PMOS/Infertility

follicle stimulating hormone

FSH

luteinizing hormone

LH

gonadotropin releasing hormone (antagonist)

GnRH(a)

abnormal uterine bleeding

AUB

Polycystic Ovary Syndrome

PCOS

PCOS

• Affected 1 in 10 women and is the leading cause of anovulatory infertility

• Is one of the most common causes of abnormal uterine bleeding (AUB)

1. Abnormal Gonadotropin-releasing hormone (GnRH) which leads to increased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) which leads to increased androgens

2. Insulin resistance

3. Excess androgen production

What are the 3 potential mechanisms of PCOS/PMOS?

polymetabolic ovarian syndrome

PMOS (new PCOS name)

Abnormal Gonadotropin-releasing hormone (GnRH) which leads to increased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) which leads to increased androgens

• This interrupts the follicle development process and leads to immature follicles

• With immature follicles a patient may have anovulation (not releasing an oocyte during menstrual cycle)

• This leads to unopposed estrogen which can increase the risk for endometrial cancer, polycystic ovaries, and insulin resistance

insulin resistance

• Usually insulin stimulates the release of FSH and LH

• In the liver insulin inhibits the synthesis of sex hormone binding globulin (SHBG) which increases the free fraction of androgens

excess androgen production

women with PCOS are more efficient at converting androstenedione to testosterone

clinical presentation of PCOS

• Oligo-ovulation = less than 8 periods a year or anovulation

• Irregular menstrual cycles

• Amenorrhea = absence of menstruation for more than 3 months with out pregnancy

• Polycystic ovaries

• Impaired glucose tolerance

• Hirsutism

90%

What % of pts with PMOS attend infertility clinics, if they conceive they are at risk for preg complications?

endometrial hyperplasia

Anovulation causes exposure of estrogen in endometrium

metabolic syndrome

• Caused by insulin resistance

• 10% of PMOS can develop diabetes by the time they reach 30's to 40's

• Increased concentrations of c reactive protein

• Increases CV risk as patients get older

counseling

What is the first line tx for depression in PMOS?

PMOS manifestations and long term complications

-reproductive challenges

-endometrial hyperplasia

-metabolic syndrome

-depression

-Hyperandrogenism

-Oligo-ovulation or anovulation OR polycystic ovaries by ultrasound

-exclusion of related disorders

NIH/NICHD dx of PMOS:

must meet 2 of these 3 :

-hyperandrogenism

-oligo-ovulation or anovulation

-polycystic ovaries by ultrasound

ESHRE/ASRM dx of PCOS:

-hyperandrogenism

-oligo-ovulation or anovulation

-exclusion of related disorders

Dx of AE-PCOS society guidelines:

must meet 2 of these 3 criteria:

-hyperandrogenism

-oligo-ovulation or anovulation

-polycystic ovaries by ultrasound

Dx of PCOS per AACE/ACE/AE-PCOS:

-maintain normal endometrium

-block the actions of androgens on target tissues

-reduce insulin resistance and hyperinsulinemia

-reduce weight and prevent long term complications

-prevent preg, correct anovulation, or oligo-ovulation or improve fertility

What are the tx goals of PCOS?

-weight loss

-diet

-exercise

What are the non-pharm tx of PCOS?

5-15%

_____% less can improve infertility rate, improves endocrine parameters, ovulation rate and lowers CV risk.

low calorie, low in saturated fats, fruits/veggies

Diet for PCOS:

150 mins/week

What is the recommended amount of moderate intensity exercise for PCOS?

• Combined oral contraceptives (COC)

• Progestins

• Metformin

• TZD's

What meds can you take for menstrual irregularities in PCOS?

combined oral contraceptives (COC)

• Reason for use: suppress LH and FSH and ovarian androgen

• ADE: N/V, increased BP, weight gain, breast tenderness, breakthrough bleeding, blood clots, mood swings

COC

TOC: for irregular menstrual cycles, pregnancy preventing, relief of acne, and hirsutism

LOW estrogen content in contraceptive NO GREATER than 35 mcg of estradiol and low progestin

• Progestins with low androgenic activity include:

• Desogestrel

• Norgestimate

• Drospireonone

What is key to picking a COC to use in menstrual irregularities in PCOS?

