Gonadotropin Ovarian Stimulation Aboubakr elnashar elnashar53@hotmail.com

Contents Types of ovarian stimulations Types of Gnt Patient selection Indications Contraindications Protocols Monitoring Results Complications Conclusion

Types of ovarian stimulation Induction of ovulation: To induce monofollicular development in anovulatory patients Superovulation: Intentional production of more than one mature follicles

Controlled ovarian hyperstimulation (COH): Regulated superovulation by turning off the patient’s own hormones (down regulation) followed by stimulation 1. Multiple follicles growth. 2. Control timing of ovulation: ova can be retrieved before they are ovulated. 3. Prevention of premature LH surge.

Gonadotropin Preparations 3 main preparations: FSH, LH & HCG 2 types I. Urinary 1. HMG Prepared from: urine of postmenopausal women Content: equivalent amounts (75 IU) of FSH & LH/amp or vial U proteins: significant amounts, can be antigenic. Route: IM

2. Highly purified HMG: Content: Equal amounts of FSH (75IU) & LH (75IU) U Pr: <5% Route: SC

3. Purified FSH Developed by: Removing LH from u extracts (using immunoaffinity columns containing anti-hCG antibodies). Content: FSH (75 IU) & <1 IU LH U protein: 95% Route: IM

4. Highly purified FSH Content: <0.001 IU LH U protein: <5% Route: SC minimal or no reaction at the injection site.

5. Urinary HCG {structural & biologic similarity to LH} Prepared from: human pregnancy urine & placental tissue To simulate the LH surge: induce final follicular maturation Dose: 5000–10,000 IU.

II. Recombinant 1. Rec FSH Prepared by Content: genetic engineering. FSH isoforms less acidic shorter half-life stimulate estrogen secretion as or even more efficiently.

Advantages: Absence of u protein More consistent supply Less batch-to-batch variation in biologic activity.

2. Rec HCG Produced using: techniques similar to rec FSH. Approved: 2001 in USA Dose: 250 µg

3. Rec LH {physicochemical, immunologic& biologic activities comparable to those of human LH} Advantage: An effective alterative to hCG lower risk of OHSS. Approved: 2000 in Europe Dose: 15,000-30,000 IU

Advantages of Rec technology: Control of source material Purity& specific activity Consistency of active product Efficacy & efficiency Safety : 1. Tailor ovarian stimulation regimens to the needs of the individual woman 2. Optimize oocyte quality& cycle fecundity.

I. Urinary Gonadotropins Preparation Trade name Route U.pr FSH LH Company 1. HMG Pergonal, Humegon, Menogon, Merional IM 95% 75 Serono Organon Ibsa 2. H.P.HMG Menopur SC <5% Ferring 3. Purified FSH Metrodine Urofillotropin <0.1 4. H.P.FSH Fostimon Metrodine HP Bravelle SC, IM <0.001 5. HCG Pregnyl Profasi 6. H.P.HCG Choriomon SC,IM

II. Recombinant Gonadotropins Preparation Trade name Route U.pr FSH LH company 1. FSH Gonal-f (follitropin) Gonal-f FbM Pen Puregon (follitropin) Puregon pen SC, IM SC,IM SC, Im - 75,150 300,450,900 50,100 300,600 Serono Organon 2. HCG Ovitrelle Choriogonadotropin SC 3. LH Luveris lutotropin

Ready to use pre-filled pen Rec Consistent FSH in terms of protein content (Bassett et al, 2005). More precise dose More consistent ovarian response: less treatment days less cancelled cycles Better embryo quality Higher implantation rate (Hugues et al.,2002 Balasch et al, 2004) Pen: Easy to use Patients prefer prefilled pen (Weiss et al, 2007) xx/xx/xxxx Editor: Presentation name here

Patient selection Basic investigations of infertility Semen analysis HSG Midluteal P II. If amenorrhea &/or galactorrhea: Workup

Indications Induction of ovulation 1. Hypogonadotropic Hypogonadism (hypothalamic amenorrhea, WHO Group I) Gnt secretion: extremely low Menotropin: only effective Gnt {contains both FSH and LH}. LH-containg Gnt if LH <3 IU/L (Speroff, 2005) CC& related medications: ineffective {their actions require an intact& functional hypothalamic-pituitary-ovarian axis}.

