Unexplained Infertility by Dr. Nidhi Sharma | Jindal IVF Chandigarh

Unexplained Infertility
DR NIDHI SHARMA
SENIOR CONSULTANT OBGY AND INFERTILITY SPECIALIST
JINDAL IVF CENTRE, CHANDIGARH

EXTERNAL USE
INFERTILITY - DEFINITION
2
Failure to achieve a successful pregnancy after 12 months
or more of regular unprotected intercourse
Earlier evaluation and treatment … is warranted after
6 months for women over age 35 years.
American Society
for Reproductive
Medicine
Int. Com. for Monitoring
Assisted Reproductive
Technology and WHO
A disease of the reproductive system defined by the
failure to achieve a clinical pregnancy after 12 months
or more of regular unprotected intercourse.
2008
2009
Practice Committee of the American Society for Reproductive Medicine. Fertil Steril 2013;100:631–7.
Gurunath S et al. Hum Reprod Update 2011; 17:575-588

EXTERNAL USE
INFERTILE COUPLES – IT TAKES TWO TO
TANGO
3
• Infertility affects 15% of couples
globally
• Prevalence and causes differ
between nations
• 20-30% of infertile couples are
affected solely due to male factors
• Male factors contribute overall to
50% of infertility
Agarwal A et al. Reprod Biol Endocrinol 2015 Apr 26; 13:37.

EXTERNAL USE
FEMALE INFERTILITY – PREVALENCE OF
SEEKING A CHILD
4
Overall, the prevalence of seeking a child due to primary infertility in
2010 was 1.9%. The prevalence of secondary infertility was 10.5%.
<1%
1% - 1.99%
2% - 2.99%
≥ 3%
Primary infertility
Mascarenhas MN et al. PLoS Med 2012; 9 (12):e1001356.

EXTERNAL USE
Ovulation
failure
Tubal
factor
Endometriosis
Not
known
INFERTILITY AND SUBFERTILITY – CAUSES
AND RISK FACTORS
5
• Problems with ovulation 25%1
• Blocked fallopian tubes 30%2
• Endometriosis (with no other
diagnosable infertility problem) 35%1
• No identifiable cause 10%1
Female Factors
1. Adapted from https://www.asrm.org/Booklet_Infertility_An_Overview/ 2012.
2. Briceag I et al. J Med Life. 2015;8:129-31.

EXTERNAL USE
UNEXPLAINED INFERTILITY
6
ASRM guidelines for infertility evaluation:
1) Semen Analysis
2) Assessment of ovulation
3) Tubal evaluation by hysterosalpingogram
4) Tests for ovarian reserve ( if indicated)
5) Laparoscopy.
When the results of a standard infertility evaluation are
normal, practitioners assign a diagnosis of unexplained
infertility
American Society
for Reproductive
Medicine
1. Optimal evaluation of the infertile female.Practice Committee of the American Society for Reproductive Medicine Effectiveness and treatment for unexplained infertility
Fertil Steril. 2006 Nov; 86(5 Suppl 1):S264-7.
2. Gnoth C, Godehardt E, Frank-Herrmann P, Friol K, Tigges J, Freundl G. Definition and prevalence of subfertility and infertility. Hum Reprod. 2005 May;20(5):1144-7. doi:
10.1093/humrep/deh870. Epub 2005 Mar 31. PMID: 15802321.
The diagnosis of unexplained infertility can be made only after excluding
common causes of infertility using standard fertility investigations.
Approximately 15% to 30% of couples will be diagnosed with unexplained
infertility after their diagnostic workup.

EXTERNAL USE
CAUSES OF UNEXPLAINED INFERTILITY
7
• Standard fertility investigations are far from comprehensive and
unable to identify subtle abnormalities in the reproductive
pathway.
• The cause of unexplained infertility is likely to be heterogeneous.
Proposed causes can be endocrinological, immunological and
genetic factors.
• In addition, compromised ovarian reserve is a factor which may
not be always captured in the diagnostic pathway, can be
responsible for a diagnosis of unexplained infertility in older
women.
Kamath, Mohan S, and Siladitya Bhattacharya. “Demographics of infertility and management of unexplained infertility.” Best practice & research. Clinical obstetrics & gynaecology vol.
26,6 (2012): 729-38. doi:10.1016/j.bpobgyn.2012.08.001

EXTERNAL USE
RISK FACTOR - AGE
8
• Female age has an important impact on fecundity rates.
• Female age is a strong predictor of both natural and treatment-
related live birth rates, with rates decreasing after 35 years of age.
• Of those females who do not conceive in the first year, about half
will do so in the second year (cumulative pregnancy rate ≥ 90%) also
for women 35-39 years of age.
1. Fertility: Assessment and Treatment for People with Fertility Problems NICE 2013.
2. Kamel R.M. Management of the infertile couple: an evidence-based protocol.Reprod. Biol. Endocrinol. 2010; 8: 21-28
Age
(years)
Pregnant after 1
year (12 cycles)
Pregnant after 2
years (24 cycles)
19 - 26 92 % 98 %
27 - 29 87 % 95 %
30 - 34 86 % 94 %
35 - 39 82 % 90 %

EXTERNAL USE
DIAGNOSTIC EVALUATION FOR INFERTILITY
9
Uterus (fibroids, polyps, septum)
Hydrosalpinx removal.
Duration of infertility, coital frequency, any fertility
treatments
Menstrual history, previous pregnancies, outcomes
Past surgery, PID, STDs, pelvic pain, hormone
disorders
Medical
history
Male
partner
Physical
examination
Ovarian
reserve
Sperm count
Semen analysis
Including BMI, BP, thyroid, galactorrhea, hirsutism, acne
Pelvic examination, ultrasound, pap smear, cultures for
chlamydia
Procedures: HSG, laparoscopy (tubal obstruction,
endometriosis)
FSH and estradiol
Antimüllerian hormone
Clomiphene challenge test
Correcting
abnormalities
Practice Committee of the American Society for Reproductive Medicine. Fertil Steril 2012;98:302-307.
HSG = Hysterosalpingogram
PID = Pelvic infectious disease
STD = Sexually transmitted disease

