Module 3. Infertility: Protocols and Patient Management

Transcription

1 Module 3 Infertility: Protocols and Patient Management Ann Scalia, BSN, RN, CNOR Manager Clinical Education Specialists Mary Vietzke, BSN, RN Senior Clinical Educational Specialist Walgreens Faculty Ann Scalia, BSN, RN, CNOR Manager Clinical Education Specialists Mary Vietzke, BSN, RN Senior Clinical Educational Specialist Disclosure: Ann Scalia and Mary Vietzke are employees of Walgreens. There will be discussion regarding off label use of medications during this activity. It is the policy of ProCE, Inc. and NASP to ensure balance, independence, objectivity and scientific rigor in all of its continuing education activities. Faculty must disclose to participants the existence of any significant financial interest or any other relationship with the manufacturer of any commercial product(s) discussed in an educational presentation. 1

2 Objectives Discuss recommended appropriate nonpharmacologic and pharmacologic plans to address infertility Identify monitoring parameters for a patient undergoing treatment for infertility Discuss the different commonly used medication protocols used in an ART cycle Infertility Treatments Varies depending on: Evaluation outcomes Day of cycle Goals of treatment 2

3 Surgical Pretreatments Transvaginal cyst removal Rescued corpus luteum Large anovulatory follicle(s) Endometrioma ( Chocolate cyst ) Laparoscopy Fibroids Adhesions Endometriosis Hydrosalpinx Song Xm, et al. Journal of Obstetrics and Gynaecology Research. 2017;43(1): Karasu T, Ola B. Reproductive Surgery in Assisted Conception: Springer; 2015: Menstrual Cycle Follicular Recruitment Selection of Dominant Follicle LH Surge Follicular Phase Luteal Phase Day 1 Day 7 Day 14 Day Day 28 Speroff, Fritz. Clinical Gynecologic Endocrinology and Infertility. 2005:188. Stauss, Barbieri. Yen & Jaffe s Reproductive Endocrinology: physiology, pathophysiology, and clinical management. 2014: Window of Receptivity for implantation 3

4 Non Pharmacologic Treatment Cycles Natural cycle + timed intercourse Natural cycle + Intrauterine insemination (IUI) Non pharmacologic Biological Markers Menstrual cycle Cervical mucus Basal Body Temperature (BBT) Urinary hormones Pasha H, et al. Iranian journal of reproductive medicine. 2013;11(6):495 Martin PL. American journal of obstetrics and gynecology. 2016;46:

5 Luteinizing Hormone (LH) Levels One step urinary kits that measure LH Easy to use at home Used clinically for timing for intercourse or intrauterine inseminations Martin PL. American journal of obstetrics and gynecology. 2016;46:53 62 Intrauterine Insemination Treatment and monitoring is similar to timed intercourse Sperm sample is specially prepared Sperm are introduced into the uterine cavity via a catheter Used to help overcome negative cervical mucus environments or mild male factor Martin PL. American journal of obstetrics and gynecology. 2016;46:

6 Cervical Mucus Changes During Ovulation Phase Beginning Growth Peak End Estrogen causes cervical mucus production Dominant follicle maturation and estrogen production increases The corpus luteum produces progesterone which dries up the mucus and causes the temperature rise This is the after window of receptivity Martin PL. American journal of obstetrics and gynecology. 2016;46:53 62 Non IVF Ovulation Induction and Controlled Ovarian Stimulation (COS) 6

7 Controlled Ovarian Stimulation (COS) Carefully monitored stimulation of ovaries to produce multiple follicles (which contain eggs) First step in IVF process Protocols designed to decrease risk of OHSS Generally involve 3 classes of medications GnRH analogs (agonist or antagonist) FSH or FSH containing LH gonadotropin hcg final maturation of eggs inside the follicle Assisted reproductive technologies: a guide for patients. American Society for Reproductive Medicine Web site. Monitoring Methods Transvaginal Ultrasound Scans Follicular diameter and count Endometrial thickness Hormone Assay Estrogen levels (baseline and during COS) LH levels (baseline) FSH levels (baseline) Progesterone levels (specific days of cycle) Assisted reproductive technologies: a guide for patients. American Society for Reproductive Medicine Web site. 7

8 Follicular Ultrasound Monitoring Follicle growth documentation Results plotted to observe progression of growth Allows for the most accurate assessment for hcg administration Other documentation Early signs of OHSS such as abdominal fluid, ovarian enlargement, too many follicles Ovarian pathology such as endometriomas or other cyst Assisted reproductive technologies: a guide for patients. American Society for Reproductive Medicine Web site. Hormone Assay Baseline done around cycle day 3 Estrogen, (FSH, LH and progesterone levels may also be evaluated) Helps decision of dose and type of gonadotropin Throughout ovarian stimulation Estrogen levels Assess ovarian response Dosage adjustments hcg Administration Based on estrogen levels with ultrasound Assisted reproductive technologies: a guide for patients. American Society for Reproductive Medicine Web site. 8

9 Monitoring for COS Transvaginal Ultrasound Follicle diameter 16 20mm (typical) Follicle count depending on patient Endometrial thickness >7mm Hormone Assay Estrogen (estradiol) levels coincide with follicle diameter and number ASRM. Fertil Steril. 2015;103(6): Protocol Guide Various protocols used Based on patient, type of cycle (non IVF, IVF) and physician preference Monitoring is required Avoid Ovarian Hyperstimulation Syndrome (OHSS) Goal is safe treatment to achieve birth of healthy singleton baby Alper MM, et al. Reproductive biomedicine online

10 Ovarian Reserve Describes a woman s reproductive potential with respect to ovarian follicle number and oocyte quality Adapted from: Speroff. Clinical Gynecologic Endocrinology and Infertility. 8th ed. Response Types Normal Responder Typically follicles Normal ovarian function Good prognosis (but still limited by maternal age) Poor/Low Responder Usually <4 follicles Typically related to ovarian age factor Possible increased chance of poor outcome Hyper/High Responder Typically >20 follicles Some women at higher risk Low and Slow approach La Marca A, et al Human reproduction update. 2013:

11 Oral Contraceptive Pills (OCP) Oral contraceptive pills, may be prescribed to regulate a patient s menstrual cycle In an ART cycle: Used to suppress or downregulate activity in the ovaries in the prestimulation phase Allows manipulation of the patient's cycle to fit into a set schedule (Batching) Combination hormonal OCP Progestin component of a combination pill prevents ovulation by inhibiting gonadotropin secretion of LH; also alters endometrium Estrogenic component suppresses FSH Stauss, Barbieri. Yen & Jaffe s Reproductive Endocrinology: physiology, pathophysiology, and clinical management. 2014: 895. GnRH GnRH Analogs GnRH Agonists Binds to a receptor and exhibits a desired response GnRH Antagonists Binds to a receptor and inhibits another molecule from binding to the receptor, thus inhibiting the desired response Leuprolide Acetate Cetrotide Ganirelix Acetate Prapas Y, et al. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2013;166(1):

12 Downregulation and Flare Effect Downregulation Process of decreasing cells sensitivity to specific hormones Specific drugs turns off ovaries temporarily gaining control over ovarian function Flare Effect Initial "flare up" response (FSH and LH release) from pituitary gland occurs first 3 days of agonist administration Continuing agonist > 3 days temporarily suppresses pituitary gland Prapas Y, et al. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2013;166(1): GnRH Agonist Loss of response to continued stimulation Downregulation of GnRH receptors Uncoupling of GnRH receptors from intracellular signaling mechanisms E 2, P 4 LH, FSH Flare Effect Start Administration Days Prapas Y, et al. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2013;166(1): Follicular Luteal 12

13 GnRH Antagonist E 2, P 4 LH, FSH NO Flare Effect Start Administration Hours Prapas Y, et al. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2013;166(1): Gonadotropins FSH and/or LH injectable medications Two formulations Urinary extracts Recombinant FSH ASRM. Medications for Inducing Ovulation: Patient Information Series: 2012:

14 Human Chorionic Gonadotropin (hcg) Pregnyl Urinary derived Novarel Urinary derived Generic hcg Urinary derived Ovidrel Recombinant technology CHORIONIC GONADOTROPIN [prescribing insert]. Fresenius, Kabi, Lake Zurich, IL February Pregnyl (chorionic gonadotropin for injection) [prescribing information]. Parsippany, NJ: Ferring Pharmaceuticals Inc.; January OVIDREL PreFilled Syringe (choriogonadotropin alfa injection) [prescribing information]. Rockland, MA: EMD Serono, Inc., September NOVAREL (chorionic gonadotropin for injection) [prescribing information]. Parsippany, NJ: Ferring Pharmaceuticals Inc.; September Human Chorionic Gonadotropin (hcg) Referred to as a trigger shot Mimics LH surge for final oocyte (egg) maturation Very time sensitive medication Ovulation occur within hours after injection Egg retrieval is scheduled 36 hours after injection Too soon or too late will negatively impact cycle resulting in cancellation Costello M, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:

15 Leuprolide Trigger Alternative type of trigger that may be ordered by a fertility office if the patient is responding too well to medications May also be referred to as Lupron trigger Pituitary gland is capable of producing an LH surge sufficient for maturation of follicles in response to a Leuprolide trigger as long as premature ovulation was being prevented by the use of an antagonist like Ganirelix or Cetrotide Costello M, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:454. Leuprolide trigger protocol Most common dosages in a prefilled syringe or vial 1 mg (20 units) 2 mg (40 units) 4 mg (80 units) 5mg (100 units) Some physicians in addition may order a small amount of hcg (such as 1000 or 1500 units) along with the Leuprolide injection to reduce the risk of inadequate maturation of follicles and still keep the risk for OHSS low Costello M, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:

16 Endometrial Support: Estrogen May be prescribed for additional support for the uterine lining, embryo implantation and resulting pregnancy Used in IVF cycles, before and after a frozen embryo transfer and in pregnancy Available formulations: Estradiol valerate injection (intramuscular injection) Estradiol tablets (oral and occasional inserted vaginally) Estradiol patch (Estradiol transdermal system) Role of Progesterone Progesterone for luteal phase support of the endometrium is needed in stimulation cycles Used to build up lining of endometrium for successful implantation Administration begins the day of egg retrieval and continues until pregnancy test If pregnancy occurs the patient will continue on progesterone support Stauss, Barbieri. Yen & Jaffe s Reproductive Endocrinology: physiology, pathophysiology, and clinical management. 2014: Lockwood G, Griesinger G et al. Fertil & Steril. 2014;101(1):

17 Non IVF Ovulation Induction / Stimulation Clomiphene Citrate / Letrozole Non IVF Start either Clomiphene Citrate/ Letrozole Days , 5 9 Stimulation 5 Days Menses Follicular Phase LH monitoring Possible hcg injection IUI / intercourse hrs after positive LH kit or hcg injection Luteal Phase Pregnancy test ~14 days after IUI or intercourse Progesterone support Day 1 Day 7 Day 14 Day 28 Al In any H, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:

18 Gonadotropin Protocol Non IVF Start gonadotropin stimulation Cycle Day 3 Gonadotropin Stimulation ~10 Days Menses Follicular Phase hcg injection IUI or intercourse hrs after hcg injection Luteal Phase Pregnancy test ~14 days after IUI or intercourse Progesterone support Day 1 Day 7 Day 14 Day 28 Al In any H, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:260. IVF Cycle Protocol Phases Prestimulation Downregulation Phase Stimulation Phase Supportive Phase Starts with cycle day one of menses Baseline monitoring Ovarian suppression Oral contraceptive pills (OCP) GnRH agonist Baseline monitoring Start of gonadotropin stimulation medications Development of ovarian follicles Control premature LH surge with GnRH analog Periodic monitoring with blood assays and transvaginal ultrasounds for medication adjustments Trigger shot Egg retrieval Sometimes referred to as Luteal Phase Support Focused on uterine environment for embryo(s) Embryo/Blastocyst Transfer Medication support Progesterone Estrogen 18

19 Supportive Phase Embryo transfer The ET procedure is the last one of the IVF process. Critically important to choose the best quality embryo. Either day 2 or 3 after oocyte retrieval Blastocyst transfer Transferred on day 5 of oocyte retrieval. Chance of selecting best quality embryo for chance at pregnancy. eset Freeze all Center preference Option for those with OHSS Banking embryos for future use ASRM. Fertil Steril. 2012;97 (4): Ovarian Stimulation Protocols Most commonly used Long Luteal (GnRH Agonist Downregulation) Oral Contraceptives optional GnRH Antagonist Oral Contraceptives optional Poor/Low responders/advanced Maternal Age (AMA) Microdose Flare GnRH Antagonist Luteal Estradiol Protocol (Estrogen Priming) Mild Stimulation Protocol (Clomiphene Citrate Priming) Hyper/High responders Long Luteal (GnRH Downregulation) 19

20 Long Luteal Protocol Prestimulation Downregulation Phase Stimulation Phase Progesterone Hormone Assay ~Cycle Day 21 Leuprolide Acetate 0.5 (10U) or 1.0 (20U) mg/day Gonadotropin stimulation ~10 Days hcg Leuprolide Acetate Injection 0.25 (5U) or 0.5 (10U) mg/day Menses Day 21 Baseline Monitoring Egg Retrieval 36 hrs after hcg injection Alper MM, et al. Reproductive biomedicine online Costello M, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:454. Fukuda A. Ovarian Stimulation Protocols: Springer; 2016: La Marca A, et al. Human reproduction update. 2013:dmt037 Long Luteal Protocol Using Oral Contraceptive Pills (OCPs) Prestimulation Downregulation Phase Stimulation Phase Start OCPs first week menses minimum of ~14 days Leuprolide Acetate 0.5 (10U) or 1.0 (20U) mg/day Gonadotropin stimulation ~10 Days Leuprolide Acetate 0.25 (5U) or 0.5 (10U) mg/day hcg Menses Start Leuprolide Acetate Overlap OCPs for 3 days Alper MM, et al. Reproductive biomedicine online Costello M, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:454. Fukuda A. Ovarian Stimulation Protocols: Springer; 2016: La Marca A, et al. Human reproduction update. 2013:dmt037 Menses Baseline Monitoring Egg Retrieval 36 hrs after hcg injection 20

21 GnRH Antagonist Protocol Stimulation Phase Start gonadotropin stimulation Cycle Day 3 GnRH Antagonist start when dominant follicle ~12 14 mm Menses Baseline Monitoring GnRH Antagonist continued daily Gonadotropin stimulation ~10 Days ~Stimulation Day 5 First monitoring check hcg Egg Retrieval 36 hrs after hcg injection Alper MM, et al. Reproductive biomedicine online Costello M, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:454. Fukuda A. Ovarian Stimulation Protocols: Springer; 2016: La Marca A, et al. Human reproduction update. 2013:dmt037 GnRH Antagonist Protocol Using OCPs Prestimulation Downregulation Phase Stimulation Phase Start OCPs first week menses ~14 21 days GnRH Antagonist start when dominant follicle ~12 14 mm GnRH Antagonist continued daily Gonadotropin stimulation ~10 Days hcg Menses OCPs Stopped Alper MM, et al. Reproductive biomedicine online Costello M, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:454. Fukuda A. Ovarian Stimulation Protocols: Springer; 2016: La Marca A, et al. Human reproduction update. 2013:dmt037 Menses Baseline Monitoring ~Stimulation Day 5 First monitoring check Egg Retrieval 36 hrs after hcg injection 21

22 Microdose Flare Protocol Prestimulation Downregulation Phase Stimulation Phase Start OCPs first week menses ~14 21 days Start Microdose Leuprolide Acetate 40 mcg or 50 mcg/10 units twice daily after 3 days of no OCPs On third day of microdose Leuprolide acetate Start gonadotropins hcg Menses Alper MM, et al. Reproductive biomedicine online Costello M, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:454. Fukuda A. Ovarian Stimulation Protocols: Springer; 2016: La Marca A, et al. Human reproduction update. 2013:dmt037 Menses Baseline Monitoring OCPs Stopped Egg Retrieval 36 hrs after hcg injection Luteal Estradiol Protocol Prestimulation Downregulation Phase Stimulation Phase Cycle Day 21 Start Estradiol GnRH Antagonist start when dominant follicle mm Estradiol 1mg 2 tablets bid GnRH Antagonist continued daily Gonadotropin Stimulation hcg Menses Menses Stimulation Day 5 First monitoring check Egg Retrieval 36 hrs after hcg injection Alper MM, et al. Reproductive biomedicine online Costello M, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:454. Fukuda A. Ovarian Stimulation Protocols: Springer; 2016: La Marca A, et al. Human reproduction update. 2013:dmt037 Baseline Monitoring 22

23 Mild Stimulation Protocol Stimulation Phase Start either Clomiphene Citrate/ Letrozole Days 3 7 for 5 Days GnRH Antagonist start when dominant follicle ~12 14 mm GnRH Antagonist continued daily with IVF Cycle ONLY Gonadotropin stimulation hcg Menses Baseline Evaluation Cycle Day 3 Day 5 of Gonadotropin First monitoring check Gonadotropin Stimulation Start Check Egg Retrieval 36 hrs after hcg injection Ferraretti AP, et al Mild ovarian stimulation with clomiphene citrate launch is a realistic option for in vitro fertilization. Fertility and sterility. 2015;104(2): Supportive Phase: All Fresh IVF Protocols Supportive Phase hcg Egg Retrieval 36 Hours after hcg Embryo/Blastocyst Transfer 3 6 Days after Retrieval Pregnancy Test ~14 Days after Transfer Progesterone support started day of retrieval Possible Estrogen support started day of retrieval Alper MM, et al. Reproductive biomedicine online Costello M, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:454. Fukuda A. Ovarian Stimulation Protocols: Springer; 2016: La Marca A, et al. Human reproduction update. 2013:dmt037 23

24 Frozen Embryo Transfer Protocol Embryo/Blastocyst Transfer 3 6 Days after Progesterone Start Progesterone Hormone Assay ~Cycle Day 21 Leuprolide Acetate 0.5 (10U) or 1.0 (20U) mg/day Day 15 of Estradiol Start Progesterone Estradiol 1mg 2 tablets bid or sliding scale Leuprolide Acetate 0.25 (5U) or 0.5 (10U) mg/day Menses Day 21 Baseline Monitoring Endometrium Lining & Estradiol Level Monitoring Fukuda A. Ovarian Stimulation Protocols: Springer; 2016: La Marca A, et al. Human reproduction update. 2013:dmt037 In vitro fertilization (IVF) Ovarian stimulation (daily injections of fertility hormones) Retrieval of oocytes/eggs Eggs and partner or donated sperm combined (through IVF) in lab Fresh embryo transfer or freezing of embryos/oocyte ICSI to assist in fertilization 2017 Walgreens Co. All Rights Reserved 24

25 Prevention of Multiple Gestation The goal of any infertility treatment is a healthy SINGLE full term birth Number of embryos transferred impacts multiple gestation rates With non IVF treatments no control over how many eggs will fertilize IVF use of elective single embryo transfer (eset) is increasing Gerris J. Complications and Outcomes of Assisted Reproduction. 2017:33. Review of Objectives Discuss recommended appropriate non pharmacologic and pharmacologic plans to address infertility Thorough evaluation required so the best individualized plans of treatment can be utilized Identify monitoring parameters for a patient undergoing treatment for infertility Blood assay draws and transvaginal ultrasounds are required for all treatment protocols to minimize risk of developing OHSS Discuss the different commonly used medication protocols used in an ART cycle Many different protocols used and each protocol is applied individually to optimize positive outcome potentials 25

26 Thank You References Song Xm, Jiang H, Zhang Wx, Zhou Y, Ni F, Wang Xm. Ultrasound sclerotherapy pretreatment could obtain a similar effect to surgical intervention on improving the outcomes of in vitro fertilization for patients with hydrosalpinx. Journal of Obstetrics and Gynaecology Research. 2017;43(1): Karasu T, Ola B. Endometrioma and Infertility: Principles and Techniques of Management. Reproductive Surgery in Assisted Conception: Springer; 2015: Mastroianni L, Jr., Laberge JL, Rock J. Appraisal of the efficacy of artificial insemination with husband's sperm and evaluation of insemination technics. Fertility and Sterility. 1957;8(3): Speroff L, Fritz MA. Clinical Gynecologic Endocrinology and Infertility. 7th ed. Philadelphia, PA : Lippincott Williams & Wilkins; 2005:1143, Stauss, Barbieri. Yen & Jaffe s Reproductive Endocrinology: physiology, pathophysiology, and clinical management. 2014: Pasha H, Faramarzi M, Esmailzadeh S, Kheirkhah F, Salmalian H. Comparison of pharmacological and nonpharmacological treatment strategies in promotion of infertility selfefficacy scale in infertile women: A randomized controlled trial. Iranian journal of reproductive medicine. 2013;11(6):495 Martin PL. Detection of ovulation by the basal temperature curve with correlating endometrial studies. American journal of obstetrics and gynecology. 2016;46:

27 References Alper MM, Fauser BC. Ovarian stimulation protocols for IVF: is more better than less? Reproductive biomedicine online Costello M, Koch J, Ledger W. Recombinant LH, Recombinant hcg and GnRH Agonist to Trigger Ovulation: A Critical Evaluation. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:454. Fukuda A. Ovarian Stimulation for Poor Responders. Ovarian Stimulation Protocols: Springer; 2016: La Marca A, Sunkara SK. Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice. Human reproduction update. 2013:dmt037. Prapas Y, Petousis S, Dagklis T, et al. GnRH antagonist versus long GnRH agonist protocol in poor IVF responders: a randomized clinical trial. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2013;166(1):43 46 Costello M, Koch J, Ledger W. Recombinant LH, Recombinant hcg and GnRH Agonist to Trigger Ovulation: A Critical Evaluation. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:454. References Al Inany H, El Mazny A. The Efficacy of Clomiphene Citrate in Preventing a Premature LH Surge during Controlled Ovarian Stimulation with Human Menopausal Gonadotropins. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:260. Ferraretti AP, Gianaroli L, Magli MC, Devroey P. Mild ovarian stimulation with clomiphene citrate launch is a realistic option for in vitro fertilization. Fertility and sterility. 2015;104(2): Gerris J. Minimizing Multiple Pregnancy After Assisted Reproductive Technology. Complications and Outcomes of Assisted Reproduction. 2017:33. 27

28 References Medications Fertility medication information: CLOMIPHENE CITRATE. DailyMed Web site d 93d3 1dedd4d Updated March Accessed January 19, Fertility medication information: CRINONE 8%. DailyMed Web site. d521 41c0 b419 48e028f59f15. Updated August Accessed January 19, Fertility medication information: ENDOMETRIN. DailyMed Web site. b349 40cb 9a4b 1af8faa4ec09#section 1. Updated September Accessed January 19, Fertility medication information: FEMARA. DailyMed Web site f 45ac a7dd 1f5c038bf406. Updated January Accessed January 19, Fertility medication information: FOLLISTIM AQ Cartridge. DailyMed Web site. cc7b 48aa 830aa28e1962d871. Updated December Accessed January 16, Fertility medication information: GANIRELIX ACETATE Injection. DailyMed Web site e d 424a59d574b6. Updated March Accessed January 19, References Medications Fertility medication information: GONAL f Multi Dose. DailyMed Web site. e7eb 4981 a5d e8f189. Updated April Accessed January 19, Fertility medication information: GONAL f RFF Redi ject. DailyMed Web site. b e bb28 2ff596ea259c. Accessed January 19, Fertility medication information: LETROZOLE. DailyMed Web site b7d7 5cb4b5cdcf6a#section 1. Updated October Accessed January 19, Fertility medication information: LEUPROLIDE ACETATE. DailyMed Web site a346 bc5e3acbba0b. Updated January 18, Accessed February 10, Fertility medication information: NOVAREL. DailyMed Web site. 9dc3 40d b26e4bdfc8. Updated September Accessed January 19, Fertility medication information: PREGNYL (chorionic gonadotropin for injection USP) 9c7a 4517 a1b6 9362aab0b86c. Merck Sharp & Dohme B.V., a subsidiary of Merck & Co., Inc. Updated January Accessed January 19,