Endocrine 2 Exam 2: Koerner Fertility

Infertility: Failure to achieve a successful pregnancy after __ months or more of appropriate, timed unprotected intercourse or therapeutic donor insemination

12

If over the age of ___, early evaluation and treatment for infertility may be considered after only 6 months

35

Treatment for infertility is directed at the ___

cause

Primary Infertility Causes

1. primary ___ ___ (premature ovarian failure)

2. PCOS

3. Obesity

4. Weight Changes

5. Excessive ___

6. __ dysfunction

7. Hyperprolactinemia

ovarian insufficiency, exercise, thyroid

Follicular Phase

-pituitary gonadotropins stimulate follicle growth

-increasing estradiol levels with growing follicle

-__mm follicle causes increase in LH and triggers ___ of ovum

20, release

Luteal Phase

-remainder of the follicle transforms to corpus luteum which produces progesterone

-progesterone changes the endometrium and prepares it for embryo implementation

-if no pregnancy, corpus luteum dissolves, __ in progesterone level and menstruation occurs

drop

FSH

-produced by the __ ___ and stimulates early maturation of follicles and estrogen secretion

anterior pituitary

LH

-produced by the __ ___ and stimulates ovulation; maintains the corpus luteum

anterior pituitary

GnRH

-produced by the __ and stimulates secretion of FSH and LH

hypothalamus

Estrogen

-produced by the __ and stimulates growth of follicles

ovaries

Progesterone

-produced by the __ ___/corpus luteum and prepares for implantation

ovarian follicle

hCG

-produced by the ___/___ and maintains hormone synthesis during early pregnancy

trophoblast/placenta

Fertilization occurs in ___ ___

fallopian tube

Fertilization occurs in fallopian tube and implants there, this is an ___ pregnancy (medical emergency)

ectopic

Normal menstrual cycle ranges from 25-35 days (day 0 is first day of __)

menses

Ovulation is typically __ days before the next cycle

14

After ovulation, the egg is viable for fertilization for __ hours (differs from sperm, which is 5-7 days)

24

Male Infertility Common Problems

-low sperm ___

-poor sperm ___

-malformed sperm

-blocked sperm ducts

count, motility

Female Infertility

1. Tubal/pritoneal causes, including ___ and ___ ____ ___

endometriosis, pelvic inflammatory disease

Treatment for infertility caused by tubal/pritoneal causes is ___

surgical

Female Infertility

2. Ovulation dysfunction, including __ axis abnormalities, ___, and ___

HPA, hyperprolactinemia, PCOS

Treatment for infertility caused by ovarian dysfunction causes is ___

medications

Note that ___ accounts for up to 40% of infertility and commonly presents as menstrual disturbances, either oligomenorrhea or amenorrhea

PCOS

Female Infertility

3. Pelvic/Uterine causes including ___ or ___, and congenital/structural abnormalities

fibroids, polyps

Treatment for infertility caused by pelvic/uterine causes is ___

surgical

Female Infertility

4. ___

5. ___ (chlamydia, ureaplasma, mycoplasma)

6. unknown

immune, infectious

Medications that increase __ levels can lead to infertility in women

prolactin

Medications that increase prolactin:

-chlorpromazine

-cimetidine

-estrogen

-haloperidol

-medroxyprogesterone acetate

-methyldopa

-prenothiazine

-pimozide

-reserpine

-___

-___

TCAs, verapamil

Medications that decrease __ count can lead to infertility in men

sperm

Medications that decrease sperm count:

-alcohol

-allopurinol

-anabolic/androgenic ____

-caffeine

-CCBs

-chemo

-___

-colchicine

-____

-nitrofurantoin

-spironolactone

-sulfasalazine

-tetracycline

steroids, cocaine, marijuana

Evaluation-female

1. duration

2. ___ history

3. ___ history (eg history ectopic pregnancy?)

menstrual, pregnancy

Evaluation-female

4. PMH (including abnormal pap smears, PID, and STDs)

5. ___ history

6. ___ history (recent weight/exercise changes)

family, social

Evaluation-female

7. ___ and exposure to environmental hazards

8. History of alcohol, tobacco, and recreational or __ drug use

9. ___ function tests should be performed

occupation, illicit, thyroid

Infertility Testing

1. First patient we test is the ___ (less invasive, less expensive)

male

Infertility Testing

2. __ detection (ovulation prediction kits that show surge occurring 1-2 days before ovulation)