EXTERNAL USE
DIAGNOSTIC EVALUATION OF OVULATORY
FUNCTION
10
Methods to Detect Ovulation
 Luteal phase progesterone levels
 LH measured with commercial ovulation prediction kits
 Increase of basal body temperature in the luteal phase
 Ovarian follicles monitored by transvaginal ultrasound
Women with irregular menstrual cycles or amenorrhea are likely to
have ovulatory dysfunction

EXTERNAL USE
MALE INFERTILITY - SEMEN ANALYSIS
11
In addition, semen analysis can indicate
infection of reproductive system
https://www.nlm.nih.gov/medlineplus/ency/article/003627.htm/
Analysis of sperm
• Volume
• Total count
• Concentration
• Motility
• Morphology

EXTERNAL USE
WHO 2021 NORMAL SEMEN ANALYSIS CRITERIA
12
S. Parameter Value
Semen Volume (ml) 1.4 (1.3-1.5)
Total sperm number (Mill/ml) 39 (35-40)
Total motility(%) 42 (40-43)
Progressive motility (%) 30 (29-31)
Non- Progressive motility(%) 1 (1-1)
Immotile sperm(%) 20( 19-20)
Vitality (%) 54 (50-56)
Normal Forms (%) 4 (3.9-4)

EXTERNAL USE
DIAGNOSIS IN UNEXPLAINED INFERTILITY
13
• Unexplained Infertility is a diagnosis of exclusion.
• To establish the diagnosis of Unexplained Infertility, the clinician
should consider:
Was the infertility evaluation complete?
Was it performed correctly?
Was it interpreted properly?
Moghissi K.S., Wallach E.E. Unexplained infertility.Fertil. Steril. 1983; 39: 5-21

EXTERNAL USE
LAPAROSCOPY IN UNEXPLAINED INFERTILITY
• Laparoscopy used to be part of the basic infertility
investigations; it is now reserved for selected cases.
• It is the test of choice to identify otherwise
unrecognized peritoneal factors that influence
fertility, specifically endometriosis and pelvic
adhesions.
• According to the guidelines of the ASRM,
laparoscopy should be performed in women with
unexplained infertility or signs and symptoms of
endometriosis or in whom reversible adhesive tubal
disease is suspected.
• In the absence of evidence for tubal or other pelvic
pathology, laparoscopy is not warranted in UEI
(Level II-2B), although the recommendations
concede that there may be a place for diagnostic
laparoscopy in young women with a long period
(over 3 years) of infertility but no recognized
abnormalities.
14
Quaas, A., & Dokras, A. (2008). Diagnosis and treatment of unexplained infertility. Reviews in obstetrics & gynecology, 1(2), 69–76.
Canadian Task Force on Preventive Health Care New grades for recommendations from the Canadian Task Force on Preventive Health Care.
Can. Med. Assoc. J. 2003; 169: 207-208

TREATMENT OF
UNEXPLAINED INFERTILITY

EXTERNAL USE
TREATMENT OF UNEXPLAINED INFERTILITY
16
• The prognosis for spontaneous pregnancy in couples with
unexplained infertility is better than in those with diagnosed
causes of infertility.
• The principal treatments for unexplained infertility include
expectant observation with timed intercourse and lifestyle
changes, clomiphene citrate and intrauterine insemination
(IUI), controlled ovarian hyperstimulation (COH) with IUI, and
IVF.

EXTERNAL USE
EXPECTANT MANAGEMENT
17
 In couples with a good prognosis (based on age and duration of infertility)
expectant management can be offered (Level 1A)
• The relatively high possibility of spontaneous pregnancy in unexplained infertility
supports the strategy of expectant management. Couples are made aware of the
fertile period and advised to continue regular unprotected intercourse.
• Expectant management plays an important role, especially if the woman is
relatively young (around 25 years) and the period of infertility is short.
• Retrospective data have shown a cumulative pregnancy rate over 2 years as high
as 72% in young women, with a decline to 45% in women aged over 35, and
further to 30% in couples with more than 5 years of infertility
Guzick DS, Sullivan MW, Adamson GD, Cedars MI, Falk RJ, Peterson EP, et al. Efficacy of treatment for unexplained infertility. Fertil Steril 1998;70:207-13
•Hull M.G. et al. Population study of causes, treatment, and outcome of infertility.Br. Med. J. (Clin. Res. Ed.). 1985; 291: 1693-1697
•William et al. The management of unexplained infertility: an evidence-based guideline from the Canadian Fertility and Andrology Society Reprod. Biomed. Online.2019

EXTERNAL USE
CONTROLLED OVARIAN STIMULATION (COS)
18
 COS combined with intercourse or intrauterine insemination (IUI)
 COS as component of IVF - stimulation with exogenous gonadotropins to
maintain the development of gonadotropin-sensitive follicles and inhibit atresia
of non-dominant follicles
Most commonly used drugs
• Clomiphene citrate
• Letrozole
• Follicle Stimulating Hormone
• Human Menopausal Gonadotropin
https://www.asrm.org/BOOKLET_Medications_for_Inducing_Ovulation/ 2012.
The theoretical rationale for COS in women with a normal ovulatory assessment
is that subtle ovulatory defects missed by standard testing may be overcome,
and that an increased number of eggs available for fertilization may increase the
likelihood of pregnancy

EXTERNAL USE
CLOMIPHENE CITRATE
19
1. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril 2013;100:341–8.
2. Hughes E. et al. Clomiphene citrate for unexplained subfertility in women.Cochrane Database Syst Rev. 2010; CD000057
 Empiric treatment of unexplained
infertility
 It is believed that oral clomifene
citrate acts in unexplained
infertility by correcting subtle
ovulatory dysfunction and inducing
multiple follicular growth.

EXTERNAL USE
LETROZOLE
20
Robert F. Casper and Mohamed F. M. Mitwally. REVIEW: Aromatase Inhibitors for Ovulation Induction. J Clin Endocrinol Metab, March 2006, 91(3):760–771
Liu A. et al. Letrozole versus clomiphene citrate for unexplained infertility: a systematic review and meta-analysis.J. Obstet. Gynaecol. Res. 2014; 40: 1205-1216
 A systemic review (Liu et al., 2014)
compared the use of letrozole
alone and clomiphene citrate
alone in UEI. (Included data from
three studies)
 Letrozole use was associated with
a pregnancy rate of 24.5% in
randomized trials, while the use of
clomiphene citrate was associated
with a pregnancy rate of 20.8%.
 There was no statistically
significant difference in the rate of
multiple pregnancies with respect
to letrozole or clomiphene citrate
 Aromatase inhibitors, such as letrozole, have also been used extensively in
couples with UEI.

