Stimulation Protocols for IUI | Dr. Laxmi Shrikhande

 Chairperson Indian College of OB/GY 2022--2023
 National Corresponding Editor-Journal of OB/GY of
India JOGI since last 8 years
 National Corresponding Secretary- Association of
Medical Women, India
 Member-SAFOG Education Committee
 Vice President Elect ISOPARB 2016-17
 Joint Secretary-Indian Menopause Society 2024
 President –ISOPARB Vidarbha Chapter 2019-21
 Chairperson-IMS Education Committee 2021-23
 Chairperson-fertility enhancement Committee-
ISOPARB 2023-24
 President-Association of Medical Women, Nagpur
AMWN 2021-24
 President Menopause Society, Nagpur 2016-18
 Senior Vice President FOGSI 2012
 President Nagpur OB/GY Society 2005-06
Dr. Laxmi Shrikhande
MBBS; MD(OB/GY); FRCOG
FICOG;FICMU;FICMCH;FIMS
Medical Director &
Senior Consultant -
Shrikhande Hospital &
Research Centre Pvt Ltd,
Nagpur, Maharashtra
 FRCOG –Fellow Hon. Causa by
Royal College of OB/GY, UK
 Nagpur Ratan Award at the
hands of Union Minister Shri
Nitinji Gadkari
 Received Bharat excellence
Award for women’s health
 Best Committee Award as
Chairperson HIV/AIDS
Committee, FOGSI 2007-2009
 Received appreciation letter
from Maharashtra Government
for her work in the field of
SAVE THE GIRL CHILD
• Delivered 32 orations and
550 guest lectures
• Publications- 62 National &
31 International
• Sensitized 2 lakh boys and
girls on adolescent health
issues
Awards
Positions

Ovarian Stimulation
Protocols for IUI Cycle
Dr Laxmi Shrikhande
Consultant –Shrikhande Fertility Clinic
Nagpur, Maharashtra

Clinical approach to ovulation induction
 The clinical approach to ovulation induction requires an
understanding of the causes of anovulation.
The four most common ovulatory disorders include
 Polycystic ovary syndrome (PCOS),
 Hypogonadotropic hypogonadism (HA),
 Primary ovarian insufficiency (POI), and
 Hyperprolactinemia

Unstimulated cycles —
Natural (unstimulated) cycle procedures are most appropriate for patients
with ejaculatory dysfunction, vaginismus, or cervical factor infertility
Ovulation should be documented prior to proceeding with the unstimulated
(natural) cycle IUI.
The most cost-effective method is use of an over-the-counter urine ovulation
predictor kit.
Once the LH surge is documented in first morning urine, IUI is performed the
next day.
A large randomized trial showed that ovulation monitoring resulted in higher
pregnancy rates than hCG triggering to time insemination in natural cycles .
Kyrou D, Kolibianakis EM, Fatemi
HM, et al. Spontaneous triggering of ovulation versus HCG administration in patients undergoing IUI: a prospective ran
domized study.

Unstimulated cycles —
In our experience, couples are nearly always able to arrange their
schedules to allow IUI timed by urinary LH monitoring.
The use of LH for timing ovulation in natural cycles actually might be
the best way to maximize the probability of pregnancy for patients
undergoing IUI.
In a randomized trial of clomiphene citrate with IUI, pregnancy rates
were higher with urinary LH surge monitoring than with hCG-timed
IUI .
Kyrou D, Kolibianakis EM, Fatemi
HM, et al. Spontaneous triggering of ovulation versus HCG administration in patients undergoing IUI: a prospective ran
domized study.

Ovulation induction- When
Ovulation induction is the method for
treating anovulatory infertility1
The World Health Organization
(WHO) categorises ovulation
disorders into three groups
Patients eligible for ovulation
induction belong either to WHO
group I or to WHO group II
Messinis IE. Hum Reprod 2005;20(10):2688–2697;
https://www.ncbi.nlm.nih.gov/books/NBK327781/ as accessed on 24th
nov 2018,
Group Gonadotropin
levels
Estrogen
secretion
Cause
I Low Low Hypothalamic-
pituitary failure
II Normal Normal Hypothalamic-
pituitary-ovarian axis
failure
III High Low Ovarian failure

Most experts have moved away from the WHO
Most experts have moved away from the World Health Organization (WHO)
terminology which assign women to three categories of anovulation:
WHO class 1 – Hypogonadotropic hypogonadal anovulation
WHO class 2 – Normogonadotropic normoestrogenic anovulation (almost
all women in this category have polycystic ovary syndrome [PCOS]), when
using the Rotterdam criteria for the diagnosis of PCOS . This is the most
common cause of anovulation.
WHO class 3 – Hypergonadotropic hypoestrogenic anovulation (primary
ovarian insufficiency [POI; premature ovarian failure])
Hyperprolactinemia did not have a separate WHO category.

Hypogonadotropic Hypogonadism —
 Hypothalamic causes of hypogonadotropic hypogonadism include functional
hypothalamic amenorrhea (FHA) and isolated gonadotropin-releasing hormone
(GnRH) deficiency.
 Multiple factors may contribute to the pathogenesis of FHA, including eating
disorders (such as anorexia nervosa), exercise, and stress.
 Although rare, hypogonadotropic hypogonadism presenting as primary amenorrhea
can be due to complete congenital GnRH deficiency.
 This syndrome is called idiopathic hypogonadotropic hypogonadism or, if it is
associated with anosmia, Kallmann syndrome.
 Many infiltrative diseases and tumors of the hypothalamus and pituitary can also
result in hypogonadotropic hypogonadism (due to diminished GnRH release or
gonadotropin deficiency).

Copyrights apply
Polycystic Ovary Syndrome —

Primary Ovarian Insufficiency —POI
 POI, formerly referred to premature ovarian failure (POF) and
defined as menopause before age 40 years, occurs in only 1 percent
of all women but accounts for 5 to 10 percent of cases of anovulation.
In most cases, the follicle pool is exhausted due to accelerated follicle
loss of unknown origin
The only effective option is IVF with donor oocytes.
Women with POI have other important health issues related to their
estrogen deficiency, including an increased risk of osteoporosis and
cardiovascular disease if estrogen is not replaced.

Hyperprolactinemic Anovulation —
 Hyperprolactinemia accounts for 5 to 10 percent of women with
anovulation.
 These women are anovulatory because hyperprolactinemia inhibits
gonadotropin secretion, presumably by inhibiting GnRH.
 Most have oligomenorrhea or amenorrhea.
 Their serum gonadotropin concentrations are usually normal or
decreased.

Goals of Ovulation Induction
Induce mono follicular rather than multi follicular development and
subsequent mono ovulation and,
ultimately, a singleton pregnancy and
birth of a healthy newborn .

General principles of Ovulation Induction
 The method of ovulation induction selected by the clinician should be
based upon the
 underlying cause of anovulation and
 the efficacy,
 costs,
 risks,
 patient burden, and
 potential complications associated with each method as they apply to
the individual woman.

Why Pre Conception Counselling

What is Preconception Counseling —
 Preconception care is a broad term that refers to the process of
identifying
 social, behavioral, environmental, and biomedical risks to a woman's
fertility and
 pregnancy outcome and then
 reducing these risks through education, counseling, and appropriate
intervention.

What Pre conception advice should be given
 BMI
 BP
 Lifestyle counselling
 Garbh sanskar spiritual
 Folic acid supplimentation
 Anemia correction if detected
 Sugar / Thyroid
 Correction of endocrine factors
 Thalassemia screen wherever indicated

Pre-conceptional counseling-Vaccination
 FOGSI recommends vaccination counseling as a part of
pre-pregnancy counseling (unvaccinated women)
 History of occurrence of vaccine preventable diseases,
previous vaccinations administered and allergic reactions
to vaccinations must be recorded.
 Rubella ,Hepatitis B and Varicella vaccination should be
given preferably during postmenstrual period
 Pregnancy should be deferred for 3 months in case of
Rubella vaccine

Ideal Ovulation Induction Drug
18
Oral Administration
Minimal monitoring of cycle
No hostile effect on endometrium & cervical mucus
Better ovulation rate & pregnancy rate
Less risk of Ovarian hyperstimulation syndrome (OHSS) & multiple
pregnancy

Ovarian Stimulation Protocols
Clomiphene
Letrozole
CC + Gonadotrophins.
Letrozole + Gonadotrophins
Gonadotrophins
Gonadotrophins and antagonists

When to start stimulation ?
 Early follicular phase –Recruitment
 Late follicular phase – Growth

Clomiphene citrate
 Drug of choice in women with oligoovulatory and anovulatory cycles
 1st line treatment for OI for >55 yrs
 Simple to use
 Cost effective
 Fewer complications
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.; Banerjee Ray P, et al. Arch Gynecol Obstet. 2012 Mar;285(3):873-7.;
Pavone ME, et al. J Clin Endocrinol Metab. 2013 May; 98(5): 1838–1844.

