LECTURE 21.

1: PRIMARY AND SECONDARY AMENORRHEA AND PRECOCIOUS

PUBERTY
Dr. Barrot-Gler | May 6, 2021

OUTLINE: • incidence significantly higher in women:

o younger than 25 years
I. INTRODUCTION
o prior history of menstrual irregularity
II. DELAYED MENARCHE
III. PRIMARY AMENORRHEA WHO Classification of Amenorrhea
A. Causes of Primary Amenorrhea
a. Breasts Absent and Uterus Present Type I Type II Type III
o Gonadal Failure (Hypergonadotropic Estrogen ↓ N ↓
Hypogonadism) FSH ↓ N ↑
o 45,X Anomalies Prolactin ↓ N
o Structurally Abnormal X Chromosome Others Without Denotes
▪ Pure Gonadal Dysgenesis CNS ovarian
▪ 17α-Hydroxylase Deficiency lesions failure
with 46,XX Karyotype
o Genetic Disoders with » BEFORE PUBERTY
Hyperandrogenism
o CNS-Hypothalamic-Pituitary
Disorders
b. Breast Development Present and Uterus
Absent
o Androgen Resistance
o Congenital Absence of the Uterus
c. Absent Breast and Uterine Development
d. Secondary Characteristic (Breast)
Present and Female Genitalia (Uterus)
Present
e. Primary Amenorrhea with Absent
Endometrium
B. SECONDARY AMENORRHEA
A. Uterine Factor » DURING PUBERTY AND BEFORE MENARCHE
B. CNS and Hypothalamic Causes • body undergoes a progressive series of morphological
C. REFERENCES changes
D. APPENDIX • produced by the pubertal ↑ estrogen and androgen
production
• hypothalamus responds → puberty starts

» PUBERTY
• breast budding → pubic hair → breasts enlarge →
external pelvic contour → rapid growth rate →
β INTRODUCTION menarche

Amenorrhea – absence of menstrual bleeding » MARSHALL & TANNER 5 STAGES OF BREAST

• Types DEVELOPMENT AND PUBIC HAIR DEVELOPMENT
o Primary (never occurring)
o Secondary (cessation sometime after
initiation)
Cryptomenorrhea – another condition presenting as a problem
with outflow of menses
• Caused by anatomic disorders such as imperforate
hymen or transverse vaginal septum

Primary Amenorrhea
• Definitions:
o absence of menses in a woman who has
never menstruated by the age of 15 y.o. (» 16
OR 16.5 years)
o girls who have not menstruated within 5 years
of breast development, if occurring by age 10
o normal female external genitalia
• incidence: < 0.1%

Secondary Amenorrhea – absence of menses for an arbitrary

period, usually longer than 6-12 months

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 LECTURE 21.1: PRIMARY AND SECONDARY AMENORRHEA AND PRECOCIOUS
PUBERTY
Dr. Barrot-Gler | May 6, 2021

• Body weight and body fat – important for menstruation

as depicted in the fatness nomogram below

β DELAYED MENARCHE

• appearance of breast budding – first sign of puberty

• menarche – latest sign of puberty • Well-nourished individuals with prepubertal strenuous
• mean interval between breast budding and menarche: exercise programs (athletes: swimmers, ballet
2.3 years (SD approx. 1 year) dancers, runners) → less total body fat → delayed
• NOTE: If thelarche has not occurred by age 13, a onset of puberty (if they began exercising strenuously
diagnostic evaluation should be performed before menarche)
• Ratio of fat to both total body weight and lean body o Not a health problem
weight (body composition) – most relevant factor o Must be informed that they will most likely
that determines the time of onset of puberty and have regular ovulatory cycles when they stop
menstruation exercising or become older
o Previously thought to be based on a critical o Metabolic features of amenorrheic athletes (in
body weight of approx. 48kg (106lb) a state of negative energy balance)
o Those who are moderately obese (20-30% ▪ Elevated serum FSH and insulin-like
above body weight) → earlier onset of
growth factor-binding protein 1
menarche
o Malnutrition (anorexia nervosa, starvation) → (IGFBP-1)
delay of onset of puberty ▪ Low insulin-like growth factor (IGF)
• Leptin levels
o Adipocyte hormone
o » Important feedback involving GnRH release
and pulsatility of LH
o » Binds to specific receptor sites on ovary and
endometrium
o Plays a role in menstrual cyclicity; links body
composition and HPO axis
o Acts on hypothalamic cells → release of
GnRH triggering gonadotropin release →
release of FSH and LH → gonadal steroid
secretion → development of reproductive
tract and induction of puberty