EXTERNAL USE
GONADOTROPIN THERAPY
21
Efficacy of treatment for unexplained infertility.Guzick DS, Sullivan MW, Adamson GD, Cedars MI, Falk RJ, Peterson EP, Steinkampf MP Fertil Steril. 1998 Aug; 70(2):207-13.
Welner S, DeCherney AH, Polan ML. Human menopausal gonadotropins: a justifiable therapy in ovulatory women with long-standing idiopathic infertility. Am J Obstet Gynecol 1988;158:111–7.
Risks:
• Ovarian hyperstimulation
syndrome
• Multiple gestations
• Increased risk of preterm birth
• Associated neonatal morbidity
and costs
 A review of descriptive and randomized studies suggested that empiric
gonadotropin therapy is an effective therapy for unexplained infertility,
especially when combined with IUI.
 While gonadotropin ovarian stimulation
(gonadotropin-OS) alone may offer benefit in the
treatment of UEI, it is associated with a high risk of
multiple pregnancy.
 A recent Cochrane review on the use of IUI in UEI (Veltman
Verhulst et al., 2016) showed that gonadotropin/IUI is
associated with a higher pregnancy rate per couple compared
with gonadotropin alone

EXTERNAL USE
In unexplained or mild male-factor infertility, couples –
• No difference between 6 cycles of IUI alone vs expectant management
• Compared to natural-cycle IUI, there were significantly higher pregnancy rates in stimulated cycle IUI
(clomiphene citrate with IUI, letrozole with IUI or gonadotropins with IUI)
• It is not recommended to use gonadotropins with timed intercourse
• There is strong evidence that there is no significant difference following letrozole with IUI as compared
to CC with IUI. Both are superior to expectant management and natural-cycle IUI.
• No difference in pregnancy outcomes with gonadotrophins compared to oral agents. (DEBATEABLE)
• These couples should be offered OS and IUI with oral agents (typically 3 or 4 cycles). If unsuccessful,
IVF is recommended rather than OS and IUI with gonadotropins.

ASSISTED REPRODUCTIVE
TECHNIQUES (ART)

EXTERNAL USE
ASSISTED REPRODUCTIVE TECHNIQUES (ART)
24
Any treatment that deals with “means of conception other than vaginal
intercourse” is termed as ART.
NICE guidelines 2013
 IUI – Intra Uterine Insemination (Husband/Donor)
 IVF + ET – In Vitro Fertilization + Embryo transfer
 ICSI – Intra Cytoplasmic Sperm Injection

EXTERNAL USE
INTRA-UTERINE INSEMINATION (IUI)
25
• Intrauterine insemination involves the placement of washed sperm into
the uterine cavity around the time of ovulation.
• It can be performed in conjunction with
natural ovulation timed with LH kit,
ovulation induction using clomiphene
citrate, or injectable gonadotropins.
• IUI is the simplest and the least
expensive method of ART
• The role of unstimulated IUI in the
treatment of unexplained infertility is
questionable

EXTERNAL USE
INTRA-UTERINE INSEMINATION (IUI) WITH
OVARIAN STIMULATION
26
IUI alone (natural cycle) does not improve pregnancy chances,
hence mild ovarian stimulation is usually recommended.
 A recent Cochrane review (Intra-uterine insemination for unexplained subfertility)
confirmed that IUI with ovulation induction increased the live birth rate compared
with IUI alone.
 A significant increase in pregnancy rate was also found for women where IUI with OH
was compared with IUI in a natural cycle (three RCTs, 415 women: OR 2.33, 95% CI
1.46 to 3.71).
 Live birth rates of approximately 6% to 10% per cycle have been reported for infertile
couples with unexplained infertility undergoing IUI with or without ovarian
stimulation. (Huang 2018)
Verhulst SM, Cohlen BJ, Hughes E, Te Velde E, Heineman MJ Cochrane Database Syst Rev. 2006 Oct 18; (4):CD001838.
Huang S, Wang R, Li R, Wang H, Qiao J, Mol BWJ. Ovarian stimulation in infertile women treated with the use of intrauterine insemination: a cohort study from China. Fertility and
Sterility 2018;109(5):872‐8.

EXTERNAL USE
INDICATIONS FOR INTRA UTERINE
INSEMINATION (IUI)
27
• At least one Fallopian tube must be normal and patent
– Mild male infertility
– Unexplained infertility
– Ovulatory dysfunction, PCOS
– Mild endometriosis
– Cervical factors
– Coital problems
– Immunological factors
– HIV, HBs Ag infection
– Donor Sperm

EXTERNAL USE
SEMEN QUALITY AND IUI
28
• The sperm parameters that are most frequently examined were the
following:
– Sperm morphology using strict criteria,
– TMSC (total motile sperm count in the native sperm sample) and
– TM (total motility in the native sperm sample)
Willem Ombelet. Middle EastFertilitySocietyJournal(2013) 18, 74–77

EXTERNAL USE
SEMEN QUALITY AND IUI – IMPROVEMENT
IN SUCCESS RATES
29
• Success rate of IUI is improved with the following:
– Morphology score of more than 4% normal forms,
– TMCS of more than 5 million and
– Initial total motility of more than 30%.

EXTERNAL USE
SEMEN PREPARATION TECHNIQUES (SPT)
30
• Although Density gradient centrifugation (DGC) showed to be
superior to swim-up and wash technique concerning laboratory
outcomes (e.g. semen parameters) there is insufficient evidence to
recommend any specific SPT when speaking about clinical outcome
after IUI.
• It is clear that quality control and quality management in semen
preparation for IUI are mandatory.

EXTERNAL USE
OVARIAN STIMULATION AND PREVENTION
OF MULTIPLE PREGNANCIES
31
• IUI in combination with mild ovarian stimulation is effective in
couples with unexplained subfertility, minimal to mild endometriosis
and mild male subfertility
• The goal of ovarian stimulation should be the development of a
maximum of two dominant follicles.

