsent or poor secondary sex Characteristics

AMENORRHEAAMENORRHEANormal secondary sex CharacteristicsNormal secondary sex Characteristics

- FSH, LH, Prolactin, TSH- Provera 10 mg PO daily x 5 days

+ Bleeding No bleeing Prolactin TSH

FurtherWork-up(Endocrinologist)

- Mild hypothalamic dysfunction - PCO (LH/FSH) Review FSH result

And history (next slide)

FSH

Low / normalHigh

Hypothalamic-pituitaryFailure

Ovarian failure

If < 25 yrs or primary amenorrhea karyoptype If < 35 yrs autoimmune disease

?? Ovarian biopsy

head CT- scan or MRI

- Severe hypothalamicdysfunction

- Intracranial pathology

AMENORRHEA Utero-vaginal absence

Karyotype

46-XX

Mullerian Agenesis

(MRKH syndrome)

Andogen Insenitivity

(TFS syndrome)

. Gonadal regression

. Testicular enzymes deficiency. Leydig cell agenisis

46-XY

Normal breasts& sexual hair

Normal breasts& absent sexual

hairAbsent breasts& sexual hair

AMENORRHEASigns of androgen excess

Testosterone, DHEAS, FSH, and LH

DHEAS 500-700 mug/dL DHEAS >700 mug/dLTEST. >200 ng/dL

Serum 17-OHProgesterone level

Late CAH Adrenal hyperfunction

U/S ? MRI or CT

OvarianOr adrenal

tumor

Lower elevations PCOS (High LH / FSH)

AMENORRHEA

PRIMARY AMENORRHEA

Ovarian failure 36%

Hypogonadotrophic hypogonadism 34%

PCOS 17%

Congenital lesions (other than dysgenesis) 4%

Hypopituitarism 3%

Hyperprolactinaemia 3%

Weight related 3%

GONADAL DYSGENEGONADAL DYSGENESSISIS

Chromosomally incompetentChromosomally incompetent

- Classic - Classic TTurnerurner’s syndrome (45XO)’s syndrome (45XO)

- Turner variants (45XO/46XX),- Turner variants (45XO/46XX),

(46X-abnormal X)(46X-abnormal X)

- Mixed gonadal dygenesis (45XO/46XY)- Mixed gonadal dygenesis (45XO/46XY)

Chromosomally competentChromosomally competent

- 46XX (- 46XX (ppure gonadal dysgeneure gonadal dysgenessis)is)

- 46XY (Swyer’s syndrome)- 46XY (Swyer’s syndrome)

TURNERTURNER’S SYNDROME’S SYNDROME•• Sexual infantilism and short stature.Sexual infantilism and short stature.• • Associated abnormalities, webbed neck,Associated abnormalities, webbed neck,

coarctation of the aorta,coarctation of the aorta, high-arched high-arched pallate, cubitus valgus, broad shield-like pallate, cubitus valgus, broad shield-like chest with wildely spaced nipples, low chest with wildely spaced nipples, low hairline on the neck, short metacarpal hairline on the neck, short metacarpal bones and renal anomalies.bones and renal anomalies.

• • High FSH and LH levels.High FSH and LH levels.• • Bilateral streaked gonads.Bilateral streaked gonads.• • Karyotype - 80% Karyotype - 80% 45, X0 45, X0 - 20% mosaic forms (46XX/45X0)- 20% mosaic forms (46XX/45X0)• • Treatment: HRT Treatment: HRT

Mosaic (46-XX / 45-XO) (Classic 45-XO)

TURNER’S SYNDROMETURNER’S SYNDROME

OVARIAN DYSGENESIS

NONE-DYSGENESIS NONE-DYSGENESIS OVARIAN FAILUREOVARIAN FAILURE

Steroidogenic enzyme defects (17-Steroidogenic enzyme defects (17-hydroxylase)hydroxylase)Ovarian resistance syndromeOvarian resistance syndromeAutoimmune oophoritisAutoimmune oophoritisPostinfection (eg. Mumps)Postinfection (eg. Mumps)Postoopherectomy Postoopherectomy PostradiationPostradiationPostchemotherapy Postchemotherapy

HYPOGONADOTROPHIC HYPOGONADOTROPHIC HYPOGONADISMHYPOGONADISM

• • Normal hightNormal hight• • Normal external and internal Normal external and internal

genital organs (infantile)genital organs (infantile)• • Low FSH and LHLow FSH and LH• • MRI to intra-cranial MRI to intra-cranial

pathology.pathology.• • 30-40% anosmia (30-40% anosmia (KKallmannallmann’s ’s

syndrome)syndrome)• • Sometimes Sometimes constitutional constitutional

delaydelay• • Treat according to the cause Treat according to the cause

(HRT), potentially fertile.(HRT), potentially fertile.

