Amenorrhea

• Menstruation


  Dependent on ovulation, estrogen, progesterone

  
• Menarche


  Average age is 12.7 years
• 2/3 girls experience menarche in genital tanner stage IV
• Amenorrhea


  Origin from Greek: A {without} meno {relating to menstruation} rrhea {discharge; flow}
• Thelarche


  • Breast development, requires estrogen
• Pubarche/adrenarche


  • Pubic hair development, requires androgens
• Pubertal changes and sequence of events between ages 10-16yrs in girls

  • Growth support (8-14 years, 6 - 10 cm/year, 2.5 years duration)
  • Breast growth (Thelarche, 8-13 years, 11 years)
  • Pubic Hair (Pubarche, 9-13 years, 1st pubertal sign in 25%)
  • Axillary Hair (Adrenarche, 9.5-15 years)
  • Menstruation (Menarche, 10-16 years, 13 years, may follow menarche)
• HPOU axis


  Menarche requires GnRH from the hypothalamus ! FSH and LH from the pituitary ! estrogen (thickens) and progesterone (sloughs/thins out) from the ovaries ! normal uterus and outflow tract
• Menstrual cycle


  Actually 3 different inter-related cycles synchronously taking place at the same time: Ovarian cycle, Hormonal cycle, Endometrial cycle
• Estrogen


  Estradiol (ovary – follicles) + estrone (androstedione – aromatization), low in early proliferative phase, rise 1 week before ovulation, maximum 1 day before LH surge, marked drop, rise again to its maximum 5-7 days after ovulation (mid luteal), baseline before menstruation
• Progestins


  Progesterone (conversion from adrenal pregnenolone + pregnenolone sulphate) + 17-OHP minimal during follicular phase, just because ovulation start to increase (from luteinized graafian follicle), rise to its maximum 5-7 days after ovulation (mid-luteal), baseline before menstruation, if pregnancy continue
• Androgens

  Directly (small amount) from ovaries + adrenals, indirectly (most amount) (metabolism from androstenedione from ovaries and adrenals)
• SHBG


  Binds most estrogens and androgens
• Prolactin


  Levels do not change strikingly during cycle
• Proliferative/follicular phase might change (may last for 14-20 days) BUT the secretory phase will always stay 14, even when you have a 35 day cycle. Compute basing on the first day of the last menstruation, when did the patient ovulate or peak? Say 35 days – 14 days. If you are expecting your period to happen on April 21, minus 14 days to know when you are ovulating.
• TVS on day 5 of menstruation because this is when endometrial lining is thinnest.
• Amenorrhea


  A symptom; not a disease. The final diagnosis should be a pathological diagnosis.
• Classification of Amenorrhea


  • Physiological (Pre-puberty, Pregnancy related, Menopause)
  • Pathological (Primary, Secondary)
• Primary Amenorrhea


  Absence of menarche by age 14 without secondary sexual characteristics, Absence of menarche by age 16 with secondary sexual characteristics, Incidence of primary amenorrhea – 1%
• Secondary Amenorrhea


  Absence of menses in a previously menstruating woman, Absence of menses for >6 months or duration of 3 menstrual cycles
• Causes of Primary Amenorrhea


  • Breast Development (30%): Müllerian agenesis (10%), Androgen insensitivity (9%), Transverse vaginal septum (2%), Imperforate hymen (1%), Physiologic delay of puberty (8%)
  • No Breast Development: high FSH (40%): 46XX (15%), 46XY (5%), Abnormal (20%)
  • No Breast Development: low FSH (30%): Constitutional delay of puberty (10%), Prolactinomas (5%), Kallman syndrome (2%), Other CNS (3%), Stress, weight loss, anorexia (3%), PCOS (3%), Congenital adrenal hyperplasia (3%), Other (1%)
• Top causes of Primary Amenorrhea