EXTERNAL USE
TIMING AND NUMBER OF IUIs PER CYCLE,
BED REST AFTER IUI
32
• Double IUI results in higher pregnancy rates compared with single
IUI in couples with male factor subfertility, but not in unexplained
infertility cases.
• The optimal time-interval between HCG injection and IUI seems
between 12 and 36 h and at least 10–15 min of immobilization should
be applied after every insemination attempt.
Comparison of the effectiveness of single intrauterine insemination (IUI) versus double IUI per cycle in infertile patients.Alborzi S, Motazedian S, Parsanezhad ME, Jannati S
Fertil Steril. 2003 Sep; 80(3):595-9.7

EXTERNAL USE
INDICATIONS FOR IVF
34
Tubal disease
https://www.glowm.com/resources/glowm/cd/pages/v5/v5c097.html. Kashyap Vol. 5, Chapter 97. In Vitro Fertilization.
Male factor infertility
Intracytoplasmic sperm injection (ICSI)
Preservation of reproductive capacity
IVF with embryo transfer to gestational surrogate for women with
irreparable uterine abnormalities or disorders that contraindicate
pregnancy.
High responders at risk of multiple pregnancies (e.g. PCOS)
Conversion of a stimulated IUI cycle to an IVF cycle
e.g. cancer patients
Endometriosis

EXTERNAL USE
IN-VITRO FERTILIZATION FOR UNEXPLAINED
INFERTILITY
35
• IVF is the treatment of choice for unexplained infertility when the less costly,
but also less successful treatment modalities have failed.
• IVF has long been accepted as effective treatment for UEI, and international
guidelines have recommended IVF in the treatment of UEI.
• Given the higher multiple pregnancy rates seen with gonadotropin-COS/IUI,
IVF is also seen as offering a benefit in the reduction of multiple pregnancy
• The UK national guidelines have advised against gonadotropin/IUI and
moving to IVF because of the risk of multiple pregnancy associated with
gonadotropin/IUI, which is reduced with elective single-embryo transfer in
IVF.
William et al. The management of unexplained infertility: an evidence-based guideline from the Canadian Fertility and Andrology Society Reprod. Biomed. Online.2019
In-vitro fertilization remains the treatment of choice in longstanding unresolved
infertility and, when coupled with the use of elective single embryo transfer, can
minimize the risk of multiple pregnancies.

EXTERNAL USE
ICSI IN UNEXPLAINED INFERTILITY
36
• During IVF for UEI, failed fertilization occurs in around 5–10% of
cases (Bungum et al., 2004)
• In couples with UEI, adding ICSI could overcome subtle male factor
infertility and increase live birth rates.
• However, RCT comparing conventional IVF with ICSI in non-male
factor infertility have not found a benefit for adding ICSI
(Bhattacharya et al., 2001, Bukulmez et al., 2000).
• There is insufficient evidence to recommend the routine addition of
ICSI in couples with UEI undergoing IVF to increase the live birth
rate, although the addition of ICSI in IVF for UEI may reduce the
incidence of TFF (Level 1B)
Bungum et al. A strategy for treatment of couples with unexplained infertility who failed to conceive after intrauterine insemination.Reprod. Biomed. Online. 2004; 8: 584-589
William et al. The management of unexplained infertility: an evidence-based guideline from the Canadian Fertility and Andrology Society Reprod. Biomed. Online.2019

EXTERNAL USE
IVF – BASIC STEPS
37
Procedures differ considerably in order to optimize treatment and to
adjust to individual needs
1
• Ovarian stimulation
2
• Oocyte retrieval
3
• Fertilization (ICSI)
4 • Embryo culture
5 • Embryo transfer
https://www.glowm.com/resources/glowm/cd/pages/v5/v5c097.html. Kashyap Vol. 5, Chapter 97. In Vitro Fertilization.

EXTERNAL USE
OVARIAN STIMULATION FOR IVF
38
Following compounds are used for controlled ovarian stimulation:
 Follicle stimulating hormone (FSH)
 Luteinizing hormone (LH) in conjunction with FSH
 Human menopausal gonadotropin (hMG = LH/FSH)
Premature ovulation is prevented by GnRH agonists or antagonists.
hCG is administered to induce final
maturation of follicles for oocyte
retrieval
Ovarian follicles on ultrasound
http://www.asrm.org/BOOKLET_Assisted_Reproductive_Technologies/ 2011.

EXTERNAL USE
PREVENTING PREMATURE OVULATION
39
GnRH agonists
• Leuprolide acetate
• Nafarelin acetate
• Goserelin acetate
GnRH antagonists
• Cetrorelix acetate
• Ganirelix acetate
GnRH agonists down-regulate
secretion of FSH and LH after
initial stimulation
GnRH antagonists suppress FSH
and LH without initial stimulation
GnRH agonists and antagonists are used to prevent LH surge thereby
preventing ovulation before the oocytes can be retrieved
Use of an antagonist during ovarian stimulation eliminates estrogen
withdrawal symptoms because estrogen levels are already high when the
antagonist is started
https://www.asrm.org/BOOKLET_Medications_for_Inducing_Ovulation/ 2012.
https://www.glowm.com/resources/glowm/cd/pages/v5/v5c097.html . Kashyap Vol. 5, Chapter 97. In Vitro Fertilization.

EXTERNAL USE
OOCYTE RETRIEVAL
40
Transvaginal aspiration - a
procedure in which an ultrasound
probe is inserted into the vagina
to identify follicles, and a needle
is guided through the vagina and
into the follicles to retrieve the
oocytes. The oocytes are removed
from the follicles through the
needle which is connected to a
suction device
Adapted from http://www.mayoclinic.org/diseases-conditions/female-infertility/multimedia/fertilization/img-20006429.

EXTERNAL USE
INSEMINATION AND FERTILIZATION
41
Intracytoplasmic sperm injection (ICSI): If the chance of fertilization is
low, a sperm may be directly injected into the oocyte.
After selection of the oocytes, the sperm is mixed for insemination.
Fertilization usually takes place a few hours later.

EXTERNAL USE
EMBRYO TRANSFER
42
1
• One or more embryos, suspended in a culture
medium, are drawn into a thin catheter
2
• Catheter is inserted through vagina and cervix
into the uterus
3
• Embryo(s) are placed in the uterine cavity
with a syringe
4
• To avoid multiple pregnancies, the number of
embryos transferred is limited
5
• Unused embryos may be frozen and implanted
at a later date.

