unexplained infertility BY DR REJI MOHAN.pptx

Unexplained infertility-an overview
DR REJI MOHAN, MD DNB , short term FELLOW RM(university of ghent , Belgium)
ASSISTANT PROFESSOR
DEPT. OF REPRODUCTIVE MEDICINE AND SURGERY
SREE AVITTOM THIRUNAAL HOSPITAL
GOVT MEDICAL COLLEGE
THIRUVANANTHAPURAM
12/25/2023 drrrejimohan@gmail.com 1

Outline
• Introduction
• Aetiology and pathophysiology
• Diagnosis and Evaluation
• Treatment options
• Conclusion
So many things are unexplained

We were diagnosed with 'unexplained infertility,' which sounds good in one
respect, but on the other hand you almost want something wrong so there
is a problem so you can fix it.
- CINDY MARGOLIS
• Doubts
• Frustration
• Hopelessness
• For us this is one of the most fascinating challenges in Reproductive
medicine
• Couples with unexplained infertility range from 15% to 30% and will increase with increasing age
• Definition
• Couples with unexplained infertility, according to the International Committee for
Monitoring Assisted Reproductive Technologies definition, have ‘‘apparently normal
ovarian function, normal fallopian tubes, uterus, cervix and pelvis, adequate coital
frequency, apparently normal testicular function, genitourinary anatomy and a
normal ejaculate’’

Prognosis
• Maternal age is the most important prognostic factor
• Duration of infertility -The success rate of interventions decreases with
increase in the duration of infertility despite regular sexual intercourse
• In the general population, of couples attempting conception, 84% will
conceive after 1 year and 92% will conceive after 2 years
• Couples with UI might be reassured that even after one year of unsuccessful
attempts 50% will conceive in the following 12 months and another 12% in
the year after.

Fecundity and prognosis
• Average monthly fecundity is <35 years have 20%
• After 35years the fecundity reduces and reaches almost zero by 40 years
• For each year of females age the conception rate is decreased by about 9%
after 30 years
• Good prognosis –
 Less than two years
 Partners age is less than 35
 Patient has conceived earlier.
• (Bhattacharya et al., 2008; Collins et al., 1995)
• Worst prognosis - duration of infertility exceeds 3 years and the female partner is >35 years of age
• (Collins et al., 1995)

Aetiology
• Most diagnostic tests in the assessment of infertility do not
detect abnormalities that may be rare or subtle.
• Advanced tests may detect these etiologies and narrow
down the cause of infertility

Aetiology
• Male
• Can be idiopathic or unexplained
• Defective spermatogenesis
• Genetic abnormalities
• Functional integrity problems
• Defective sperm fertilisation potential
• Immunological
• ROS &DNA fragmentation were
significantly higher in men with UE
• FEMALE
• Ovarian: defective folliculogenesis,
genetic problems, ovulatory
dysfunction
• Tubal: defective OPU, disturbed
transportation
• Toxic fluids, peritubular adhesions.
• Uterine: Altered ER, Altered uterine
peristalsis
• Vaginal: raised pH, Altered flora…
• Cervical : cervical mucous
abnormalities, immunological,
functional efficiency

Endocrine abnormalities
Oxidative stress
Environmental contaminants
Minimal or mild endometriosis

Possibilities
In follicle
development
Ovulation
The luteal
phase
Sperm concentration and motility
Subtle
cervical
factors
Problems
with sperm
and egg
transport or
interaction
Embryo
implantation

Observation
• Couples with unexplained infertility who are treated with in vitro fertilization (IVF)
• -demonstrate reduced oocyte fertilization and embryo cleavage rates (52%)compared with
couples in whom tubal factor is the cause of the infertility(60%)
• -a higher rate of complete fertilization failure when treated with IVF than couples with tubal
factor infertility (6 versus 3 percent).
• This suggest that couples with unexplained infertility probably have subtle functional
abnormalities in oocyte and/or sperm function.
• Defective endometrial receptivity may account for some cases of unexplained infertility and
recurrent pregnancy loss
• IVF can be considered as a diagnostic procedure