2. CC resistance or failure Resistance (No ovulation) or Failure (No pregnancy) PCOS(WHO Group II) Gnt: normal LH: may be high

Clomiphene Citrate Resistantce Incidence: 20% Define No ovulation after treatment with CC, {100 mg, for 5 days in 3 cycles} (Coelingh Bennink, 1998). Causes: Hyperandrogenic Obese Severe insulin resistance (Murakawa et al., 1999; Speroff et al., 1999).

Clomiphene citrate failure: Define: No pregnancy despite of ovulation with CC Causes: long half-life& peripheral anti-estrogenic effects on endometrium& cervical mucus. low fertilization rate variable implantation rate deficient corpus luteum function (Speroff et al., 2005)

Dosage: minimum to cause development of a single dominant follicle. {Response can vary greatly from individual to individual& from cycle to cycle} Monitoring: Adjust dosage Timing of ovulation.

Luteal-phase support seldom necessary {endogenous LH levels typically are more than sufficient to support normal luteal function}. Indication GnRHa used Evidence of poor luteal function after otherwise successful ovulation induction How: progesterone {higher risk of OHSS associated with hCG}

1. Unexplained Infertility II. Superovulation 1. Unexplained Infertility Aim: increase cycle fecundity PR/cycle (%) Guzik et al, 1998 1.3 No treatment 4 IUI 5 CC 8 CC with IUI HMG 17 HMG with IUI 21 IVF/ICSI

2. IUI Most effective when combined with IUI PR/cycle: 17 %

Monitoring: {avoid obviously excessive stimulation}. Risks Multiple pregnancy: > in clomiphene-resistant anovulatory women Luteal support: Not required {combined contributions of two or more corpora lutea may be reliably expected to yield supraphysiologic luteal-phase serum progesterone concentrations}

COH IVF or ICSI Aim: induce multifollicular rather than monofollicular growth. maintaining a sub-threshold level of Gnt during the time of follicular recruitment thus overriding the process of selection of a single dominant follicle. How: GnRHa, or antagonist to block endogenous LH production& LH surges. Gnt HCG When an appropriate follicular size is observed: final maturation of the follicles

Contraindications Rare: 1. Hypersensitivity to Gnt or to any of the excipients. 2. Ovarian, uterine, or breast cancers. 3. Ovarian enlargement or cyst not due to polycystic ovarian disease. 4. Tumors of the hypothalamus& pituitary gland. 5. Pregnancy& lactation. 6. Gynecological hemorrhages of unknown origin.

Protocols Dose& duration vary among Women: extremely sensitive to relatively low doses (75-225 IU daily), others require greater stimulation (300-450 IU daily). B. wt & dose Response cannot be predicted, even in the obese. 2. Cycles within women The intended goal: unifollicular ovulation or superovulation?.

I. Step-up: II. Step-down III. Step-up, step-down 1. Conventional=Standard 2. Low dose 3. Chronic low dose II. Step-down III. Step-up, step-down

I. Step up Principle: Stepwise increase in FSH {determine the FSH threshold for follicular development}

Duration of starting dose: 5 d Increased by: 75 IU/3-5 d Conventional: Starting dose: 150 IU/d: Duration of starting dose: 5 d Increased by: 75 IU/3-5 d Excessive follicle development Increased OHSS (Thompson and Hansen, 1970; Dor et al., 1980; Wang and Gemzell, 1980). No longer recommended (Buvat et al., 1989; Brzyski et al., 1995)

If Starting dose: 150 IU/d No response® 3 FSH/day for 3 more days Follicle > 12 mm E2 > 400U Continue 2 FSH/d If No response® 3 FSH/day for 3 more days Endocrine Rev. 1997; 18: 71

2. low-dose Stating dose: 37.5-75 IU/d (White et al., 1996; Hayden et al., 1999; Balasch et al., 2000; Calaf et al., 2003). Duration of starting dose: 5-7 d -No follicle development: increase the dose by 100% -Follicle growth: maintain same dose until follicular selection is achieved.