EXTERNAL USE
ETIOLOGY OF LUTEAL PHASE DEFICIENCY
44
Practice Committee of the American Society for Reproductive Medicine. Fertil Steril 2015;103:e27-e32.
LPD
Treatment Induced (ART)
Use of GnRH
analogues to
prevent
LH surge
Aspiration of
granulosa cells
during oocyte
retrieval
Impair Corpus
Luteum’s ability to
produce sufficient
progesterone

EXTERNAL USE
TREATMENT: LPD
45
Fertil Steril 2015;103:e27-e32. 2015 by American Society for Reproductive Medicine
• Supplemental progesterone
• Progesterone plus estrogen
• hCG in luteal phase, or ovulation induction with clomiphene or
gonadotropins

EXTERNAL USE
FOGSI RECOMMENDATIONS: USE OF
PROGESTOGENS IN EARLY PREGNANCY
46
Progestogens for Luteal Support
• Luteal function is usually compromised in ART cycles both in GnRH
agonist & antagonist protocol
• Endogenous progesterone deficiency is responsible for implantation
failure & early miscarriages
• Adequate luteal phase support is required during ART to improve
implantation and pregnancy rates, which can be achieved by either
hCG or directly by using progesterone
Good Clinical Practice Recommendations. Position Statement on the use of Progestogens. Published by Elsevier. http://www.fogsi.org/fogsi-gcpr/

EXTERNAL USE
47
• Progesterone supplementation is advisable starting just
after Oocyte Retrieval/Embryo Transfer
• Duration of exogenous progesterone therapy generally
varies up to 10 – 12 weeks of gestation

EXTERNAL USE
48
• Dydrogesterone: 20-30 mg/day
Oral Route
Vaginal Route
• Micronized Progesterone: 600 – 800 mg/day
capsules & Gel: 8% (90 mg) OD
• Intramuscular progesterone: 50-100 mg/day
IM Route

EXTERNAL USE
LUTEAL PHASE SUPPORT IN WOMEN
UNDERGOING IUI
50
LOTUS I STUDY:
A DOUBLE-BLIND, DOUBLE-DUMMY, RANDOMIZED, TWO-
ARM, MULTICENTER STUDY COMPARING THE EFFICACY,
SAFETY, AND TOLERABILITY OF ORAL DYDROGESTERONE
30 MG DAILY VERSUS INTRAVAGINAL MICRONIZED
PROGESTERONE CAPSULES 600 MG DAILY FOR LUTEAL
SUPPORT IN IN-VITRO FERTILIZATION

EXTERNAL USE
INCLUSION/EXCLUSION CRITERIA
52
• Subjects with >3 unsuccessful IVF attempts
• History of recurrent pregnancy loss
(≥3 miscarriages)
• Evidence of diseases affecting the various
body systems
• Allergy
• Recent major surgery (within 3 months)
• History of chemotherapy or radiotherapy
• Current or recent substance abuse,
including alcohol
• Smokers
• Intake of other progesterone products
was not permitted during the study
• Signed, informed consent
• Premenopausal females,
>18 to <42 years of age
• BMI ≥18 and ≤30 kg/m2
• Documented history of infertility
– Unable to conceive for ≥1 year (or 6 months
for women ≥38 years of age), or as having
bilateral tubal occlusion or absence
• Planning IVF with a fresh embryo
– Single or dual embryo transfer
• Normal transvaginal ultrasound
Inclusion criteria Exclusion criteria
BMI, body mass index; IVF, in vitro fertilization
Tournaye H, Sukhikh GT, Kahler E, Griesinger G. A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesterone
versus micronized vaginal progesterone for luteal support in in vitro fertilization. Hum Reprod 2017;1–9

EXTERNAL USE
STUDY DESIGN
53
DYD, dydrogesterone; MVP, micronized vaginal progesterone
Tournaye H, Sukhikh GT, Kahler E, Griesinger G. A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesterone
versus micronized vaginal progesterone for luteal support in in vitro fertilization. Hum Reprod 2017;1–9
Assessed for eligibility (n=1143)
Excluded (n=112)
• Screening failures (n=104)
• Terminated prematurely (n=8)
Full analysis sample (n=497)
• Excluded from analysis:
• Embryo transfer not successful (n=22)
• Did not receive allocated intervention (n=1)
Per protocol sample (n=492)
• Excluded from the full analysis sample (n=23)
• Major protocol deviations unrelated to treatment (n=5)
Lost to follow-up (n=5)
Discontinued (n=342)
Allocated to oral DYD (n=520)
• Received allocated intervention (n=519)
– Safety Sample
Lost to follow-up(n=5)
Discontinued (n=364)
Allocated to MVP (n=511)
• Received allocated intervention (n=510)
– Safety Sample
Full analysis sample (n=477)
• Embryo transfer not successful (n=33)
Per protocol sample (n=475)
• Excluded from the full analysis sample (n=34)
• Major protocol deviations unrelated to treatment (n=2)
Randomized (n=1031)

EXTERNAL USE
STUDY DESIGN AND SAMPLE SIZE
54
• An evaluation of clinical studies using oral dydrogesterone, MVP
capsules or gel for treatment in IVF predicted a ~35% pregnancy rate
at 12 weeks of gestation
• With a non-inferiority margin of 10%, it was estimated that a sample
size of 479 subjects per treatment arm would provide 90% power to
demonstrate non-inferiority, should there be no difference in
pregnancy rate at 12 weeks of gestation between the two treatment
groups
• With the addition of a dropout rate of 10%, it was estimated that
533 subjects per group would be required, or a total sample size of
1066 subjects
IVF, in vitro fertilization; MVP, micronized vaginal progesterone
Tournaye H, Sukhikh GT, Kahler E, Griesinger G. A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesterone versus micronized
vaginal progesterone for luteal support in in vitro fertilization. Hum Reprod 2017;1–9