• Many cases of unexplained infertility are probably caused by the
presence of multiple factors each of which on their own do not
significantly reduce fertility, but can reduce the pregnancy rate when
combined
Better understanding of mechanisms underlying UI could lead to less invasive
and less expensive treatment strategies

Evaluation of a Couple with Unexplained
Infertility
• History and examination of both the partners
• Standard evaluation

The standard evaluation Tests of ovulatory function:
Husband’s semen analysis :twice
Tests to assess tubal patency
(HSG/laparoscopy/saline infusion
sonography)
Ultrasound of the pelvis
Investigations should include a basic
workup to assess the following
ASRM recommends laparoscopy in women with UI,those with signs and symptoms of
endometriosis or suspected tubal adhesions but still can miss tubal dysfunction spasm or
proximal tubal occlusion

UI is a diagnosis of exclusion and does not have a definite
pathophysiologic basis.
Multifactorial
Impossible to find out all the etiologies
Gleicher and Barad suggested substitution of term UI to undiagnosed
One should not offer experimental tests or unnecessary additional
tests
Remember subfertility may not be a permanent disability

APPROACH-Basic principles
• The management of couples with unexplained infertility should
balance the efficacy, cost, safety, and risks of various treatment
alternatives.
• Treatment is empirical as it is not meant for any particular defect
• The approach to treatment should be individualized for each couple
• In general, if a specific fertility treatment does not result in pregnancy
after three cycles, alternative treatments should be considered

Management Options for Unexplained
Infertility
• Clinical guidelines for the management of unexplained infertility
recommend starting with the least invasive intervention before
moving on to those that are more invasive
• (ASRM 2006; NICE 2013; NVOG 2010)
• Effective fertility treatment for unexplained infertility must
demonstrate an increase in the pregnancy rate above the baseline
fecundability
• No single algorithm
• Extensive counselling of the couples

Patient controlled approaches-Lifestyle changes
• Cigarette smoking, abnormal body mass index, and excessive caffeine consumption
reduce fertility in the female partner and possibly the male partner.
• Stop smoking
• Try to achieve a body mass index between 20 and 27 kg/m2
• Reduce caffeine intake to no more than approximately 250 mg daily (two cups of coffee)
• Reduce alcohol intake to no more than four standardized drinks per week .
• These changes may be useful for enhancing both natural and assisted conception .
• Couple centered approach

Management Options for Unexplained
Infertility
The options are as follows:
Expectant management(TIC)
Ovarian stimulation(CC,Letz,Gonadotropins)
Intrauterine insemination (IUI) with or without OS
In vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI)
Most successful and most expensive

Expectant Management
Plays an important role in limited resource settings, especially if the woman is
relatively young (around 25 years) and the period of infertility is short
It is often the first line of treatment
The average cycle fecundity of 1.3% to 4.1% has been reported with expectant
management
The couple is advised to follow up regular intercourse during the fertile period
Couples have a good chance of achieving pregnancy without treatment.
The age of the female partner , duration of infertility and proven prior fertility
influences the pregnancy rate associated with expectant management
Women with unexplained infertility older than 37 years of age have a pregnancy
rate of less than 1 percent per cycle with expectant management

TEM –Hunault model
Identify couples that are eligible for TEM (Tailored expectant management)
A prognostic model of Hunault-age, duration,type, and quality of semen
TEM advises on fertile period, optimal coital frequency, and healthy lifestyle
Expectant management may be an option for a couple with unexplained
infertility in whom the female partner is less than 32 years of age and there
is no immediate concern about oocyte depletion.
In women over 37 years of age, inevitably causes ovarian aging and
depletion to become a major component of the fertility problem and
expectant management should not be an option.