2 stereoisomers of CC
The commercially available form of clomiphene is the dihydrogen citrate salt
(clomiphene citrate).
It contains two stereoisomers: zu-clomiphene (38 percent) and en-
clomiphene (62 percent), which were originally called the cis-isomer and
trans-isomer, respectively.
En-clomiphene is cleared rapidly, while zu-clomiphene has a long half-life .
The two clomiphene isomers have mixed estrogenic and antiestrogenic
effects that vary among species.
En-clomiphene is the more potent isomer with greater antiestrogenic activity
and the one primarily responsible for inducing follicular development .

Depletion of ER in pituitary &
hypothalamus due to prolonged
stimulation
Estrogen feedback loop gets
interrupted
FSH secretion increased leading to
multiple follicle growth
Clomiphene citrate: Mechanism of action
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.

Patient selection
• The primary indication for the antiestrogen clomiphene citrate is
infertility secondary to oligoovulation or anovulation in women with
PCOS .
• Some amount of endogenous estrogen is necessary for a response to
clomiphene; women with PCOS do produce estrogen (as evidenced by
spontaneous menses or withdrawal bleeding in response to a
progesterone challenge).
• Women who are hypoestrogenemic are unlikely to respond (eg, those
with hypogonadotropic amenorrhea or primary ovarian insufficiency)

Ovulatory disorder-confirmation
 Pre treatment evaluation — Before initiating therapy, the presence of
ovulatory dysfunction must be established.
 The menstrual history alone may be diagnostic (eg, one can be
confident that ovulatory dysfunction is present in women with
amenorrhea or irregular menses [>45 day intermenstrual interval]).
 If the diagnosis of ovulatory dysfunction is uncertain, additional
testing should be performed.
 This can include simple, noninvasive tests such as basal body
temperature and/or urinary luteinizing hormone (LH) monitoring,
although a luteal phase serum progesterone level is more definitive.

Copyrights apply
Ovulatory disorder-confirmation

Patient selection
Disorders of
 pituitary,
 adrenal, and
 thyroid origin that can cause anovulation
 should be excluded prior to the initiation of therapy as
 targeted treatment of these endocrinopathies can result in normal
ovulation.

The pre treatment evaluation should include :
A complete history and physical examination.
Semen analysis of the partner to identify seminal abnormalities that might
contribute to the infertility.
A pelvic examination or a pelvic ultrasound to rule out ovarian cysts, especially
in patients with known tendency to form functional cysts.
Hysterosalpingogram if the clinical history suggests uterine or tubal pathology
may also be present and in women over 35 years of age to avoid ineffective
treatment when fertility is in decline. In women with no risk factors for tubal
disease, the hysterosalpingogram can be postponed but should be performed
if women have not conceived after three ovulatory cycles
Ovarian Reserve Tests- Maternal age / AFC / AMH ??

When to start CC —
 Typically started on the D2/D3 of a cycle, following either
spontaneous or induced bleeding.
However, the results of therapy (in terms of ovulatory rates,
pregnancy, or spontaneous miscarriage) are comparable when
clomiphene is started on cycle day 2, 3, 4, or 5 .
Wu CH, Winkel CA. The effect of therapy initiation day on clomiphene citrate therapy. Fertil Steril 1989; 52:564.
Dehbashi S, Vafaei H, Parsanezhad MD, Alborzi
S. Time of initiation of clomiphene citrate and pregnancy rate in polycystic ovarian syndrome. Int J Gynaecol
Obstet 2006; 93:44.

What dose —
 There are no laboratory or clinical parameters that predict the dose necessary to
achieve ovulation.
 The initial dose, empirically, is 50 mg daily for five days; starting with a higher
dose does not result in higher pregnancy rates.
 If ovulation does not occur in the first cycle of treatment, the dose is increased to
100 mg.
 Thereafter, the dose is increased by increments of 50 mg to a maximum daily
dose of 150 mg (100 mg is the maximum dose approved by the US Food and Drug
Administration [FDA], and the American Society for Reproductive Medicine
[ASRM] suggests that doses >100 mg add little to clinical pregnancy rates) .
 Once ovulation is achieved, the same dose should be continued for four to six
cycles.
Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in infertile women
: a committee opinion.

CC Failure failure & CC resistance
Failure of ovulation is “clomiphene resistance”,
About 20-25% of anovulatory women are CC-resistant
Whereas failure of pregnancy despite ovulation is
“clomiphene-failure” .

When to stop CC-
 Because of the observations that pregnancy rates are low after six cycles of
treatment and that 12 or more cycles may increase the risk of ovarian neoplasms ,
 the American College of Obstetricians and Gynecologists (ACOG) has suggested
that clomiphene treatment be limited to fewer than 12 cycles and that the
number of gonadotropin cycles be minimized, as well .
 Further evaluation and/or a change in therapy for women who do not conceive
after three to six ovulatory CC cycles is recommended
Rossing MA, Daling JR, Weiss NS, et al. Ovarian tumors in a cohort of infertile women. N Engl J Med 1994; 331:771.
ACOG Committee on Practice Bulletins-Gynecology. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-
gynecologists
number 34, February 2002. Management of infertility caused by ovulatory dysfunction. American College of Obstetricians and
Gynecologists. Obstet Gynecol 2002; 99:347.

How to monitor CC cycle—TIC
• The response to treatment should be monitored.
• Determination of the ovulatory LH surge by urinary LH kits is what most clinicians
recommend in practice.
• Urinary LH monitoring also provides information on appropriate timing of intercourse during
a given cycle .
• The LH surge typically occurs 5 to 12 days after clomiphene administration is completed.
Ovulation generally occurs 14 to 26 hours after the detection of the urinary LH surge and
almost always within 48 hours .
• Therefore, the interval of highest fertility is the day of the LH surge and the following two
days.
O'Herlihy C, De Crespigny LJ, Robinson HP. Monitoring ovarian follicular development with real-time ultrasound. Br J
Obstet Gynaecol 1980; 87:613.
Miller PB, Soules MR. The usefulness of a urinary LH kit for ovulation prediction during menstrual cycles of normal wo
men.
Obstet Gynecol 1996; 87:13.

Monitoring —
 A basal body temperature chart can also be used and does not increase
the cost of treatment. Conversion of a uniphasic to a biphasic basal
temperature curve suggests retrospectively that ovulation has
occurred. However, basal body temperature charting can be tedious for
some patients and is not useful for timing of intercourse, as the
temperature rise occurs one to five days after the midcycle LH surge
and up to four days after ovulation.
 A mid-luteal (one week after ovulation or one week before the
expected menses) serum progesterone concentration greater than 3
ng/mL (ideally greater than 10 ng/mL) provides reliable evidence that
ovulation has occurred.

Is USG monitoring Necessary —
• RCOG and NICE, suggest serial TVS to monitor the number and size of developing follicles and to
time hCG administration if necessary.
• Serial TVS may also provide evidence of ovulation (follicle enlargement followed by collapse
suggests ovulation).
• Some advocate ultrasound monitoring of just the first clomiphene cycle in order to exclude hyper-
response
• However, adding USG monitoring is costly and does not appear to improve pregnancy rates
significantly
• Baseline D2 scan is not always necessary before every new treatment cycle but should be
considered in symptomatic patients.
• Withhold CC in these cases until the cyst(s) disappear either spontaneously or after suppression
with OCP.
Kousta E, White DM, Franks S. Modern use of clomiphene citrate in induction of ovulation. Hum Reprod Update 1997; 3:359.
Vause TD, Cheung AP, Sierra S, et al. Ovulation induction in polycystic ovary syndrome: No. 242, May 2010. Int J Gynaecol Obstet
2010; 111:95.
Smith YR, Randolph JF Jr, Christman
GM, et al. Comparison of low-technology and high-technology monitoring of clomiphene citrate ovulation induction. Fertil Steril

OUTCOMES-Ovulatory and pregnancy rates —
• In women with PCOS, an ovulatory rate of 80 percent and a
cumulative pregnancy rate of 30 to 40 percent can be expected .
Dickey RP, Holtkamp DE. Development, pharmacology and clinical experience with clomiphene citrate. Hum Reprod
Update 1996; 2:483.
Gorlitsky GA, Kase NG, Speroff L. Ovulation and pregnancy rates with clomiphene citrate. Obstet Gynecol 1978; 51:265.
Gysler M, March CM, Mishell
DR Jr, Bailey EJ. A decade's experience with an individualized clomiphene treatment regimen including its effect on the
postcoital test. Fertil Steril 1982; 37:161.