Progestins

• Reason for use: Reduce risk of endometrial hyperplasia/cancer

• ADE: HA, nervousness, weight gain, abdominal pain, acne, breast pain

• Medroxyprogesterone 5-10 mg daily for 12-14 days

• Micronized progesterone 300 mg daily for 12-14 days dosed every 3-4 months

Metformin

• Reason for use: decreases hepatic glucose production, secondarily reducing insulin concentrations

• Can help with menstrual cycles, induction, ovulation, hirsutism, and acne

• ADE: GI

• TOC: for insulin sensitizer for women with PMOS not FDA approved, 2nd line for those who failed COC or adjuvant therapy for infertility

• 1,000 mg BID

TZD's

• Reason for use: improved insulin sensitivity at target-tissue level, menstrual cycle regulation, ovulation, hirsutism, acne

• ADE: edema, fatigue, HA, weight gain

• DO NOT USE IN WOMEN WHO ARE PREGNANT

• Pioglitazone 30-45 mg daily

-COC

-antiandrogens

-eflornithine

What drugs are used for hirsutism and/or acne in PCOS?

antiandrogens in hirsutism and/or acne

• Reason for use: inhibits androgens

• ADE: HyperKalemia, polymenorrhea, HA, fatigue, feminization of male fetus

• Spironolactone 50-100 mg BID

eflornithine

• Reason for use: lightens hair color

• ADE: irritation and folliculitis

• Eflornithine 13.9 % cream BID

-Metformin

-Clomiphene citrate

-Letrozole

What drugs are used for infertility in PCOS?

clomiphene citrate

• Reason for use: ovulation induction, increases GnRH secretion which increases FSH:LH

• ADE: vasomotor symptoms, GI, risk of multiple pregnancies

• 50 mg daily for 5 days can increase up to 150 mg in subsequent cycles, do not exceed 6 cycles

Letrozole

-Reason for use: ovulation induction, decreases negative feedback on hypothalamus and pituitary which increases FSH

• ADE: edema, HA, fatigue, dizziness, nausea, hot flashes

• TOC: per PCOS guidelines for ovulation induction d/t shorter half life higher live birth rates and lower risk of pregnancy with multiples

• 2.5-7.5 mg daily on cycle days 3-7 can take up to 5 cycles

metformin and TZDs

What drugs are used for weight loss in PCOS?

herbal products used in PCOS

-Inositols

• Improves insulin resistance and reduces metabolic syndrome

• 2-4 g/daily

-Cinnamon, black cohosh, licorice

• Regulate menses, reduce symptoms of hyperandrogenemia

• Can be safe when used appropriately

Weight

BP

A1c/OGTT

Lipids (every 2 years)

ADE from meds

What do you have to monitor for during PCOS?

anti-mullerian hormone

AMH

Gonadotropin releasing hormone (antagonist)

GnRH(a)

Follicle stimulating hormone

FSH

human chorionic gonadotropin

hCG

intrauterine insemination

IUI

in-vitro fertilization

IVF

luteinizing hormone

LH

ovarian hyperstimulation syndrome

OHSS

15%

What % of couples does infertility affect?

33%

Female infertility factors account for _____ ovulation disorders

26%

Female infertility factors account for _____ tubal factors

40-50%

Male infertility accounts for ______ of infertility.

19-35

Ovulation occurs for women ages ________ up to 50% compared to 25% for women ages 35-39

-1 yr of regular intercourse without conception

-> 35 yo after 6 months without conception

What is the definition of requiring intercourse without conception?

dx of infertility

Evaluation of male factors and female factors for infertility

• Assessment of lifestyle

• Ovulatory function

• Testing of reserve of ovaries

• Measuring FSH and estradiol on day 3 if FSH is >10-20 than could

indicate poor ovarian stimulation

group 1 ovulation disorders

• Hypothalamic amenorrhea

• Typically low gonadotropins and estrogen deficiency

(basically labs are crap)

group 2 ovulation disorders

• 85% of ovulation dysfunction of hypothalamic-pituitary ovarian axis

• Hyperprolactinemic amenorrhea

group 3 ovulation disorders

Premature ovarian failure due to radiation, pelvic surgery or

chemotherapy

(due to damage/mechanical)

Tubal Factors of infertility

• Pelvic inflammatory disease (PID)

• Ectopic pregnancies

• Fibroids

• Endometriosis

• Congenital anomalies

male infertility factors

• Infection

• Injury

• Medications (Ketoconazole, SSRI's, spironolactone, nifedipine,

colchicine, sulfasalazine)

• Tobacco use

• ETOH

• Age

-conception and live birth

-safety and efficacy of meds used

What are the goals of therapy in infertility?

