CONTROLLED OVARIAN HYPERSTIMULATION : …...Agonists • Leuprolide, nafarelin, goserelin, deslorelin,buserelin, triptorelin • Antagonists • Ganirelix, cetrorelix • The 1st report

CONTROLLED OVARIAN HYPERSTIMULATION : CLINICAL

INPUTS

Assist Prof Dr Sabah M. BaghdadiM.B.Ch.B., M.Sc., Ph.D

September 25, 2019American Center for Reproductive Medicine

Learning objectives1. Introduction2. Clomiphene citrate (CC)3. Gonadotropins (hMG)4. GnRH Agonists 5. GnRH Antagonists (GnRH antag)

INTRODUCTION• The aim of controlled ovarian hyperstimulation (COH) for IVF is to

produce multiple follicular development in order to harvest a suitable number of oocytes which can be fertilized and allow a selection of embryos which can be replaced into the uterus.

• Individually tailoring the programme attempts to achieve the best live birth rates while taking into account the avoidance of ovarian hyperstimulation syndrome (OHSS) and the promotion of patient comfort, performed by utilizing several known facts such as ovarian response in any previous cycles, age, AMH or other predictors of ovarian reserve.

(1) Clomiphene Citrate (CC)

• Clomiphene Citrate (CC) was 1st synthesized and introduced in 1956, and was entered clinical trials in 1960.Food and drug administration (FDA) was granted in 1967.The use of it as single agent for multiple follicular development in IVF was 1st

attempted by Lopata et al, 1978• Clomiphene was a revolutionary advance in reproductive

medicine and quickly became popular for induction of ovulation alone or in conjunction with other medications (e.g. dexamethsone, metformin, bromocriptine (Parlodel), or gonadotropins) because of its ease of administration and minimal side effects, in other side it is a powerful drug and should not be given empirically.

• The standard dosage is 50 mg of CC per day for five consecutive days. Treatment begins early in the cycle, usually on the second, third, fourth or fifth day after menstruation begins. If a woman does not have periods, a period can be induced by administering progesterone or some other progestin. Ovulation rates, pregnancy rates (PRs), and pregnancy outcomes are similar regardless of whether treatment begins on cycle day 2, 3, 4 or 5.

• Clomiphene can reduce the quantity and wateriness of cervical mucus, making it a barrier for sperm. Intrauterine insemination (IUI) frequently is used in conjunction with CC. Clomiphene sometimes can alter endometrial thickness, making it thin and unreceptive to implantation.

• The commercially available form of clomiphene is the dihydrogen citrate salt (clomiphene citrate) it is present as mixture of 2 isomers (configuration) for that it is called Clomid twins.

• It acts as a selective estrogen receptor modulator, similar to tamoxifen, raloxifene, cyclofenil .

• All the three drugs are not steroids but triphenylethylenescompetitive inhibitors of estrogen binding to estrogen receptors in the hypothalamus their configuration shows a remarkable structural similarity to estradiol (E2).

• Clomid contains two stereoisomers: zu-clomiphene (38 %) and en-clomiphene (62 %), which were originally called the cis -isomer and trans-isomer, respectively.

• Separation of the 2 Clomid isomers was expensive and difficult.• The two clomiphene isomers have mixed estrogenic and

antiestrogenic effects that vary among species.

• clomiphene citrate is water soluble and it is well and rapid absorbed by the gastrointestinal tract and is metabolized by the liver to inactive metabolites.

• 50% of the oral dose is excreted after five days, but radioactivity from labeled clomiphene appears in the feces up to six weeks after administration.

• CC has a half-life of approximately 5 days, the main rout of excretion is through the feces, although small amount are found in urine.

• A number of gonadotrophin preparations are available for COH in assisted reproductive technologies. They all contain FSH whether derived from menopausal urine and purified or from recombinant DNA technology.

Harlin J, et al Hum Reprod. 2002;17:304–9.

2-Gonadotrophins (hMG)

• Gonadotropins often are prescribed for anovulatory women who have tried clomiphene without success. They are also used to help women whose pituitary glands do not produce adequate amounts of FSH and LH, and as a result these women have decreased estrogen and amenorrhea. Additionally, this drug is used to induce development of multiple follicles for IVF or IUI.

• The first commercially available gonadotropin hMG, contains approximately equal amounts of FSH and LH. The FSH and LH in hMG are extracted and purified from the urine of postmenopausal women who have high levels of these hormones. hMG is administered by injection, and directly stimulates the ovaries to induce the development and ovulation of one or more follicles. Gonadotropin treatment involves a series of injections and careful monitoring during each treatment cycle. Most physicians begin gonadotropin treatment on day 2 or 3 of the menstrual cycle.