  • Turner syndrome (45,XO), Mullerian Agenesis, Androgen insensitivity syndrome, Swyer syndrome (XY Gonadal dysgenesis)
• History and Findings in Primary Amenorrhea

  • Completion of stages of puberty? Development of axillary and pubic hair? Breast development? (Ovarian or pituitary failure and chromosomal abnormality)
  • Family history of delayed or absent puberty? (Familial disorder, Constitutional delay of puberty)
  • Height relative to family members? (Turner's syndrome)
  • Symptoms of virilization? (PCOS, Ovarian or adrenal tumor)
  • Presence of Y chromosome (Swyer syndrome)
  • Recent stress? Change in weight, diet, or exercise? (Functional hypothalamic amenorrhea)
  • Medications (ie antidepressants, antipsychotics)? (Hyperprotactinemia)
  • Galactorrhea? (Hyperprolactinemia)
  • Headaches, visual field defects, fatigue, polyuria, or polydipsia? (Hypothalamic-pituitary disease)
• Physical Exam and Clinical Presentation in Primary Amenorrhea

  • Assess Tanner stage
  • Growth parameters evaluation of pubertal development (height, weight) and growth chart (Low BMI can delay onset of menses, Short stature (genetic or endocrine disorder), Evaluation for features of Turner's syndrome)
  • Examine skin for hirsutism, acne, striae, increased pigmentation, and vitiligo
  • Genital exam (Intactness of hymenal opening, Enlarged clitoris, Tanner stage, Vaginal exam)

  
• Signs in Primary Amenorrhea

  • Absent breast development (Inadequate estrogen production)
  • Absence of uterus (Abnormal Müllerian development or XY karyotype)
  • Presence of uterus and breasts (Obstruction of menstrual flow or HPO axis problems)
• Diagnosis of Primary Amenorrhea

  • Pregnancy test
  • Hormone levels (Androgens/male hormone test, Ovary function test measuring the amount of FSH, Thyroid function, Prolactin)
  • Karyotype
  • Pelvic ultrasound
  • MRI of head/pituitary if elevated prolactin level or abnormal neurologic findings
  • CT scan
  • Hysteroscopy

  
• Quick rules to remember

  • No breast – no or low estrogen (<FSH, LH – hypothalamic or pituitarian, >FSH, LH – ovarian)
  • No uterus (46XX – Mullerian agenesis or karyotype, 46XY - pseudohermaphroditism)
• Evaluation categories


  • Breast absent – uterus present (B-U+)
  • Breast present - uterus present (B+U+)
  • Breast present – uterus absent (B+U-)
  • Breast absent – uterus absent (B-U-)
• Etiology of Amenorrhea


  • Breast-Absent, Uterus absent (B-U-): Think low estrogen, check FSH (17,20 desmolase deficiency, 17 a hydroxylase deficiency 46XY, Agonadism, Gonadal failure turner 45X, Gonadal dysgenesis, 17 a hydroxylase deficiency with 46XX, Hypothalamic failure, Pituitary failure)
  • Breast-Absent, Uterus present (B-U+): Think low estrogen, check FSH (Gonadal failure: High FSH (hypergonadotropic), CNS-hypothalamic pituitary disorders: Low FSH (hypogonadotropic))
  • Breast-Present, Uterus absent (B+U-): AIS (T.F.)
  • Breast-Present, Uterus present (B+U+): Hypothalamic, pituitary, ovarial pt uterine etiology, Müllerian agenesis

  
• Causes of Compartment I: Breasts Absent and Uterus Present

  • Gonadal failure: High FSH (hypergonadotropic) (45X (Turner's Syndrome), 46X; abnormal X (Deletion Disorders), Mosaicism (X/XX, X/XX,/XXX), Pure XX (PGD, 46XX, or Perrault syndrome), 17 alpha-hydrogenease deficiency (46XX))
  • CNS-hypothalamic pituitary disorders: Low FSH (hypogonadotropic) (CNS lesions, Inadequate GnRH – Kallmann's, Isolated gonadotropin insufficiency)
• Causes of Compartment II: (Ovarian) pathologies

