Ovulatory Dysfunction & Infertility

Question 1

What is the difference between ovulation and anovulation?

Answer 1

• Ovulation
  
  • Menstrual bleeding at regular intervals btwn 21-35 days
  • Presence of premenstrual moliminal
  • Breast tenderness, abdominal bloating, mood disturbance
• Anovulation
  
  • Bleeding at longer or irregular intervals

Question 2

Progestin Challenge Test

Definition

When to use it

Answer 2

• When estrogen status is unclear
• Medroxyprogesterone acetate (5-10 mg) administered daily (7-14 days)
• Menstrual bleed should ensue in normally estrogenized patients
• Any spotting or bleeding in 2 wks after progestin withdrawal is considered a + progestin challenge
• See flow chart on slide 6

Question 3

What are the 4 classifications of Ovulatory Disorders?

Answer 3

• Hypothalamic-pituitary failure
• Hypothalamic-pituitary dysfunction
• Ovarian failure
• Secondary HPO dysfunction

*see table page 3 of handout

Question 4

Goals in treating ovulatory dysfunction

Answer 4

• Identify hypoestrogenic patients who lack spontaneous or progestin-induced menstrual bleeding
• Differentiate Hypogonadotropism, Hypergonadotropism & Normogonadotropism
• Exclude underlying medical conditions that produce secondary ovulatory dysfunction

Question 5

What are some contributing factors in management of ovulatory dysfunction?

Answer 5

• Stress, anxiety or depressive disorders
• Excessive weight gain
• Over or insidious eating disorders
• Strenuous exercise w/o appropriate nutritional intake
• Preoccupation w/ thinness

Question 6

Polycystic Ovarian Syndrome (POS)

Definition

Criteria

Answer 6

• Most common endocrine disorder in women
• Broad spectrum of clinical phenotypes
• 2/3 of the following criteria
  
  • Oligo-ovulation or anovulation
  • Clinical and/or biochemical signs of Hyperandrogenism
  • Polycystic ovaries
    
    • < 12 follicles in each ovary
    • 2-9 mm and/or ovarian volume < 10 mL

Question 7

**Premature Ovarian Insufficiency **

Definition

Etiology

Answer 7

• Hypergonadotropic hypogonadism before age 40 (elevated FSH/LH)
• Commonly associated w/ depletion of ovarian follicles (like menopause)
• Cessation of regular menses
• 1% of all women, 90% of cases 30-40 YO
• Etiology
  
  • Normal physiologic process but at unusually young age
  • Identifiable pathology

Question 8

**Premature Ovarian Insufficiency **

Causes

X chromosome anomalies

Fragile X syndrome

Answer 8

• Causes: genetic, autoimmune, idiopathic, iatrogenic
• Specific X chromosome anomalies
  
  • Most common: 45, X & 47, XXY
  • 2nd most common: variable mosaicism
• Fragile X syndrome
  
  • Pre-mutation carriers at increased risk for POI (16-21%)
  • Expansion of triplet repeat w/i exon 1 of the FMR1 X-linked gene
  • Expansions of 50-200 repeats are pre-mutations

Question 9

What is sufficient for a diagnosis of Premature Ovarian Insufficiency? (POI)

Answer 9

Menopausal serum FSH levels (>40 IU/L) on at least two occasions in a woman <40 YO

Question 10

Intrauterine Adhesions

Definition

Antecedent factor

Diagnosis

Answer 10

• Synechiae (Asherman’s syndrome)
• Can obliterate the endometrial cavity & produce secondary amenorrhea
• Most likely to result from procedures that damage the endometrial cavity
• Rare: missed abortion or endometrial tuberculosis
• Most frequent antecedent factor: endometrial curettage associated w/ pregnancy
• Confirmation of diagnosis
  
  • Hysterosalpingogram or hysteroscopy
• Severe cases
  
  • Endometrium obliterated
  • Amenorrhea b/c of adhesions & lack of normal endometrial tissue
• Patients still have menstrual periods but either recurrent miscarriage or infertility

Question 11

Define

Infertility

Primary Infertility

Secondary Infertility

Answer 11

• Infertility – 1 yr period of unprotected intercourse w/o successful conception
• Primary Infertility – patient who has never been pregnant
• Secondary Infertility – patient w/ previous history of pregnancy regardless of outcome

Question 12

What are the causes of Infertility?