CONSTITUTIONAL CONSTITUTIONAL PUBERTAL DELAYPUBERTAL DELAY

•• Common cause (20%)Common cause (20%)• • Under stature and delayed Under stature and delayed

bone agebone age ( X-ray Wrist joint)( X-ray Wrist joint)• • Positive family historyPositive family history• • Diagnosis by exclusion and Diagnosis by exclusion and

follow up follow up • • Prognosis is goodPrognosis is good (late developer)(late developer)• • No drug therapy is required No drug therapy is required --

Reassurance (? HRT)Reassurance (? HRT)

WEIGHT-RELATED WEIGHT-RELATED AMENORRHOEAAMENORRHOEAAnorexia NervosaAnorexia Nervosa

11o o or 2or 2o o Amenorrhea is often first signAmenorrhea is often first signA body mass index (BMI) <17 kg/mA body mass index (BMI) <17 kg/m²² menstrual irregularity and amenorrheamenstrual irregularity and amenorrheaHypothalamic suppression Hypothalamic suppression Abnormal body image, intense fear of Abnormal body image, intense fear of weight gain, often strenuous exerciseweight gain, often strenuous exerciseMean age onset 13-14 yrs (range 10-21 Mean age onset 13-14 yrs (range 10-21 yrs)yrs)Low estradiol Low estradiol risk of osteoporosis risk of osteoporosisBulemics less commonly have Bulemics less commonly have amenorrhea due to fluctuations in body amenorrhea due to fluctuations in body wt, but crash diets can cause menstrual wt, but crash diets can cause menstrual irregularity.irregularity.Treatment : Treatment : body wt. (Psychiatrist body wt. (Psychiatrist referral)referral)

EXERCISE-ASSOCIATED EXERCISE-ASSOCIATED AMENORRHOEAAMENORRHOEA

Common in Common in girlsgirls who participate in who participate in sports (e.g. competitive athletes, sports (e.g. competitive athletes, ballet dancers)ballet dancers)Eating disorders have a higher Eating disorders have a higher prevalence in female athletes prevalence in female athletes than non-athletesthan non-athletesHHypothalamic disorder caused by ypothalamic disorder caused by abnormal gonadotrophin-releasing abnormal gonadotrophin-releasing hormone pulsatility,hormone pulsatility, resulting in resulting in impaired gonadotrophin levels, impaired gonadotrophin levels, particularly LH, and subsequently particularly LH, and subsequently low oestrogenlow oestrogen levels levels

UTERO-VAGINAL AGENISISUTERO-VAGINAL AGENISIS Mayer-Rokitansky-Kuster-Hauser Mayer-Rokitansky-Kuster-Hauser

syndromesyndrome15% of 1ry amenorrhea 15% of 1ry amenorrhea

Normal breasts and Sexual Hair Normal breasts and Sexual Hair development & Normal looking development & Normal looking external female genitaliaexternal female genitalia

Normal female range testosterone Normal female range testosterone levellevel

Absent uterus and upper vagina & Absent uterus and upper vagina & nnormal ovariesormal ovaries

Karyotype 46-XXKaryotype 46-XX

15-30% renal, skeletal and middle ear 15-30% renal, skeletal and middle ear anomaliesanomalies

Treatment : Vaginal creation (Dilatation Treatment : Vaginal creation (Dilatation vsvs Vaginoplasty) Vaginoplasty)

ANDROGEN INSENSITIVITYANDROGEN INSENSITIVITYTesticular feminization syndromeTesticular feminization syndrome

X-linked trait X-linked trait

Normal breasts but no sexual Normal breasts but no sexual hairhair

Normal looking female external Normal looking female external genitaliagenitalia

Absent uterus and upper Absent uterus and upper vaginavagina

Karyotype 46, XYKaryotype 46, XY

Male range testosterone levelMale range testosterone level

Treatment : gonadectomy after Treatment : gonadectomy after puberty + HRTpuberty + HRT

? Vaginal creation (dilatation ? Vaginal creation (dilatation VSVS Vaginoplasty)Vaginoplasty)

HORMONAL TREATMENTHORMONAL TREATMENTPRIMARY AMENORRHEA WITH PRIMARY AMENORRHEA WITH ABSENT SECONDARY SEXUAL ABSENT SECONDARY SEXUAL

CHARACTERISTICSCHARACTERISTICSTo achieve pubertal developmentTo achieve pubertal development

Premarin 5mg D1-D25 + provera 10mg D15-D25 Premarin 5mg D1-D25 + provera 10mg D15-D25 X 3 months; X 3 months; 2.5mg premarin X 3 months and 2.5mg premarin X 3 months and

1.25mg premarin X 3 months1.25mg premarin X 3 monthsMaintenance therapyMaintenance therapy

0.625mg premarin + provera 0.625mg premarin + provera oror ready HRT ready HRT preparation preparation oror 3030µg oral contraceptive pillµg oral contraceptive pill

TREATMENT OF DELAYED TREATMENT OF DELAYED PUBERTYPUBERTY

* * Constitutional:Constitutional: Reassurance. Reassurance.

* Treatment of the cause* Treatment of the cause (if treatable) or (if treatable) or cyclic estrogen-progesterone hormone cyclic estrogen-progesterone hormone replacement therapyreplacement therapy.. IIf the cause is not f the cause is not treatable, for 3 cycles: Norethistrone treatable, for 3 cycles: Norethistrone acetate 5 mg twice daily for 21 d or OCPacetate 5 mg twice daily for 21 d or OCP

* * Patient with Y chromosome cell line :Patient with Y chromosome cell line : Gonadectomy + hormone replacement Gonadectomy + hormone replacement therapy therapy

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