Optimizing Fertility: Ovulation Induction in IUI - A Comprehensive Guide

• Immediate Past Chairperson –Indian College of OB/GY
• National Corresponding Editor-Journal of OB/GY of
India
• National Corresponding Secretary- Association of
Medical Women, India
• President –ISOPARB Vidarbha Chapter 2019-21
• Chairperson-IMS Education Committee 2021-23
• Chairperson-fertility enhancement Committee-
ISOPARB
• Member-SAFOG Education Committee
• President-Association of Medical Women, Nagpur
AMWN 2021-24
• Senior Vice President FOGSI 2012
• President Menopause Society, Nagpur 2016-18
• President Nagpur OB/GY Society 2005-06
Dr. Laxmi Shrikhande
MBBS; MD(OB/GY);
FICOG; FICMU; FICMCH
Medical Director-
Shrikhande Fertility Clinic
Nagpur, Maharashtra
 Nagpur Ratan Award @hands of
Union Minister Shri Nitinji
Gadkari
 Received Bharat excellence Award
for women’s health
 Received Mehroo Dara Hansotia
Best Committee Award for her
work 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 22 orations and
450 guest lectures
 Publications- 42 National &
21 International
 Sensitized 2 lakh boys and
girls on adolescent health
issues
Awards
Positions

Ovulation Induction in
IUI Cycles
Dr Laxmi Shrikhande
Consultant –Shrikhande Fertility Clinic
Nagpur

Unexplained
28%
Male factors
24%
Ovarian
dysfunction
21%
Tubal factors
14%
Other
13%
Jose-Miller AB, et al. Am Fam Physician 2007;75:849-56, 857-8.
Major causes of Subfertility in couples

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

Ovulation induction
 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

WHO Class
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.

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,
 Cost,
 Risks,
 Patient burden, and
 Potential complications associated with each method as they apply to
the individual woman.

Ideal Ovulation Induction Drug
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 oligo ovulatory 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 oligo ovulation or anovulation .
 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 hypo estrogenemic 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 (e.g., 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, non invasive 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 subfertility.
A pelvic examination & TVS 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 HSG 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. Fertil Steril 2013; 100:341.

CC 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 women.
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, BBT 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 1998; 70:165.

OUTCOMES-Ovulatory and pregnancy rates —
 An ovulatory rate of 80% and a cumulative pregnancy rate of 30-40%
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.

OUTCOMES-Ovulatory and pregnancy rates —
 Of those who ovulate, approximately 50% do so at a dose of 50 mg ,
another 20 - 25% at 100 mg, and 10% 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 the 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
clomiphene citrate. Fertil Steril 2004; 81:1187.

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 anti
estrogenic 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.

Ovulatory and pregnancy rates —
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.

Ovulatory and pregnancy rates —
• 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.

Multiple gestation —
• Induction of ovulation by clomiphene increases the probability of
multifetal pregnancy: twins have been reported in 6.9 to 9% of
pregnancies, triplets in 0.3 to 0.5 %, quadruplets in 0.3 %, and
quintuplets in 0.13 % .
• 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 2011; 26:451.

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
infants. Am J Obstet Gynecol 2003; 188:611.

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 10-20 % of women .
 They may result from hypoestrogenism at the hypothalamic level due
to clomiphene blockade of estrogen receptors.
 Additional problems 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. Obstet
Gynecol 2002; 99:347.

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 hyper stimulation 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

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
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 ,
 But 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 randomized double blind trial. Fertil Steril 2004; 82:S81.

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

Letrozole vs CC
 Available data suggest that letrozole is superior to clomiphene citrate for
the outcome of live birth rates in oligo ovulatory 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.

Letrozole vs CC
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).
Imani B, Eijkemans MJ, te Velde 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.

Letrozole vs CC
 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.

Outcomes —Letrozole vs CC
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.

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 .
Imani B, Eijkemans MJ, te Velde 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.

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.

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.
Imani B, Eijkemans MJ, te Velde 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.

Multiple Pregnancy-Rare Case
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 —letrozole
 Common side effects include hot flashes in 33 % of women
receiving clomiphene and
Fatigue and dizziness in 22 and 12 %, 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
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 treated 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 use in assisted reproductive technology. Hum Reprod 2017; 32:125.
Sharma S, Ghosh S, Singh S, et al. Congenital malformations among babies born following letrozole or clomiphene for infertility treatment.
PLoS One 2014; 9:e108219.

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
assessment and management of polycystic ovary syndrome. Fertil Steril 2018; 110:364.

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.pd

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.

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

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 LH to 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 Update 2004; 10:453.

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.

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 various
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 & Letrozole , 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 ovary
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
 In patients with PCOS, who are at particular risk for complications,
this approach has been largely abandoned in favor of a low-dose,
step-up protocol designed to allow the FSH threshold to be reached
gradually, minimizing excessive stimulation and therefore the risk of
development of multiple follicles.
White DM, Polson DW, Kiddy D, et al. Induction of ovulation with low-dose gonadotropins in polycystic ovary syndrome: an
analysis of 109 pregnancies in 225 women. J Clin Endocrinol Metab 1996; 81:3821.

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 low-dose, step-down protocol
 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.

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
 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;

Monitoring ovarian stimulation
Transvaginal ultrasound scanning :
 Number & size of follicles
 Pattern & thickness of endometrium

Monitoring —
 Baseline D2 scan
 The ovarian response to gonadotropin therapy is monitored using TVS to measure
follicular diameter. The scans during the late follicular phase, usually performed every
two or three days, should be focused on identifying follicles of intermediate size.
 hCG is given as an ovulatory trigger on the day that at least one follicle appears to be
mature. The criteria for follicle maturity are a follicle diameter of 18 mm and/or a serum
estradiol concentration of 200 pg/mL (734 pmol/L) per dominant follicle.
 If three or more follicles larger than 15 mm are present, stimulation should be stopped,
hCG withheld, and use of a barrier contraceptive advised in order to prevent multiple
pregnancies and ovarian hyperstimulation.
 Measurements of serum estradiol are useful; preovulatory concentrations above the
normal range may predict ovarian hyperstimulation.
 Serum progesterone measurements are sometimes useful before administration of hCG
to determine if a premature LH surge has occurred, although we do not suggest routine
progesterone measurements.

Trigger-when ?
HCG at 18-20 mm (CC+Gn cycles)
HCG at 20-22 mm (CC cycles)
Dose- 5000 -10,000 IU

Ovulatory triggers —
 Both urinary and recombinant hCG preparations are available.
 A dose of 250 mcg of recombinant hCG appears to be equivalent to
the standard doses of urinary hCG (5000 to 10,000 units) .
Ludwig M, Doody KJ, Doody KM. Use of recombinant human chorionic gonadotropin in ovulation
induction. Fertil Steril 2003; 79:1051.

OI 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 previous unsuccessful ovulation induction. Reprod Biomed Online 2003; 7:50.

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 / Letrozole , another therapeutic option next to
gonadotropins is laparoscopic surgery with electrocautery or laser.

LOD
 All recommend its use in highly selected cases, particularly in
those with hypersecretion of luteinizing hormone (LH), normal
body mass index, those needing laparoscopic assessment of the
pelvis or who live too far away from the hospital for the intensive
monitoring required during gonadotropin therapy.
 Monopolar diathermy is the most widely used technique, although
no technique is superior.
 Restoration of regular ovulation and menstruation as well as
reduction in androgen and LH levels persist long-term.

Luteal Phase Support
Given empirically
In most letrozole and CC
cycles
Required
Definitely with use of
Gonadotrophins
AND
GnRH analogs - Agonist and Antagonist

Progesterone
• Different routes of administration
Oral, intramuscular or vaginal

Dydrogesterone
It is structurally and pharmacologically
similar to natural progesterone, has good
oral bioavailability
has a good safety and tolerability profile
has no androgenic effects on the fetus

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 oligo ovulatory 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
If oral ovulation induction agents are unsuccessful in women with PCOS, then gonadotropin
therapy should be started.
Strict attention to follicle number is essential to avoid multiple gestation and ovarian
hyperstimulation.
To minimize the risk of multiple gestation and OHSS in PCOS, gonadotropin treatment should be
stopped if there are an excess number of follicles or extremely high serum estradiol
concentrations.
For women with primary ovarian insufficiency (POI; premature ovarian failure) no ovulation
induction strategy has been shown to be effective. However, in vitro fertilization (IVF) with donor
oocytes has high success rates
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.

• Its not what you give ……
its the way you give it!

My World of sharing happiness!
Shrikhande Fertility Clinic
Ph- 91 8805577600
shrikhandedrlaxmi@gmail.com

The Art of Living
Anything that helps
you to become
unconditionally happy
and loving is what is
called spirituality.
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