Answer 12

• Abnormalities of sperm production/transport (25%)
• Ovulation disorders (27%)
• Abnormalities of the female reproductive tract (22%)
  
  • Tubal factor (scarring due to endometriosis, surgery)
  • Peritoneal factor (endometriosis, scarring)
• Unexplained (15%)
• Immunologic factors (less common)

Question 13

What are the 2 components of a Reproductive Tract Evaluation?

Answer 13

• Hysterosalpingography (HSG)
  
  • Radiographic evaluation that allows visualization of the cavity of the uterus & tubes
• Sonohysterography & Sonohysterosalpingography
  
  • Ultrasound-based test similar to HSG
  • Fluid medium instilled through cervix to evaluate the reproductive anatomy

Question 14

What is done in an Evaluation of Oocyte Reserve?

Answer 14

• Day 2 or 3 FSH & Estradiol
  
  • Elevated levels consistent w/ diminished ovarian reserve
  • HPO feedback loop
• Anti-Müllerian hormone
  
  • β-glycoprotein synthesized by granulosa cells
  • Small antral & preantral follicles in the ovary
  • Directly proportional to a woman’s ovarian reserve
• **Antral follicle counts by ultrasound **

Question 15

What is done in an Evaluation of Ovulation?

Answer 15

• Regular menstrual cycles & moliminal symptoms = most likely ovulating
• Basal body temperature (BBT) chart
• Home urinary ovulation predictor kits
• Serum progesterone levels
  
  • >3 mg/mL provides reliable evidence of ovulation
• Endometrial biopsy
  
  • Confirm presence of secretory endometrium

Question 16

of remaining ovarian follicles _____ w/ age & become progressively ____ _________ to the gonadotropin stimulation required for maturation/ovulation.

Answer 16

decline

less sensitive

Question 17

What are the 3 ways to treat infertility?

Answer 17

Clomiphene Citrate

Aromatase Inhibitors

Gonadotropins

Question 18

Clomiphene Citrate

Indications

Mechanism

Answer 18

• Most commonly used oral agent for induction of ovulation
• 2 main indications
  
  • Induction of ovulation in women w/ Anovulatory infertility
  • Stimulation of multifollicular ovulation or enhancing ovulation in ovulatory infertile women
• Non-steroidal triphenylethylene derivative
• SERM – estrogen agonist & antagonist properties

Question 19

Clomiphene Citrate

Side Effects

Answer 19

• Hot flashes
• Bloating, cramping
• Nausea
• Mood swings
• Visual disturbances (rare)
• Multiple pregnancies (4-10%)
• Rare risk of Ovarian Hyperstimulation Syndrome

Question 20

Aromatase Inhibitors

Example

Mechanism

Answer 20

• Primary agents for ovulation induction
• Letrozole (FDA off label use)
• Inhibition of E2 production
• Negative feedback –> increases FSH levels
• Pregnancy rates comparable to those w/ CC alone
• Reduced incidence of multiple pregnancies

Question 21

Gonadotropins

Indications

Answer 21

• Patients w/ hypothalamic amenorrhea
• Anovulatory patients who don’t respond to Clomiphene Citrate or Aromatase Inhibitors
• Patients undergoing hormonal stimulation for IVF or for multifollicular recruitment to be paired w/ intrauterine insemination

Question 22

Gonadotropins

Examples

Answer 22

• Human menopausal Gonadotropin
  
  • HMG, Pergonal, Humegon, Menopur
• FSH – Bravelle, Metrodin, Gonal-F, Follistim
• GnRH antagonists
  
  • Ganirelix, Cetrorelix
  • Prevents LH surge during controlled ovarian hyperstimulation
• hCG administered intramuscularly to induce follicular maturation & ovulation