If Endocrine Rev. 1997; 18: 71 Starting dose : 37.5-75 IU/d 5 days 37.5-75 FSH/hMG/day 5 days Day 7 Follicle > 12 mm E2 > 400US Day 3 Continue 1 FSH/d If No response ®75-150 FSH/d for 1 more w (max. 3 amp.) Endocrine Rev. 1997; 18: 71

Duration of starting dose:14 d 3. Chronic low-dose Starting dose: 37.5 IU Duration of starting dose:14 d The weekly dose increment: reduced from 100% to 50% or 37.5 IU (Seibel et al., 1984; Polson et al., 1987; Sagle et al., 1991; Dale et al., 1993). :Markedly reduce excessive ov stimulation Marked dec in OHSS.

White et al. J Clin Endocrinol Metab 1996;81:3821–4 3 Amp. 225 iu 2 Amp. 187.5 iu 150 iu One Amp. 112.5 iu ½ Amp. 75 iu 37.5 iu Days 7 14 21 28 35 42 49 White et al. J Clin Endocrinol Metab 1996;81:3821–4

Monitoring 1- TVS: Baseline ovarian cyst: > 30 mm: decreased fecundity (Akin and Shepard, 1993). : postpone Gnt.

Daily SI on the day of HCG& for the next 2 days b. Follicles: 1 or 2 follicles 18-20 mm: HCG Daily SI on the day of HCG& for the next 2 days > 3 follicles > 16 mm: Stop stimulation& hCG withheld (Macklon et al, 1999). Gnt follicles mature at 15-18 mm CC follicles mature at 18-20 mm

C. Endometrial thickness: <6 mm: No pregnancies 9-10 mm or more: Chance of pregnancy is great (Isaacs et al, 1996).

2-E2 peak (pg/ml): <200 pregnancies are rare 500-1500 optimal 1500-2000 risk of OHSS is significant >2000 pg./ml: hCG is not given Cyle is cancelled (Speroff et al, 2006).

Results Ovulation >90%

II. Pregnancy Low: 1. Hyperandrogenic chronic anovulation group 2. Above 35 y CC resistant anovulatory Hypogonadotropic hypogonadism 5-15% 25% Cycle fecundity 30-60% 90% Cumulative PR after up to 6 cycles

III. Miscarriage 20-25% moderately higher than is generally (15%). {1. Advanced maternal age 2. obesity} Low in hypogonadotropic hypogonadism Higher in clomiphene-resistant anovulatory women

IV. Congenital anomalies. No increase

Complications Multiple pregnancy: II. OHSS Low dose protocol: <6% Conventional dose protocol: 36% II. OHSS Low dose protocol: <1% Conventional dose protocol: 4.5% III. Breast & ovarian cancer: No increase IV. Local allergic reactions.

Conclusion The intended goal: unifollicular ovulation or superovulation 3 main preparations: FSH, LH & HCG & 2 types Rec Gnt have more consistent ovarian response Basic investigations of infertility Indications are hypogonadotropic hypogonadism, CC failure or resistance, unexplained infertility, IUI

Contraindications are rare Step up chronic low dose protocol is recommended in PCOS US monitoring is mandatory Ovulation 90%, Pregnancy 30-90%, miscarriage 20% Complications are OHSS & multiple pregnancy

Thank you Dr Aboubakr Elnashar