IE 3: Infertility ENDO

What is infertility?

• Couple’s inability to become pregnant after:

  • 1 year of unprotected intercourse (women ≤ 35 yo)

  • 6 months of unprotected intercourse (women > 35 yo)

    • Certain abnormal menstruation patterns

What is fecundity?

• The likelihood of becoming pregnant within a given period

What is sterility?

• Complete inability to create off-spring

Why has there been a decline in fertility in the USA?

• Changing roles for women

• Postponing of marriage

• Delayed childbearing age

• Increased use of contraception

• Increased use of abortion

• Deteriorating environment or unfavorable economic conditions

  
  

When is fertility peak and decline? When is significant fertility decline?

• Fertility peak ~ early 20s

• Fertility decline ~ late 20s

• Significantly fertility decline ~ late 30s

What are factors that affect fertility?

• Ovarian aging (“biological clock”)

• Gynecologic diseases

• Hormonal changes

• Increased likelihood of spontaneous abortions (chromosomal abnormalities in fetus)

What is the pathophysiology of infertility?

• Cervical Factor (<10%)

• Uterine Factor (<10%)

• Tubal/peritoneal Factor (40%)

• Ovulatory Factor (40%)

• All factors are evaluated, if none apply, couple is deemed as having “unexplained infertility”

  • Male Factor (1/3 of couples)

    
    

In ovulatory factor, what is anovulation origins?

• Hypothalamic origin: low GnRH, low or normal FSH/LH, follicle maturity compromised

  • Excessive stress, extreme weight loss due to exercise, anorexia nervosa; Kallmann syndrome

• Pituitary origin: normal GnRH, low or normal LH/FSH

  • Pituitary tumors

• Ovarian origin: PCOS (reversible, follicle immaturity due to insulin resistance), common to see LH/FSH ratio > 3; premature ovarian failure, chromosomal abnormalities, iatrogenic causes like chemotherapy

  
  

What is the WHO classification of ovulatory D/O?

• Class I – Hypogonadotropic hypogonadal anovulation

  • Least common

  • Ex: excessive exercise, low body weight

• Class II- Normogonadotropic normoestrogenic anovulation

  • Most common

  • Ex: PCOS

• Class III – Hypogonadotropic hypoestrogenic anovulation

  • Primary gonadal failure (“premature ovarian failure”)

    
    

When assessing patients, what history should you look for?

• Menstrual history (painful, irregular)

• Pregnancy history

• Contraceptive history

• Pain during intercourse, changes in hair growth, weight changes, breast discharge

In patient assessment, what is ovulation confirmation?

• Daily basal body temperature (not predictive)

• Serum progesterone > 3ng/mL (drawn 1 week before menses on ~CD21)

• Urinary LH (can have some predictive ability)

What is general assessment of ovulatory function?

• FSH & LH – r/o ovarian failure or hypothalamic/pituitary anovulation

• TSH – r/o thyroid causes for anovulation

• Prolactin – can be elevated in hypothyroidism, pituitary tumor, etc

Anti-mullerian hormone levels show what?

• Anti-Mullerian Hormone (AMH) levels measured anytime.

• Decreases with age, levels <1ng/mL have poorest outcomes

  
  

What is Antral Follicle Counts used in?

• Often used in IVF after receipt of FSH to prepare for collection

What factors are assessed through imaging and other studies?

• Tubal, uterine, peritoneal factors

What are some non-pharm recs?

• Weight and stress management

• Cessation of tobacco, alcohol, illicit substances

• Patient education!

  • Pre-conception counseling

  • Menstrual cycle

  • Home monitoring (OPK, BBT, CM changes, timing of intercourse)

    
    

When selecting therapy, what is the process?

• 1.What is the problem leading to infertility?

• 2.Options:

  • 1.Promote ovulation

  • 2.Delay ovulation to allow for adequate maturation time (prevent premature LH surge)

• 3.Can directly give gonadotropins, GnRH agonists/antagonists, or drugs to promote release of endogenous hormones (like clomiphene)

  
  

What is ovulation induction?

• Process which treats ovulation dysfunction by promoting development of at least 1 ovarian follicle through use of medications

• Controlled ovarian hyperstimulation or superovulation (meant for use with ART

What is the MOA of Clomiphene Citrate (Clomid, Serophene)?

• Oral, non-steroidal estrogen receptor modulator

  • Down-regulates estrogen receptors in the hypothalamus (inhibits negative feedback by estrogen so FSH & LH secretion can increase)

  • Stimulates follicle development and spontaneous ovulation

  • “Enhances the normal process”

What is Clomiphene best for?

• Ovulatory dysfunction

• Intact HPO axis

What is Clomiphene dosing?

• Dosing: 50mg daily on CD 5-9 after spontaneous or progesterone induced menses

  • If ovulation does not occur in first 2 cycles, can increase to 100mg/day on cycle 3

  • Doses above 100mg/day do not improve results, 6 cycle max for use

  • Can be combined with other agents like hCG, metformin, gonadotropins

    
    

What do you monitor while on Clomiphene?

• Monitoring

  • Mid-luteal progesterone levels (should be 8 to 10 ng/mL)

  • Alternatives:

    • Transvaginal ultrasound

    • Home OPK or BBT (may not be as reliable)

What are adverse effects of Clomiphene?

