Unexplained Infertility by Dr. Nidhi Sharma | Jindal IVF Chandigarh 
                     Unexplained Infertility
DR N IDHI  SHARMA
SEN IOR  CONSULTAN T OBGY A ND IN FERTIL ITY  SPEC IALIST
J INDAL IVF  CENTRE,  CHAN DIGARH
INFERTILITY - DEFINITION
Failure to achieve a successful pregnancy after 12 months 
or more of regular unprotected intercourse
2008 Earlier evaluation and treatment … is warranted after 
American Society 6 months for women over age 35 years.
for Reproductive 
Medicine
A disease of the reproductive system defined by the 
failure to achieve a clinical pregnancy after 12 months 
2009 or more of regular unprotected intercourse.
Int. Com. for Monitoring 
Assisted Reproductive 
Technology and WHO
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 2
INFERTILE COUPLES – IT TAKES TWO TO 
TANGO
• 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 3
FEMALE INFERTILITY – PREVALENCE OF 
SEEKING A CHILD
Primary infertility
3 unsuccessful IVF attempts
• Premenopausal females, • History of recurrent pregnancy loss 
18 to 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
BMI, body mass index; DYD, dydrogesterone; MVP, micronized vaginal progesterone; SD, standard deviation
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 56
COURSE AND OUTCOMES OF 
TREATMENT/PREGNANCY
Oral DYD MVP Total 
(30 mg) (600 mg) population
Number of subjects who underwent 497 477 974
embryo transfer, n
Subjects who underwent embryo transfer 
a 368 (74.0) 338 (70.9) 706 (72.5)after ICSI, n (%)
Day of embryo transfer after oocyte 
retrieval, n (%)a
2 7 (1.4) 8 (1.7) 15 (1.5)
Number of subjects who had at least one 
172 (34.6) 142 (29.8) 314 (32.2)
newborn, n (%)a
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 
DYD, dydrogesterone; ICSI, intracytoplasmic sperm injection; 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 57
ORAL DYDROGESTERONE WAS NON-INFERIOR TO 
MICRONIZED VAGINAL PROGESTERONE AT 
12 WEEKS OF GESTATION
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
% (n/N)
Difference in 
Pregnancy 
rate pregnancy rate
a 95% CI Non-inferiority 
Oral DYD MVP (Oral DYD– MVP) margin
37.6 33.1 
FAS (187/497) (158/477) 4.7 –1.2, 10.6
PPS 37.6 33.1 4.7 –1.2, 10.6
(185/492) (157/475)
-15 -10 -5 0 5 10 15
Favors MVP Favors oral DYD
aPrimary analysis was adjusted for country and age as pre-specified in the protocol
CI, confidence interval; DYD, dydrogesterone; FAS, full analysis sample; MVP, micronized vaginal progesterone; NNT, number needed to treat; 
PPS, per protocol sample.
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 58
OVERALL SUMMARY IN THE MATERNAL 
POPULATION: ADVERSE EVENTS
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
100
TEAEs reported by subjects receiving oral DYD or MVP (N=1029)
80
60 56 54
40
20
10.8 13.3
16
7.1 10.6
12.4
0
All TEAEs At least one At least one TEAEs leading to study discontinuation
serious TEAE severe TEAE
Oral DYD (n=518) MVP (n=511)
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 
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 59
Subjects, %
LOTUS I:
SAFETY AND TOLERABILITY
INFANT STATUS AT END OF PREGNANCY
Infant safety data collected at delivery were similar between the two treatment groups
Status at end of pregnancy: Infant FAS
MVP
Category Oral DYD (n=497) (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
APGAR, appearance, pulse, grimace, activity, and respiration; DYD, dydrogesterone; FAS, full analysis sample; MVP, micronized vaginal progesterone; 
SD, standard deviation 
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 61
CONGENITAL, FAMILIAL, AND GENETIC 
DISORDERS Oral DYD MVP
Category (n=497) (n=477)
Rates of TEAEs relating to 
Congenital, familial, and genetic disorders 5 (1.0) 6 (1.2)
congenital, familial, and genetic 
disorders were similar in both Congenital hand malformation 0 (0.0) 1 (0.2)
groups (DYD 1.0%, MVP 1.2%)1 Congenital hydrocephalus 0 (0.0) 1 (0.2)
Congenital tricuspid valve atresia 0 (0.0) 1 (0.2)
Findings were lower than those 
in a previous study, which Interruption of aortic arch 1 (0.2) 0 (0.0)
reported an 8.3% birth defect Kidney malformation 0 (0.0) 1 (0.2)
rate in assisted conception 
Pulmonary artery atresia 0 (0.0) 1 (0.2)
pregnancies versus 
5.8% in those not involving in Spina bifida 0 (0.0) 1 (0.2)
assisted conecption2 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 62
CONCLUSIONS
Primary objective Secondary objectives
Lotus I demonstrated that oral DYD Rates of live births and newborn 
was non-inferior to MVP for the assessments were similar between 
presence of fetal heartbeats at the two treatment groups
12 weeks of gestation
Safety and tolerability Implications
Oral DYD treatment had a similar Oral DYD may replace MVP as the 
safety profile to MVP, with no new standard of care for luteal support in 
safety concerns identified in this study IVF, owing to the ease of oral 
administration
DYD, dydrogesterone; 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 63
LOTUS II
LUTEAL PHASE SUPPORT IN WOMEN 
UNDERGOING IUI
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 65