• A literature review including data from over 5000 patients with a
variety of indications for clomiphene therapy reported an ovulation
rate of 73 percent and a pregnancy rate of 36 percent .
Homburg R. Clomiphene citrate--end of an era? A mini-review. Hum Reprod
2005; 20:2043.

 Of those who ovulate, approximately 50 percent do so at a dose of 50
mg , another 20 to 25 percent at 100 mg, and 10 percent at 150 mg .
 There is no benefit to increasing the clomiphene dose in subsequent
cycles once ovulation occurs.
Gorlitsky GA, Kase NG, Speroff L. Ovulation and pregnancy rates with clomiphene citrate. Obstet Gynecol
1978; 51:265.
Gysler M, March CM, Mishell
DR Jr, Bailey EJ. A decade's experience with an individualized clomiphene treatment regimen including its effect on th
e
postcoital test. Fertil Steril 1982; 37:161.
Glasier AF. Clomiphene citrate. Baillieres Clin Obstet Gynaecol 1990; 4:491.
Rostami-Hodjegan
A, Lennard MS, Tucker GT, Ledger WL. Monitoring plasma concentrations to individualize treatment with clomiph
ene citrate.

Why pregnancy rate is low as compared to
ovulation rate ?
 Clomiphene acts primarily as an antiestrogen in the uterus, cervix,
and vagina.
 The following findings may explain why pregnancy rates are relatively
low when ovulatory rates are so high in women administered
clomiphene cycles:
 The normal increase in uterine volume and endometrial thickening that
occurs during spontaneous menstrual cycles is largely absent during
clomiphene-induced cycles, despite higher estradiol levels .
 Abnormal luteal phase endometrial morphology has been found in some , but
not all , studies.

Clomiphene citrate: Anti-estrogenic effects

Strategies to prevent thin endometrium
Strategies such as giving half-dose clomiphene (25 mg/day),
early administration (starting day 1), or
adding exogenous estrogen have been tried to minimize the
antiestrogenic effect of clomiphene on the endometrium, with limited
success.

Effect on cervical mucus
 Data on the effect of clomiphene on cervical mucus are conflicting.
 While one study found no detrimental effect another noted a decrease
in the quality and quantity of cervical mucus at all clomiphene doses .
 In a meta-analysis, a detrimental effect was seen only with doses ≥100
mg/day .
 Clomiphene citrate has no apparent progestational, corticotropic,
androgenic, or antiandrogenic effects, nor does it interfere with adrenal
or thyroid function.
Thompson LA, Barratt CL, Thornton SJ, et al. The effects of clomiphene citrate and cyclofenil
on cervical mucus volume and receptivity over the periovulatory period. Fertil Steril 1993; 59:125.
Gelety TJ, Buyalos RP. The effect of clomiphene citrate and menopausal gonadotropins on cervical mucus in ovulatory cycles. Fertil
Steril 1993; 60:471.

The ovulatory rate is lower with increasing age, body mass index
(BMI), insulin resistance, and free androgen index
After six months of treatment, the pregnancy rate per cycle falls
substantially despite regular ovulation
Imani B, Eijkemans MJ, te Velde
ER, et al. Predictors of chances to conceive in ovulatory patients during clomiphene citrate induction of ovulation in
normogonadotropic oligoamenorrheic infertility. J Clin Endocrinol Metab 1999; 84:1617.
Macgregor AH, Johnson JE, Bunde CA. Further clinical experience with clomiphene citrate. Fertil Steril 1968; 19:616.

• The incidence of miscarriage and congenital anomalies appears to be
similar to that in spontaneous pregnancies, and the rate of ectopic
pregnancy is probably not increased .
• The risk of ovarian hyperstimulation syndrome is less than 1 percent.
Dickey RP, Matis R, Olar
TT, et al. The occurrence of ectopic pregnancy with and without clomiphene citrate use in assisted and
nonassisted reproductive technology. J In Vitro Fert Embryo Transf 1989; 6:294.

OUTCOMES- Multiple gestation —
• Induction of ovulation by clomiphene increases the probability of
multifetal pregnancy: twins have been reported in 6.9 to 9 percent of
pregnancies, triplets in 0.3 to 0.5 percent, quadruplets in 0.3 percent,
and quintuplets in 0.13 percent .
• The risk may be reduced by ultrasound monitoring and withholding
human chorionic gonadotropin (hCG), intrauterine insemination (IUI),
or intercourse if more than two follicles >15 mm diameter are seen.
McDowell S, Kroon B, Yazdani A. Clomiphene ovulation induction and higher-order multiple pregnancy. Aust
N Z J Obstet Gynaecol 2013; 53:395.

Perinatal outcome —
Most , but not all , studies suggest that the frequencies of congenital
malformations and spontaneous abortion are not increased in pregnancies
after clomiphene therapy.
There is no evidence of developmental delays or learning disabilities in
children whose mothers took clomiphene .
Dickey RP, Taylor SN, Curole DN, et al. Incidence of spontaneous abortion in clomiphene pregnancies. Hum Reprod
1996; 11:2623.
Sørensen HT, Pedersen L, Skriver MV, et al. Use of clomifene
during early pregnancy and risk of hypospadias: population based case-control study. BMJ 2005; 330:126.
Reefhuis J, Honein MA, Schieve
LA, et al. Use of clomiphene citrate and birth defects, National Birth Defects Prevention Study, 1997-2005. Hum Reprod

Perinatal outcome — LBW
 Several studies have found a mildly increased risk of preterm birth in pregnancies (singleton
and multiple) after assisted reproduction compared with natural pregnancies .
 This effect has not been shown to be specific to clomiphene and is likely to be due, at least
in part, to comorbidities in subfertile women rather than the ovulation stimulation.
 There does not appear to be an increase in cancer risk in children conceived using ovulation
induction drugs.
Lambalk CB, van Hooff M. Natural versus induced twinning and pregnancy outcome: a Dutch nationwide survey of primiparous
dizygotic twin deliveries. Fertil Steril 2001; 75:731.
Källén B, Olausson PO, Nygren KG. Neonatal outcome in pregnancies from ovarian stimulation. Obstet Gynecol 2002; 100:414.
Gaudoin
M, Dobbie R, Finlayson A, et al. Ovulation induction/intrauterine insemination in infertile couples is associated with low-birth-weight in

Role of modified regimens- Higher doses —
 High-dose clomiphene citrate (200 to 250 mg daily) may be given for
8 to 10 days in women who are refractory to standard doses.
This extended regimen of clomiphene is sometimes used for women
who cannot receive exogenous gonadotropins, but the overall
experience is limited and the dose exceeds current US Food and Drug
Administration (FDA) recommendations.
Use of these high doses is not recommended

Adverse effects- Common side effects —
 Hot flashes are common, occurring in 10 to 20 percent of women .
 They may result from hypoestrogenism at the hypothalamic level due
to clomiphene blockade of estrogen receptors.
 Additional problems related to the hyperestrogenic environment
induced by CC include abdominal distention and pain (5.5 percent),
nausea and vomiting (2.2 percent), and breast discomfort (2 percent).
These symptoms abate soon after cessation of therapy.
 Mood swings, depression, and headaches can also occur but are
rarely serious enough to consider terminating treatment.
ACOG Committee on Practice Bulletins-Gynecology
. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists number 34, February 2002.
Management of infertility caused by ovulatory dysfunction. American College of Obstetricians and Gynecologists.

Adverse effects- Common side effects —
 Side effects of clomiphene are not dose related, as they can occur at
the 50 mg dose.
Uncomplicated ovarian enlargement develops in approximately 14
percent of women, but true ovarian hyperstimulation syndrome is
rare.

Adverse effects-
 Visual disturbances — Visual symptoms, such as blurring, double
vision, and/or scotomata, develop in 1 to 2 percent of women and are
usually reversible.
 However, because they may persist, their onset warrants
discontinuation of therapy .
Purvin VA. Visual disturbance secondary to clomiphene citrate. Arch Ophthalmol 1995; 113:482.
Racette L, Casson PR, Claman
P, et al. An investigation of the visual disturbances experienced by patients on clomiphene citrate. Fertil Steril
2010; 93:1169.