• STRESS
o May lead to inhibition of GnRH axis
o Stress → increased secretion of CRH
(corticotropin-releasing hormone) → release
of ACTH, opioid peptides such as β-
endorphin, and cortisol
o CRH → inhibition of GnRH → amenorrhea
• Ghrelin
o Interacts with leptin

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Dr. Barrot-Gler | May 6, 2021
• Episodic pulses of LH occurring during sleep
o initial endocrinologic change associated with
the onset of puberty
o absent before onset of puberty
o after menarche, episodic secretions of LH
occur during sleep and while awake
• activation of positive gonadotropin response to
increasing levels of E2
o last endocrinologic event of puberty
o results in the midcycle gonadotropic surge
and ovulation
» PATHOLOGIC AMENORRHEA: FALSE OR TRUE
• cryptomenorrhea (see definition above)
• menstruation takes place
• there is an obstruction to menstrual flow
• congenital or acquired
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» FALSE AMENORRHEA
» Imperforate Hymen
• most common form of vaginal outflow obstruction
• normal young girls complaining of:
o cyclic lower abdominal (menstrual) pain
o lower abdominal swelling
o retention of urine or difficulty of micturition
• PE:
o Normal secondary sex characteristics: (+)
breast development, (+) pubic hair
o (+) pelvic-abdominal swelling: (+) mass,
uterus
o Bulging membranes at the introitus
o Dark blue or purple color due to retained
blood
• Management:
o Hymenectomy: incision and drainage
» Vaginal Septum and Atresia
• Uterus develops normally
• Failure of canalization of the entire vagina
• Transverse vaginal septum
• Hematometra & hematosalpinx during menstruation
cycle
• Management:
o Vaginal septum: incision
o Vaginal atresia: laparotomy – open the
uterine cavity for drainage
» TRUE AMENORRHEA
β PRIMARY AMENORRHEA
• see introduction for definition
CAUSES OF PRIMARY AMENORRHEA
• grouped on the basis of whether secondary sexual
characteristics (breasts) and female internal genitalia
(uterus) are present or absent
CLASSIFICATION OF DISORDERS
Primary Amenorrhea & Normal Female External Genitalia
I Absent breast dev’t Largest
Uterus present
II Breast Dev’t 3rd
Uterus Absent
III Absent Brest dev’t Least common
Uterus Absent
IV Breast Dev’t 2nd largest
Uterus Present
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Dr. Barrot-Gler | May 6, 2021

Breasts Absent and Uterus Present

• Breast development – biomarker of ovarian estrogen
production
• no breast development → no estrogen production
despite presence of uterus

a. Gonadal Failure (Hypergonadotropic Hypogonadism)

• Failure of gonadal development – most common
cause of primary amenorrhea (50%)
• FSH >30 mIU/mL
• Causes:
o chromosomal d/o
o deletion of all or part of an X chromosome –
most common
▪ probably due to random meiotic or
mitotic abnormality (nondisjunction,
anaphase lag)
▪ not inherited
• exception: pure gonadal dysgenesis
(46,XX) – gene disorder reported to
occur in siblings
o other genetic defects: 17α-hydroxylase
deficiency (rare)
• Lab: peripheral white blood cell karyotype to
determine presence of a Y chromosome
o If Y chromosome is present → streak of
• problem with HPO axis involves breast development
gonads should be excised due to high
• problem with Mullerian duct involves the uterus