EXTERNAL USE
DEMOGRAPHICS AND BASELINE CHARACTERISTICS:
SIMILAR BETWEEN THE GROUPS
56
BMI, body mass index; DYD, dydrogesterone; MVP, micronized vaginal progesterone; SD, standard deviation
Oral DYD
(n=497)
MVP
(n=477)
Total population
(N=974)
Mean age, years (SD) 32.5 (4.5) 32.5 (4.4) 32.5 (4.4)
Age category, n (%)a
≤35 years of age 352 (70.8) 348 (73.0) 700 (71.9)
>35 years of age 145 (29.2) 129 (27.0) 274 (28.1)
Race or ethnicity, n (%)a
Caucasian 485 (97.6) 453 (95.0) 938 (96.3)
Black or African American 9 (1.8) 14 (2.9) 23 (2.4)
Asian 4 (0.8) 9 (1.9) 13 (1.3)
Other 0 (0.0) 2 (0.4) 2 (0.2)
Mean BMI, kg/m2 (SD) 23.3 (3.1)b 23.2 (3.1)c 23.2 (3.1)d
Prior treatment, n (%)a 30 (6.0) 25 (5.2) 55 (5.6)
aPercentages are based on the number of subjects in the full analysis sample with data available. BMI values were calculated from
the following populations: bn=496; cn=476; dn=972

EXTERNAL USE
COURSE AND OUTCOMES OF
TREATMENT/PREGNANCY
57
DYD, dydrogesterone; ICSI, intracytoplasmic sperm injection; MVP, micronized vaginal progesterone
Oral DYD
(30 mg)
MVP
(600 mg)
Total
population
Number of subjects who underwent
embryo transfer, n
497 477 974
Subjects who underwent embryo transfer
after ICSI, n (%)a 368 (74.0) 338 (70.9) 706 (72.5)
Day of embryo transfer after oocyte
retrieval, n (%)a
<5 days 350 (70.4) 328 (68.8) 678 (69.6)
≥5 days 147 (29.6) 149 (31.2) 296 (30.4)
Number of embryos transferred, n (%)a
1 212 (42.7) 217 (45.5) 429 (44.1)
2 278 (55.9) 252 (52.8) 530 (54.4)
>2 7 (1.4) 8 (1.7) 15 (1.5)
Number of subjects who had at least one
newborn, n (%)a 172 (34.6) 142 (29.8) 314 (32.2)
aPercentages calculated according to the number of subjects in the full analysis sample who received embryo transfer in the
respective oral DYD and MVP groups

EXTERNAL USE
ORAL DYDROGESTERONE WAS NON-INFERIOR TO
MICRONIZED VAGINAL PROGESTERONE AT
12 WEEKS OF GESTATION
58
CI, confidence interval; DYD, dydrogesterone; FAS, full analysis sample; MVP, micronized vaginal progesterone; NNT, number needed to treat;
PPS, per protocol sample.
Pregnancy
rate
% (n/N) Difference in
pregnancy ratea
(Oral DYD– MVP)
95% CI
Oral DYD MVP
FAS
37.6
(187/497)
33.1
(158/477)
4.7 –1.2, 10.6
PPS
37.6
(185/492)
33.1
(157/475)
4.7 –1.2, 10.6
Lotus I achieved its primary objective, demonstrating non-inferiority of oral DYD versus MVP
assessed by the presence of fetal heartbeats at 12 weeks of gestation
aPrimary analysis was adjusted for country and age as pre-specified in the protocol
-15 -10 -5 0 5 10 15
Non-inferiority
margin
Favors MVP Favors oral DYD

EXTERNAL USE
OVERALL SUMMARY IN THE MATERNAL
POPULATION: ADVERSE EVENTS
59
56.0
10.8
7.1
12.4
54.0
13.3 10.6
16.0
0
20
40
60
80
100
All TEAEs At least one
serious TEAE
At least one
severe TEAE
TEAEs leading to study
discontinuation
Subjects,
%
TEAEs reported by subjects receiving oral DYD or MVP (N=1029)
Oral DYD (n=518) MVP (n=511)
Oral DYD was well tolerated, with reported TEAEs being in line with its known safety and
tolerability profile, and as expected in this patient population
Possible differences in TEAEs related to the route of administration of oral DYD versus MVP
(e.g. vaginal discharge) could not be observed due to the double-dummy study design
DYD, dydrogesterone; MVP, micronized vaginal progesterone; TEAE, treatment-emergent adverse event

LOTUS I:
SAFETY AND TOLERABILITY

EXTERNAL USE
INFANT STATUS AT END OF PREGNANCY
61
Category
Oral DYD
(n=497)
MVP
(n=477)
Total number of newborns 213 158
Male (%) 120 (56.3) 88 (55.7)
Female (%) 93 (43.7) 70 (44.3)
No abnormal findings of physical examination, n (%) 199 (93.4) 146 (92.4)
Height, cm (mean ± SD) 48.8 ± 3.9 49.4 ± 2.8
Weight, kg (mean ± SD) 2.9 ± 0.7 3.0 ± 0.6
Head circumference, cm (mean ± SD) 33.4 ± 2.4 33.8 ± 1.9
APGAR 1 minute postpartal score (mean ± SD) 8.1 ± 1.5 8.2 ± 1.5
APGAR 5 minute postpartal score (mean ± SD) 9.0 ± 1.3 9.2 ± 1.1
Infant safety data collected at delivery were similar between the two treatment groups
Status at end of pregnancy: Infant FAS
APGAR, appearance, pulse, grimace, activity, and respiration; DYD, dydrogesterone; FAS, full analysis sample; MVP, micronized vaginal progesterone;
SD, standard deviation

