Approach to ovulation induction and superovulation in women with a history of infertility. Anatte E. Karmon, MD

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1 Approach to ovulation induction and superovulation in women with a history of infertility Anatte E. Karmon, MD

2 Disclosures- Anatte Karmon, MD No financial relationships to disclose 2

3 Objectives At the end of this presentation, participants will be able to: Understand the mechanisms of and indications for the currently available treatments for ovulation induction Understand the risk of multiples with various ovulation induction agents Follow evidence based practices regarding the treatment of patients with ovulatory dysfunction 3

4 Ovarian stimulation Ovulation induction- goal of mono-follicular response Superovulation- goal of multifollicular response 4

5 Ovulation induction Superovulation PCOS Unexplained infertility Hypothalamic dysfunction Diminished ovarian reserve Other etiologies of infertility 5

6 Follicular development Fauser, BC et al. Manipulation of human ovarian function: Physiological concepts and clinical consequences. Endocr Rev 1997; 18:71. 6

7 Ultrasound appearance of dominant follicle 7

8 Anovulatory disorders PCOS Hypogonadotropic hypogonadism Ovarian failure Other endocrine (prolactin, thyroid) 8

Initial work-up History/ physical exam Gonadotropins/ estradiol/ AMH Transvaginal pelvic ultrasound TSH Prolactin ***Preconception counseling*** PCOS: reverse FSH/LH ratio, clinical signs of

9 Initial work-up History/ physical exam Gonadotropins/ estradiol/ AMH Transvaginal pelvic ultrasound TSH Prolactin ***Preconception counseling*** PCOS: reverse FSH/LH ratio, clinical signs of hyperandrogenism, PCOM Hypogonadotropic hypogonadism: low FSH/LH, normal or polycystic ovaries Ovarian failure: high gonadotropins, small quiet ovaries Other endocrine: high TSH and/or prolactin 9

10 Secondary work-up PCOS- androgens, PCOS lab work discussed in PCOS talk Hypogonadotropic hypogonadism- If etiology unknown- MRI, TSH and free T4, AM cortisol Ovarian failure- If under 40 and etiology unknown- karyotype, fragile X, anti-adrenal antibodies Other endocrine- If high fasting prolactin- MRI 10

11 Goals of ovulation induction Achieve live birth Singleton pregnancy Minimize cost Minimize risk 11

12 Clomiphene citrate First (or second to letrozole?) line in treatment of PCOS Binds and depletes hypothalamic estrogen receptors blocks negative feedback of estradiol increase in GnRH pulse frequency Adashi EY. Fertil Steril Sep;42(3):

13 How to use clomiphene citrate Rx mg PO CD3-7 or CD 5-9 Timed intercourse starting CD 12 or LH kit monitoring/ti after surge OR IUI day after LH surge Check CD 21 progesterone Additional options: Stair step protocol Adjuvants for clomiphene citrate resistance Ultrasound monitoring HCG Micronized progesterone 13

14 Outcomes, risks, and drawbacks of clomiphene citrate Outcome (PCOS): ovulatory rate of 80%, cumulative pregnancy rate 30-40% Multiples- 7% No benefit after 3-6 treatment cycle Anti-estrogenic on uterus, cervix, vagina Study linking to ovarian cancer- not confirmed Retinal toxicity Thin endometrium Common side effects- hot flashes, headaches, mood swings 14

15 Letrozole First line in treatment of PCOS (in particular obese PCOS patients) Aromatase inhibitor blocks negative feedback of estradiol increase in GnRH pulse frequency 15

16 How to use letrozole Rx 2.5-5mg PO CD3-7 or CD 5-9, Consider checking HCG Timed intercourse starting CD 12 or LH kit monitoring/ti after surge OR IUI day after LH surge Check CD 21 progesterone Additional options: Stair step protocol Adjuvants Ultrasound monitoring HCG Micronized progesterone 16

17 Outcomes, risks, and drawbacks of letrozole Higher live birth and ovulation rate in obese women with PCOS compared to clomiphene Multiples (PCOS)- 3%, lower than clomiphene No direct anti-estrogenic effect on endometrium Off-label use Animal data suggest teratogenicity, human studies have not confirmed Used for fertility treatment among breast cancer patients due to low estradiol levels 17

18 Clomiphene citrate for unexplained infertility? No benefit First line treatment No benefit of clomiphene with or without IUI ASRM- no benefit of clomiphene alone Reproductive medicine network- first line treatment Higher success rate than letrozole Hughes E et al. Cochrane Database Syst Rev 2010: CD Practice Committee of the American Society for Reproductive Medicine. Fertil Steril 2013;100: Diamond MP et al. Fertil Steril 2014;102:e39. 18

19 Gonadotropins First line in treatment hypogonadotropic hypogonadism FSH/LH directly acts on ovary to stimulate growth of one or more follicles 19

20 How to use gonadotropins Rx depends on ovarian reserve, start CD 3 take every day Follicular monitoring after 5 days of treatment, adjust dose HCG TI or IUI 36 hours after HCG Additional options: Gonadotropins + femara or clomiphene citrate Micronized progesterone 20

21 Outcomes, risks, and drawbacks of gonadotropins High success rate in women with hypogonadotropic hypogonadism Superovulation can be used for women with ovarian reserve issue or unexplained infertility High rate of multiples, especially with gonadotropin doses at or above 150IU Ovarian hyperstimulation syndrome Costly 21

22 Take home message Various ovulation induction agents have varying degrees of success depending on indication Letrozole is first line agent in obese women with PCOS, clomiphene/iui is first line in women with unexplained infertility Gonadotropins require monitoring and carry a higher rate of multiples compared to the oral agents If no success after 3-6 months of oral agents, refer to a specialist 22

23 Questions 23

Polycystic Ovary Syndrome (PCOS):

Polycystic Ovary Syndrome (PCOS): Current diagnosis and treatment Anatte E. Karmon, MD Disclosures- Anatte Karmon, MD No financial relationships to disclose 2 Objectives At the end of this presentation,