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Dr. Barrot-Gler | May 6, 2021
possibility of subsequent malignancy
(gonadoblastomas)
o If Y chromosome is absent → excision of
gonads unnecessary unless there are signs
of hyperandrogenism
• Turner syndrome (45,X)
o deletion of entire X chromosome or short
arm (p) of X chromosome → short stature
(<60 inches in height)
o deletion of long arm does not affect height
o gonadal streak (band of fibrous tissue) in
place of the ovary
o absent ovarian follicles → no synthesis of
ovarian steroids and inhibin
▪ no inhibin + negative hypothalamic
action of estrogen → markedly elevated
gonadotropin levels, FSH higher than
LH
o absent breast development (low E2 levels)
o internal and external genitalia phenotypically
female (estrogen not necessary for mullerian
duct development or wolffian duct
regression)
• individuals with occasional mosaicism, an abnormal X
chromosome, pure gonadal dysgenesis (46,XX) or
even Turner syndrome may have few follicles from
endogenous gonadotropin stimulation early in puberty
→ limited estrogen → breast development, few
episodes of uterine bleeding → premature ovarian
failure before age 25
• primary amenorrhea + plasma FSH level higher than
40 mIU/mL → no functioning ovarian follicles in
gonadal tissues → gonadal failure
b. 45,X Anomalies
• Turner Syndrome – refer to last page
o short stature (<60 inches in height) – most
prevalent somatic abnormality
o webbing of neck, short 4th metacarpal,
cubitus valgus
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o cardiac abnormality, renal abnormalities,
hypothyroidism
o diagnosis made before puberty
o treatment: hormonal replacement therapy
• Chromosomal mosaics with primary amenorrhea and
normal female genitalia: X/XX, X/XXX, X/XX/XXX
o Generally taller and have fewer anatomic
abnormalities than 45,X karyotypes
o May have few gonadal follicles
o 20% estrogen production to menstruate
o Ovulation may occur
• Noonan syndrome
o Isolated phenotypic features of Turner
syndrome without gonadal failure
o May also occur in males
c. Structurally Abnormal X Chromosome
• Pure Gonadal Dysgenesis (46,XX and 46,XY with
Gonadal Streaks)
o Familial/genetic association
o Primary amenorrhea
o Normal stature and phenotype
o Absence of secondary sexual characteristics
o Some may a few ovarian follicles, develop
breasts, even menstruate spontaneously for
few years
o 46,XY gonadal dysgenesis
▪ Previously referred to as Swyer
syndrome
▪ Abnormal testis in utero
▪ Dysgenetic streak as in other forms
of ovarian dysgenesis
o if a Y chromosome is present with or without
any clinical signs of androgenization →
gonadectomy
• 17α-Hydroxylase Deficiency with 46,XX Karyotype
o P450 C17
o Rare
o No breast development, normal female
internal genitalia
o Have hypernatremia and hypokalemia
▪ hypertension
▪ decreased cortisol → ACTH,
mineralocorticoid levels elevated
o elevated serum progesterone levels
(3ng/mL)
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Dr. Barrot-Gler | May 6, 2021
o low 17α-hydroxyprogesterone level (0.2
ng/mL)
o elevated serum deoxycorticosterone level
(>17 ng/100mL)
o cystic ovaries, viable oocytes
o Labs:
▪ FSH
▪ Karyotype: (+) Y chromosome
▪ (+) streak gonads
o management:
▪ remove the streak gonad
▪ sex steroid replacement:
✓ conjugated equine
estrogen → develop breast
tissue
✓ progesterone: minimize
endometrial CA incidence
✓ prevent osteoporosis
▪ cortisol administration
▪ pregnancy possible by in vitro
fertilization-embryo transfer (IVF-
ET)
d. Genetic Disoders with Hyperandrogenism
• Occur in 10% of women with gonadal dysgenesis
• Most have Y chromosome or a its fragment
• Some only have a DNA fragment which contains
testes-determining gene (probably SRY) without a full
Y chromosome
e. CNS-Hypothalamic-Pituitary Disorders
• Abnormal or absent signal to the ovary → very low
circulating gonadotropin levels → low estrogen
• Conditions that may cause low gonadotropin
