Obstetrics & Gynecology: Ovulation Induction Mala Arora, Richard Fleming, Padma Rekha Jirge
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fm1World Clinics Obstetrics and Gynecologyfm2
fm3Ovulation Inductionfm4
Editor-in-Chief Mala Arora FRCOG (UK) FICOG FICMCH Guest Editors Richard Fleming BSc PhD Padma Rekha Jirge MRCOG FICOG
December 2015 Volume 4 Number 2
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Cover images: (Left) A mature MII oocyte at ICSI. Courtesy: Padma Rekha Jirge. (Middle) TVS monitoring of a stimulated ovary. Courtesy: Padma Rekha Jirge. (Right) A grade I embryo on day 3. Courtesy: Padma Rekha Jirge.
WORLD CLINICS Obstetrics and Gynecology: Ovulation Induction
December 2015, Volume 4, Number 2
ISSN: 2248-9517
9789352501922
Printed in India
fm5Contributors
Editor-in-Chief
Guest Editors
Contributing Authors
fm11Editorial
Mala Arora FRCOG (UK) FICOG FICMCH Editor-in-Chief
Human oocytes are fragile cells, destined for atresia, unless recruited for ovulation. During fetal life the ovaries contain 3–4 million oogonia, which are reduced to 1–2 million at birth and 300,000 at puberty. A healthy woman will ovulate 12 oocytes per year for an average of 25 years during her reproductive life span. That amounts to 300 oocytes, 0.1% of the number present at puberty, and 0.01% of the number present at birth. Apoptosis of 99.9% of ovarian follicles is predestined. In the majority of circumstances, it is growth factor controlled and depends on granulosa cell apoptosis. However, atresia of antral follicles is driven by deprivation by follicle-stimulating hormone (FSH). Although hundreds of follicles undergo initial recruitment each month, typically, in a 30-year-old woman, say 50 follicles mature from pre-antral to antral stage, each month of which only one will ovulate. There is a possibility of rescuing more oocytes from atresia by the judicious use of ovulation induction, thereby, enhancing the number of oocytes available for fertilization, which in turn increases the chances of achieving a pregnancy. However, ovulation induction requires to be tailored to the patient profile. It is a double edged sword, which in cases of hyperstimulation may alter the endometrial receptivity thereby defeating its very purpose.
There is a high degree of variation among the natural population, in the available follicles at a given age and the rate of recruitment from that pool. This explains the varied response to ovulation induction regimes. At age 30, with 12 days of FSH stimulation, we may achieve 40 follicles in high responders and as low as 2 follicles in poor responders. A high response will pose health risks and a low response will lower the pregnancy rates. Hence, the art of ovulation induction is to optimize the yield of follicles to an optimum of 1 to 3 for non-in vitro fertilization (IVF) cycles and an optimum of 10 to 15 for IVF cycles.
Predicting the response to ovulation induction is based on:
In terms of assisted reproductive technologies (ARTs) success, it is better to be older with a normal AMH than to be young and have a low AMH.
Ovulation induction is required in the following circumstances:
World Health Organization classified anovulation as follows:
Superovulation in ovulatory women is best achieved with clomiphene citrate, with or without the addition of GT. Superovulation may induce premature luteinizing hormone (LH) surge in 10–15% of patients, thereby reducing the yield of mature oocytes and pregnancy rates. GnRH agonist or antagonist may be administered in this subgroup, particularly in the IVF setting.
Controlled ovarian hyperstimulation requires suppression of the pituitary. This is achieved by GnRH agonist administered as a long/short protocol, or by GnRH antagonist multiple/single dose regime. Choice of gonadotropin and its protocol of administration will depend on the patient profile. In PCOS patients and other women with a high ovarian reserve, use of GnRH antagonist reduces fm13the incidence of ovarian hyperstimulation syndrome (OHSS) compared with using GnRH agonists.