Ovarian stimulation
• Subtle defects in ovulation can be overcome
• Increases the number of oocytes available and change in endometrial
receptivity
• Anti-oestrogens (e.g. clomiphene), gonadotropins (e.g. urinary or
recombinant follicle-stimulating hormone), and aromatase inhibitors
(e.g. letrozole) are the most commonly used medications for OS.

Clomiphene Citrate
• Very commonly used drug for ovulation induction
• Its role in unexplained infertility is debatable.
• CC use is best paired with IUI in patients with unexplained infertility.
• The main complication of clomiphene is an increase in the incidence of multiple gestation.
• The combination of CC plus IUI may simultaneously treat mild abnormalities of ovulation,
oocyte function, and sperm function.
• CC/IUI is generally the first line treatment for unexplained infertility because of its good
clinical pregnancy rate, relatively low rate of multiple gestations, oral route of intake, lack of
need for monitoring, and low cost

Evidence
• In trial of 900 women with unexplained infertility randomly assigned to treatment with CC, letrozole, or
gonadotropin (all combined with IUI), the clinical pregnancy rates were 28 (CC), 22 (letrozole), and 36
(gonadotropin) percent . However, the rates of multiple gestation were lowest for the women treated
with CC/IUI (9 percent) compared with letrozole (13 percent) or gonadotropin (32 percent)
• Diamond MP, Legro RS, Coutifaris C, et al. Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility. N Engl J Med 2015; 373:1230.
• According to ASRM cc is associated with a small but significant treatment effect,one additional
pregnancy with 40 cycles of clomiphene compared to no treatment.
• A Cochrane review including 1159 patients and 7 trials has shown that there is no evidence of
clomiphene citrate being more effective than no treatment or placebo.
• Recommendation is not to use clomiphene in unexplained infertility
• In limited resources, empirical treatment with clomiphene citrate starting with 50 mg up to a
maximum of 250 mg can be used for 3–6 cycles, especially in younger women.
• The aim should be mono follicular growth to avoid complications such as ovarian hyperstimulation and
multiple gestations.

• In comparative treatment trials, clomiphene was not as effective as gonadotropin injections.
• Typically three to four treatment cycles before moving on to another modality.
• Age should be taken into account; multiple treatment cycles are not beneficial in older women.
• One study showed that on a per patient treated basis, cumulative pregnancy rates by age were
24.2 percent under age 35, 18.5 percent ages 35 to 37, 15.1 percent ages 38 to 40, 7.4 percent
ages 41 to 42, and 1.8 percent age above 42 (one pregnancy in 55 patients) .
• In this study, there were no pregnancies beyond the fourth cycle in women age 41 and older.

Aromatase inhibitors plus IUI
• Ovarian stimulation with aromatase inhibitors (AIs) plus IUI may result in pregnancy for women
with unexplained infertility who do not respond to CC plus IUI and who cannot or choose not to
use IVF or gonadotropin therapy.
• AIs have similar clinical pregnancy, multiple gestation, and live birth rates compared with CC and
they are easier to use (oral dosing, no monitoring required) and less expensive compared with
injectable gonadotropin therapy.
• AIs are associated with a lower clinical pregnancy rate compared with gonadotropin treatment,
AIs are also associated with a lower rate of multiple gestations, including a much lower rate of
triplet pregnancy.
• When other treatment options do not result in pregnancy, AI treatment is a reasonable option

• A trial of 900 women, 18 to 40 years of age with unexplained infertility, who were randomly
assigned to receive the AI letrozole, CC, or gonadotropin for ovulation induction in addition to
timed IUI .
• The overall LBR were 19 % for the letrozole group, 23 % for the CC group, and 32 percent for the
gonadotropin group.
• Multiple gestations occurred in 13 percent of the gonadotropin group, 1 percent of the CC group,
and 3 percent of the letrozole group.
• For women receiving gonadotropin treatment, approximately 30 percent of the multiple
pregnancies were triplet pregnancies. In contrast, the women receiving letrozole and CC who
conceived multiple gestations had only twin pregnancies; no triplet pregnancies occurred.
• Diamond MP, Legro RS, Coutifaris C, et al. Letrozole, Gonadotropin, or Clomiphene for
Unexplained Infertility. N Engl J Med 2015; 373:1230.