EXTERNAL USE
CONGENITAL, FAMILIAL, AND GENETIC
DISORDERS
62
Rates of TEAEs relating to
congenital, familial, and genetic
disorders were similar in both
groups (DYD 1.0%, MVP 1.2%)1
Findings were lower than those
in a previous study, which
reported an 8.3% birth defect
rate in assisted conception
pregnancies versus
5.8% in those not involving in
assisted conecption2
Category
Oral DYD
(n=497)
MVP
(n=477)
Congenital, familial, and genetic disorders 5 (1.0) 6 (1.2)
Congenital hand malformation 0 (0.0) 1 (0.2)
Congenital hydrocephalus 0 (0.0) 1 (0.2)
Congenital tricuspid valve atresia 0 (0.0) 1 (0.2)
Interruption of aortic arch 1 (0.2) 0 (0.0)
Kidney malformation 0 (0.0) 1 (0.2)
Pulmonary artery atresia 0 (0.0) 1 (0.2)
Spina bifida 0 (0.0) 1 (0.2)
Talipes 1 (0.2) 0 (0.0)
Tracheo-esophageal fistula 1 (0.5) 0 (0.0)
Univentricular heart 0 (0.0) 1 (0.2)
Ventricular septal defect 0 (0.0) 0 (0.0)
Trisomy 21 1 (0.2) 2 (0.4)
Trisomy 13 0 (0.0) 1 (0.2)
Turner syndrome 1 (0.2) 0 (0.0)
DYD, dydrogesterone; MVP, micronized vaginal progesterone; TEAE, treatment-emergent adverse event
1. Tournaye H, Sukhikh GT, Kahler E, Griesinger G. A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesterone versus micronized
vaginal progesterone for luteal support in in vitro fertilization. Hum Reprod 2017;1–9;
2. Davies MJ, Moore VM, Willson KJ, et al. Reproductive technologies and the risk of birth defects. N Engl J Med 2012;366(19):1803–1813

EXTERNAL USE
CONCLUSIONS
63
Primary objective
Lotus I demonstrated that oral DYD
was non-inferior to MVP for the
presence of fetal heartbeats at
12 weeks of gestation
Safety and tolerability
Secondary objectives
Rates of live births and newborn
assessments were similar between
the two treatment groups
Oral DYD treatment had a similar
safety profile to MVP, with no new
safety concerns identified in this study
Implications
Oral DYD may replace MVP as the
standard of care for luteal support in
IVF, owing to the ease of oral
administration
DYD, dydrogesterone; IVF, in vitro fertilization; MVP, micronized vaginal progesterone

EXTERNAL USE
LUTEAL PHASE SUPPORT IN WOMEN
UNDERGOING IUI
65
LOTUS II STUDY:
A RANDOMIZED, OPEN-LABEL, TWO-ARM, MULTICENTER
STUDY COMPARING THE EFFICACY, SAFETY AND
TOLERABILITY OF ORAL DYDROGESTERONE 30MG DAILY
V/s CRINONE 8% INTRAVAGINAL PROGESTERONE GEL
90MG DAILY FOR LUTEAL SUPPORT IN IN-VITRO
FERTILIZATION

EXTERNAL USE
STUDY DESIGN
67
Phase III
Study Design Dydrogesterone vs. Micronised Progesterone
Open label, 2-arms, randomized
Primary Objective Non-inferiority
Primary Endpoint Presence of fetal heart beats at 12 weeks’ gestation
(10 weeks´ pregnancy) determined by transvaginal
ultrasound
Patients Included Women undergoing IVF
Treatment Duration 12 weeks’ gestation (10 weeks´ pregnancy)
Arms/Daily Dose Dydrogesterone 10 mg tid versus Micronized
Progesterone 8% intravaginal gel once
Sample Size 1066
Observation/Follow-up
Period
30 days after delivery

EXTERNAL USE
EFFICACY OBJECTIVES:
68
• Primary objective is to demonstrate non-inferiority of
Dydrogesterone 30 mg daily versus Crinone 8% intravaginal gel once
daily
• Primary efficacy parameter is the pregnancy rate defined as:
• Presence of gestational sac(s) with viable fetal heart beats at 12 weeks`
gestation by transvaginal ultrasound
• Secondary parameters - positive pregnancy test on Day 14 after
embryo transfer and incidence of live births and healthy newborns

EXTERNAL USE
MAJOR INCLUSION & EXCLUSION CRITERIA
69
Inclusion Criteria
• Signed, informed consent
• Premenopausal females, non-pregnant, non-
smokers , aged between >18 to <42 years of age,
BMI ≥18 and ≤30 kg/m2
• Documented history of infertility
•Unable to conceive for ≥1 year (or 6 months for women
≥38 years of age), or as having bilateral tubal occlusion
or absence
• Normal transvaginal ultrasound at screening
• Early follicular phase (Day 2-4) FSH (Follicle
stimulating hormone) less than or equal to 15 IU/L
and estradiol (E2)within normal limits
• LH (luteinizing hormone), PRL (prolactin), T
(testosterone) and TSH, within the normal limits for
the clinical laboratory, or considered not clinically
significant by the Investigator within 6 months prior
to screening
• Single or dual embryo transfer
• Clinical indicated protocol for induction of IVF with
fresh embryo
Exclusion Criteria
• Subjects with >3 unsuccessful IVF attempts
• History of recurrent pregnancy loss (≥3
miscarriages)
• Evidence of diseases affecting the various body
systems that could limit participation or completion
of the study
• Known allergies
• Acute urogenital disease
• Recent major surgery (within 3 months)
• History of chemotherapy
• Current or recent substance abuse, including alcohol
• Smokers
• Intake of other progesterone products was not
permitted during the study
• Contraindication to pregnancy
• Participation in any other clinical trial within 30
days
• Mental disability or any other lack of fitness

EXTERNAL USE
STUDY SCHEDULE
70
Main inclusion/exclusion criteria:
• >18 to <42 years of age
• BMI ≥18 kg/m2 and ≤30
kg/m2
• NOT: >3 unsuccessful IVF
attempts
• NOT: ≥3 miscarriages
aDay 15 after embryo transfer
hCG, human chorionic gonadotropin; MVP, micronized vaginal progesterone; TID , three times daily
Griesinger G, Blockeel C, Sukhikh G, et al. Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in in vitro fertilization (LOTUS II): a
randomized, open-label, multicenter,
phase III, non-inferiority study. In preparation
Day
−40
Day 1
Treatment start
Days 3–6
Embryo transfer
Post-treatment
safety
surveillance
(Day 101 and
Day 157)
Follow-up
30 days
after
delivery
Oral dydrogesterone 30 mg (10mg TID) (n=520)
8% MVP gel 90 mg daily (n=514)
Day −1
Days 17–20ª
Week 4
Day 43
Week 8
Day 71
Week 12
Oocyte
retrieval
Pregnancy test
(serum β hCG and
urine strip test)
Transvaginal
ultrasound
Day of treatment
Week of gestation
Newborn
assessments
Screening
and
enrollment