  • Hypergonadotropic hypogonadism (Turner syndrome – 45XO/Mosaic/Partial Deletions (1o amenorrhea), Pure gonadal dysgenesis (1o amenorrhea), Mixed gonadal dysgenesis (1o amenorrhea), PCOS (2 o amenorrhea), Savage syndrome (2 o amenorrhea))
  • Gonadal Dysgenesis (Tuner syndrome (45,X) – MC chromosomal abnormality causing gonadal failure and primary amenorrhea, Pure gonadal dysgenesis (Swyer's dynrome: 46; XY + Defect in SRY-Gene, Bilateral streak gonads, Geno – male; phenol – female, Infantile uterus present, Height – normal/Tall, 1o amenorrhea), Mixed gonadal dysgenesis (Mosaics (46; XY + 45;XO), Testis present, Streak ovary (1o amenorrhea), Ambiguous Genitalia)

  
• Causes of Compartment IV: (Hypothalamic) Pathologies

  • Hypogonadotropic hypogonadism (Constitutional delay (physiological), Genetic – Kallman syndrome, Malnutrition (both 1o and 2 o), Anorexia/Bulimia nervosa (both 1o and 2 o), Vigorous exercise/stress/anxiety (both 1o and 2 o))
  • Kallman Syndrome (Congenital GnRH deficiency, Anosmia + amenorrhea + color blindness, Poorly developed secondary sexual characters, Cleft lip/palate, Congenital disorder characterized by: Anosmia or hyposmia, Primary amenorrhea, Caused by defect in synthesis and release of gonadorelin (LH releasing hormone))

  
• Category 2: Breasts present and uterus absent


  Think (+) estrogen, (?) MIF: check karyotype
• Mayer Rokitansky Kuster Hauser Syndrome (46XX)

  • Vaginal agenesis and no uterus, Caused by random birth defect, 15% of primary amenorrhea, 2nd MC cause, Normal 2o development and external female genitalia, Testosterone level – normal female range, Absent uterus and upper vagina and normal ovaries, Karyote 46XX
• Hypogonadotropic hypogonadism

  Insufficient pulsatile secretion of GnRH, leading to developmental or genetic defects, inflammatory processes, tumors, vascular lesions, or trauma
• Causes of hypogonadotropic hypogonadism


  • Constitutional delay (physiological)
  • Genetic – Kallman syndrome
  • Malnutrition (both 1o and 2 o)
  • Anorexia/Bulimia nervosa (both 1o and 2 o)
  • Vigorous exercise/stress/anxiety (both 1o and 2 o)
• Kallman syndrome


  • Congenital GnRH deficiency
  • Anosmia + amenorrhea + color blindness
  • Poorly developed secondary sexual characters
  • Cleft lip/palate
  • Congenital disorder characterized by anosmia or hyposmia and primary amenorrhea
• Kallman syndrome is caused by a defect in synthesis and release of gonadorelin (LH releasing hormone)
• Mayer Rokitansky Kuster Hauser Syndrome


  Vaginal agenesis and no uterus, caused by a random birth defect, 15% of primary amenorrhea, 2nd most common cause, normal 2o development and external female genitalia, testosterone level – normal female range, absent uterus and upper vagina and normal ovaries, karyotype 46XX, 15-50% renal, skeletal, and middle ear abnormalities

  
• Androgen insensitivity syndrome


  Cells are not receptive to testosterone thus patient has intra-abdominal testes and no uterus or vagina, previously called testicular feminization/pseudohermaphrodite, most common cause of male intersex, normal breasts but sparse/absent sexual hair, normal looking female external genitalia, testosterone level – male range, absent uterus and upper vagina, karyotype 46XY, gynotype: XY, phenotype: female