Gonadotropins
• Along with IUI and oral agents
• Gn and IUI may double the pregnancy rate at the cost of multiple pregnancy rates
• Disadvantage is cost, OHSS, overresponse, and multiple pregnancies
• Gn therapy is more effective than CC or Letrozole and when both are combined
with IUI,their cumulative effect increases.
• A recent SR by Gunn and Bates (2016)concluded CC is more effective than LETZ
but Gns have a better response than both CC and LETZ

Intrauterine Insemination
• The rationale behind doing IUI in unexplained infertility is that it increases the gamete density and brings
together the gametes into close proximity
• Superovulation IUI is advised in which ovarian stimulation is done with clomiphene, gonadotropin, or in
combination to achieve more than one follicle development.
• A recent Cochrane review published in 2012 suggests that IUI in stimulated cycles
is better than IUI in natural cycles

• In a meta-analysis of eight trials comparing gonadotropins versus oral agents with IUI for patients
with unexplained infertility, gonadotropin use did not result in improved live birth rates
• To gain additional live births, high doses of gonadotropins with more relaxed cancellation
protocols were required, which resulted in a higher risk of multiple gestation.
• While the lower gonadotropin dose was no better than the oral agents, with higher doses, 13
cycles were needed to treat to exceed the oral medications, but only 7 were needed to harm
patients with multiple gestations.
• The data do not support the use of gonadotropins with IUI in patients with unexplained
infertility.
• Zolton JR, Lindner PG, Terry N, et al. Gonadotropins versus oral
ovarian stimulation agents for unexplained infertility: a systematic
review and meta-analysis. Fertil Steril 2020; 113:417.

Intrauterine Insemination
• Success rate In a meta-analysis by van Rumste et al the pregnancy rate was 8.4% for
monofollicular growth and 15% for multi follicular growth
• A study published by Kamath et al has shown pregnancy rates of 11.3% with stimulated IUI
cycles in patients with unexplained infertility.
• 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)
• Pregnancy rates with IUI are higher with a higher follicular number but this carries a risk of
higher-order pregnancy (more than 2). 10 times more
• A disadvantage of superovulation IUI is that it is often difficult to control the number of
follicles.
• It will be advisable to aim for 1–2 follicles and keep a low threshold for cancellation when
superovulation IUI is being offered in low-resource setting.
• Strict cancellation policy
• Ideally after 3 to 4 attempts of IUI and OI one must move to IVF

In Vitro Fertilization/Intracytoplasmic Sperm
Injection
• IVF is an effective and expensive method of treatment for unexplained infertility
• IVF is the intervention that results in the highest per cycle pregnancy rate in the
shortest time interval.
• It is also the most costly intervention and has a high rate of high order multiple
pregnancy, unless single embryo transfer is performed
•
• Success rate The ASRM reports a pregnancy rate of 30.4% with IVF.
• A recent Cochrane review has shown that IVF is associated with higher live birth rates
than expectant management (45.8% vs. 3.7%) and unstimulated IUI.
• Multiple pregnancy rates are lower with IVF because of greater control over the number
of follicles being fertilized when compared to IUI.
• IVF must be considered in a woman if age >35 years or with prolonged duration of
infertility or if the cycles have undergone 3–4 cycles of IUI without conception

• IVF other than treatment purpose we can learn about the fertilisation process
• Decreased fert,cleavage rate and fert failure seen in couples with UI
• ICSI can be offered after one failed cycle
• Two landmark trials in UI
• 2010 FASTT trial :less than 40 years CC/IUI,Gn/IUI and IVF was compared.
• Fast track approach to IVF lead to lesser time to conception,lesser no of cycles
and cost benefit
• Best protocol suggested was directly proceeding to IVF after trial with CC/IUI.
• FSH/IUI no advantage.
• FORT-T trial between 38 and 40
• They inferred that in older women 2 cycles of IVF will lead to greater conception
and LBR as compared to with two attempts of CC/IUI or Gn /IUI

• Another review proposed that 2 cycles of Gn /IUI can be tried before
going for IVF in some patients as IVF has its own complications like
OHSS,Multiple pregnancies and perinatal morbidity.