LOTUS II: EFFICACY
RESULTS AND SAFETY

EXTERNAL USE
PRIMARY EFFICACY VARIABLE: PREGNANCY
RATES AT 12 WEEKS OF GESTATION
72
CI, confidence interval; DYD, dydrogesterone; FAS, full analysis sample; MVP, micronized vaginal progesterone; NNT, number needed to treat;
PPS, per-protocol sample
Griesinger G, Blockeel C, Sukhikh G, et al. Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in in
vitro fertilization (LOTUS II): a randomized, open-label, multicenter,
Pregnancy
rate
% (n/N) Adjusted difference,%
(Oral DYD–MVPgel)
Adjusted
95% CI
Oral DYD MVP gel
FAS
38.7
(191/494)
35.0
(171/489)
3.7 −2.3, 9.7
PPS
36.7
(180/490)
34.7
(167/481)
2.0 −4.0, 8.0
Lotus II achieved its primary objective, demonstrating non-inferiority of oral DYD versus MVP gel
assessed by the presence of fetal heartbeats at 12 weeks of gestation
In the FAS, the NNT with oral DYD to obtain a benefit versus MVP gel would be
27 (95% CI for absolute risk reduction of NNT [benefit] 10.3 to NNT [harm] 43.5)
Non-inferiority
margin
Favors MVP gel Favors oral DYD
-15 -10 -5 0 5 10 15

EXTERNAL USE
LOTUS II: OVERALL PREGNANCY STATUS
POST-TREATMENT
73
CI, confidence interval; DYD, dydrogesterone; FAS, full analysis sample; MVP, micronized vaginal progesterone; PPS, per-protocol sample
vitro fertilization (LOTUS II): a randomized, open-label, multicenter,
Favors MVP gel Favors oral DYD
Non-inferiority
margin
Outcome
% (n/N) Adjusted difference, %
(Oral DYD–MVP gel)
Adjusted 95%
CI
Oral DYD MVP gel
Pregnancy rate
FAS
PPS
47.4
(234/494)
46.9
(230/490)
43.8
(214/489)
44.1
(212/481)
3.6
2.9
−2.6, 9.8
−3.4, 9.1
FAS
PPS
40.7
(201/494)
39.0
(191/490)
36.8
(180/489)
36.6
(176/481)
3.9
2.4
−2.2, 9.9
−3.7, 8.5
FAS
PPS
38.7
(191/494)
36.7
(180/490)
35.0
(171/489)
34.7
(167/481)
3.7
2.0
−2.3, 9.7
−4.0, 8.0
Live birth rate
FAS
PPS
34.4
(170/494)
34.3
(168/490)
32.5
(159/489)
32.9
(158/481)
1.9
1.5
−4.0, 7.8
−4.5, 7.4
-15 -10 -5 0 5 10 15
Adjusted difference, % (95% CI)

EXTERNAL USE
LOTUS II – CONCLUSIONS
74
Primary objective
Lotus II demonstrated that oral DYD
was non-inferior to MVP gel for the
presence of fetal heartbeats at
Safety and tolerability
Secondary objectives
Rates of positive pregnancy test,
clinical pregnancy, live births and
newborn assessments were similar
between the two treatment groups
Oral DYD treatment had a similar
safety profile to MVP gel, with no new
safety concerns identified in this
study
Implications
Oral DYD may replace MVP as the
standard of care for luteal support in
IVF, owing to the ease of oral
administration
DYD, dydrogesterone; MVP, micronized vaginal progesterone;
vitro fertilization (LOTUS II): a randomized, open-label, multicenter, phase III, non-inferiority study. In preparation

EXTERNAL USE
2013 RANZCOG - AUSTRALIAN AND NEW
ZEALAND GUIDELINES
75
Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) 2013.
http://www.ranzcog.edu.au/doc/progesterone-support-of-the-luteal-phase-and-early-pregnancy.html
Recommendation
Grade and
Reference
For luteal support in ART, exogenous progesterone is
associated with significantly higher pregnancy rate than
placebo or no treatment with better results obtained with
synthetic progesterone (dydrogesterone) than micronized
progesterone.
Currently, synthetic progesterone (dydrogesterone) is the
best option for luteal phase support in women undergoing
ART treatment.
Consensus-
based
recommendati
on
Reference: van
der Linden M.
Cochrane
Database Syst
Rev. 2011

EXTERNAL USE
RISK FACTOR - POLYCYSTIC OVARY
SYNDROME (PCOS)
78
Adapted from Gervásio CG et al. ISRM Obstet Gynecol 2014:818010.
Prevalence: 5-10% of women of reproductive age
Increased ovarian androgen
production
Impaired follicular
development
Chronic anovulation
Infertility

EXTERNAL USE
RISK FACTOR - ENDOMETRIOSIS
79
Adapted from Buletti C et al. J Assist Reprod Genet 2010; 27:441-447.
Prevalence
General female population 6-10%
Among women with pain, infertility or
both
35-50%
Among infertile women 25-50%
30-50% of women with endometriosis are
infertile
Severity depends on stage and location

EXTERNAL USE
MISDIAGNOSIS
80
• The diagnosis of Unexplained Infertility is highly subjective.
• It is dependent on which diagnostic tests have been performed (or have been
omitted) and at what level of quality.
• Most frequently misdiagnosed as Unexplained Infertility:
Endometriosis
Premature ovarian ageing
Tubal infertility (especially distal & peritubal disease)
Immunological infertility
Gleicher N, Barad D. Unexplained infertility: does it really exist? Hum Reprod. 2006 Aug;21(8):1951-5. doi: 10.1093/humrep/del135. Epub 2006 May 9. PMID: 16684842.

EXTERNAL USE
INDICATIONS FOR DONOR SPERM IUI
81
• Azoospermia (where ICSI is not an option)
• Severely subnormal semen parameters (ICSI not an option)
• Persistent failure of ICSI
• Rh Isoimmunization
• Hereditary disease in the male partners

EXTERNAL USE
PRE-IMPLANTATION GENETIC TESTING (PGT)
82
Preimplantation Genetic Testing (PGT)
– Embryos are tested for abnormal chromosomes before transfer
– Done in a lab, using in vitro fertilization
– One or more cells from each embryo is sent for genetic testing
– Genetically healthy embryos are transferred to the uterus
https://www.asrm.org/FACTSHEET_Preimplantation_genetic_testing.

Unexplained Infertility by Dr. Nidhi Sharma | Jindal IVF Chandigarh

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