Amenorrhea Flashcards
What are the 3 most common causes of amenorrhea?
1) Hyper-hypo (gonadal dysgenesis)
2) Mullerian Agenesis
3) Congenital AIS
Etiology of MRKH
Activating (gain of fxn) mutation in AMH or AMH-R; association with GALT mutation?
Presentation of MRKH
Normal therlarche and pubarche
Short vagina without symptoms of obstructed menses
Some with skeletal and urologic abnormalities
What percentage of MRKH women have concomitant urologic abnormalities?
15-40%
Imaging of choice for MRKH eval
MRI
Treatment for MRKH
Creation of fxnl vagina (dilators, McIndoe, Vecchieti); gestational carrier
Anatomy of congenital defect in urogenital sinus development
Agenesis of lower vagina
Imperforate hymen
2 etiologies of intrauterine adhesions
Asherman syndrome
TB endometritis
3 categories of anatomic abnormalities leading to amenorrhea
Congenital abnormalities of Mullerian development (MRKH, AIS, 5-alpha reductase def)
Congenital defect in urogenital sinus development
Intrauterine adhesions
3 categories of disorders of HPO axis leading to amenorrhea
Hypothalamic dysfunction
Pituitary dysfunction
Ovarian dysfunction
Pathophysiology of Kallman’s syndrome
Failure of olfactory and GnRH neuronal migration from olfactory placode
Genetics of Kallman’s syndrome
X-linked (most common): Anosmin 1 – males only!
Encoded by KAL1 gene on X chromosome (short arm)
Part of fibronectin family, responsible for cell adhesion and protease inhibition
Autosomal:
Fibroblast growth factor receptor (FGF-1 R/KAL2) – autosomal dominant;
female with amenorrhea/anosmia
Prokinecticin (PROK2) – autosomal recessive; can be normosmic or anosmic
Mechanism of anovulation in anorexia
CRH-mediated opioid suppression of GnRH
Metabolic abnormalities with anorexia
- Decreased: FSH, LH, E2, IGF-1, leptin, T3
- Increased: cortisol, reverse T3, ghrelin, GH, NPY
- Normal: PRL, TSH, T4
3 main categories of hypothalamic dysfunction
Isolated GnRH deficiency (Kallman’s)
Functional hypothalamic amenorrhea (ie eating d/o, stress, excessive exercise)
Brain tumors, cranial radiation, TBI
% of non-functional pituitary tumors that derive from gonadotrophs
80-90%
Pathophys of how gonadotroph tumors affect HPO axis
Stalk compression
- Interrupt GnRH
- Block dopamine –> increase prolactin
LH, FSH, TSH, HCG structure
Common alpha subunit, different beta subunit
Messenger system for GnRH stimulation of LH and FSH production
G protein second messenger, calcium dependent system
Rate limited step in synthesis of LH and FSH
Synthesis of beta subunits of each gonadotropin (prior question: alpha subunits common and secreted with non-functional tumors)
Clinical presentation of gonadotropin adenomas
Markedly supranormal FSH level associated with a subnormal LH concentration
A serum free alpha subunit concentration that is supranormal when intact FSH and LH are not
Markedly elevated serum estradiol concentration and an FSH concentration that is not suppressed, associated with endometrial hyperplasia and polycystic ovaries (a la OHSS); even a “normal” FSH is not appropriate when the estradiol is markedly elevated and the LH suppressed.
