Reviewer: PRIMARY AMENORRHEA PRIMARY AMENORRHEA

SIGNS OF PUBERTY • Defined as:

• Thelarche (breast budding) – 1st sign of puberty  Never menstruated by age 15
• Pubarche – hair growth  (+) Breast budding at age 10 but no menstruation within
• Rapid growth rate 5 years
• Menarche – 4th and final sign of puberty  ≥ 13 y/o without breast budding → needs evaluation
• Group according to: (+) or (-) of secondary sex characteristics
DELAYED MENARCHE (breast and uterus)
• Body composition is more important than total body weight in
determining the onset of puberty and menstruation BREAST ABSENT, UTERUS PRESENT
• Most relevant factor that determines onset of puberty and • Breast development is a biomarker of ovarian estrogen
menstruation: RATIO of FAT to TOTAL BODY WEIGHT and production, so absent breast and present uterus would signify
LEAN BODY WEIGHT NO ESTROGEN production → can be d/t:
 Moderately obese – earlier onset  Primary ovarian disorder
 Malnutrition, less body fat (ex. athletic) – delayed onset  CNS-hypothalamic-pituitary abnormality
• LEPTIN – produced by adipocytes → correlate with BW  Gonadal failure
 For feedback of GnRH and LH pulsatility  Genetic disorders w/ hyperandrogenism
• STRESS – inhibits GnRH axis
 Stress = release of CRH → CRH inhibits GnRH GONADAL FAILURE (HYPERgonadotropic Hypogonadism)
Features of amenorrheic athletes: • Most common cause of primary amenorrhea
• Negative energy balance • Gonadal failure = (-) ovaries or testis
• ↑ FSH • Present as:
• ↑ IGFBP-1 (-) Breast
No ovaries → no estrogen
• ↓IGF development
Before puberty: No ovaries → no ovarian follicle → no
• FSH and LH are both low (ratio > 1) kasi the CNS-hypothalamic ESTROGEN and INHIBIN prod. → no
↑ FSH
axis is very sensitive to the low levels of estrogen present which negative feedback by estrogen +
exerts a negative feedback inhibitory action of inhibin
• When critical weight and body composition is reached, the Gonadal streak In place of ovary; band of fibrous tissue
axis becomes less sensitive → secretion of more GnRH → External and internal genitalia are
increase in FSH and LH NORMAL FEMALE (estrogen not
Phenotypically
Endocrinologic changes after puberty onset: needed for Mullerian duct development
or Wolffian duct regression)
1st change Episodic pulses of LH during sleep
After Episodic LH pulses occur during sleep AND • Causes of gonadal failure:
menarche while awake  Chromosomal disorders – mitotic or meiotic abnormality
→ NOT inherited
Activation of positive gonadotrophin response
 Deletion of all or part of an X chromosome
Last change to increasing levels of estrogen (E2) →
 17-a hydroxylase deficiency
midcycle gonadotrophic surge and ovulation
• Diagnosis of Gonadal failure: FSH LEVEL CONSISTENTLY
ELEVATED without requiring ovarian tissue evaluation

• Deletion of entire X chromosome

• Short stature (<60 in.), webbing of neck,
45, X
short 4th metacarpal, cubitus vaginalis
• Cardiac, renal abnormality, hypothyroid
• Karyotype: 46, XX
Structurally
• Deletion of short arm (p) – short stature
abnormal X chr.
• Deletion of long arm (q) – normal height
• Karyotype: X/XX, X/XXX, X/XX/XXX
Chromosomal • Primary amenorrhea with normal female
mosaics external genitalia
• Noonan’s syndrome – in men
• Karyotype: 46, XX and 46, XY
Pure Gonadal • Primary amenorrhea, (-) 2ndary sex
Dysgenesis characteristics, normal stature and
phenotype, gonadal streaks
• ↑ Aldosterone and progesterone
• ↓ cortisol and androgens
17a hydroxylase
• Hypernatremia, hypokalemia
def.
• Treatment: estrogen + progesterone,
cortisol

