Gonadotropin Protocols for Non IVF cycle

 Chairperson Elect ICOG –Indian College of OB/GY
 National Corresponding Editor-Journal of OB/GY of India JOGI
 National Corresponding Secretary Association of Medical Women, India
 Founder Patron & President –ISOPARB Vidarbha Chapter 2019-21
 Chairperson-IMS Education Committee 2021-23
 President-Association of Medical Women, Nagpur AMWN 2021-24
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
 Senior Vice President FOGSI 2012
 President Menopause Society, Nagpur 2016-18
 President Nagpur OB/GY Society 2005-06
Delivered 11 orations and 450 guest lectures
Publications-13 National & 11 International
Sensitized 2 lakh boys and girls on adolescent health issues

Gonadotropin Stimulation
Protocols for Non IVF Cycle
Dr Laxmi Shrikhande
Consultant –Shrikhande Hospital
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 - 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

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

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 Update 2004; 10:453.

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, urinary human
chorionic gonadotropin in inducing final follicular maturation and ovulation in in vitro fertilization procedures: results 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 2009; 24:3063.

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 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
 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;

GnRH antagonists (2 protocols) –
Both equally effective
Lubeck Protocol
Gonadotropins are started as usual and antagonist is started when the follicle
reaches a the size of 14 mm, or from 6 day of stimulation onwards in a dose of
0.25mg / day till the 17 day of HCG injection
French Protocol
Gonadotropins are started as usual and a single dose (3 mg) of antagonist is
given when 18 serum E2 level is about 150-200 pg/ml and follicular size is 14
mm
Diedrich K, et al. Hum Reprod. 1994; 9: 788-791.
Olivennes F, et al. Fertil Steril. 1994; 62: 468

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 transvaginal
ultrasonography 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.

Outcomes-Pregnancy —
 A series of 225 women with PCOS treated over a 10-year period in one center
found rates of ovulation and pregnancy of 72 percent and 45 percent,
respectively, after use of the low-dose, step-up protocol .
Multiple folliculogenesis and ovarian hyperstimulation are less common than that
seen with the standard protocol, and pregnancy rates appear similar .
However, the results of the low-dose, step-up protocol are negatively influenced
by age and obesity.
Shoham Z, Patel A, Jacobs HS. Polycystic ovarian syndrome: safety and effectiveness of stepwise and low-dose administration of purified
follicle-stimulating hormone. Fertil Steril 1991; 55:1051.
Calaf Alsina J, Ruiz Balda JA, Romeu Sarrió A, et al. Ovulation induction with a starting dose of 50 IU of recombinant follicle stimulating
hormone in WHO group II anovulatory women: the IO-50 study, a prospective, observational, multicentre, open trial. BJOG 2003;
110:1072.
Mulders AG, Eijkemans MJ, Imani B, Fauser BC. Prediction of chances for success or complications in gonadotrophin ovulation induction
in normogonadotrophic anovulatory infertility. Reprod Biomed Online 2003; 7:170.

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)--including polycystic ovary syndrome--following previous
unsuccessful ovulation induction. Reprod Biomed Online 2003; 7:50.

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 previous 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 of
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 infertility.
Cochrane Database Syst Rev 2013; :CD008215.

 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. Hum 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 breast 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
Study. J Natl Cancer Inst 2012; 104:1021.

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 fertility 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 drugs. Fertil Steril 2004; 81:1083.

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

GT
CC
CC+
GT
No benefit
Benefit
Benefit
Supported by
Meta-
analysis
in
Journal of
Assisted
Reproduction
and Genetics
January 2014

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 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
 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!

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

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

Gonadotropin Protocols for Non IVF cycle

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