10/16- Disorders of the Ovary and Female Reproductive Tract Flashcards
Describe the genetics influencing ovary development
- No gene generates an ovary from an undifferentiated gonad
- It is the absence of SRY (sex determining region Y aka testis-determining factor)
Describe formation/maturation of the ovary
- Embryological origin?
- Primordial germ cells migrate to the genital ridge -> primary oocytes
- Remainder of female reproductive organs formed from the paramesonephric (Müllerian) ducts in the absence of AMH
- Recall, AMH formed by Sertoli cells in testes
What are the Mullerian structures?
?
- Uterus
- Fornix
- Upper 1/3 of vagina

What hormones do the ovaries produce?
- Pathway of these hormones/conversion
Ovaries:
- Vast majority of estrogens and
- 1/3 of circulating testosterone
- And contribute to another 1/3 of T by generating androstenedione)
- Peripheral conversion of this ovarian androstenedione and adrenally produced androstenedione and DHEAS results in the other 2/3 of circulating testosterone
Describe the hormones behind the menstrual cycle
- Hypothalamus secretes GnRH (pulsatile)
- GnRH stimulates pituitary to secrete LH and FSH
- LH and FSH trigger ovulation
- The ovaries secete hormones that act on the endometrial lining and feed back to the hypothalamus and pituitary
- GnRH pulsatility (90-120 min) -> FSH -> estradiol -> inhibits FSH
- Estradiol -> increases GnRH pulse frequency to 60 min -> LH
- Estradiol -> directly on pituitary -> LH
- LH -> ovary -> estradiol -> increases pituitary sensitivity to GnRH -> LH surge -> ovulation
- Ruptured follicle (corpus luteum) -> progesterone -> reduces GnRH pulse frequency
What is primary amenorrhea?
- Secondary?
- Hypomenorrhea?
- Primary amenorrhea: the delay of menarche beyond the age of 16, or, in the absence of secondary sexual characteristics, beyond age 13
- Secondary amenorrhea: is a condition in which menstruation begins at the appropriate age, but later ceases for 6 or more months in the absence of normal causes such as pregnancy, lactation, or menopause.
- Hypomenorrhea: a diminution in the quantity of menstrual flow based on tampon or napkin requirement
What is hypermenorrhea?
An increase in duration, quantity or both of menstrual flow that occurs at normal cycle intervals
What is oligomenorrhea?
A recurrent prolongation of intermenstrual intervals leading to a decreased frequency of menses (fewer than 6 to 8 per year).
What is polymenorrhea?
A menstrual flow that is near normal in quantity and duration but which occurs too frequently
What is anovulation?
Most common cause of amenorrhea during the reproductive years
- Differs from ovarian failure in that oocytes remain in the ovary
What can cause amenorrhea?
(Go up/down hypothalamic/pituitary/gonadal axis):
- Hypothalamic defects (estrogen deficient state)
- Pituitary defects (estrogen deficient state)
- Ovarian failure (estrogen deficient state)
- Anovulation despite adequate estrogen
- Outflow tract disorders (anatomical)
What hypothalamic disorders could result in amenorrhea?
- Isolated GnRH deficiency
- Functional hypothalamic amenorrhea
- Tumors (craniopharyngioma, metastatic carcinoma, lymphoma)
- Infiltrative
- Sarcoidosis
- Histiocytosis
- Hemochromatosis
What causes isolated GnRH deficiency?
- Genetics
- Pathogenesis
- Symptoms
- Treatment
Several genetic lesions, most famously Kallman’s syndrome
PATHOGENESIS
- GnRH neurons originate from the olfactory area during embryogenesis
- GnRH and olfactory neurons migrate together along cranial nerves connecting the nose and forebrain to the hypothalamus
- Mutations that affect this migration result in hypogonadotropic hypogonadism and anosmia
- Kal-1 and FGFR1
GENETICS
- Mostly sporadic, some familial
- Mostly XLR (AD and AR patterns much less common)
Treatment: replace hormones to stimulate secondary sex characteristics and bone density
What is going on in Functional Hypothalamic Amenorrhea?
- Causes
- Responsible for 15-35% of amenorrhea cases
- Reduced GnRH drive -> low/low-normal serum levels of FSH and LH -> anovulation
Causes:
- By definition, no pathologic disease; no organic anatomic problem
- Possibly mediated through leptin (an adipocyte hormone)
- Anorexia or extreme exercise
- Associated with hypercortisolemia
- Mild hypercortisolemia can be induced by extreme psychological distress, anorexia… (not Cushing’s levels)
What are risk factors for Functional Hypothalamic Amenorrhea?
