01-12 Management of ovulation induction and ovarian stimulation

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Management of ovulation induction and ovarian stimulation

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José Bellver Pradas MD, PhD Gynecologist Reproductive Medicine Unit IVI Valencia Professor. Department of Pediatrics, Obstetrics, and Gynecology. Faculty of Medicine. University of Valencia

Index

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Introduction: PhysiologyOvulation induction Controlled ovarian (hyper)stimulation Controlled ovarian stimulation GnRH agonist vs GnRH antagonist Type of gonadotropins Alternative protocols Conclusions

Introduction. Physiology

Primordial Follicle

Preantral Follicle

FSH - LH independient

Introduction. Physiology

Preovulatory Follicle

Antral Follicle

FSH dependent

LH dependent

Introduction. Physiology

Feedback system

Hypothalamus

Hypothalamic peptides: GnRH

Anterior hypophysis

Estrogens Inhibin

Ovary

Introduction. Physiology

Two cell-two gonadotropin theory

Ovulation induction

Monofollicular development

Ovulation induction

Involves monitoring the folliculogenesis through a vaginal ultrasound, which reveals a single or slightly multiple follicular development (2 to 3 follicles), supported by measuring serum estradiol levels.

Clomiphene citrate Aromatase inhibitors: Letrozole Gonadotropins:

• HMG: Human Menopausal Gonadotropin
• FSHu: Urinary FSH
• FSHr: Recombinant FSH

Ovulation induction

Clomiphene citrate

Clomiphene citrate

Ovary

Hypothalamus

Estrogens

Ovulation induction

Clomiphene citrate

Ovulation induction

Clomiphene citrate - Side effects

Infrequent (11%) Disappear when concluding the treatment

• Flushes
• Visual alterations
• Abdominal distention
• Nausea and vomits
• Mammary congestion

Ovulation induction

Clomiphene citrate - Results

Ovulations

Disadvantages: 30% are resistant Antiestrogenism

Pregnancies

• Cervical mucus
• Endometrium

70-80% of patients ovulate, pregnancy percentage per cycle is 15-20%, cumulative rate of 40-45% after 4-6 cycles.

Ovulation induction

Aromatase inhibitor (letrozole, anastrozole)

Ovulation induction

Aromatase inhibitor (letrozole, anastrozole)

Ovulation induction

Aromatase inhibitors: LETROZOLE (Femara®) – Side effects

Less common than with Clomiphene No antiestrogenic action on the endometrium

• Flushes
• Headaches
• Fatigue
• Nausea

Ovulation induction - no audio

Ovulation induction

Gonadotropins – Mechanism of action

Ovulation induction

• Requires ultrasound and laboratory control
• More expensive and annoying (injections)
• Higher risk of OHS and multiple gestation

Gonadotropins

Similar pregnancy rates to letrozole

Controlled ovarian (hyper)stimulation

Multiple follicular development

Controlled ovarian stimulation

Ovarian response and live birth rate

N = 400,135

Controlled ovarian stimulation

LBR according to age and ovarian response

Controlled ovarian stimulation

LBR according to age and ovarian response

N = 1099

Fresh LBR

Cumulative LBR

1-3 oocytes

4-9 oocytes

10-15 oocytes

>15 oocytes

Controlled ovarian stimulation

LBR according to age and ovarian response

• 14,469 patients (1 cycle per patient).
• 15 centers: IVI-Spain + UZ Brussels.
• 2009-2014.

Controlled ovarian (hyper)stimulation

LBR according to age and ovarian response

Hypothalamus

Menstrual cycle

Hypothalamic peptides: GnRH

Anterior hypophysis

Gonadotropins: FSH, LH

Estrogens Inhibin

Ovary

Controlled ovarian stimulation

Basic principle of COS

Controlled ovarian stimulation

Mechanism of action

Long protocol with GnRH agonists

Protocol with GnRH antagonists

Hypothalamus

GnRH

GnRH

GnRHantagonist

GnRH agonists

Hypophysis

GnRH receptors

GnRH receptors

Desensitization of receptors

FSH LH

FSH LH

FSH LH

Flare-up

Suppression of gonadotropins

Direct suppression of gonadotropins

GnRH agonist vs GnRH antagonist

Cycles with GnRH antagonist are shorter than cycles with GnRH agonist

GnRH agonist vs GnRH antagonist

Live birth rate

Transcript: Studies comparing both GnRH analogs for pituitary suppression have shown similar live birth rates

GnRH agonist vs GnRH antagonist

OHSS

but a lower risk of ovarian hyperstimulation syndrome (OHSS) with GnRH antagonists, possibly due to the need for lower gonadotropin doses, as there is no need to compensate for the prolonged pituitary suppression induced by GnRH agonists.

GnRH agonist vs GnRH antagonist

Although the natural LH surge is significantly longer, the surge induced by agonists effectively stimulates LH release, final oocyte maturation, and ovulation.