Conventionally, ovulation induction starts from the early follicular phase but in cancer patients requiring fertility preservation, we employ a random start protocol. This commences as soon as the patient presents so as not to delay her cancer treatment. In patients presenting in the late follicular phase (day 7 onwards), FSH may be commenced to recruit a secondary cohort of follicles, and stimulation is continued during and after the spontaneous LH surge. For patients presenting in the luteal phase, a single dose GnRH antagonist is administered to induce luteolysis and ovulation induction is started simultaneously with recombinant FSH to avoid exogenous LH activity. For estrogen sensitive cancers (endometrium and breast), concomitant use of letrozole lowers the estrogen levels. GnRH antagonist suppression with an agonist trigger is preferred as the post ovulation rise of estrogen and progesterone is lower than with human chorionic gonadotropin (HCG).
Once the desired number of oocytes have reached maturity (18 mm for GT and >20 mm for CC), trigger for ovulation is administered with a single dose of HCG. However, the risk of OHSS is reduced if ovulation is triggered with GnRH agonist. Hence, this is preferred in all patients considered at risk of OHSS as well as oocyte donors and cancer patients undergoing fertility preservation. Kisspeptin is a protein that has been identified in the arcuate nucleus of the brain and may, in the future, offer therapeutic advantage over GnRH agonist for inducing LH surge.
The luteal phase is deficient in many patients with ovulation induction, especially if pituitary is suppressed with GnRH agonist/antagonist. Hence, supplementing the luteal phase with progesterone is essential. Supplemental HCG is required in women with oligo-ovulation to rescue the corpus luteum, but it may enhance ovarian hyperstimulation in ART cycles.
A number of complications may occur with ovulation induction, the most serious of which is OHSS. In order to achieve an OHSS free clinic, careful selection of ovulation induction protocol, lower dose of GT, use of GnRH antagonist with an agonist trigger, and cryopreservation of all embryos is recommended. Administration of dopamine agonist will decrease the levels of vascular endothelial growth factor. HCG should be avoided both for trigger of ovulation as well as luteal support in these cases.
Multiple pregnancy is an undesirable complication and its incidence has increased 100-fold since the advent of ovulation induction. Softer ovulation induction protocols for IUI and converting hyper-responders to IVF will reduce its incidence. Higher order multiple births (triplets and above) require fetal reduction to improve perinatal outcome.fm14
Ectopic and heterotopic pregnancies increase with ovulation induction. The incidence of ovarian torsion is increased due to ovarian enlargement. These cases may present as acute emergency requiring urgent surgical intervention. Maternal thromboembolism is increased, and in susceptible patients thromboprophylaxis with low molecular weight heparin is desirable.
The association of ovulation induction with cancer has raised concerns. It was hypothesized that epithelial ovarian cancer was linked to recurrent breach of ovarian epithelium at ovulation. However, epidemiological studies show a steady decline in its incidence in spite of widespread use of ovulation induction, thus negating the above hypothesis. Recently, it has been postulated that nests of tubal cells on ovarian surface predispose to epithelial ovarian cancers.
Endometrial cancer is estrogen dependent and ovulation induction results in supraphysiological levels of estrogen. Besides, tamoxifen and to some extent clomiphene may increase the risk of endometrial cancer. Hence, it is advisable to limit the use of clomiphene to six cycles only. Breast cancer is also hormone dependent and some studies have shown an increased risk with four or more IVF cycles.
The future research in this field is directed towards prevention of oocyte apoptosis. Currently, five cell death ligand receptor systems have been identified that control atresia of granulosa cells and oocytes. Identifying factors that will block these ligands will rescue oocytes from atresia. Enhanced levels of nitrogen oxide in rat ovaries can prevent atresia of the ovarian follicle. Amniotic fluid stem cells have been used in some mice experiments to reverse premature ovarian failure. Identification of anti-apoptotic factors in the human ovary may one day replace or enhance the use of gonadotropins for ovulation induction, but the final stages of follicle maturation are likely to remain under the control of gonadotropins for some time.