• Weight loss

• Reduced stress

• Reduced tobacco/cessation, caffeine, and illicit drugs

non-pharm tx of infertility:

Lifestyle changes + ovulation

First line tx of ovulatory dysfunction in infertility:

IUI

second line tx of ovulatory dysfunction in infertility:

IVF

third line tx of ovulatory dysfunction in infertility:

surgery or meds

first line tx of uterine disease in infertility:

IVF

second line tx of uterine disease in infertility:

surgery or IVF if severe or > 35 yo

first line tx of tubal disease in infertility:

IVF

second line tx of tubal disease in infertility:

lifestyle changes or tx of cause

male factors first line tx in infertility:

lifestyle changes

first line in unexplained infertility:

ovulation induction + IUI

second line in unexplained infertility:

IVF

third line in unexplained infertility:

IVF

fertilization by extracting oocytes, retrieving sperm sample then manually combining oocytes and sperm to then transfer to the uterus

ICSI

similar process to (IVF) above however a single sperm is injected into the cytoplasm of the oocyte

Selective estrogen receptor modulator

Clomiphene Citrate MOA

Nausea, vomiting, breast tenderness, blurred vision,flushing/hot flashes (33%), irritability

Clomiphene Citrate ADE:

Can be used alone or in conjunction with other medications (dexamethasone) with timed intercourse or assisted

reproductive technologies used to trigger ovulation

Clomiphene Citrate place in therapy:

50 mg daily for 5 days on cycle days 5-9

Dosing of Clomiphene Citrate in infertility

Inhibits the conversion of androgens to estrogens

Aromatase inhibitors MOA

hot flashes (20.3%), headache (40%)

Aromatase inhibitor ADEs

used to ovulation induction, can be used with timed intercourse or assisted reproductive technology and other medications

Aromatase inhibitor place in therapy:

aromatase inhibitors for infertility

Anastrazole 1 mg or Letrozole 2.5 mg daily for 5 days on

cycle day 3-7 or 5-9

FSH preparation of recombinant DNA, stimulates follicular growth, maturation

Gonadotropins MOA

bloating, abdominal/pelvic/breast pain (27-34%), ovarian enlargement, mood swings, OHSS (1-5%), injection site reaction (10%)

Gonadotropins ADEs:

Stimulate follicle growth, used in step up or step down protocol

Gonadotropins place in therapy:

Gonadotropins in infertility

• Gonal-F® (alpha), Menopur® (FSH:LH) SQ 50-75 units after 7-14 days then increase by 37.5 units weekly, doses may vary

• Storage: Unmixed powder should be stored in the fridge or room temp for 28 days for Gonal-F®, Menopur® is room temperature and both needs to be reconstituted

suppress spontaneous LH surge

GnRH agonist MOA

Hot flashes, similar ADE to gonadotropins

GnRH agonist ADEs:

allow duration of gonadotropin and to maximize follicular maturation

GnRH agonist place in therapy:

GnRH agonist used in infertility

Leuprolide is dosed daily and can be adjusted until the day

of hCG administration

competes with GnRH for binding to the receptors

GnRH antagonists MOA

similar to gonadotropins

GnRH antagonists ADEs:

Prevent LH surge until hCG is administered, alternative to agonists

GnRH antagonists place in therapy:

GnRH antagonists in infertility

• Cetrorelix® 0.25 mg or Ganirelix® 250 mcg/0.5 mL SQ daily late

in follicular phase days 7,8,9, days may vary

• Storage: Refrigerated (Cetrorelix), room temperature (Ganirelix)

stimulate a LH surge

hCG MOA:

site inflammation, HA, hot flashes, fatigue

hCG ADEs:

end of ovulation

hCG place in therapy: