GnRH Analogues Clinical Applications Pros and Cons

GnRH Analogues Clinical Applications Pros and Cons Bulent Gulekli,M.D. Professor & Chairman Department of Obstetrics & Gynecology Dokuz Eylul University School of Medicine Izmir

Nobel prize 1977 Andrew Schally Roger Guilleman

GnRH-a, Relative Potency

GnRH-a, Trade names and dosage

Luteal phase GnRH-a start

Follicular phase GnRH-a start

Physiology &Action • Native form: synthesized in hypothalamus acts on pituitary, results in LH FSH • GnRH Agonist: initial stimulation effect. • Sustained exposure: Leads to down regulation of Pituitary target cells FSH&LH.Results in Gonadal steroidogenesis. • Longer ½ life, and bioavailibity. 150-300 active than native form. Differ with the preparation.

Route of Administration • SC injection (Daily & Depot) • Intranasal • I.M • Implants

Side Effects • Breakthrough bleeding (initially) • Hypoesterogenic Status : Hot flushes, palpitations, increased sweating, vaginal dryness, change of libido, headache or migraine. • Osteoporosis: Duration dependant, 6% possible loss, reversible

Side Effects (Rare) • Hot flashes • Sweating, • Mood swings, • Vaginal dryness, • Decreased libido, • Nausea, vomiting, • Breast tenderness, • Insomnia, headaches, and • Injection site reaction (redness, itching, swelling at the injection site).

Contra-indications • Pregnancy • Breast feeding • Undiagnosed vaginal bleeding

Clinical Application(1) Endometriosis Uterine fibroids DUB Central precocious puberty Premenstrual syndrome Hyperandrogenism (PCOS,Hirsutism) Chronic Pelvic pain

Clinical Application (2) Infertility Ovulation induction Stimulation for IVF cycles Trigger of ovulation(to prevent OHSS) Oncology Breast malignancy Ovarian malignancy Endometrial malignancy

GnRH-a(Infertility) • Avoidance of premature LH surge • Synchronization of follicular growth • Increases the number of oocytes recovered

GnRH-a (Infertility) • Organization of cycles and less cancellation • Improves the clinical pregnancy rates per cycle and per embryo transfer

Utilization of GnRH agonists

LONG PROTOCOL • Reduced cycle cancellation rate (Advantage) • Cost and more needed Gns. (Disadvantage) • Longer duration of therapy (Disadvantage)

LONG PROTOCOL • Follicular Phase (Long follicular) • Luteal Phase (Long Luteal) • No sig difference in terms of pregnancy rate • 10 – 12 duration of Tx ; E2 < 30 pg/ml • Follicular phase protocol;Inc. ovarian cyst risk • Luteal phase protocol ; Application in a probablepregnancy

Long Foll vs Long Luteal Long Follicular… …1. day of Menses Long Luteal………..20-21. day of Menses Long Luteal………….More profound and prompt supression Started with leuprolide 1 mg/day, dose reduced to 0.5 mg/day when Gn started. (=Buserelin intranasal 600µg/day)

Down Regulasyon Criteria • By USG • regression of follicles to less than 5 mm diameter and/or thin or no endometrial echo • By Hormone Assay • Serum oestradiol < 180 pmol/l (30 pg/ml), or both. • These criteria are usually met after 12 or 14 days treatment. • Onset of Gn usually occur 2-3 days of menses.

Premature LH Surge • LH > 10 IU/L • Progesterone > 2 ng/ml

Long protocol A major advantage ……………..the initiation of exogenous GNs after pituitary desensitization can be delayed to prevent ovum pickup (OPU) in the weekends Thursday….Friday;………. Gn initiation

OC Use in Long Protocol • Prevention of functional cysts and spontaneous pregnancy • Prevention of LH surges • Improved response to gonadotropins, • Programming of the IVF cycle

Pregnancy Rates in Different Protocols

SHORT PROTOCOL • Flare – up protocol • Started on the first or second day of cycle • Gn started 2 or 3 days later • Pituitary suppresion during follicular aspiration (Advantage) • Early Gn starting (Advantage) • Preferred for poor ovarian response • Pregnancy rates are low compared with long protocol

GnRH-a protocols

ULTRA-SHORT PROTOCOL • Only 2 or 3 days application in follicular phase • Enough for endogen LH suppression • Preferred for the poor responder patients • Lower doses can also be applicated

Early Cessation (Stop) Protocols The agonist is started midluteal in the preceding cycle and discontinued during or even before the Gns treatment is started.

Microdose flare-up • One cycle OCs. • 3 days after the last dose of OCs2x40 µgLeuprolide acetate started • Leuprolide acetate 1 mg/0.2 ml ;0.2 ml LA diluted with SF to obtain a volume of 10 ml. Ins syringe contains10 U=0.1 ml. Therefore10 U=10 µg LA. • Diluted LA should be used in 30 days • Gn started 2 days after GnRH-a.

Schematic view of Different Protocols

Minimal Effective Doses of Agonists ► Minimal effective doses of agonists are unknown ► It is very likely that the dosage of the commonly used GnRH agonists is far too high.

Agonists and OHSS The risk of OHSS in agonist COH cycles ranges from 6.6 to 8.4%. The use of GnRH agonist in COH protocols allows continuous stimulation by gonadotropins, which will drive more follicles to maturation,increasing the risk of OHSS.

The use of GnRH agonist in IVF protocols The survey includes reports from 273 centres worldwide performing 151,000 IVF cycles annually. www.IVF-Worldwide.com

www.IVF-Worldwide.com

GnRH Analogues Clinical Applications Pros and Cons