Amenorrhea

Question 1

What are the 3 most common causes of amenorrhea?

Answer 1

1) Hyper-hypo (gonadal dysgenesis)
2) Mullerian Agenesis
3) Congenital AIS

Question 2

Etiology of MRKH

Answer 2

Activating (gain of fxn) mutation in AMH or AMH-R; association with GALT mutation?

Question 3

Presentation of MRKH

Answer 3

Normal therlarche and pubarche
Short vagina without symptoms of obstructed menses
Some with skeletal and urologic abnormalities

Question 4

What percentage of MRKH women have concomitant urologic abnormalities?

Answer 4

15-40%

Question 5

Imaging of choice for MRKH eval

Answer 5

MRI

Question 6

Treatment for MRKH

Answer 6

Creation of fxnl vagina (dilators, McIndoe, Vecchieti); gestational carrier

Question 7

Anatomy of congenital defect in urogenital sinus development

Answer 7

Agenesis of lower vagina

Imperforate hymen

Question 8

2 etiologies of intrauterine adhesions

Answer 8

Asherman syndrome

TB endometritis

Question 9

3 categories of anatomic abnormalities leading to amenorrhea

Answer 9

Congenital abnormalities of Mullerian development (MRKH, AIS, 5-alpha reductase def)
Congenital defect in urogenital sinus development
Intrauterine adhesions

Question 10

3 categories of disorders of HPO axis leading to amenorrhea

Answer 10

Hypothalamic dysfunction
Pituitary dysfunction
Ovarian dysfunction

Question 11

Pathophysiology of Kallman’s syndrome

Answer 11

Failure of olfactory and GnRH neuronal migration from olfactory placode

Question 12

Genetics of Kallman’s syndrome

Answer 12

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

Question 13

Mechanism of anovulation in anorexia

Answer 13

CRH-mediated opioid suppression of GnRH

Question 14

Metabolic abnormalities with anorexia

Answer 14

Low serum FSH, LH, E2, IGF-1, leptin, T3
Increased cortisol, reverse T3, GH, NPY
Normal PRL, TSH, T4

Question 15

3 main categories of hypothalamic dysfunction

Answer 15

Isolated GnRH deficiency (Kallman’s)
Functional hypothalamic amenorrhea (ie eating d/o, stress, excessive exercise)
Brain tumors, cranial radiation, TBI

Question 16

% of non-functional pituitary tumors that derive from gonadotrophs

Answer 16

80-90%

Question 17

Pathophys of how gonadotroph tumors affect HPO axis

Answer 17

Stalk compression

• Interrupt GnRH
• Block dopamine –> increase prolactin

Question 18

LH, FSH, TSH, HCG structure

Answer 18

Common alpha subunit, different beta subunit

Question 19

Messenger system for GnRH stimulation of LH and FSH production

Answer 19

G protein second messenger, calcium dependent system

Question 20

Rate limited step in synthesis of LH and FSH

Answer 20

Synthesis of beta subunits of each gonadotropin (prior question: alpha subunits common and secreted with non-functional tumors)

Question 21

Clinical presentation of gonadotropin adenomas

Answer 21

 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.

Question 22

Ddx of pituitary dysfunction leading to amenorrhea (4)

Answer 22

Hyperprolactinemia
Pituitary tumors
Empty sella syndrome
Pituitary infarct of apoplexy

Question 23

Most common chromosomal abnormality in gonadal dysgenesis

Answer 23

Turner syndrome

Question 24

Most frequent abnormal karyotype in SABs

Answer 24

45X

Question 25

Genetics of Turner Syndrome

Answer 25

 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

Question 26

Mosaic Turner syndrome presentation

Answer 26

Visible (non-streak) ovaries + spontaneous breast development/uterine growth

Question 27

Autoimmune disorders seen with Turner syndrome

Answer 27

Thyroiditis (hypothyroidism), type 1 DM, autoimmune hepatitis

Question 28

Fragile X mutation

Answer 28

FMR1 (Fragile X Mental Retardation -1) gene = (terminal end) of long arm of X chromosome