LOTUS II - STUDY 
DESIGN 
STUDY DESIGN
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 30 days after delivery
Period
EXTERNAL USE 67
EFFICACY OBJECTIVES: 
• 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 68
MAJOR INCLUSION & EXCLUSION CRITERIA
Inclusion Criteria Exclusion Criteria 
• Signed, informed consent • Subjects with >3 unsuccessful IVF attempts
• Premenopausal females, non-pregnant, non- • History of recurrent pregnancy loss (≥3 
smokers , aged between >18 to 18 to 3 unsuccessful IVF 
Day of treatment attempts
Week of gestation
• NOT: ≥3 miscarriages
Days 3–6 Days 17–20ª Day 43 Day 71
Embryo transfer Week 4 Week 8 Week 12
Day 1
Treatment start
Day 
−40 Day −1
Oral dydrogesterone 30 mg (10mg TID) (n=520) Post-treatment Follow-up
Screening safety
30 days 
and surveillance 
after 
enrollment (Day 101 and 
delivery
8% MVP gel 90 mg daily (n=514) Day 157)
Pregnancy test
Oocyte Transvaginal Newborn 
(serum β hCG and 
retrieval ultrasound assessments
urine strip test)
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 
EXTERNAL USE 70
LOTUS II: EFFICACY 
RESULTS AND SAFETY
PRIMARY EFFICACY VARIABLE: PREGNANCY 
RATES AT 12 WEEKS OF GESTATION
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
% (n/N)
Pregnancy Adjusted difference, % Adjusted Non-inferiority 
rate Oral DYD MVP gel (Oral DYD–MVP gel) 95% CI margin
FAS 38.7 35.0 3.7 −2.3, 9.7
(191/494) (171/489)
PPS 36.7 34.7 2.0 −4.0, 8.0
(180/490) (167/481)
-15 -10 -5 0 5 10 15
Favors MVP gel Favors oral DYD
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)
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, 
phase III, non-inferiority study. In preparation 
EXTERNAL USE 72
LOTUS II: OVERALL PREGNANCY STATUS 
POST-TREATMENT
% (n/N) Adjusted difference, % Adjusted 95% 
Outcome
Oral DYD MVP gel (Oral DYD–MVP gel) CI Non-inferiority 
Pregnancy rate margin
4 weeks of gestation
FAS 47.4 43.8 3.6 −2.6, 9.8
(234/494) (214/489)
PPS 46.9 44.1 2.9 −3.4, 9.1
(230/490) (212/481)
8 weeks of gestation
FAS 40.7 36.8 3.9 −2.2, 9.9
(201/494) (180/489)
PPS 39.0 36.6 2.4 −3.7, 8.5
(191/490) (176/481)
12 weeks of gestation
FAS 38.7 35.0 3.7 −2.3, 9.7
(191/494) (171/489)
PPS 36.7 34.7 2.0 −4.0, 8.0
(180/490) (167/481)
Live birth rate
FAS 34.4 32.5 1.9 −4.0, 7.8
(170/494) (159/489)
PPS 34.3 32.9 1.5 −4.5, 7.4
(168/490) (158/481)
-15 -10 -5 0 5 10 15
Adjusted difference, % (95% CI)
Favors MVP gel Favors oral DYD
CI, confidence interval; DYD, dydrogesterone; FAS, full analysis sample; MVP, micronized vaginal progesterone; 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, 
phase III, non-inferiority study. In preparation  
EXTERNAL USE 73
LOTUS II – CONCLUSIONS
Primary objective Secondary objectives
Lotus II demonstrated that oral DYD Rates of positive pregnancy test, 
was non-inferior to MVP gel for the clinical pregnancy, live births and 
presence of fetal heartbeats at newborn assessments were similar 
12 weeks of gestation between the two treatment groups
Safety and tolerability Implications
Oral DYD treatment had a similar Oral DYD may replace MVP as the 
safety profile to MVP gel, with no new standard of care for luteal support in 
safety concerns identified in this study IVF, owing to the ease of oral 
administration
DYD, dydrogesterone; MVP, micronized vaginal progesterone;
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 
EXTERNAL USE 74
2013 RANZCOG  - AUSTRALIAN AND NEW 
ZEALAND GUIDELINES
Grade and 
Recommendation  Reference
For luteal support in ART, exogenous progesterone is 
associated with significantly higher pregnancy rate than Consensus-
placebo or no treatment with better results obtained with based 
recommendati
synthetic progesterone (dydrogesterone) than micronized 
on 
progesterone. 
Reference: van 
der Linden M. 
Currently, synthetic progesterone (dydrogesterone) is the Cochrane 
best option for luteal phase support in women undergoing Database Syst 
ART treatment. Rev. 2011
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
EXTERNAL USE 75
              ESHRE 2019 
EXTERNAL USE 76
THANK YOU
RISK FACTOR - POLYCYSTIC OVARY 
SYNDROME (PCOS)
Increased ovarian androgen Impaired follicular 
production development
Chronic anovulation
IInfferttiilliitty
Prevallence::  5-10%  off  women  off  reproducttiive  age
Adapted from Gervásio CG et al. ISRM Obstet Gynecol 2014:818010. 
EXTERNAL USE 78
RISK FACTOR - ENDOMETRIOSIS
Prevalence
General female population 6-10%
Among women with pain, infertility or 35-50%
both
Among infertile women 25-50%
30-50% of women with endometriosis are 
infertile
Severity depends on stage and location
Adapted from Buletti C et al. J Assist Reprod Genet 2010; 27:441-447.
EXTERNAL USE 79
MISDIAGNOSIS
• 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 Tubal infertility (especially distal & peritubal disease)
Premature ovarian ageing 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 80
INDICATIONS FOR DONOR SPERM IUI
• 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 81
PRE-IMPLANTATION GENETIC TESTING (PGT)
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.
EXTERNAL USE 82