IE 3: Infertility ENDO

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43 Terms

1

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

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2

What is fecundity?

  • The likelihood of becoming pregnant within a given period

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3

What is sterility?

  • Complete inability to create off-spring

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4

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


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5

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

  • Fertility peak ~ early 20s

  • Fertility decline ~ late 20s

  • Significantly fertility decline ~ late 30s

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6

What are factors that affect fertility?

  • Ovarian aging (“biological clock”)

  • Gynecologic diseases

  • Hormonal changes

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

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7

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)


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8

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


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9

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”)


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10

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

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11

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)

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12

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

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13

Anti-mullerian hormone levels show what?

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

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


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14

What is Antral Follicle Counts used in?

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

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15

What factors are assessed through imaging and other studies?

  • Tubal, uterine, peritoneal factors

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16

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)


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17

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)


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18

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

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19

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”

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20

What is Clomiphene best for?

  • Ovulatory dysfunction

  • Intact HPO axis

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21

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


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22

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)

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23

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

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24

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

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25

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

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26

What are aromatase inhibitors best for?

  • Ovulatory dysfunction

  • Intact HPO axis

  • PCOS, BMI > 30kg/m²

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27

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

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28

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)


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29

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

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30

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

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31

What are some AE of exogenous gonadotropins?

  • Hot flashes, breast pain, ab pain

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32

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

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33

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

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34

What are AE of GnRH Agonist?

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

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35

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

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36

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)

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37

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)


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38

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


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39

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

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40

When is metformin given?

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

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41

What is dopamine agonists (bromocroptine, cabergoline) for?

  • Hyperprolactinemia

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42

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

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43

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!


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