Primary amenorrhea

Question 1

Definition of primary amenorrhea

Answer 1

• Lack of menarche (3 categories)
• Age 16, no menses regardless of secondary sex characteristics
• Age 14, no menses and no secondary sex characteristics
• No period 5 yrs after breast development
• We differentiate the causes of primary amenorrhea based on presence (or absence) of breasts (+/- estrogen) and the presence or absence of a uterus (+/- absence of AMH, absence is genetically female)
• Possible areas of pathology: hypothal, pit, ovary, uterus/vagina

Question 2

Causes of Br+/Ut+ primary amenorrhea

Answer 2

• If the pt is Br+/Ut+ then they are genetically female and are making estrogen (form ovaries)
• Hypothal/pit causes: hypo or hyperthyroidism (thyroid hormone inhibits GnRH), prolactinoma indicated by breast discharge (prolactin inhibits GnRH)
• Vaginal causes: imperforate hymen, tranverse vaginal septum
• These are characterized by cyclic abd pain, bluish budge at perineum (MRI)
• Asherman’s syndrome: scarring of uterine cavity

Question 3

Causes of Br+/Ut- primary amenorrhea 1

Answer 3

• Pt is making estrogens, but does not have uterus
• Must identify if pt is genetically male or female, usually done by karyotyping
• If 46XY then its androgen insensitivity syndrome: mutations in androgen receptor make it unresponsive to T
• Testes are present (usually in groin- first part of descent is AMH dependent but second part is DHT/T dependent), but external genetalia and phenotype are of female (either have blind vaginal pouch or dimple on perineum)
• Wolffian structures are lost (not sensing the T), thus have no internal genitalia
• Pts have no pubic hair (can’t respond to T), and large breasts due to aromatization of the T to E via aromatase in fat cells
• Testes must be removed after puberty b/c high risk of malignancy

Question 4

Causes of Br+/Ut- primary amenorrhea 2

Answer 4

• If 46XX its mullerian agenesis: unknown cause of failure to develop internal female gentalia
• These pts also either have dimple on perineum or blind vaginal pouch, they have full secondary sex characteristics including pubic hair
• The uterine remnant (if present) must be removed b/c high risk for endometriosis
• Easy way to tell if the pt is XX or XY: look at pubic hair
• 46XY (androgen insensitivity) will not have pubic hair (and T levels will be equivalent to men)
• 46XX (mullerian agenesis) will have pubic hair (T levels will be female levels)

Question 5

Causes of Br-/Ut+ primary amenorrhea

Answer 5

• Most common cause of primary amenorrhea, problem must be in ovary or above b/c don’t have breasts (not making E)
• Must check the levels of gonadotrophic hormones: if FSH/LH< 5 then problem is in hypothal/pit (hypogonadotropic hypogonadism)
• If FSH> 20 and LH>40 then problem is in ovary (hypergonadotropic hypogonadism)

Question 6

Hypogonadotrophic hypogonadism hypothalamic and pituitary causes of primary amenorrhea (Br-/Ut+) 1

Answer 6

• Constitutional delay (hypothal): all stages of puberty absent, family Hx, Dx of exclusion
• Hypothalamic dysfxn (athlete, anorexia, stress): interruption of pulsatile GnRH due to high cortisole (clinical Hx)
• Kallmann’s syndrome (rare): failure of GnRH neurons to migrate to hypothalamus, accompanied by anosmia (olfactory neurons also don’t migrate)

Question 7

Hypogonadotrophic hypogonadism hypothalamic and pituitary causes of primary amenorrhea (Br-/Ut+) 2

Answer 7

• Pituitary tumor (including stalk effect): mass compression suppressing gonadotropin release, either from craniopharyngiomas or macroadenomas
• Can lead to bitemporal hemianopsia
• Must check to see if adenomas are functional or not: acromegaly (GH, test IGF1), cushings (ACTH, 24hr cortisol), galactorrhea (prolactin)
• Can infuse GnRH and measure LH response to see if problem is in hypothal or pit (LH pit)

Question 8

Ovarian causes of primary amenorrhea (hypergonadotrophic hypogonadism, Br-/Ut+)

Answer 8

• Must do karyotyping to see if 46XX, 45X or 46XY
• Causes if 46XX: gonadal dysgenesis (most common, deafness= perrault syndrome), autoimmune, resistant ovary syndrome, galactosemia
• If 45X (turner’s syndrome): accelerated oocyte loss, appear short, shielded chest, webbed neck w/ cardiac and skeletal abnormalities
• If 46XY: gonadal dysgenesis (absence of SRY region) leads to ovaries and female internal/external genetalia but insufficient E production for breast development
• Must remove gonads due to risk of malignancy

Question 9

Br-/Ut- primary amenorrhea etiologies

Answer 9

• XY 17 hydroxylase deficiency (very rare), no steroid hormones are made but AMH is made (no internal genitalia)
• Like androgen insensitivity and mullerian degeneration have blind vaginal pouch/perineum dimple as external female genitalia
• No steroid hormones = no male internal genitalia, no breast development
• Do get build of hormone precursors-> cortisol and mineral corticoids (young pt presenting w/ HTN and hypokalemia)