Question 29

% sporadic and familial POF with Fragile X

Answer 29

1-7% sporadic | 14% familial

Question 30

Amino acid repeat sequence in fragile X

Answer 30

CGG

Question 31

Repeats for normal, premutation, and fragile X

Answer 31

Normal = 30 Premutation = 55-200 Fragile X Syndrome = >200

Question 32

Most common genetic cause of mental retardation and autism

Answer 32

Fragile X

Question 33

Pathophysiology of Fragile X

Answer 33

```  trinucleotide repeat expansion  hypermethylation of gene  gene silencing  no production of FMR protein (a translational inhibitor)  overproduction of mRNAs ```

Question 34

Two syndromes in Fragile X

Answer 34

Fragile X-associated tremor/ataxia syndrome | Premature ovarian insufficiency

Question 35

Fragile X-associated tremor/ataxia syndrome: persons affected

Answer 35

Primarily male pre-mutation carriers, usually after age 50

Question 36

Fragile X-associated tremor/ataxia syndrome phenotype

Answer 36

Intention tremor, ataxia, autonomic dysfunction, cognitive deficits, behavioral abnormalities, peripheral neuropathy

Question 37

Galactosemia genetics

Answer 37

Very rare; autosomal recessive deficiency of galactose 1-phosphate uridyl transferase

Question 38

Galactosemia fertility finding

Answer 38

Low AMH, POI

Question 39

POI Ddx (7)

Answer 39

Gonadal dysgenesis, Fragile X, galactossemia, chemotherapy/raditation, autiommune, receptor abnormalities/enzyme deficiencies, idiopathic

Question 40

+anti-thyroid (TPO) antibodies

Answer 40

Hashimonto's

Question 41

% women with POI with Hashimoto's

Answer 41

14-27%

Question 42

+anti-adrenal (21-OH) antibodies

Answer 42

Auto-Immune oophoritis

Question 43

% women with POI with auto-immune oophoritis

Answer 43

2-10%

Question 44

Eval for adrenal insufficiency in setting of POI

Answer 44

Check for 21-OH antibodies  If positive, AM cortisol level (>18 excludes adrenal insufficiency)  If 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

Question 45

Genetics of 17-alpha hydroxylase deficiency

Answer 45

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

Question 46

17-alpha hydroxylase deficiency: cortisol, ACTH, corticosterone, and deoxycorticosterone levels

Answer 46

Cortisol decreased | ACTH, corticosterone, deoxycorticosterone overproduced

Question 47

17-alpha hydroxylase deficiency: adrenal and gonadal sex steroids

Answer 47

Not produced

Question 48

17-alpha hydroxylase deficiency phenotype

Answer 48

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

Question 49

What is BMP15?

Answer 49

Oocyte specific growth factor that stimulates (+) folliculogenesis and granulosa cell proliferation (TGF-B superfamily)

Question 50

BMP15 mutation inheritance?

Answer 50

Heterozygous

Question 51

BMP15 mutation implications for fertility

Answer 51

Identified in a small number of women with idiopathic POI

Question 52

What is FOXL-1/2?

Answer 52

Forkhead box transcription factor = required for normal granulosa cell function

Question 53

FOXL-1/2 mutation inheritance?

Answer 53

Autosomal dominant

Question 54

What does FOXL-1/2 mutation cause?

Answer 54

Blelpharophimosis/ptosis/epicanthus inversus syndrome (BPES)

Question 55

Name 3 steroidogenic enzyme defects

Answer 55

 StAR enzyme (congenital lipoid adrenal hyperplasia)  CYP 17A1 (17 hydroxylase) mutation  CYP 19A1 (aromatase)

Question 56

Diagnosis of inactivating FSH or LH B subunit mutation?

Answer 56

Normal level of one gonadotropin/undetectable level of other gonadotropin

Question 57

Ddx receptor abnormalities and enzyme deficiencies leading to POI (8)

Answer 57

``` 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 ```

Question 58

PCOS, hyper/hypo-thyroidism, uncontrolled DM, and exogenous androgen use can all lead to what fertility outcome?

Answer 58

POI