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 Genetic disorders with HYPERANDROGENISM CONGENITAL ABSENCE OF UTERUS (Uterine Agenesis)
• Most have Y chromosome (46,XY), a fragment of Y chromosome • NO UTERUS + shortened or absent vagina
or DNA fragment (SRY) that contains testes-determining gene • NORMAL ovaries, regular cyclic ovulation, normal endocrine
• Gonadal dysgenesis + hyperandrogenism = increased risk for function, normal breasts, pubic and axillary hair development
dysgerminoma and gonadoblastoma → GONADECTOMY • Inherited
• May be able to have kids via surrogate or IVF
CNS-Hypothalamic-Pituitary Disorders
• Low secretion of gonadotropins = low estrogen Remember for ddx:
• LOW FSH AND ESTROGEN • Uterine agenesis – endocrinologically female
• Androgen resistance – endocrinologically male
CNS lesions = low gonadotropin production
• Congenital – stenosis of aqueduct, (-) stellar floor BREAST AND UTERUS ABSENT
• Acquired – tumors (ex. pituitary adenoma • Male karyotype, elevated gonadotropin levels, testosterone
levels in the normal or below normal female range
IF: primary amenorrhea, low FSH, with or without elevated
• Differentials:
prolactin level = CT or MRI of hypothalamic-pituitary
 17a-hydroxylase deficiency – have female genitalia since
region → rule out lesions
may (-) synthesis ng sex steroids (androgens)
 Agonadism – “vanishing testes syndrome” → no gonads
HYPOgonadotropic Hypogonadism (Hypothalamus) and female internal genitalia (hypothesis: AMH-MIS
• Inadequate GnRH release: hypothalamic or CNS production occurred during fetal life → regression of
neurotransmitter Mullerian duct → no uterus)
• Stimulation by GnRH = increased FSH and LH
• Anosmia – defect in KAL gene BREAST ABSENT, UTERUS ABSENT
• Hyperprolactinemia and prolactinomas
Isolated Gonadotropin Deficiency (Pituitary Gland)
• Associated with: thalassemia major, retinitis pigmentosa SUMMARY
• NO INCREASE in FSH and LH upon GnRH stimulation Breast absent, uterus present
• Gonadal failure (High FSH, low estrogen)
Gonadal Failure (HYPER) CNS-Hypo-Pit (HYPO) • Genetic disorders w/ hyperandrogenism (virilization)
High FSH, Low estrogen Low FSH and estrogen • CNS-hypothalamic-pituitary disorders (Low FSH and estrogen)
• Estrogen resistance – mutation in Era
BREAST PRESENT, UTERUS ABSENT
• Androgen Resistance Breast present, uterus absent
• Congenital Absence of Uterus • Androgen resistance: MALE (XY) → no female internal genitalia,
normal female external genitalia and breast development
ANDROGEN RESISTANCE • Congenital Absence of Uterus – no uterus, normal ovaries
• X-linked recessive or sex-linked autosomal dominant
• Absence of X-chromosome gene responsible for cytoplasmic or Breast and Uterus absent
nuclear testosterone receptor function • Male karyotype, elevated gonadotropin levels, testosterone
• Patient is MALE (has XY karyotype) → therefore they have levels in the normal or below normal female range
TESTES → produces testosterone and MIF (AMH)
 MIF (AMH) – regression of Mullerian duct → NO OVARIES Breast and Uterus present
and UTERUS → primary amenorrhea • Hyperprolactinemia and prolactinomas
 Testosterone – however, target organs lack receptors for
androgens → regression of Wolffian duct → automatically Secondary Amenorrhea
develops FEMALE EXTERNAL GENITALIA • (-) Menses for 6-12 months
• NORMAL breast development – lack of androgen action on • More common
breast → estrogen breast stimulation
• Absent or scanty axillary
or pubic hair – lack of
receptors = lack of response
to androgens
• Short or absent vagina
• Management: Remove
abnormal gonad after 18
y/o to avoid malignancy
• No uterus → can never be
pregnant

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