Infertility - Mansukhani

Learning Objectives

1. ID factors and primary causes of infertility

2. CC phases in menstrual cycle and how each affects hormonal levels

3. ID first line pharmacotherapy used to treat infertility (dosing, CI, ADE)

4. ID counseling points for infertility treatment on endometrial support

What is infertility?

failure to achieve clinical pregnancy after 12 mo or more of regular unprotected sex if <35 yrs

• only 6 mo if older than 35 yrs

What are the contributing factors to infertility?

1. age (peak later 20s, decline at age 30)

2. pelvic infections or STI

3. tobacco, alcohol, illicit drug use

4. extreme weights

5. excess exercise

What are medications that may affect fertility?

1. anabolic steroids

2. antidepressants

3. anti-inflammatory

4. propanolol, dipines, clonidine, spironolactone, HCTZ

5. benzodiazepines

6. corticosteroids

7. metoclopramide

What are the overall causes of infertility?

What are the primary causes of female inferility?

1. ovulation disorders (PCOS, hyperprolactinemia, thyroid disorders, hormonal disorders)

2. uterine/cervical abnormalities

3. fallopian tube dmg or blockade

4. endometriosis

5. primary ovarian insufficiency (early menopause)

pt presents with (atleast 2 of following) irregular periods, hyperandrogenism, and polycystic ovaries. They have an imbalance of reproductive hormones, and are insulin resistant. What condition does this patient have and what is the first line treatment?

PCOS; clomiphene (not metformin anymore)

When screening a female for inferitlity, what should you test for?

1. ovarian reserve test: anti-mullerian hormone, day 3 labs for FSH and/or estradiol

2. TH

3. prolactin

4. DHEAS/Testosterone

5. Progesterone

Which hormone is important to test for some who has had multiple miscarriages or is within their first trimester of pregnancy?

progesterone

when screening a male for infertility, what should you test for? (spermatogenesis is 90 days)

semen analysis: fluid volume, sperm conc, motility, morphology

What medications can inhibit spermatogenesis?

1. alcohol

2. anabolic/androgenic steroids

3. caffeine

4. CCBs

5. Sprinolactone

Which phase of the menstural cycle is this?

• Day 1: first day of menses

• Day 1-4: several follicles develop

• Day 5-7: one follicle dominates, endometrial lining readied for implantation

• Days 13-14: follicular maturation → rupture, corpus luteum created

Follicular Phase

What phase of the menstrual cycle releases an egg from the follicle on day 14?

ovulation

which phase of the menstrual cycle thickens endometrial lining and CL continues to thrive on days 15-28?

luteal

Which hormones INC/DEC during the follicular phase?

INC: FSH (initially, then dec), Estradiol (response to low FSH), LH surge

Which hormones INC during the luteal phase?

progesterone, estradiol

When does ovulation onset occur?

after LH surge in follicular phase

if the egg isn’t fertilize during the luteal phase, what happens to the hormones?

decreased, then endometrial tissue breaks down

What is IUI? What is the typical timeline for intrauterine insemination (IUI)? ASK FOR HELP

1. Procedure: wash and concentrate the sperm, place at top of uterus with a catheter

2. SEQ: follicular stimulation → trigger → insemination → endometrial support

What is In Vitro Fertilizaiton (IVF)? What is the timeline?

1. fertilization outside the body

2. timeline: follicular stimulation (injections) and ovulation suppression (prevent premature ovulation)→ trigger → egg retrieval/fertilization → embryo transfer (endometrial support/prophylaxis)

What is the difference between IUI and IVF?

1. IUI: less meds/invasive, inexpensive

2. IVF: higher success rate, more meds (injections), more invasive and expensive

pt has PCOS and needs a sperm donor. Which fertility treatment is she a candidate for?

IUI

pt is older than 35 and their ovarian reserve is not as good. They also have fallopian tube dmg/blockage and have endometriosis. Which fertility treatment are they a candidate for?