Cancer risks —
 The use of clomiphene citrate for ovulation induction does not
appear to be associated with an excess risk of ovarian or breast
cancer.
One retrospective cohort study reported an excess risk of
endometrial cancer with clomiphene, but this has not been confirmed
.
Althuis MD, Moghissi KS, Westhoff
CL, et al. Uterine cancer after use of clomiphene citrate to induce ovulation. Am J Epidemiol 2005; 161:607.
Topic 7400 Version 25.0

SUMMARY AND RECOMMENDATIONS-CC
 Clomiphene is initially begun on cycle day 2,3, 4, or 5 at a dose of 50
mg daily for five days.
 If ovulation does not occur in the first cycle of treatment, the dose is
increased to 100 mg.
 Thereafter, the dose is increased by increments of 50 mg to a maximum
daily dose of 150 mg until ovulation is achieved.
 The couple is advised to have intercourse every other day for one week
beginning five days after the last day of medication.
 Most clinicians have their patients use home urinary luteinizing
hormone (LH) kits for monitoring their cycles.

SUMMARY AND RECOMMENDATIONS-CC
 A mid-luteal serum progesterone level may be obtained once to document that clomiphene
citrate caused ovulation.
 Serial TVS may also be used, although it increases the cost without having a significant
effect on pregnancy rates.
 Further evaluation or change in therapy is indicated for women who do not conceive after
having six ovulatory cycles.
 Risks and complications should be discussed.
 True ovarian hyperstimulation is rare.
 Clomiphene citrate does not appear to be associated with adverse perinatal outcomes or
an increased risk of congenital malformations.

Letrozole-When
3rd
generation aromatase inhibitor (AI)
 Letrozole is now considered to be the drug of choice for ovulation
induction in women with PCOS.
Clomiphene citrate has been the first-line drug for this population for
many years, with metformin used as an alternative.
 However, both clomiphene and metformin appear to be less effective
for live birth rates than letrozole .
Legro RS, Barnhart HX, Schlaff
WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007; 356:551.

1. Inhibits aromatase in
ovaries & peripheral tissues
reducing estrogen levels
2. & 3. Negative feed back
being not active stimulates
hypothalamus-pituitary axis
4. GnRH release produces FSH
leading to stimulation of
follicle
5. & 6. Rising estrogen level
from follicle suppresses FSH
leaving a single dominant-
follicle
Letrozole: Mechanism of action

Standard Dose Regimen
 Letrozole is typically administered at 2.5 to 7.5 mg daily & dose can be adjusted
in 2.5-mg increments
 Administered in very similar regimen to that of CC (for 5 days orally, usually
starting on cycle day 2)
 Prolonged treatment courses (for 10 days) have been studied with some positive
results
 However, most trials have focused on 2.5- and 5-mg doses of letrozole
Hofe JV, et al. Obstret Gynecol Clin N Am. 2014.

Letrozole regimen —
• Sequential dose escalation of 2.5, 5, and 7.5 mg if ovulation does not
occur on lower doses is widely used by reproductive endocrinologists.
Al-Fadhli R, Sylvestre C, Buckett W, et al. A randomized trial of superovulation with two different doses of
letrozole. Fertil Steril 2006; 85:161.
Legro RS, Brzyski RG, Diamond MP, et al. Letrozole
versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med 2014; 371:119.

Letrozole regimen —
Higher doses (7.5 mg) appear to be associated with a thinning of the
endometrium similar to that seen with clomiphene citrate .
Two proof-of-concept studies have reported that a single-dose
regimen (20 mg) on D3 may also be effective ,
 at this time, data are limited and further studies are underway.
Mitwally MF, Casper RF. Single-dose administration of an aromatase inhibitor for ovarian stimulation. Fertil Steril
2005; 83:229.
Biljan MM, Tkalec DD, Lachgar H. A study comparing a single dose of 25mg of letrazole
given on day 3 of menstrual cycle with a daily dose of 5mg of letrazole
given between day 3 and day 7 of menstrual cycle in patients with unexplained infertility: Prospective rando
mized double blind trial.
Fertil Steril 2004; 82:S81.

Extended Letrozole Therapy
 Administered in the step up doses consisting of one, two, three, and
four tablets of letrozole (2.5mg) daily on menstrual cycle days 2, 3, 4
and 5 respectively
 Associated with multifollicular development and a higher clinical
pregnancy rates/ treatment cycle (27.3% vs 11.8%)
Mitwally et al. Fertil Steril 2008; 89; S23-4.

1. https://www.monash.edu/__data/assets/pdf_file/0004/1412644/PCOS_Evidence-Based-Guidelines_20181009.pdf
2. ACOG Committee Opinion No. 738 Summary: Aromatase Inhibitors in Gynecologic Practice
GUIDELINES
• Letrozole should be considered first line pharmacological treatment for
ovulation induction in women with PCOS with anovulatory infertility and no
other infertility factors to improve ovulation, pregnancy and live birth rates.1
• ACOG, 2018 Guidelines: For women with polycystic ovary syndrome and a
body mass index greater than 30, letrozole should be considered first-line
therapy for ovulation induction because of the increased live birth rate
compared with clomiphene citrate.2

Advantages over Clomiphene Citrate
Robert F. Casper and Mohamed F. M. Mitwally. J Clin Endocrinol Metab, March 2006, 91(3):760–771

Outcomes —Letrozole vs CC
 Available data suggest that letrozole is superior to clomiphene citrate for
the outcome of live birth rates in oligoovulatory women with PCOS .
 Early data suggested that clomiphene and letrozole resulted in similar
ovulatory and pregnancy rates .
ACOG Committee Opinion No. 738: Aromatase Inhibitors in Gynecologic Practice. Obstet Gynecol 2018; 131:1.
Badawy A, Abdel Aal I, Abulatta M. Clomiphene citrate or letrozole
for ovulation induction in women with polycystic ovarian syndrome: a prospective randomized trial. Fertil Steril
2009; 92:849.
He D, Jiang F. Meta-analysis of letrozole versus clomiphene citrate in polycystic ovary syndrome. Reprod
Biomed Online 2011; 23:91.

The cumulative live birth rate was higher in the letrozole group (103 of 374 [27.5
percent]) compared with the clomiphene group (72 of 376 [19.1 percent]) (relative risk
[RR] 1.44, 95% CI 1.10-1.87).
The live birth rate of 19.1 percent with clomiphene citrate (mean body mass index
[BMI] of subjects was 35 kg/m2
) was considerably lower than previously reported rates
in women with PCOS using clomiphene citrate (38 percent in a prospective cohort study
of 240 women with a mean BMI of 26 kg/m2
) .
The cumulative ovulation rate was also higher with letrozole (834 of 1354 treatment
cycles [62 percent] versus 688 of 1425 treatment cycles [48 percent]; RR 1.28, 95% CI
1.19-1.37).
ER, et al. A nomogram to predict the probability of live birth after clomiphene citrate induction of ovulation in
normogonadotropic oligoamenorrheic infertility. Fertil Steril 2002; 77:91.

 However, a randomized trial and a meta-analysis of 14 trials in nearly
3000 anovulatory women with PCOS suggest that letrozole therapy
results in higher live birth rates compared with clomiphene therapy.
The Randomized trial which was a multicenter study in 750 women with
PCOS (diagnosed using modified Rotterdam criteria), who were randomly
assigned to receive five days of letrozole (2.5 mg) or clomiphene citrate
(50 mg) beginning on cycle day 3 for up to five cycles .
Franik S, Eltrop SM, Kremer JA, et al. Aromatase inhibitors (letrozole) for subfertile
women with polycystic ovary syndrome. Cochrane Database Syst
Rev 2018; 5:CD010287.

In a 2018 meta-analysis of 14 trials comparing letrozole and clomiphene
citrate monotherapy (including the multicenter trial ), letrozole was more
effective than clomiphene for live birth rates (n = 2954 patients; odds ratio
[OR] 1.68, 95% CI 1.42-1.99; number needed to treat [NNT] for an additional
live birth was 10).
There were no differences in rates of miscarriage or multiple pregnancies
between the two therapies.
Unlike the multicenter trial that reported a higher live birth rate with letrozole
only in obese women BMI greater than 30 kg/m2
, a subgroup analysis of the
pooled trials in the meta-analysis observed no significant impact of a mean
BMI above or below 25 kg/m2
on the primary outcome (live birth rate) .
Franik S, Eltrop SM, Kremer JA, et al. Aromatase inhibitors (letrozole) for subfertile
women with polycystic ovary syndrome. Cochrane Database Syst Rev 2018; 5:CD010287.