ALTERNATIVE TO IN VITRO FERTILIZATION
• For women with unexplained infertility who do not pursue in vitro fertilization
due to cost or other reasons, laparoscopy can be offered as the next step after
ovulation induction.
• Laparoscopy provides visualization of the pelvis, can identify causes for infertility
and failed therapy, and allows for surgical intervention.
• Surgical treatment of conditions such as endometriosis or pelvic adhesions can
improve fertility.
• Other options are donor-egg pregnancy, gestational surrogacy, adoption, and
cessation of treatment.

Recent publications
• Effect of endometrial scratching on unassisted conception for unexplained infertility: a
randomized controlled trial Fertil Steril. 2022 Mar;117(3):612-619
• 220 women
• Conclusion(s): This trial did not find evidence that endometrial scratching improves the
live birth rate in women with unexplained infertility trying to conceive without assistance.
The effect of endometrial scratching on pregnancy rate after failed
intrauterine insemination: A Randomised Controlled Trail
168 women
• M S Madhuri 1, Chitra Thyagaraju 2, Archana Naidu 1, Papa Dasari Eur J Obstet Gynecol
Reprod Biol. 2022 Jan;268:37-42
• Endometrial Scratching improves clinical pregnancy rate in patients with Unexplained
infertility and mild male factor infertility with previous failed IUI cycles. ES will be an
inexpensive alternative to IVF for couples after IUI failures especially in developing
countries, with an acceptable pregnancy rate and does not demand any special
qualification or equipment and can be trained easily in primary settings. Larger and
adequately powered studies are needed to elucidate the beneficial effects of endometrial
scratching on implantation.

• IVF and IUI in couples with unexplained
infertility (FIIX study): study protocol of a
non-inferiority randomized controlled trial
• Lucy Prentice 1 2, Lynn Sadler 2 3, Sarah Lensen 4, Melissa
Vercoe 2, Jack Wilkinson 5, Richard Edlin 6, Georgina M
Chambers 7 8, Cynthia M Farquhar 1 2
• 580 couples with unexplained infertility comparing four cycles of
IUI-OS with clomiphene citrate and one completed cycle of IVF.
• Study Not over

• Comprehensive genetic studies are needed to better understand the etiologies of unexplained
infertility.
• A comprehensive, 10-year evaluation is underway by the National Institutes of Health entitled "The
All Of Us Research Program," which is inviting one million people to help build one of the most
diverse health databases in history; the database will combine genetic histories, lifestyle, medical
conditions, and whole genome application .
• From this information, multiple breakthroughs are expected, such as recurrent pregnancy wastage
and unexplained infertility. Study still going on

Conclusion
• Unexplained infertility poses a great challenge to both patients and treating
physicians. Infertility is not only a medical condition but also has a significant
negative psychological and social impact.
• In addition to the medical treatment, some couples may require additional
psychological support and counseling.
• The pros and cons have to be discussed before going ahead with treatment.
• Any intervention or invasive diagnostic tests on the female partner to be
withheld till semen analysis is available.
• Expectant management is associated with satisfactory pregnancy rates in selected
group of patients.
• Clomiphene citrate has a limited role in unexplained infertility, probably in a low-
resource setting. Superovulation with IUI is an effective second-line treatment,
and IVF/ICSI is the final treatment option for unexplained infertility generally
offered in a tertiary level center.

9447044485
drrejimohan@gmail.com
Thank you
Thank god
God Bless You

unexplained infertility BY DR REJI MOHAN.pptx

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