IVF

pt has PCOS. What is the first line pharmacological therapy? What is its mechanism of action

2.5-7.5mg PO QD 5 days letrozole (femara)

• MOA: reduces estrogen synthesis → INC FSH secretion → stim ovulation

What are the ADE of Letrozole?

hot flashes, fatigue, dizzy, arthralgia BUT it lowers multiple gestation risk vs clomiphene

What are the CI of letrozole?

Pregnancy, premenopausal women not pursuing fertility treatment

pt is using an IUI and is doing timed intercourse. They have anovulation (or unexplained infertility). It was determined that letrozole is not an effective therapy. What is the alternative therapy?

50mg PO QD 5D clomiphene (clomid); start 5th day of cycle

• 25mg/d for PCOS pts

• higher dose has higher chance of multiple gestation

What are the ADE of Clomiphene?

hot flashes, GI fx, vision changes, ovarian hyperstimulation syndrom (severe NVD, SOB, abdominal pain, ovaries swollen/painful)

What are the CI of clomiphene?

liver disease, abnormal uterine bleeding , ovarian cysts not due to PCOS, uncontrolled thyroid/adrenal dysfunction

What is primarily used in IVF cycles in combinations

OR in IUI if refractory to clomiphene

OR to increase spermatogenesis?

gonadotropins such as recombinant follitropin (follistrim/gonal-f), menotropins (Menopur), and urofollitropin.

What is the mechanism of action for gonadotropins?

FSH and/or LH preparations used to promote folliculogenesis, mature the follicle, INC gonadal steroid production

What is the dosage of gonadotropins?

SQ/IM injection (75-200units/d) depending on FSH/LH levels; start day 3 until ovulation (12days), but ensure that follicle size is >18mm

Which medication is used in conjunction with stim meds to control ovarian hyperstimulation?

SQ prefille syringes of Centrorelix (Cetrotide)/Ganirelix starting 5-6 days after stimulation meds

• GnRH antag that suppresses LH production and surge

What are the clinical pearls about cetrorelix and genirelix?

1. less OHSS risk compared to GnRH agonist

2. few ADE: HA, injection site rx, nausea

Which medication is used with both IUI and IVF cycles and timed intercourse?

human chroionic gonadotropins (HCG):

• exogenous: novarel/pregnyl

• recombinant (ovidrel)

MOA: high dose HCD stimulates production of gonadal steroid hormones leading to LH surge. This helps complete follicular maturation, induces ovulation, and promotes development of corpus luteum. What is the dosing of HCG such as Novarel/Pregnyl and Ovidrel?

Novaarel/Pregnyl: 5,000 or 10,000 IU IM/SQ

Ovidrel: 250mcg SQ

• Both are administered once follicles are correct size, usually 36h before insemination /oocyte retrieval

During timed intercourse, what medication should you give and what dosage?

Novaarel/Pregnyl: 5,000 or 10,000 IU IM/SQ

Ovidrel: 250mcg SQ

within 24-48 hrs after

What are the ADE of HCG?

irritability, HA, injection site rxn, OHSS

Progesterone prepares and maintains uterine lining. When is considered to be progesterone administered?

IUI due to more extensive use of medicaitons, but also IVF

• required if using leuprolide as a suppressor

Progesterone avoid significant 1st pass hepatic metabolism. What are the different formulations of progesterone?

1. oil injections

2. suppositories

3. vaginal capsules vs inserts

4. gel

What are possible medications for embryo transfer prophylaxis?

1. oral antibiotics: both male/female

2. metronidazole 0.75% vaginal gel (1 before appt)

3. anticoagulants:

   1. baby aspirin if fhx clotting and to improve embryo implantation

   2. enoxaprin if PMH of clotting

wait for answers to be posted on canvas

What are important counseling points for fertility treatment?

1. success rate decreases with age, <50%

2. expensive

3. may require multiple medications, may need refrigeration

4. risk: OHSS or allergic rxns

5. emotional burden: injections, anxiety, hormonal side fx

6. don’t use at home pregnancy tests after a cycle, get bloodwork done to confirm pregnancy due to medications