Another reason why the risk of ovarian hyperstimulation syndrome (OHSS) is reduced with the use of GnRH antagonists is the possibility, as mentioned earlier, of administering a final bolus of GnRH agonist to trigger ovulation instead of hCG. The LH surge induced by the agonist bolus has a shorter half-life than that of a natural LH surge, and much shorter than the LH-like action of hCG. This results in a shorter luteotropic stimulus on the corpus luteum, thereby preventing, except in rare cases, the development of this feared syndrome. However, this shortened luteal phase makes fresh embryo transfer impossible unless strong luteal phase support is provided. Consequently, embryo transfer must be deferred to a subsequent cycle, requiring embryo cryopreservation — which also serves as an effective strategy to prevent the late-onset form of the syndrome.

GnRH agonist vs GnRH antagonist

Hippocrates: 460 B.C. – 370 B.C.

GnRH agonist vs GnRH antagonist

GnRH ANTAGONIST

• No initial flare-up effect.
• No symptoms of estrogenic deprivation.
• Shorter treatment.
• < Gonadotropin dose.
• Beginning of stimulation with recruitment.
• Less aggressive and more customized protocol.
• Possibility of using CC with or without gonadotropins.
• Cheaper.
• < Incidence of OHSS.
• Possibility of inducing ovulation with a GnRH agonist.

GnRH agonist vs GnRH antagonist

IVF stimulation protocols

Pituitary suppression protocol (n=1760)

AntagonistsProgestins NH Long-cycle agonists Depot analog No analog Others

In fact, they remain the most widely used strategy in most assisted reproduction centers, such as IVI Valencia, for fresh embryo transfers. However, as deferred transfers of frozen embryos are becoming increasingly common for various indications, other methods of early ovulation suppression in these deferred cycles are now matching GnRH antagonists in frequency — particularly the use of progestins, as will be discussed later.

GnRH agonist vs GnRH antagonist

IVF stimulation protocols

Pituitary suppression protocol (n=1760)

AntagonistsProgestins NH Long-cycle agonists Depot analog No analog Others

This becomes evident when differentiating ovarian stimulation cycles for in vitro fertilization with and without preimplantation genetic testing, since for genetic or chromosomal analysis of the embryo, freezing is required in order to perform a deferred transfer once the test results are available.

GnRH agonist vs GnRH antagonist

Variations of the long protocol with GnRH agonists in poor response

Objective → maximum number of oocytes

Type of gonadotropin

Medication for ovarian stimulation

• Gonadotropins:

• Recombinant FSH

• Follitropin α: Gonal-F®; Bemfola®; Ovaleap®

• Follitropin β: Puregon®
• Corifollitropin: Elonva®
• Follitropin δ: Rekovelle®
• Urinary FSH: Fostipur®
• HMG-hp: Menopur®; Meriofert®
• HMG: HMG lepori®
• Recombinant LH: Luveris®
• Recombinant FSH+LH (2:1): Pergoveris ®

• Antiestrogens:

• Clomiphene citrate: Omifin®
• Letrozole: Femara®

Type of gonadotropin

Administration of LH activity

• Necessary in hypo-hypo

(Balasch et al, 1995; Loumaye et al, 1998)

• No benefit in the population selected

(Kolibianakis et al, 2006)

• No benefit in normoresponders < 35

(Griesinger et al, 2005; Bosch et al, 2011)

• Benefit in patients with GnRH agonist and hyporesponse to FSH

(De Placido et al, 2001; Ferrareti et al, 2004)

• Controversial benefit in normoresponse from 36 to 39

(Bosch et al, 2011; Hill et al, 2012, Konnig et al, 2013 )

• Without benefit evidenced in PR, but plausible

(ESHRE 2016; Humaidan, 2017)

Type of gonadotropin

LH supplement at advanced age

Forest plot of clinical pregnancy Hill. Recombinant LH in patients of advanced reproductive age. Fertil Steril 2012

Type of gonadotropin

LH activity administration

The use of recombinant FSH (rFSH) and human menopausal gonadotropin (hMG) for controlled ovarian stimulation is equally recommended. Strong ⊕⊕⊕

Controlled ovarian stimulation for IVF/ICSI. ESHRE Guideline. February 2019

Type of gonadotropin

LH activity administration

Prior poor response to FSH monotherapy; those with DOR on antagonist cycles; and women aged 36–39 years.

However, more recent studies have shown that in conditions where there is greater suppression of endogenous LH levels, its administration during ovarian stimulation may be beneficial — including in patients with a poor response to FSH in previous stimulations, those with a reduced response in GnRH antagonist cycles, or women aged between 36 and 39 years.

Type of gonadotropin

LH activity administration

• Older patients (↓ androgens).
• Fresh transfer (↑ P4).

Type of gonadotropin

Corifollitropin: long-acting FSH

For the past several years, a long-acting FSH, corifollitropin, has also been available on the market. With this formulation, FSH activity can be sustained for more than seven days with a single injection.

Aternative protocols

Alternative protocols

Mild stimulation

Alternative protocols

Natural cycle and modified cycle

Alternative protocols

Natural cycle and modified cycle in PR

• “Friendly” protocol.
• Low cost (cost-effective) compared with the conventional protocol, even when repeated for 3–6 cycles.
• Convenient.
• Low pregnancy rate, but perhaps acceptable in these patients (≤10%).
• If modified, better outcomes than in a purely natural protocol (better control).