Ovulation induction continues to help a large number of infertile women to achieve their goal of pregnancy. The protocols have been refined over the years to give maximum benefit in each cycle initiated. However, it should be carefully monitored to attain adequate yield of oocytes while avoiding complications.
Mala Arora FRCOG (UK) FICOG FICMCH
Director, Noble IVF Centre, Faridabad, Haryana, India
Consultant, Fortis La Femme, Greater Kailash, New Delhi, India
fm15Abbreviations 3D-US
Three-dimensional ultrasound
AFC
Antral follicle count
AMH
Anti-Müllerian hormone
ART
Assisted reproductive technique
ASCO
American Society of Clinical Oncology
ASRM
American Society for Reproductive Medicine
AUC
Area under the curve
BBT
Basal body temperature
BMI
Body mass index
CC
Clomiphene citrate
CL
Corpus luteum
COC
Combined oral contraceptive
COH
Controlled ovarian hyperstimulation
CoQ10
Coenzyme Q10
COS
Controlled ovarian stimulation
CRP
C-reactive protein
DEX/CC
Dexamethasone plus clomiphene citrate
DHEA-S
Dehydroepiandrosterone sulfate
DNA
Deoxyribonucleic acid
DVT
Deep vein thrombosis
EB
Endometrial biopsy
EOC
Epithelial ovarian cancers
ER
Endoplasmic reticulum
ESD
Effective sterilizingdose
ET
Embryo transfer
FET
Frozen embryo transfer
FTE
Frozen thawed embryos
FSH
Follicle-stimulating hormone
FSH-CTP
Carboxy terminal peptide FSH
FSH-HP
Highly purified urinary FSH
FSH-P
Purified urinary FSH
GH
Growth hormone
GLUT 1
Glucose transporter 1
GnRH
Gonadotropin-releasing hormone
GnRHa
GnRH agonist
GT
Gonadotropins
hCG
Human chorionic gonadotropin
HMG
Human menopausal gonadotropins
HP
Heterotopic pregnancy
HPO
hypothalamic pituitary ovarian
HSA
Human serum albumin
ICSI
Intracytoplasmic sperm injection
ICSI
Intracytoplasmic sperm injection
IGF-1
Insulin-like growth factor-1
IGFBP-1
Insulin-like growth factor-binding protein-1
IRS1
Insulin receptor substrate 1
IUI
Intrauterine insemination
IVF
In vitro fertilization
IVM
In vitro maturation
LH
Luteinizing hormone
LMWH
Low molecular weight heparin
LOD
Laparoscopic ovarian diathermy
LOD
Laparoscopic ovarian drilling
LPD
Luteal phase defect
LRF
Luteinizing hormone releasing factor
MII
Metaphase II
NAC
N-acetylcysteine
NGF
Non-growing follicle
NICE
National Institute for Clinical Excellence
NIH
National Institute of Health
OGTT
Oral glucose tolerance test
OHSS
Ovarian hyperstimulation syndrome
OI
Ovulation induction
OR
Oocyte recovery
PCOS
Polycystic ovarian syndrome
PCT
Postcoital test
PDA
Power Doppler angiography
PL
Premature luteinization
POR
Poor ovarian response
PPARγ
Peroxysome proliferator-activated receptor-gamma
PR
Pregnancy rate
fm16RCOG
Royal College of Obstetricians and Gynecologists
RCT
Randomized controlled trial
r-FSH
Recombinant FSH
r-hFSH
Recombinant human FSH
rLH
Recombinant LH
RI
Resistance index
RR
Risk ratio
SC
Subcutaneous
SERM
Selective estrogen receptor modulator
SHBG
Sex hormone-binding globulin
SLE
Systemic lupus erythematosus
SNPs
Single nucleotide polymorphisms
SOET
Self-operated endovaginal telemonitoring
TSH
Thyroid-stimulating hormone
TVS
Transvaginal ultrasonography
uLH
Urinary LH
USG
Ultrasonography
VEGF
Vascular endothelial growth factor