• In addition to the combination of FSH and LH found in menopausal gonadotropins, FSH, without significant LH, is available. There are two methods for obtaining this “pure” FSH, urinary extraction and through recombinant DNA technology. Early advances in extraction and separation techniques allowed for 99% of LH to be removed from hMG. The first urinary FSH product was introduced in 1986 (uFSH). The application of tools used in molecular biology has allowed FSH to be produced by recombinant DNA technology (recFSH). These products contain no LH. They are also administered via subcutaneous injection. As with hMG, these FSH medications bypass the hypothalamus and pituitary and directly stimulate follicular growth in the ovary. Pharmaceutical companies have introduced premixed ready-to-use gonadotropin formulations that reduce patient concerns about preparing their injections from separate vials of powder and liquid. Pen injector devices, analogous to those used for insulin-requiring diabetic patients, are safe, effective and easy for patients to use.

NH2pGlu His Trp Ser Tyr Gly Leu Arg Pro Gly

Native GnRH

• Synthesized and secreted in the hypothalamus• Released in coordinated pulses by the hypothalamus• Reaches the pituitary via the HP portal system• Stimulates the release of FSH, LH, and GnRH receptors of the

anterior pituitary• Quickly metabolized with a half-life of <5 minutes• GnRH pulsatile secretion from the arcuate nucleus

• After the discovery of chemical structure of native GnRH, (after 1971), analogs were soon developed & for that it is called GnRH-agonist & that lead to produce a huge FSH & LH release from the pituitary. However, under continues administration of a GnRH-agonist the normal synthesis & subsequent release of LH &FSH become blocked.

• GnRH-agonist act through desensitization of the pituitary gonadotropin cells & a reduction of the number of GnRH receptors (down-regulation). So initially GnRH-agonist cause a surge of FSH & LH followed by blockage of the receptor thus preventing further production of LH & FSH which take 7-10 days after initiating of treatment followed by a depletion of endogenous FSH & LH , thus rendering the ovarian quiescent ( medical hypophysectomy, medical castration, medical gonadectomy, hypogonadotrophic hypogonadism).

• GnRH-agonist analogues differ from native GnRH in amino acid position 6&10, for that it increase GnRH stability & binding affinity to its receptors by modifying the amino acid sequence, they are resistant to degradation, giving then long half-life ( few hours) whereas the native GnRH have half life of only a few minutes, the GnRH-agonist have 100-200 times higher binding affinity for GnRH receptors than dose the native molecules.

• Since treatment with GnRH-agonist abolishes the endogenous ovarian cycle, it allows hMG (rFSH) treatment for ovulation induction to be initiated on any day thereafter according to a fixed schedule, the blockade of the GnRH receptor also abolishes the LH surge thus preventing premature ovulation, this result to increase number of mature oocytes at retrieval, which is particularly useful in programming cycles for IVF.

• From above we can suggest that GnRH analogs are synthetic hormones similar to natural GnRH, but which are chemically modified.

• A GnRH analogue often is used to prevent spontaneous ovulation when gonadotropins are given to women undergoing IVF• Agonists

• Leuprolide, nafarelin, goserelin, deslorelin,buserelin, triptorelin

• Antagonists• Ganirelix, cetrorelix

• The 1st report on the use of the combination of the GnRH-agonist (Buserlin) & gonadotropins for ovarian stimulation for IVF was on 1984

GnRH-Antagonist

• It have been more recently introduced , it may offer advantages over GnRH-agonist.It have emerged as an alternative in preventing LH surges. GnRH-antagonist bind to gonadotropin releasing hormone receptors in pituitary gland & compete successfully with endogenous agonist GnRH molecules for receptor occupancy, this leads to an immediate effect by competitive blockade of GnRH receptors that lead to arrest of gonadotropin secretion that last as long as they are present in sufficient concentration, for that pharmacological mode of action are more physiological. The main objective of using GnRH-antagonist in ovarian stimulation for IVF, is the avoidance of a premature LH rise.

• GnRH-antagonist become commercially available for use in the UK in April 1999 & in North America in May 2000

• The 1st generation of GnRH-antagonist was on 1991 introduction of Nal-Glu , that cause allergic side effect due to histamine release. The 3rd generation introduced was on 1999,

Two GnRH-antagonists now commonly used in IVF centers word wide are:

1. Cetrolix ( Cetrotide; Serono; Switzerland)2. Ganirelix (Organlutran;Organon,Germany)

0.0625,0.125,0.25,0.5,1.0,2.0 SC

• Both these compound seem to be equipotent fully effective within 4-8 hours after administration

Mechanism of action of GnRH agonistinhibition of endogenous LH surge

0

40

20

80

100LH level [U/L]

Days

Fatemi 2002, Antalya 2003

Mechanism of action of antagonistsPrevention of premature LH surge

0

4

2

6

8

10LH level [U/L]

Hours

Antagonist

Antagonist Protocol Is Shorter Than Agonist Protocol

Day 2 or 3of menses

rFSH

GnRH agonist

Cycle day21-24

Downregulation

Luteal phasesupport

Embryo transfer

GnRH antagonist

Day 6 of FSH

rFSH

hCG

Luteal phase (current cycle)Luteal phase (prior cycle)

Start of cycle

IVF

or

ICSI

Conclusion• GnRH antagonist protocol provides significant advantages:

• Shorter stimulation periods• Option for the use of soft friendly protocol• No cyst formation• Lower incidence of OHSS

• Less stressful GnRH antagonist results in: Similar pregnancy rates to GnRHa long protocol

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