• Vasomotor symptoms (“hot flashes”)

• Abdominal discomfort, ovarian enlargement, HA, nausea, mood swings

• Visual disturbances (dose-related)

• Anti-estrogenic AEs: decreased quantity/quality of CM, thinning of endometrium

• Multiple births

What are the aromatase inhibitors and what is the MOA?

• Aromatase Inhibitors (Letrozole (Femara®), Anastrozole
  (Arimidex®)

• Off-label Use

• Oral, aromatase inhibitors that prevent conversion of androgens into estrogens

• Like clomiphene citrate, “enhance natural ovulation process”

• Testosterone → block to Estradiol

• Androstenedione → block to Estrone

What is dosing for Letrozole and Anastrozole?

• Letrozole 2.5mg to 5mg daily (max 7.5mg/day) given on CD 3-7 or 5-9

  • Better data, similar efficacy to clomiphene for pregnancies, pregnancy loss, multiple births

• Anastrozole 1mg, 5mg, or 10mg daily given on CD 3-7 or 5-9

What are aromatase inhibitors best for?

• Ovulatory dysfunction

• Intact HPO axis

• PCOS, BMI > 30kg/m²

What are AE of aromatase inhibitors?

• Vasomotor symptoms (“hot flashes”)

• Nausea, vomiting, leg cramps, fatigue, dizziness

• No changes to endometrium since estrogen receptors are not affected

• Multiple births

• Concern for fetal teratogenicity in early fetal development

What do exogenous gonadotropins do and what can it be?

• Recruitment & development of multiple follicles by exposing ovarian follicles to increased levels of FSH (maintains follicular growth)

• May be FSH alone or FSH + LH (derived from various sources)

  
  

What is the dosing strategies for exogenous gonadotropins? Which is preferred?

• Low-dose, step-up

  • Pros: gradual increase in FSH, prevents hyperstimulation

  • Start at 50 IU to 75 IU FSH given IM or Sub-Q, after 1 – 2 weeks dose is increased weekly by 37.5 IU

• Step-down

  • Start with 150 IU FSH until one follicle reaches 10mm on ultrasound, then reduce dose until ovulation

• No difference seen in pregnancy outcomes with either protocol, but
  step-up preferred for safety

CLOSE MONITORING of what is required in exogenous gonadotropins?

• Serum estradiol & follicle size (adjust for inadequate response or explosive response)

• Trigger shot of hCG once matured

What are some AE of exogenous gonadotropins?

• Hot flashes, breast pain, ab pain

What is the MOA of GnRH AGONIST?

• Suppress natural LH surge during ovulation induction treatments

  • Allows max window for administering gonadotropins

  • Allows max window for follicle maturation

GnRH agonist daily injections will first do what? Then what?

• Daily injections will first stimulate (“flare effect”), then down-regulate natural pulsatile activity

  • Long protocol

What are AE of GnRH Agonist?

• hot flashes, HA, mood swings, breast tenderness, OHSS

What are the GnRH antagonists? What is the MOA?

• Cetrorelix (Cetrotide®), Ganirelix (Antagon®)

• Suppress natural LH surge during ovulation induction treatments

  • Allows max window for administering gonadotropins

  • Allows max window for follicle maturation

What is noted about the suppression of LH in GnRH antagonist?

• Immediate suppression and prevention of natural LH surge (can be given during treatment cycle)

  • Single dose (cetrorelix)

  • Multiple dose (cetrorelix or ganirelix)

What are AE in GnRH antagonists? What allergy should you note?

• AEs: hot flashes, headache, mood swings, breast tenderness, OHSS

  • Note: Ganirelix has rubber latex in needle shield (allergy)

    
    

What is hCG similar to? When is it given?

• Structurally similar to LH

  • Given at the end of induction to simulate natural LH surge (“trigger shot”)

  • Given IM or Sub-Q depending on product

• Patients should be counseled to follow timing set by induction
  protocol to ensure full follicle maturation

  
  

How is Progesterone given and when? What for?

• Given IM, vaginal, or oral to supplement in IVF

• Started after oocyte retrieval and continued up to 8 to 10 weeks gestational age (placenta takes over here)

• Other supportive roles

When is metformin given?

• Commonly seen in PCOS to aid with insulin resistance (only recommended in women with insulin resistance)

What is dopamine agonists (bromocroptine, cabergoline) for?

• Hyperprolactinemia

What are the assisted reproductive technology?

• Intra-uterine insemination (IUI): washed sperm placed in uterine cavity

• In-vitro fertilization (IVF): follicles punctured and oocytes collected via needle, fertilization in a petri dish then transferred back to uterus

• Intracytoplasmic sperm injection (ICSI): inject single sperm into egg cytoplasm

• Donor oocytes

What are complications of infertility treatment?

• Ovarian Hyperstimulation Syndrome (OHSS)

  • Most common in those receiving gonadotropins with or without ART

  • Ovarian enlargement, ascites, hypercoagulability, and electrolyte imbalance → kidney failure, thrombosis, stroke

  • Treatment is supportive, should resolve spontaneously (may be avoided if trigger shot is omitted)

• Multiple births

• Cancer Risk

  • Ovarian cancer risk – controversial!