LH

Infertility Testing

3. serum ___ (timed to show if ovulation is occurring about 1 week prior to next menses, cycle day 21)

progesterone

Infertility Testing

4. ____

5. ___

6. ___

prolactin, FSH, estradiol

Infertility Testing

7. serum ___ hormone (predicts how successful assisted reproductive technology will be)

antimullerian

Infertility Testing

8. Trans-vaginal ____

9. Endometrial biopsy

10, Laparoscopy

11. Hysterosalingography (___)- puts dye into uterus to evaluate if tubes are patent (ie open)

ultrasound, HSG

Infertility Non-Pharm Treatment

-____ contributing medications/agents (eg nicotine, alcohol, illicit drugs)

avoid

Infertility Non-Pharm Treatment

-___ adjustments (remember BMI that is too low or too high can cause infertility)

weight

Infertility Non-Pharm Treatment

-multivitamin with ___ ___

folic acid

A ___ ___ containing folic acid should be started immediately in patients who are trying to conceive or experiencing difficulty becoming pregnant.

prenatal vitamin

Considerations for Ovulation Induction/Ferility Procedures

1. ___ (most insurances don't pay for this)

2. adverse effects of meds

3. risks of __ births (twins, triplets)

4. Invasive nature of intervention

cost, multiple

Goal of infertility treatment: Induce ____ to achieve development of at least one ovarian follicle and therefore enable conception

ovulation

Remember

-Some patients use just ___ or just ___ ___ __ (ART)

meds, artificial reproductive technology

Remember

-Dosing is ____ driven and therefore may not be the same as on drug monographs

-Varying ___ of medications may be used

-Multiple gestations depends on med combo and procedure

-ADR rates will vary on dosing and combinations

protocol, combinations

To treat infertility caused by hyperprolactinemia:

1. ____

2. ___

bromocriptine, cabergoline

What is 1st line for infertility?

Clomiphene Citrate

Clomiphene Citrate (Clomid)

-estrogen ___

-inhibits negative feedback on HPA axis to increase release of gonadotropin ___

antagonist, FSH

Clomiphene Citrate (Clomid)

-enhances normal follicular maturation process and ovulation without __ stimulating the ovary

directly

Clomiphene Citrate (Clomid)

-given ___ on days 5-9 (so that by day 14, ovulation will hopefully occur)

orally

Clomiphene Citrate (Clomid)

-titrate dose up each cycle; after __ cycles with no pregnancy, consider another therapy

6

Clomiphene Citrate (Clomid)

-we do not give this med for >12 months because it can increase for __ ___

ovarian cancer

Clomiphene Citrate (Clomid) ADRs

-vaginal dryness and moodiness

-abdominal discomfort

-___ disturbances ("floaters")

-thickening cervical mucus

visual

Clomiphene Citrate (Clomid)

-increases risk for multiple births

-80-85% of patients will ovulate; 40-50% will become ___ in 6 months

pregnant

Clomiphene Citrate Positive Predictors

-age <___

-history of ___ (vs oligomenorrhea)

30, amenorrhea

What is the brand name of letrozole?

Femara

What is the brand name of anastrozole?

Arimidex

Anastrozole and Letrozole

-aromatase inhibitors; prevent conversion of androgen to estrogen (antiestrogen)

-therefore, similar to clomid, this will decrease negative feedback and cause hypothalamus to release ___ and ___

FSH, LH

Anastrozole and Letrozole

-given ___ on cycle days 3-7

-ADRs= vasomotor symptoms, headache, breast tenderness

orally

Anastrozole and Letrozole

-44-90% will ovulate with PCOS; 9.7-40% will become __ with PCOS

pregnant

Anastrozole and Letrozole Problems

-optimal dose

-question of increase risk of spontaneous loss of pregnancy

-may cause ___ abnormalities

congenital

Anastrozole and Letrozole

-can be combined with ___

gonadotropins

There is data that shows individuals with PCOS have some insulin ____ which affects there ovulatory function through hyperinsulinemia

resistance

Metformin

-given for insulin resistance in PCOS

-MOA is insulin-sensitizing agent

-given orally

-success rate is 90% when given with ___

clomiphene

Metformin

-ADR= ___ symptoms (important counseling point)

abdominal

Metformin

-not considered 1st line over clomiphene

-BMI may be predictor of ___

-some studies show improvement in ovulation rates and clinical pregnancy rates, but no improvement in live births

success

Metformin

-Consider as 1st line IN COMBINATION with clomiphene for clomiphene ___ patients

resistant

Metformin

-potential advantage is no endometrial ADR, no increase in multiple birth rates, and no known long term ovarian risk