Ddx of pituitary dysfunction leading to amenorrhea (4)
Hyperprolactinemia
Pituitary tumors
Empty sella syndrome
Pituitary infarct of apoplexy
Most common chromosomal abnormality in gonadal dysgenesis
Turner syndrome
Most frequent abnormal karyotype in SABs
45X
Genetics of Turner Syndrome
Deletion in SHOX (short stature homeobox-containing gene located on the psuedoautosomal region (PAR) at the distal end of Xp -> haploinsufficiency of SHOX
Other genes located on Xp (mental retardation, X-linked Icythosis, Kallman’s syndrome
Mosaic Turner syndrome presentation
Visible (non-streak) ovaries + spontaneous breast development/uterine growth
Autoimmune disorders seen with Turner syndrome
Thyroiditis (hypothyroidism), type 1 DM, autoimmune hepatitis
Fragile X mutation
FMR1 (Fragile X Mental Retardation -1) gene = (terminal end) of long arm of X chromosome
% sporadic and familial POF with Fragile X
1-7% sporadic
14% familial
Amino acid repeat sequence in fragile X
CGG
Repeats for normal, premutation, and fragile X
Normal = 30
Premutation = 55-200
Fragile X Syndrome = >200
Most common genetic cause of mental retardation and autism
Fragile X
Pathophysiology of Fragile X
trinucleotide repeat expansion
hypermethylation of gene
gene silencing
no production of FMR protein (a translational inhibitor)
overproduction of mRNAs
Two syndromes in Fragile X
Fragile X-associated tremor/ataxia syndrome
Premature ovarian insufficiency
Fragile X-associated tremor/ataxia syndrome: persons affected
Primarily male pre-mutation carriers, usually after age 50
Fragile X-associated tremor/ataxia syndrome phenotype
Intention tremor, ataxia, autonomic dysfunction, cognitive deficits, behavioral abnormalities, peripheral neuropathy
Galactosemia genetics
Very rare; autosomal recessive deficiency of galactose 1-phosphate uridyl transferase
Galactosemia fertility finding
Low AMH, POI
POI Ddx (7)
Gonadal dysgenesis, Fragile X, Turner’s, galactosemia, chemotherapy/raditation, autiommune, receptor abnormalities/enzyme deficiencies, idiopathic
+anti-thyroid (TPO) antibodies
Hashimonto’s
% women with POI with Hashimoto’s
14-27%
name of condition: +anti-adrenal (21-OH) antibodies
Auto-Immune oophoritis
% women with POI with auto-immune oophoritis
2-10%
Eval for adrenal insufficiency in setting of POI
Check for 21-OH antibodies
→ If positive, AM cortisol level
→ high: (>18) excludes adrenal insufficiency; low AM cortisol → ACTH stim test
• 0.25 mg cosyntropin → check cortisol level before and 1 hour after
• stimulated cortisol level > 18 ug/dL is a normal response
Genetics of 17-alpha hydroxylase deficiency
Deficiency of the product of the CYP17 gene, which is an enzyme that has both 17-hydroxylase and 17,20-lyase activities
Can occur in 46,XX or 46,XY patients
17-alpha hydroxylase deficiency: cortisol, ACTH, corticosterone, and deoxycorticosterone levels
Cortisol decreased
ACTH, corticosterone, deoxycorticosterone overproduced
17-alpha hydroxylase deficiency: adrenal and gonadal sex steroids
Not produced
17-alpha hydroxylase deficiency phenotype
Phenotypic females with hypertension (due to mineralocorticoid excess), lack of pubertal development, and either female (if 46,XX) or incompletely developed (if 46,XY) external genitalia
What is BMP15?
Oocyte specific growth factor that stimulates (+) folliculogenesis and granulosa cell proliferation (TGF-B superfamily)
BMP15 mutation inheritance?
Heterozygous (on X-chromosome)
BMP15 mutation implications for fertility
Identified in a small number of women with idiopathic POI
What is FOXL-1/2?
Forkhead box transcription factor = required for normal granulosa cell function
FOXL-1/2 mutation inheritance?
Autosomal dominant
What does FOXL-1/2 mutation cause?
Blelpharophimosis/ptosis/epicanthus inversus syndrome (BPES)
Name 3 steroidogenic enzyme defects that cause amenorrhea/POI
StAR enzyme (congenital lipoid adrenal hyperplasia)
CYP 17A1 (17 hydroxylase) mutation
CYP 19A1 (aromatase)
Diagnosis of inactivating FSH or LH B subunit mutation?
Normal level of one gonadotropin/undetectable level of other gonadotropin
Ddx receptor abnormalities and enzyme deficiencies leading to POI (8)
- 17-alpha hydroxylase def
- P450 oxidoreductase (POR) deficiency
- Estrogen resistance
- BMP15 mutations
- FOXL-1/FOXL-2 mutation
- Steroidogeneic enzyme defects
- Inactivating FSH or LH B subunit mutation
- FSH receptor or LH receptor mutations
PCOS, hyper/hypo-thyroidism, uncontrolled DM, and exogenous androgen use can all lead to what fertility outcome?
POI