- Eating disorders (anorexia nervosa)
- Exercise
- Psychological stress/perfectionism
- Weight (> 10% below IBW)
- Nutritional deficiencies (severely reduced fat intake)
- “Female athlete triad”
- Disordered eating
- amenorrhea
- Osteoporosis
Treatment for Functional Hypothalamic Amenorrhea?
- Cognitive behavioral therapy for stress
- Returning BMI to normal
What is happening in pituitary amenorrhea
- Causes
Genetic causes:
- GnRH receptor mutations
- FSHβ
- Prop-1
Prolactinoma
- Prolactin supresses GnRH secretion and can increase DHEA-S
Sheehan’s syndrome
- Pituitary infarction from postpartum hemorrhage
Any other cause of panhypopituitarism
What FSH levels are seen in ovarian amenorrhea?
FSH > 40
What can cause ovarian amenorrhea?
- Ovarian agenesis/dysgenesis
- Premature failure
- Menopause
What is seen here?

Streak gonads that have undergone fibrotic degeneration in a patient with Turner’s syndrome
- Turner’s is characterized by gonadal agenesis/dysgenesis
- Genetics = 45X
- Mosaic Turner’s (45X, 46XX) may not present with full Turner’s phenotype, but perhaps just premature failure
Characteristics of Turner’s syndrome?
- Genotype
- Phenotype
Genotype:
- Majority are mosaics (45X / 46XX, etc)
- Varying degrees of phenotype
- May have some secondary sexual development or menstruation
Classic findings:
- Primary amenorrhea
- Short stature
- Sexual immaturity
- Webbed neck
- Short metacarpals
- Broad chest and widely spaced nipples
- Droopy eyelids
- Low hairline
- Low-set ears
- Short fourth toe and short fingers
- Coarctation of the aorta
What is seen here?

Features of Turner’s syndrome (45X)
- Short stature, short neck
- Rotated and low-set ears
- Webbed neck
- Broad chest and widely spaced nipple
- Genu valgum
What is Premature Ovarian Failure?
Ovarian failure after puberty but before age 40
What are causes of premature ovarian failure?
- Karyotype abnormalities (e.g., Turner’s mosaics)
- Autoimmune
- Part of polyglandular autoimmune syndrome
- Hard to diagnose outside of characteristic syndrome
- Iatrogenic
- Radiation/chemotherapy
- Idiopathic (> 50%)
What is menopause?
- Permanent cessation of menstrual periods
- Diagnosis made after 12 mo of amenorrhea without other obvious pathological or physiological cause
- Mean age 51 yo
- Fertility diminishes beginning 10 years prior
What are symptoms of Menopause?
- Hot flashes (80-85%)
- Night sweats
- Irregular menses during transition
- Vaginal dryness
- Sleep disturbances
- Late consequences:
- Bone loss (1-2% per year)
- Increased LDL, decreased HDL
- Increased risk of stroke and CVD
What is happening when you have anovulation with estrogen present?
- Causes?
Excess estrogen or androgen leads to inappropriate feedback and ovulatory failure
Causes
- Polycystic Ovarian Syndrome
- Congenital Adrenal Hyperplasia
- Cushing’s Syndrome
- Obesity
- Androgen Secreting Tumor
What is Polycystic Ovarian Syndrome
- # 1 cause of what?
- Criteria for diagnosis
- Must exclude
- Age
- Responsible for 30% of amenorrhea
- # 1 cause of hyperandrogenic anovulation
Criteria: 2 of the following 3
- Oligo- or anovulation
- Clinical (acne, hirsuitism) and/or biochemical signs of hyperandrogenism
- Polycystic ovaries (by imaging)
Exclusion of other etiologies:
- Congenital adrenal hyperplasia
- Androgen-secreting tumors
- Cushing syndrome
Usually manifests in the peripubertal years
Describe Polycystic Ovarian Syndrome
- Prevalence
- Associations
- Etiology
- Occurs in 5-7% of reproductive age women
Associations:
- 40-50% are overweight
- 50-60% have insulin resistance
- Can manifest as acanthosis nigricans or metabolic syndrome
Etiology unclear, but there is a strong genetic component
What are sequelae of Polycystic Ovarian Syndrome?
- Infertility
- Long term risks of insulin resistance
- Unopposed estrogen -> endometrial cancer
How should Polycystic Ovarian Syndrome be managed/treated?