Clomiphene
citrate
Letrozole
Mono-follicular vs. Multi-follicular Development

Letrozole vs CC
Unlike Clomiphene citrate, letrozole does not have any effect on endometrium or
cervical mucus because of absence of estrogen receptor depletion and its short half
life
Promising in women failed with CC
Associated with thicker endometrium and increased stromal blood flow, thereby
providing a better uterine environment more favorable for implantation.
Compared to clomiphene, letrozole has been shown to have higher pregnancy rates
Hofe JV, et al. Obstret Gynecol Clin N Am. 2014.

Outcomes —BMI-Letrozole vs CC
For women with a BMI ≥30.3 kg/m2
, the cumulative live birth rate
was significantly higher with letrozole when compared with
clomiphene (20 versus 10 percent).
The obese women in both treatment groups had lower live birth
rates than non obese women, consistent with previous ovulation
induction trials demonstrating a negative impact of obesity on
fecundity .

Outcomes
The American College of Obstetrics and Gynecology (ACOG) has
published revised recommendations for the choice of ovulation
induction agents in women with PCOS .
While they previously suggested letrozole as first-line therapy (over
clomiphene citrate) only for women with a BMI >30 kg/m2
, they now
recommend it for all women with PCOS, regardless of BMI.
 In addition, they recommend lifestyle changes and weight loss for all
obese women with PCOS to try to restore ovulatory cycles without
the use of ovulation induction agents.
ACOG Committee Opinion No. 738: Aromatase Inhibitors in Gynecologic Practice. Obstet
Gynecol 2018; 131:1.

Outcomes-Letrozole vs CC-miscarriage
Miscarriage rates were similar with the two therapies (49 of 154
pregnancies in the letrozole group [31.8 percent] versus 30 of 103
pregnancies in the clomiphene citrate group [29.1 percent]).
There were no differences in birth weights or rates of neonatal
complications (including anomalies).
The twin pregnancy rate was lower with letrozole (4 of 117 [3.4
percent]) than with clomiphene (6 of 81 [7.4 percent]), but the study
was underpowered to detect a significant difference between the two
groups.

Outcomes-Multiple Pregnancy
Although high-order multiple births would not be anticipated with letrozole, the first
case of sextuplets with letrozole ovulation induction has been reported .
A 32-year-old woman with PCOS, anovulatory infertility, and an antral follicle count
>50 underwent clomiphene citrate (50 mg) therapy without success (no ovulation
and poorly tolerated side effects).
She was switched to letrozole and had no response to 2.5 or 5 mg, but developed
five follicles on 7.5 mg.
Although the patient was advised to abstain from intercourse, she did not; at seven
weeks, she was noted to have a sextuplet pregnancy.
The pregnancy was reduced to twins, but she experienced pregnancy loss at 19
weeks. This case highlights the importance of ultrasound monitoring with ovulation
induction to assess follicular number and cancel cycles when necessary.
Warraich G, Vause TD. First reported case of sextuplets conceived via letrozole for ovulation induction.
Fertil Steril 2015; 103:535.

Side effects —CC vs letrozole
 Common side effects included hot flashes in 33 percent of women
receiving clomiphene and
fatigue and dizziness in 22 and 12 percent, respectively, of women
taking letrozole.
Legro RS, Brzyski RG, Diamond MP, et al. Letrozole
versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med 2014; 371:119.

Fetal safety —
A study comparing the incidence of congenital malformations in 911
newborns of women who conceived following treatment with
letrozole or clomiphene citrate did not find a statistically significant
difference .
Tulandi T, Martin J, Al-Fadhli R, et al. Congenital malformations among 911 newborns conceived after infertility treatment with
letrozole or clomiphene citrate. Fertil Steril 2006; 85:1761.
Forman R, Gill S, Moretti M, et al. Fetal safety of letrozole and clomiphene citrate for ovulation induction. J Obstet Gynaecol
Can 2007; 29:668.
Akbari Sene A, Ghorbani
S, Ashrafi M. Comparison of the pregnancy outcomes and the incidence of fetal congenital abnormalities in infertile women tre
ated with
letrozole and clomiphene citrate. J Obstet Gynaecol Res 2018; 44:1036.
Tatsumi T, Jwa SC, Kuwahara
A, et al. No increased risk of major congenital anomalies or adverse pregnancy or neonatal outcomes following letrozole

LBW —
A follow-up study did observe a significant increase in low birth
weight infants with use of clomiphene .
Infants born after use of letrozole were similar in birth weight to
infants conceived spontaneously.
Forman R, Gill S, Moretti M, et al. Fetal safety of letrozole
and clomiphene citrate for ovulation induction. J Obstet Gynaecol Can 2007; 29:668.

Summary & Recommendations-Letrozole
 Letrozole is first-line therapy over clomiphene citrate.
 The starting dose is 2.5 mg administered days 3 to 7; this can be
titrated up to a maximum dose of 7.5 mg/day if ovulation has not
occurred.
• Both letrozole and clomiphene citrate are pregnancy category X.
• Based on the half-life of letrozole, administration in the early follicular
phase should result in clearance of letrozole before implantation takes
place.
• Nevertheless, as with any ovulation induction agent, one must confirm
that the patient is not pregnant before starting therapy.
Teede HJ, Misso
ML, Costello MF, et al. Recommendations from the international evidence-based guideline for the assessme

SUMMARY AND RECOMMENDATIONS
• ●Letrozole, an aromatase inhibitor, is effective for ovulation induction in women with polycystic ovary syndrome (PCOS). (See
'Ovulation induction in PCOS' above.)
• ●Letrozole appears to result in higher live birth rates than clomiphene citrate. (See 'Comparison with clomiphene' above.)
• ●Most studies have reported similar rates of congenital malformations with letrozole and clomiphene citrate. (See 'Fetal safety'
above.)
• ●For oligoovulatory women with PCOS undergoing ovulation induction, we suggest letrozole as first-line therapy over
clomiphene citrate (Grade 2C). The greatest advantage in live birth rates with letrozole appears to be most important for
women with a body mass index (BMI) ≥30 kg/m2
. Before starting letrozole, the clinician must discuss that this use of the drug is
not US Food and Drug Administration (FDA) approved and that there is an available alternative. (See 'Suggested approach'
above.)
• ●For obese women with PCOS, lifestyle changes and weight loss are the initial strategy to restore ovulatory cycles. (See
'Suggested approach' above.)
• ●We suggest performing a blood pregnancy test prior to administering letrozole in premenopausal women. Although data are
reassuring, letrozole should be used with caution for ovulation induction since this is an off-label indication. (See
'Suggested approach' above.)
• ●In women with breast cancer undergoing follicle-stimulating hormone (FSH) therapy for ovarian stimulation for
cryopreservation of embryos or oocytes prior to undergoing gonadotoxic therapy, we suggest the addition of letrozole (
Grade 2C). (See 'Women with breast cancer' above.)

COH-Unexplained infertility —
 Letrozole + IUI has been used for women with unexplained
(ovulatory) infertility who do not respond to CC + IUI and
Who cannot or choose not to use IVF or gonadotropin therapy
Mitwally MF, Casper RF. Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders.
Mitwally
MF, Casper RF. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate.

COH-Unexplained infertility —
Letrozole has also been used alone or as an adjunct to gonadotropin therapy in
women with unexplained infertility.
The addition of letrozole to gonadotropin therapy appears to reduce the dose
of FSH required to achieve optimal COH, without adverse antiestrogenic
effects .
Mitwally MF, Casper RF. Aromatase inhibition reduces gonadotrophin dose required for controlled ovarian stimulation in
women with unexplained infertility. Hum Reprod 2003; 18:1588.
Mitwally MF, Casper RF. Aromatase inhibition reduces the dose of gonadotropin required for controlled ovarian hyperstimulation.
J Soc Gynecol Investig 2004; 11:406.
Healey S, Tan SL, Tulandi T, Biljan MM. Effects of letrozole on superovulation with gonadotropins in women
undergoing intrauterine insemination. Fertil Steril 2003; 80:1325.