In the modified natural cycle, both the number of retrieved oocytes and the control of ovarian stimulation appear to be superior to those in a true natural cycle, resulting in a higher cumulative ongoing pregnancy rate. For this reason, it is more commonly used. It is convenient, easy to manage, cost-effective, and provides acceptable pregnancy rates in patients who are initially considered to have a very poor prognosis.

Alternative protocols

mini-ovarian stimulation

Alternative protocols

Follicular recruitment hypothesis

• Single recruitment episode.
• Continuous recruitment.
• Follicular waves.

Since it was discovered a few years ago that a single ovarian cycle contains several waves of follicular development—at least two or three—the approach to ovarian stimulation in poor responders has changed considerably. This finding has made it possible to stimulate patients both in the follicular and luteal phases. Stimulation during the luteal phase will necessarily require freezing the generated embryos, as the endometrium will not be in a suitable receptive state for implantation, meaning embryo transfer must always be deferred.

Alternative protocols

Stimulation during luteal phase

Alternative protocols

Stimulation during luteal phase

Table 1. Pregnancy outcomes from frozen-thawed embryos originating from ovarian stimulation during the lueal phase.

Alternative protocols

Stimulation during luteal phase

In fact, this meta-analysis confirms that although there are no clear differences in reproductive outcomes, luteal-phase stimulation involves a longer stimulation period and higher gonadotropin consumption.

Alternative protocols

Double stimulation, follicular and luteal phases

Follicular phase

Luteal phase

Alternative protocols - no audio

Double stimulation, follicular and luteal phases (Duo Stim)

Alternative protocols

This change in strategy has also led to the “random start” approach, meaning that ovarian stimulation can begin at any point in the menstrual cycle to freeze oocytes or embryos for future use. This protocol is particularly important for patients who have limited time to undergo stimulation, such as oncology patients who need to start chemotherapy or radiotherapy as soon as possible.

Alternative protocols

Ovarian suppression (PPOS)

Progestin-primed ovarian stimulation

• Easy to use.
• Cost-effective.
• Comparable clinical outcomes to other protocols for embryo cryopreservation.

Alternative protocols

Combinations of GnRH analogues and different gonadotropins and co-treatments

GnRH agonist

GnRH antagonist

Without analogues

Luteal phase

Modified natural

Standard

Mild

Mini

Natural

Single

Duo-stim

Long

Short

Microflare

FSH

HMG

FSH+LH

Others: Clomiphene Letrozole Testosterone Estrogens

Alternative protocols

Therefore, at present—and considering that most patients fall outside the “ovarian perfection” observed in many of the classic studies evaluating ovarian stimulation drugs—there are numerous protocols and drug combinations available. As in all fields of Medicine, the treatment regimen should always be individualized according to each patient’s specific profile.

Alternative protocols

Decision-making

• Type of pituitary suppression.
• FSH dose.
• Administration of LH activity (LH, hMG, hCG).
• Alternative protocols.

Decision-making regarding ovarian stimulation in each patient should be based on selecting the type of pituitary suppression, determining the appropriate FSH dose, deciding whether to include LH activity, and considering the use of alternative protocols—particularly in poor responders or patients with previous unsuccessful conventional stimulations.

Conclusions

• Ovulation induction and ovarian stimulation regimens are based on the understanding of the physiology of the hypothalamic–pituitary–ovarian axis.
• Ovulation induction for timed intercourse or artificial insemination begins with the use of oral agents, mainly aromatase inhibitors followed by clomiphene citrate, while low-dose gonadotropins represent the second-line option.
• Ovarian stimulation for IVF aims to obtain an optimal number of oocytes (10–20) with the lowest possible risk and cost for the patient.
• There is no ideal COS protocol for IVF. Treatment must be individualized according to patient characteristics to optimize outcomes.

Ovulation induction and ovarian stimulation regimens are based on the understanding of the hypothalamic–pituitary–ovarian axis physiology. For ovulation induction in timed intercourse or artificial insemination, the first-line approach involves oral agents, particularly aromatase inhibitors followed by clomiphene citrate, while low-dose gonadotropins constitute the second-line option. Ovarian stimulation for in vitro fertilization aims to obtain an optimal number of oocytes (10–20) with the lowest possible risk and cost to the patient. There is no ideal controlled ovarian stimulation protocol for in vitro fertilization. Treatment should always be individualized according to the patient’s characteristics to optimize outcomes.

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Several studies and recent meta-analyses have shown that letrozole results in higher ovulation rates, greater endometrial thickness, and higher pregnancy rates (both per cycle and cumulative after 4–6 cycles) compared with clomiphene citrate. Clomiphene citrate: 70% ovulation rate; pregnancy rate per cycle 15–20%; cumulative pregnancy rate 40–45% after 4–6 cycles. Letrozole: 80% ovulation rate; pregnancy rate per cycle 20–25%; cumulative pregnancy rate 50–60% after 4–6 cycles.