- Diet and exercise
- Insulin sensitizers (metformin)
- OCPs: for irregular menses, reduction of endometrial ca risk, and hirsuitism
What are some Outflow Tract Disorders
- What is the structural problem
Müllerian Agenesis
aka Mayer-Rokitansky-Küster-Hauser syndrome (46XX)
- No Müllerian structures + renal and bone abnormalities
Complete Androgen Insensitivity (46XY)
- This person will have AMH (have Y chromosome and SRY gene driving teste devo and testosterone + AMH production)
- Can’t stabilize Wolffian structures; can’t virilize; functional deficiency in testosterone (actual levels normal or high)
- Appears externally female, but blind vagina, scant hair;
- No Müllerian structures + decreased body hair
Congenital outflow obstruction
- Transvaginal septum, imperforate hymen
- Cyclic lower abdominal pain because pelvic organs are present
- These pts will present at time of normal menarche with cyclic abdominal pain
Asherman Syndrome
- Intrauterine adhesions
- Frequent etiology is endometrial curettage (post-miscarriage?)
What is hypertrichosis?
Excessive growth of non-androgen dependent hair (hairiness; NOT Hirsuitism)
What is Hirsuitism?
Excessive androgen dependent hair growth
- Upper lip, chin
- Midsternum, upper abdomen
- Back, buttocks
What is seen in virilization?
Hirsutism + additional signs and symptoms such as:
- Deepening of the voice
- Breast atrophy
- Increased muscle bulk
- Clitoromegaly
What causes hirsuitism and virilization?
The result of the interaction between circulating serum androgens and the sensitivity of the hair follicle to androgens
Cause:
- Excessive adrenal or ovarian secretion of androgens or
- Excessive conversion of weak androgens to testosterone and dihydrotestosterone in peripheral tissues
- Adrenal secretory products (DHEA, DHEA sulfate, and androstenedione) = weak androgens, but can be peripherally converted to testosterone and dihydrotestosterone
Describe etiology of Hirsuitism and Virilization
- Prevalence
- Ethnicity
5-10% of women of reproductive age
- Up to 30% in some populations
Different ethnic groups vary in the normal amount of body hair
What is the scoring system for Hirsuitism?
Ferriman-Gallwey
- Each of the nine body areas is rated from 0 (absence of terminal hairs) to 4 (extensive terminal hair growth)
- Upper lip, upper arms, chin, groin, upper chest, linea alba, upper back, lower back, mons pubis
- Total score of > 6–8 generally defines hirsutism
What is the differential diagnosis for Hirsuitism/virilization?
- Most important: rule out malignancy (adrenal or ovarian adenocarcinoma)
- Check T and DHEAS
- Cushing’s syndrome
- Non-classic adrenal hyperplasia
- PCOS
- Drugs:
- Androgens
- Anabolic steroids
- Progestins
- Hyperprolactinemia
- Idiopathic
What is Idiopathic Hirsuitism?
- Severity
- Menstrual cycle features
- Sporadic or familial
- Serum T
- Mild to moderate hirsutism
- Normal menses
- Onset with adrenarche/menarche or weight gain
- Positive family history
- Serum total T levels not necessarily elevated, but bioavailable T levels may be increased
- LB, a 34 y/o female, has not achieved a pregnancy despite 3 years of unprotected intercourse.
- Her menarche was at age 12, menses have been irregular, she had amenorrhea for 3 months, she has moderate hirsutism.
Appropriate w/u includes:
A. Serum testosterone, free testosterone
B. Pregnancy test
C. Serum prolactin
D. Serum DHEAS
A. Serum testosterone, free testosterone
B. Pregnancy test
C. Serum prolactin
D. Serum DHEAS
- Whenever you see a pt with amenorrhea, the most important test is pregnancy test; the rest are appropriate, but…
- Looking at testosterone levels for adrenal secreting tumor or POS
- Look at prolactin for prolactinoma
- Look at serum DHEAS for adrenal secreting tumor
- 17 year old presents with primary amenorrhea, she has breast development, however she lacks pubic and axillary hair, and has a small blind ending vagina.
- You request an ultrasound, but in the meantime the labs are coming back and you find elevated testosterone and LH.
What do you expect?
A. Asherman Syndrome
B. Mullerian agenesis
C. Androgen Insensitivity
D. Swyer’s syndrome (XY gonadal dysgenesis)
E. Turner syndrome
A. Asherman Syndrome- scarring of the uterus; would not expect elevated testosterone
B. Mullerian agenesis
C. Androgen Insensitivity- no sex hormone dependent hair despite elevated testosterone levels. Not responding to testosterone levels, so receptor problem
D. Swyer’s syndrome (XY gonadal dysgenesis)- gonads scarred and fibrotic form very early age; no AMH so Mullerian structures are present and testosterone level is low (dysfunctional gonads from early development on)
E. Turner syndrome- no testis determining factor or AMH, so should have uterus/cervix (not the case here)