production
o CNS Lesions
▪ Elevated prolactin levels → primary
amenorrhea
▪ Congenital (stenosis of aqueduct,
absence of sellar floor); Acquired
tumors (pituitary adenomas)
▪ Individuals with primary amenorrhea
+ low gonadotropin levels → CT
scan or MRI to rule out presence of
a lesion
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o Inadequate Gonadotropin-Releasing
Hormone Release (Hypogonadotropic
Hypogonadism)
▪ May be familial/inherited; majority
(2/3) is sporadic
▪ KAL gene (Xp 22-3) – responsible
for neuronal migration
✓ Defect in gene may result
to absent GnRH secretion
→ gonadotropin deficiency
✓ Anosmia also observed
✓ May be given a single
bolus of GnRH to stimulate
release of FSH and LH
▪ Other genetic defects: involve X
chromosome or autosomes
(FGFR1, PROKR2, GNRHR)
▪ Labs: head CT or MRI to rule out
lesions
▪ Kallmann syndrome
✓ Females: gonadotropic
deficiency, normal height,
increased growth of long
bones (greater wingspan—
to-height ratio); anosmia
(not in all cases)
✓ Males: hypogonadism,
increase wingspan-to-
height-ratio, altered spatial
orientation abilities
▪ Management:
✓ Estrogen-progesterone to
induce breast development
and cause epiphyseal closure
✓ Fertility is desired: give
human menopausal
gonadotropins or pulsatile
GnRH
✓
o Isolated Gonadotropin Deficiency
(Pituitary Disease)
▪ Does not respond to GnRH even
after 4 days of administration
▪ Almost always have thalassemia
major (iron deposits in pituitary) or
retinitis pigmentosa
▪ Associated with prepubertal
hypothyroidism, kernicterus, or
mumps encephalitis
o Estrogen Resistance
▪ Mutation in Erα
▪ Does not allow estrogen signaling
and a biologic response to estrogen
action
▪ High endogenous estrogen, higher
than normal range gonadotropins
▪ Cystic ovaries
▪ No response to exogenous
estrogen
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Dr. Barrot-Gler | May 6, 2021
Breast Development Present and Uterus Absent
• Androgen Resistance
o testicular feminization
o XY karyotype
o Normal functioning male gonads
o produce normal male levels of testosterone
and dihydrotestosterone
o Absence of androgen receptor synthesis or
action
o 1/60,000
o Cause: absence of an X-chromosome gene
responsible for cytoplasmic or nuclear
testosterone receptor function
o X-linked, sex-linked autosomal dominant
disorder; transmission via mother
o Lack of receptors in target organs → lack of
differentiation of the external and internal
genitalia (remain feminine)
o No female or male internal genitalia
o Feminine external genitalia, short or absent
vagina
o No pubic pubic and axillary hair due to
absence of androgen receptors
o Management:
▪ gonad should be removed after full
development & epiphyseal closure
✓ increased risk of
developing malignancy,
rarely before 20 years old
▪ give lower doses of estrogen
• Congenital Absence of the Uterus
o Uterine agenesis, uterovaginal agenesis,
Rokitansky-Ksuter-Hauser Syndrome
o 2nd most frequent cause of primary
amenorrhea
o Isolated developmental defect
o Congenital absence of Mullerian ducts
o Genetically inherited
o Hox-genes – important for uterine
development
o 1 in 4, 000 to 5, 000 female births
o 15% of individuals with primary amenorrhea
o Have normal ovaries with regular cyclic
ovulation and normal endocrine function
o Normal breast, pubic, and axillary hair
development
o Have shorted or absent vagina
o History: amenorrhea, but has PMS
o PE:
▪ Normal secondary sexual
development
▪ Female external genitalia
▪ Shortened or absent vagina
▪ Renal & cardiac abnormalities
o Diagnostic:
▪ Scan / urography for other
associated abnormalities
o Management:
▪ Dilatation or vaginoplasty for a normal
sexual life
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▪ Surgical reconstructions of an absent
vagina (McIndoe procedure)
▪ Pregnancy: use of surrogate or
gestational carrier
▪ One woman had uterine transplantation
from a donated postmenopausal uterus