Oral agents –Insulin Sensitizers —
Correction of hyperinsulinemia with metformin has been shown to
have a beneficial effect in anovulatory women with PCOS by
increasing menstrual cyclicity and improving spontaneous ovulation.
However, it does not appear to improve live-birth rates when given
alone or in combination with clomiphene citrate.
There is some experience with the use of another insulin-sensitizing
drug, (myo)inositol.
 Results of well-designed studies of sufficient sample size should be
awaited

Insulin sensitizers- GUIDELINES:
CC could be combined with metformin, rather than persisting
with CC alone, in women with PCOS who are CC resistant,
with anovulatory infertility and no other infertility factors, to
improve ovulation and pregnancy rates.
Messinis IE. Hum Reprod 2005;20(10):2688–2697
2. https://www.monash.edu/__data/assets/pdf_file/0004/1412644/PCOS_Evidence-Based-Guidelines_20181009.p
d

Insulin sensitizers Safety..
 Metformin appears to be safe during pregnancy.
 In addition, metformin reduces first trimester spontaneous
miscarriage rate and
 the incidence of gestational diabetes
Messinis IE. Hum Reprod 2005;20(10):2688–2697

Candidates —
 There are several indications for gonadotropin therapy in anovulatory
women:
 Women with polycystic ovary syndrome (PCOS) who have not
ovulated or conceived with weight loss, clomiphene, or letrozole
therapy .
 Hypogonadotropic anovulatory women with hypopituitarism or
women with hypothalamic amenorrhea (HA) who do not have access
to pulsatile gonadotropin-releasing hormone (GnRH) therapy.

Therapy
 Since their introduction into clinical practice in 1961, gonadotropins extracted
from the urine of postmenopausal women (human menopausal gonadotropins
[hMG]), in which the ratio of luteinizing hormone (LH) to follicle-stimulating
hormone (FSH) bioactivity is 1:1, have assumed a central role in ovulation
induction .
 Refinement of the initially crude preparation resulted in the availability of purified
and highly purified urinary FSH (uFSH).
 Since 1996, recombinant human FSH (rhFSH, >99 percent purity) has been
available.
 Recombinant preparations are appealing due to their ease of administration
(subcutaneous rather than intramuscular), purity, and batch-to-batch consistency.
Lunenfeld B. Historical perspectives in gonadotrophin therapy. Hum Reprod

Which Gonadotrophins in Non IVF cycles
 HMG
 Highly Purified HMG
 Urinary FSH
 Highly Purified FSH
 Recombinant FSH

Does Preparations affects outcome ?
 hMG and FSH — The degree to which the type of FSH compound employed may influence
outcome of ovulation induction has been controversial.
 However, in a meta-analysis of 14 trials in 1726 women (10 trials comparing rhFSH and urinary
gonadotropins [FSH-highly purified (HP) or human menopausal gonadotropins(hMG)] and four
trials comparing FSH-purified [P] and hMG or HP-hMG), the following results were seen :
 There were no differences in clinical pregnancy or live-birth rates for rhFSH and urinary-derived
gonadotropins.
 There also were no differences between hMG preparations and urinary FSH-P.
 After pooling the data, there were no differences in the rates of OHSS between rhFSH and
urinary-derived gonadotropins.
 The evidence for all outcomes was of very low quality.
Weiss NS, Nahuis M, Bayram
N, et al. Gonadotrophins for ovulation induction in women with polycystic ovarian syndrome. Cochrane Database Syst
Rev 2015; :CD010290.

Does Preparations affects outcome ?
 Purified uFSH has some LH activity, but rhFSH does not.
 The experience with rhFSH in hypogonadotropic hypogonadal women indicates
that those women who have very low serum LH concentrations (<0.5
international units/L) need exogenous human chorionic gonadotropin (hCG) (or
75 international units/day subcutaneous recombinant LH) to maintain adequate
estradiol biosynthesis and follicle development .
 Long-acting rhFSH preparations are currently registered in some countries for use
in in vitro fertilization (IVF) , but their use is not advised for ovulation induction.
European Recombinant LH Study Group. Human recombinant luteinizing hormone is as effective as, but safer than, urinar
y human chorionic gonadotropin in inducing final follicular maturation and ovulation in in vitro fertilization procedures: res
ults of a multicenter double-blind study. J
Clin Endocrinol Metab 2001; 86:2607.
Devroey P, Boostanfar R, Koper NP, et al. A double-blind, non-inferiority RCT comparing corifollitropin alfa
and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol. Hum Reprod

Practical considerations while using gonadotropins
 Where gonadotropins are to be prescribed, the following should be
considered:
 Cost of intervention for ovulation induction
 Expertise required for use of intervention for ovulation induction
 Degree of intensive monitoring that is required
 Implications of potential multiple pregnancy
 Implications of the potential risk of OHSS
 Most cost-effective gonadotropin should be used
 Evidence indicates no significant difference in effectiveness between preparations
Balen AH. Mol Cell Endocrinol. 2013 Jul 5;373(1-2):77-82.

Problems with gonadotrophin therapy
Multiple follicle development
 -Multiple pregnancies
- OHSS

Goal —
 The aim of ovulation induction
with gonadotropins, as with
clomiphene, is the formation of a
single dominant follicle.
Because ovarian sensitivity to FSH
stimulation varies among individual
women, specific protocols are
needed to achieve development of
a single follicle when exogenous
gonadotropin is administered.

Non IVF Gonadotrophin cycles – what should be the starting dose
Age.
Antral Follicle count.
AMH
Previous response.

Conventional gonadotropin protocol
 In this the starting dose of FSH is 150 international units/day.
 However, this regimen is associated with a multiple pregnancy rate of
up to 36%, and ovarian hyperstimulation occurs in up to 14% of
treatment cycles .
Fauser BC, Van Heusden
AM. Manipulation of human ovarian function: physiological concepts and clinical consequences.
Endocr Rev 1997; 18:71.
White DM, Polson DW, Kiddy D, et al. Induction of ovulation with low-dose gonadotropins in polycystic o
vary syndrome: an analysis of 109 pregnancies in 225 women. J
Clin Endocrinol Metab 1996; 81:3821.

Starting Dose for non IVF Cycle
< 35 yrs > 35 years
Non PCO 150 150
PCO 75 150

Gonadotrophins IUI Cycle
Day Of Cycle Drug and Dose
2, 3, 4, 5, 6 Gonadotrophins
7 TVS
Dose adjustments
More than 10 mm
2 to 3 follicles
4 to 6 follicles
More than 6 follicles
Same dose
Same or taper
Taper and look for OHSS
Less than 10 mm Increase the dose
When lead follicle is 18 mm Trigger for Ovulation

Low-dose, step-up protocol
White DM, Polson DW, Kiddy D, et al. Induction of ovulation with low-dose gonadotropins in polycystic ovary syndrom
e: an analysis of 109 pregnancies in 225 women. J
Serum E2 levels are measured and USG is performed on day 7.
If Serum E2 is >200 pg/ml or follicle size is above 10 mm, the same dose is continued.
Otherwise, if the parameters are less than the above described, the daily dose is increased by an increment of 37.5
units every week, till the serum E2 level rises adequately

• The step-up protocol is best utilized in WHO Group I as these individuals have not been
previously exposed to FSH, have low estrogen, and thus will likely be sensitive to
moderate levels of FSH.
• In contrast, PCOS individuals already have multiple small follicles and low levels of
FSH; therefore, they need a lower dose of FSH to reach the “FSH window” and induce a
single follicle.
• Higher doses place these women at risk of OHSS and multiple gestations.
Lindheim SR, Glenn TL, Smith MC, Gagneux P. Ovulation Induction for the General Gynecologist. The Journal of Obstetrics and Gynecology of India. 2018 Aug;68(4):242-52.
Step-up protocol

The low-dose, step-down protocol
 The low-dose, step-down protocol of ovulation induction mimics more
closely the physiology of normal cycles .
 Therapy with 150 international units FSH/day is started shortly after
spontaneous or progesterone-induced bleeding and continued until a
dominant follicle (>10 mm) is seen on transvaginal ultrasonography.
 The dose is then decreased to 112.5 international units/day followed by a
further decrease to 75 international units/day three days later, which is
continued until hCG is administered to induce ovulation.
van Santbrink EJ, Donderwinkel PF, van Dessel TJ, Fauser
BC. Gonadotrophin induction of ovulation using a step-down dose regimen: single-centre
clinical experience in 82 patients. Hum Reprod 1995; 10:1048.