-disadvantage = takes up to __ months to show effect (so not the best choice for older patient)

6

Treatment Algorithm

1. give clomiphene, potentially give aromatase inhibitor, potentially metformin

2. if non-responder, give ___ ___

exogenous gonadotropins

We can consider starting with ___ with exogenous gonadotropins, the only disadvantages are higher ADE risk and potential for multiple follicles

combination

Exogenous Gonadotropins

-either ___ alone or in combination with __ that directly works on the ovaries to induce follicular development

FSH, LH

Exogenous Gonadotropins

-many products available

-doses are customized to patient

-no advantage of one agent over another; main considerations are if it is on ___, route of ____, and delivery ___

formulary, administration, device

What are the 3 gonadotropins?

1. ___ ___ (Reponex)

2. ___ (Brevelle)

3. ___ ___ (Gonal-F) and ___ ___ (Follistim)

human menotropins, urofollitropin, follitropin alfa, follitropin beta

Urofollitropin, follitropin alfa, and follitropin beta are FSH. Human menotropins (Reponex) contains FSH and __ (but the amount is so small it doesn't do anything)

LH

human menotropins (Reponex) and urofollitropin (Brevelle) are purified FSH extracted from __ of post-menopausal women

urine

follitropin alfa (Gonal-F) and follitropin beta (Follistim) is ____ FSH

recombinant

follitropin alfa (Gonal-F) and follitropin beta (Follistim) come in a ___, and therefore is easier for patients

pen

Gonadotropins

-increase follicular recruitment and development in conjunction with __ (may get more than 1 follicle)

hCG

Gonadotropins ADRs

-hot flashes, breast tenderness, abdominal pain, nausea, diarrhea

-___ site reactions

-dry skin, rash, alopecia, hives

-____

injection, OHSS

OHSS = ___ ___ ___

ovarian hyperstimulation syndrome

OHSS

-rare but has __ threatening complications (eg kidney failure, thrombosis, stroke)

life

OHSS

-excessive response to ovulation therapy (__ estradiol and follicle number)

high

OHSS

-monitored for with serial ultrasounds and estradiol concentrations every day or 2 (goal is __-__pg/mL per follicle with no more than __ mature follicles)

150-300, 2

OHSS Risk Factors

-__ and repeated doses of exogenous gonadotropins

-___

high, PCOS

OHSS Treatment

-withhold ___ (ie stop the cycle; this is bad because it could have cost up to $10k)

hCG

OHSS Symptoms

Mild → abdominal discomfort, N/V/D

Severe → hemodynamic ___, ascites, severe ___, dyspnea and ____

instability, pain, tachypnea

When dosing a gonadotropin, you can either step ___ (less ADEs) or step ____ (patient won't have to be on med for as long)

up, down

Gonadotropins Step-up Protocols

-increase dose until desired response

-increase is based on follicular development

-dose is then maintained until ___ ___ is administered (hCG)

ovulation inducer

Gonadotropins Step-up Protocols

-Start with a ___ dose of gonadotropins, then can increase the second round

low

Advantage of starting with low dose of gonadotropins = less excessive ___ effects (eg OHSS) and less __ pregnancy risk

adverse, multiple

low dose gonadotropins = ___-___ IU daily for 14 days then increase by 37.5 IU weekly to max 225 IU daily

37.5-75

Gonadotropins Step-down Protocols

-advantage = shorter __ of medications

-disadvantage = more ___, inclusing OHSS and multiple births

duration, ADEs

Important to know that patients receiving gonadotropins can still conceive through intercourse, so gonadotropin therapy is not automatically combined with ___ (but it often is)

ART

2 STEPS for gonadotropin therapy

First= give gonadotropins (FSH) to stimulate follicle development

Next= give ____ ___ (mimics LH) to trigger ovulation.

chorionic gonadotropins

Chorionic Gonadotropins (hCG) = ___, ___, ___

Novarel, Ovidrel, Pregnyl

Chorionic Gonadotropins (hCG)

-chemical structure is similar to __

-MOA is ovulation stimulant, final development and maturation of normal ovarian follicle

LH

Chorionic Gonadotropins (hCG)

-if patient's getting these injections buy a pregancy test, it will always be ___ (even if not pregnant)

positive

Chorionic Gonadotropins (hCG)

-Novarel and Pregnyl are given ___

-Ovidrel is given __

IM, SUBQ