and was able to have a live birth
Absent Breast and Uterine Development
• Rare, male karyotype; testes present
• Elevated gonadotropin levels; testosterone levels
normal or below-normal female range
• Lack enzyme necessary to synthesize sex steroids
o 17α-hydroxylase deficiency with 46,XX
▪ Have female external genitalia
▪ Have testes, AMH-MIS is produced →
female internal genitalia regress
▪ Low testosterone level → male genitalia
does not develop
o 17,20 desmolase deficiency (occurs in
males)
• Agonadism
o AMH produced during fetal life
o Gonadal tissue regressed
o No feminine internal genitalia
o Vanishing testes syndrome
o Refer to endocrine center for
management
Secondary Characteristic (Breast) Present and Female
Genitalia (Uterus) Present
• 2nd largest category of primary of amenorrhea
• Etiology:
o Hypothalamic, pituitary, ovarian, uterine
• 25% of patients have hyperprolactinemia or
prolactinoma
• Diagnosis:
o History:
▪ Childhood growth and development
✓ Height & weight
✓ Age of thelarche
▪ Age of menarche of patient’s
mother and sisters
▪ History of chronic illness, trauma,
surgery and medications
▪ Information regarding exercise, diet
and psychosocial issues
▪ Symptoms of cyclic lower
abdominal pain, virilizing changes
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o PE:
▪ Body dimensions (height & span), B. CNS and Hypothalamic Causes
habitus • CNS Structural Abnormalities
▪ Distribution and extent of body hair o Craniopharyngiomas, Granulomatous
▪ Muscle mass or other signs of disease (TB, sarcoidosis), Sequalae of
virilization encephalitis
▪ Extent of breast development by o Circulating gonadotropins and E2 levels low
Tanner staging • Drugs
▪ Look for signs of Turner syndrome o Phenothiazines, antiHPN, diazepam
▪ Rule out pregnancy o OCPs → effect may persist for several months
▪ Pelvico-abdominal mass: ovarian after oral contraception are discontinued →
mass or hematocolpos postpill amenorrhea
▪ Pelvic exam: ▪ Should not last longer than 6 months
✓ Imperforate hymen • Stress and Exercise
✓ Evidence of exposure to o High levels of catechol estrogens and opioid
androgens: pubic hair
peptides → inhibition of GnRH and LH release
distribution or clitoromegaly
✓ Presence or absence of • Weight Loss
patent vagina or vaginal o Failure of normal GnRH release with the lack
pouch of a pituitary response under extreme
✓ Presence or absence of the conditions
uterus o May have hypoleptinemia, alterations in
✓ Pregnancy, ovarian mass, and ghrelin, GH and thyroid dysfunction
genital anomalies
o Anorexia nervosa
▪ PT
• PCOS
▪ Ultrasound
o Heterogenous disorder that may present with
✓ If genital exam is not feasible
✓ Confirm the presence of prolonged periods of amenorrhea (irregularity
absence of the uterus / oligomenorrhea)
o Confirmed by ultrasound
See Appendix for Algorithm for the Diagnosis of Primary
Amenorrhea

Primary Amenorrhea with Absent Endometrium

• Endocrine function, uterus, ovaries and fallopian tubes
normal
• Cause: genetic defect

β SECONDARY AMENORRHEA
• Patient had a period before but currently, none
• > 6-12 months without a period
• 0.7-3%
• Higher incidence in:
o <25 years old
o Prior history of irregular menstrual period
• Etiology: Anywhere in the HPO – uterus axis pathology
o Hypothalamic – 62%
o Pituitary – 16%
o Ovarian – 12%
o Uterine – 7%
CAUSES
A. Uterine Factor
• Intrauterine adhesions (IUAs) or synechiae (Asherman
syndrome) – obliterate endometrial cavity → secondary
amenorrhea
• Cause: endometrial curettage, use of mechanical
instrument to evacuate live or dead fetus or for
postabortal curettage
o IUA risk for curettage for missed abortion:
30%
• Diagnostics: hysterosalpingogram or hysteroscopy

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Dr. Barrot-Gler | May 6, 2021

REFERENCES

• Comprehensive Gynecology 7th Ed. (2017)

• Dr. Barrot-Gler’s Ppt slides and lecture

APPENDIX

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