 The appropriate starting dose can be determined by using the low-
dose, step-up regimen for the first treatment cycle .
 The robustness of the step-down regimen in everyday practice
remains to be evaluated, and hence, the low-dose, step-up regimen
should be considered the first choice treatment.
Imani B, Eijkemans MJ, Faessen
GH, et al. Prediction of the individual follicle-stimulating hormone threshold for gonadotropin induction of ovulation in
normogonadotropic anovulatory infertility: an approach to increase safety and efficiency. Fertil Steril 2002; 77:83.

The step-down regimen generally is used in older women who require ‘superovulation’ in
order to overcome an age-related decrease in oocytes, where a high dose of Gn is given to
recruit a dominant follicle, then reduced to maintain the follicle until ovulation.
Although exact protocols differ, a high dose (ie 150 IU daily) is administered until TVUS
shows a dominant follicle > 10 mm, and then reduced serially reduced 5 days apart (112.5;
75 IU) until ovulation is triggered.
Hyperstimulation rates have been reported to be as high 68% in the step-down protocol
compared to 32% in the step-up protocol.
Although the step-down protocol is highly effective, it requires more expertise and is
associated with more complications; therefore, the step-up protocol is considered a safer
alternative
Lindheim SR, Glenn TL, Smith MC, Gagneux P. Ovulation Induction for the General Gynecologist. The Journal of Obstetrics and Gynecology of India. 2018 Aug;68(4):242-52.

CC with Gonadotropins
Advantages
 Higher pregnancy rate than with CC alone
 More cost effective
 Lesser multiple pregnancy rate than with gonadotropins alone
 Lower incidence of OHSS, as compared to the conventional regime
Disadvantages
 Antiestrogenic effect (adverse pregnancy outcome)

Letrozole with gonadotropins
Used in order to reduce the requirement of gonadotropins and the
side effects of high dose gonadotropin
Pregnancy rate achieved was also significantly lower in the CC + FSH
group 16 (10.5%) compared with the letrozole + FSH group (19.1%) and
FSH only group (18.7%)
Mitwally MFM, et al. Hum Reprod. 2003; 18: 15881-597

CC / Letrozole + Gonadotrophins
Day Of Cycle Drug and Dose
2, 3, 4. C C 50 mg / Letrozole 2.5 mg
5, 6. C C 50 mg / letrozole 2.5 mg +
Gonadotrophin
7, 8 Gonadotrophins
9 and onwards Ultrasound and dose adjustments

GnRH analogue in combination with gonadotropins
Used to avoid interference from endogenous gonadotropin secretion
Use of GnRH analogues in IUI cycles is not recommended (do not
significantly improve pregnancy rates)
Cohlen et al, Cochrane Database Syst Rev 2007 Apr 18;(2):CD005356

GnRh Antagonist- Indications & Uses
 Conversion of IUI to IVF cycles i.e. flexibility of cycles
 Programming of IUI cycles – can avoid weekends
 Fixed or flexible protocol.
 Cochrane review concluded that antagonists were
not helpful in improving pregnancy rate.
Cohlen et al, Cochrane Database Syst Rev 2007 Apr 18;(2):CD005356
Ragni et al Human Reprod, Jan 2004 Bakas P. Fertil Steril.2011 May;

Outcomes-Pregnancy —
 Gonadotropin therapy CC failure has been the
"classical" approach to ovulation induction for
anovulatory infertility.
 Using this sequential approach, cumulative,
singleton live-birth rates of 71 percent (only 7
percent multiples) over 24 months have been
reported.
 These results suggest that conventional
approaches offer an effective means of treating
the majority of women with anovulatory
infertility before proceeding to more aggressive
treatments such as IVF.
Mulders AG, Laven
JS, Imani B, et al. IVF outcome in anovulatory infertility (WHO group 2)--incl
uding polycystic ovary syndrome--following previous unsuccessful ovulation
induction.

Outcomes-Pregnancy —to combine with IUI
or not ?
 Ovulation induction is sometimes combined with IUI.
 In the absence of male factor infertility, this clinical approach is not
based on sound clinical evidence.
 If both anovulatory and male factor infertility are causing the couple's
infertility, then combined ovulation induction with IUI is a useful
approach.
 Obesity and insulin resistance (but not an elevated serum LH
concentration) are associated with lower success rates.
Mulders AG, Laven
JS, Imani B, et al. IVF outcome in anovulatory infertility (WHO group 2)--including polycystic ovary syndrome--following previo
us unsuccessful ovulation induction.
Reprod Biomed Online 2003; 7:50.

Outcomes
Multiple gestation — The risk of multiple gestation is increased
with CC but to a much greater extent with gonadotropin therapy.
Fauser BC, Devroey P, Macklon NS. Multiple birth resulting from ovarian stimulation for subfertility treatment.
Lancet 2005; 365:1807.

Outcomes
Ovarian hyperstimulation syndrome — OHSS is a potentially life-
threatening complication of ovulation induction.
Mild , Moderate, severe
OPD care
In patient care
ICU admission
Delvigne A, Rozenberg S. Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS):
a review. Hum Reprod Update 2002; 8:559.
Navot D, Relou A, Birkenfeld A, et al. Risk factors and prognostic variables in the ovarian hyperstimulation syndrome.
Am J Obstet Gynecol 1988; 159:210.
Delvigne A. Symposium: Update on prediction and management of OHSS. Epidemiology of OHSS. Reprod Biomed Online 2009; 19:8.

Laparoscopic ovarian diathermy
 Laparoscopic ovarian diathermy ("ovarian drilling") represents an
alternative second-line therapy for women with polycystic ovarian
syndrome (PCOS).
 In women who are still anovulatory despite an adequate trial of
clomiphene citrate, another therapeutic option next to gonadotropins
is laparoscopic surgery with electrocautery or laser.

cancer risks-ovarian cancer –
 In some early studies, it appeared that the use of fertility drugs was
associated with neoplasia, particularly borderline ovarian tumors .
Rossing MA, Daling JR, Weiss NS, et al. Ovarian tumors in a cohort of infertile women. N Engl
J Med 1994; 331:771.
Shushan A, Paltiel O, Iscovich
J, et al. Human menopausal gonadotropin and the risk of epithelial ovarian cancer. Fertil Steril
1996; 65:13.
Ness RB, Cramer DW, Goodman MT, et al. Infertility, fertility drugs, and ovarian cancer: a pooled analysis o
f case-control studies. Am J
Epidemiol 2002; 155:217.

 Subsequent studies and meta-analyses have not confirmed an excess
risk of ovarian cancer with infertility treatment (clomiphene or
gonadotropin therapy), but in some reports, infertility itself was an
independent risk factor
Kashyap S, Moher D, Fung MF, Rosenwaks
Z. Assisted reproductive technology and the incidence of ovarian cancer: a meta-analysis. Obstet Gynecol
2004; 103:785.
Brinton LA, Lamb EJ, Moghissi KS, et al. Ovarian cancer risk after the use of ovulation-stimulating drugs. Obstet
Gynecol 2004; 103:1194.
Brinton LA, Lamb EJ, Moghissi KS, et al. Ovarian cancer risk associated with varying causes of infertility. Fertil
Steril 2004; 82:405.
Rizzuto I, Behrens RF, Smith LA. Risk of ovarian cancer in women treated with ovarian stimulating drugs for inf
ertility. Cochrane Database

 The best evidence for a lack of association comes from a systematic
review of 11 case-control studies and 14 cohort studies that included
a total of 182,972 women.
 In this analysis, there was no convincing evidence of an excess risk of
invasive ovarian tumors with fertility drug therapy .
Rizzuto I, Behrens RF, Smith LA. Risk of ovarian cancer in women treated with ovarian
stimulating drugs for infertility. Cochrane Database
Syst Rev 2013; :CD008215.

cancer risks-breast cancer –
 There does not appear to be an increased risk of breast cancer in
women treated with fertility drugs .
However, interpretation of the available data is limited by several
factors, such as survey information, small subgroup numbers, lack of
evaluation by drug type/dose or cause of infertility, and confounding
by the presence of other risk factors for breast cancer.
Doyle P, Maconochie N, Beral V, et al. Cancer incidence following treatment for infertility at a clinic in the UK. Hum Reprod
2002; 17:2209.
Brinton LA, Scoccia B, Moghissi KS, et al. Breast cancer risk associated with ovulation-stimulating drugs. Hum Reprod
2004; 19:2005.
Gauthier E, Paoletti X, Clavel-Chapelon
F, E3N group. Breast cancer risk associated with being treated for infertility: results from the French E3N cohort study. Hu
m
Reprod 2004; 19:2216.

cancer risks-breast cancer –
In a prospective cohort study of 116,671 women with 1357 incident cases of breast cancer, women
who reported infertility due to an ovulatory disorder had a lower risk of breast cancer than women
who did not report infertility (hazard ratio [HR] 0.75) ; women who had received CC were at lowest
risk (HR 0.60).
In a sister-matched, case-control study among approximately 1400 women with and 1600 sisters
without breast cancer, those who had used CC or exogenous FSH but did not conceive were at lower
risk of breast cancer compared with nonusers (odds ratio [OR] 0.62, 95% CI 0.43-0.89). Those who
used fertility drugs and did conceive (at least a 10-week pregnancy) had the same breast cancer risk
as women who had never taken fertility drugs .
Thus, women taking infertility drugs can be reassured that these drugs probably do not increase
their risk of breast cancer, although it is not clear whether some subgroups may be at increased risk.
Further investigation is required.
Terry KL, Willett WC, Rich-Edwards JW, Michels
KB. A prospective study of infertility due to ovulatory disorders, ovulation induction, and incidence of brea
st cancer. Arch Intern Med 2006; 166:2484.
Fei C, Deroo
LA, Sandler DP, Weinberg CR. Fertility drugs and young-onset breast cancer: results from the Two Sister St

cancer risks-other cancers –
In a retrospective, cohort study, neither clomiphene nor gonadotropin
use appeared to be associated with an increased risk of
melanoma or
 thyroid,
 cervical, or
colon cancers .
Althuis MD, Scoccia
B, Lamb EJ, et al. Melanoma, thyroid, cervical, and colon cancer risk after use of fe
rtility drugs. Am J
Obstet Gynecol 2005; 193:668.

Risk in offspring –
A large, population-based study found that childhood tumor risk was
not increased in children conceived following ovulation induction.
Ongoing monitoring of the long-term effects of these drugs is
warranted since the number of cases was small.
However, congenital malformation risk does not appear to be
increased with oral ovulation induction agents
Brinton LA, Krüger Kjaer
S, Thomsen BL, et al. Childhood tumor risk after treatment with ovulation-stimulating dr
ugs.

Choosing the Right Protocol
● PCOS / Anovulatory: Letrozole ± Gonadotropins.
● Unexplained Infertility: Clomiphene / Letrozole ±
Gonadotropins.
● Low Ovarian Reserve: Gonadotropins directly.
● CCResistance: Letrozole / Gonadotropins or combined protocols.

When Should the Gynecologist Refer a
Patient to an IVF Specialist?
A
In these situations intrauterine insemination treatment merits consideration before proceeding to IVF.
Ben-Ami I, et al. Textbook of Assisted Reproductive Techniques. Volume Two: Clinical Perspectives. 2012; 18–30.
Hormonal
disturbances a
Unexplained infertility
(idiopathic)a
IVF is the method of choice,
• If the duration of infertility is
3 years or longer.
• If the woman is older than
36 years, IVF may be
considered earlier.
IVF is the method of choice,
• In case of anovulatory cycle
abnormalities i.e., if 12 cycles of
treatment with ovulation induction
have been unsuccessful.

Early Referral Benefits to IVF Specialists by Gynecologists
Jirge PR. J Hum Reprod Sci. 2016;9(2):63–69.
Early Referral Benefits
Reasonable
chance of
achieving
pregnancy
Increase in
live birth
rate
Reduction in
recurrent
pregnancy
loss

Summary and recommendations
 The method of ovulation induction selected by the clinician should be
based upon the underlying cause of anovulation and the efficacy,
costs, risks, burden of treatment, and potential complications
associated with each method as they apply to the individual woman.
 For oligoovulatory women with PCOS undergoing ovulation induction
letrozole is first-line therapy over CC, regardless of the patient's body
mass index (BMI) (Grade 2B).
 For obese women with PCOS, lifestyle changes and weight loss is an
initial strategy to restore ovulatory cycles (Grade 2B).

Summary and Recommendations
For patients with mild male factor, early stage endometriosis, or
unexplained infertility, we suggest controlled ovarian
hyperstimulation with IUI rather than natural cycle IUI (Grade 2B)
Ovarian stimulation may employ clomiphene or gonadotropins.
For women undergoing IUI, we recommend a single IUI procedure (
Grade 1A). When compared with double IUI, single IUI has the same
efficacy with fewer visits and lower cost.
Semen processing for IUI is not difficult to learn and can be adapted
to use in clinical offices, but care must be taken to ensure that
adequate quality measures are in place.

Summary and recommendations
For women with hyperprolactinemic anovulation,ovulation induction
with dopamine agonists with either bromocriptine or cabergoline (
Grade 2C).
While there has been concern about a possible increased risk of ovarian
cancer with ovulation induction drugs, it appears that the risk may be
due to the infertility itself rather than the medications used to treat it.
However, because one study suggested an increase after 12 cycles of
clomiphene citrate, women should not receive more than 12 cycles.
There does not appear to be an increased risk of breast cancer with
ovulation induction drugs.

Summary and Recommendations
IUI alone is a useful technique for achieving pregnancy in couples
with severe sexual dysfunction, but can also be useful in patients with
cervical factor infertility as long as at least one fallopian tube is
patent.
When IUI is performed during an unstimulated (natural cycle) or a
clomiphene or letrozole stimulated cycle, we suggest use of an over-
the-counter ovulation predictor kit to schedule the optimum time for
the procedure.

Medication Dose
Day (D)
Initiate
treatment
Day (D)
LBR Side effects Risk of M, OHSS, MC
CC 50 mg × 5 d
Max dose 250 mg
D2–5 23.3% Mood swings, Hot flashes
Diplopia, Scotoma
Photophobia
M: <10%
OHSS: 0.5–2.5%
MC: 20%
Tamoxifen 20 mg × 5 d
Max dose 80 mg
D5 34% Hot flashes
Atrophic vaginitis
Irregular menses
Heightened risk of cataracts and
deep vein thrombosis
M: 0%
OHSS: 0%
MC: 6%
CC + Tamoxifen 150 mg CC × 5 d
40 mg tamoxifen × 5 d
D3 49.3%
(triggered
cycles)
See CC and Tamoxifen M(0%)
Letrozole 2.5 mg × 5 d
Max dose 7.5 mg
D3 27.5% Decreased bone density
Arthralgias/myalgias
Vaginal dryness
Loss of libido
Dyspareunia
M:13%
OHSS: 9%
MC: 8–9%
Metformin Initial: 500 mg/d
Titrate up 500 mg/d
every week
Max dose 2500 mg/d
Daily 7–52% Abdominal pain
Nausea, Vomiting, Diarrhea
Rare lactic acidosis
M: 0–3%
MC: 6–12.3%
(To Be Continued)
M multiple gestations, OHSS Ovarian Hyperstimulation Syndrome, MC miscarriage

Medication Dose
Day (D)
Initiate treatment
Day (D)
LBR Side effects Risk of M,
OHSS, MC
Metformin +
Letrozole
1500 mg metformin/d
2.5 mg × 5 d
Daily for 6–8 weeks
Initiate Letrozole per
normal protocol
34.5% See Metformin and
Letrozole
MC: 0%
Metformin + CC 50–250 mg/d CC
850 mg/d metformin
Daily for 6–8 weeks
Initiate CC per
normal protocol
Similar to
CC alone
BMI >35:
22.9%
See Metformin and CC MC: Refer to
CC
Gonadotropins 75 IU starting dose
Step-up protocol:
Above plus 75 IU increase every 7 d in
absence of recruited follicle
Low-dose step-up protocol: 37.5–
75 IU starting dose plus 37.5 IU
increase every 7–14 d in absence of
recruited follicle
Step-down protocol: 150 IU until
dominant follicle >10 mm; then
112.5 IU for 5 d; 75 IU for 5 d until
ovulation
D5 32.2% Potential formation of
“anti-hormones” that
counteract the
administered
hormone
Abd pain, bloating,
decreased urine
output, N/V/D, breast
tenderness
M: 8–31.8%
OHSS: 11%
MC: 4%
M multiple gestations, OHSS Ovarian Hyperstimulation Syndrome, MC miscarriag

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Stimulation Protocols for IUI | Dr. Laxmi Shrikhande

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Ph- 91 8805577600
shrikhandedrlaxmi@gmail.com

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