Diagnosis.. Catch them Young Investigation..Optimize Management..How long? Long term consequences..is there enough evidence? Practical considerations

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3.  Diagnosis.. Catch them Young
 Investigation..Optimize
 Management..How long?
 Long term consequences..is there enough
evidence?
 Practical considerations

4.  Inability to conceive after one year with routine (standard, basic)
investigations of infertility showing no abnormality.
(RCOG guidelines,1998;
Randolph,2000)
 Diagnosis made only after basic evaluation for infertility fails to
reveal any obvious abnormality
 Evidence of ovulation, adequate sperm count and fallopian tubes
patency
 30% of patient unable to conceive have unexplained
infertility.

5. Long list of putative & subtle causes of
unexplained infertility
• Many are uncertain
• Many have been found in couples of normal fertility.
• Few are actually treatable (Balen,2003)

6. 1. Abnormal follicle growth
2. Luteinized unruptured follicle
3. Hyper secretion of LH.
4. Hyper secretion of prolactin in the presence of ovulation
5. Reduced growth hormone secretion/sensitivity
6. Cytologic abnormalities in oocytes.
7. Genetic abnormalities in oocytes
8. Antibodies to zona pellucida

7. 1. Altered macrophage & immune activities
2. Mild endometriosis
3. Anti chlamydial antibodies

8. 1. Abnormal peristalsis or cilial activity
2. Altered macrophage & immune activity

9. 1. Altered cervical mucus
2. Increased cell-mediated immunity

10. 1. Abnormal secretion of endometrial proteins
2. Abnormal integrin/adhesion molecule
3. Abnormal T cell & natural killer cell activity.
4. Secretion of embryo toxic factors
5. Abnormalities in uterine perfusion

11. 1. Reduction in motility,acrosome reaction,
oocyte binding & zona penetration
2. Ultra structural abnormalities of head
abnormalities
Dr.Dhorepatil,AICOG 2017,KeyNote

12. 1. Poor quality embryo
2. Reduced progression to blastocyst in vitro
3. Abnormal chromosomal complement- increased
miscarriage rate

13. • UI is a diagnosis of exclusion
• To establish the diagnosis of UI the clinician should
consider the following (Moghissi et al,2000)
Was the infertility evaluation
. complete?
. performed correctly?
. interpreted appropriately?

14. Treatment generally indicated if
 duration ≥2 years, or
 female is >35 years
the prognosis
 worse when duration exceeds 3 years
 female >35 years of age (Collins et al.,1995).

15. The prognosis is relatively good even without
therapy, If the duration of infertility <2 years,
unless the female partner is >35 years.
(Bhattacharya et al., 2008; Collins et al., 1995).
AGE in Indian population >30yrs?

16.  Fertility problems are frequently followed by early
menopause.
 Both are an expression of accelerated ovarian ageing.
The time-interval between the onset of accelerated
decline in fertility and the
menopause is 13 yrs…
Human Reproduction, Vol. 18, No. 3, 644-648, March 2003
Subfertility reflects accelerated ovarian ageing
Medical Center Utrecht, Utrecht, The Netherlands

17. On the basis of a fixed interval of 13 years
between onset of accelerated decline of fertility
(25,000 remaining follicles) and the menopause,
it can be speculated that women who become
menopausal by the age of 45 years, have
experienced an accelerated decline of fertility
around the age of 32.
These women can be classified under a separate
clinical entity, “early ovarian ageing”

18. Epidemiological studies have shown that
 10% of women in the general population
become menopausal by the age of 45
(Treloar, 1981; van Noord et al., 1997),

19. A prospective cohort study of 863 women.
female health care workers showed that participants serum AMH
concentrations and AFC levels were significantly associated with their
mothers’ menopausal age category.
To provide an estimate of an individual women’s reproductive age, long-
term follow-up studies are still required.

20. What is the aim ?
 To increase the monthly pregnancy rate above the
natural rate of 1.5%- 3%
How?
 improve gamete quality
 increase gamete number
 facilitate gamete interaction

21. When? depends on
1. duration of infertility
2. woman's age /ovarian reserve
3. previous pregnancy history

22. Categories of unexplained infertility (ESHRECapri
Workshop Group, 2004)
† 20% of couples after the initial work-up
Couples with mild male subfertility (20–40%)
50% of those in whom conventional treatments have failed

23. Diminished ovarian reserve, as shown by
 Elevated S.FSH level, may be one cause (Cahill et al. 1995; Blacker et al. 1997;
Luborsky et al. 2000) and can result in alterations to other hormonal levels. One
study revealed that 5% of women with unexplained infertility had elevated FSH
levels in the early follicular phase (Rodin et al. 1994).
 Changes in LH levels, a low FSH/LH ratio and reduced LH concentration in
follicular fl uid have also been speculated to play a role in unexplained infertility
(Cahill et al. 1995; Omland et al.2001). FSH and LH abnormalities may reflect a
dysfunction on the pituitary-ovarian axis (Leach et al. 1997; Omland et al. 2001).
 Both the S.E2 levels in follicular phase and the E2/P ratio have been shown to be
elevated in women with unexplained infertility, suggesting altered folliculogenesis
(Blacker et al. 1997; Leach et al. 1997) and an absent midcycle elevation of the
hormone prolactin, which is present in fertile women (Subramanian et al. 1997).

24. Ovarian reserve tests provide an indirect measure of the cohort of
recruitable antral follicles present in the FSH window at the beginning
of each menstrual cycle..Functional Ovarian Reserve
Fauser and Van Heusden, 1997; McGee and Hsueh, 2000.
Ovarian reserve is a complex clinical phenomenon that is influenced
by
age, genetics and environmental variable

25.  Hormones-Day 2 FSH, LH, E2
 TSH,PROLACTIN
 AMH
 USG FOR AFC.

26.  38yrs old pt married since 6mnth,whants to know how much
more time she has to delay her pregagncy? what is her
probability of pregnancy at that time and Now?
Her AFC 6-7 and Her AMH is 2.8ng/ml
 28yrs old pt married since 2yrs,whants to know how much
more time she can plan to avoid pregnancy as she has
bright carrier option in near future?
Her AFC 3 and Her AMH is 0.8ng/ml

27.  Ovarian endocrinology is dynamic. Years of quiescence
are followed by oscillating secretion until near burnout,
 “Ovarian reserve testing” assesses where the ovaries
are within this spectrum. These measures seem to most
clearly relate to oocyte quantity, as multiple other
factors (especially age) meaningfully affect oocyte
quality.
One must always keep in mind that as with all
screening tests, no single result is definitive, since
findings must be interpreted in context.

28. AMH & AFC are the best markers available

29. 1. Expectant management
2. IUI
3. Ovarian induction with oral or injectable medications
4. IUI with OI
5. ART
Summary of t/t relies on level I evidence from RCTs.

30.  Represents lower extreme of normal distribution of fertility
with no defect present.
 Likelihood of pregnancy without treatment is less than that
of fertile couples but greater than zero.
 Hull et al. found a cumulative PR over 3 years
50%–80% as a function of female age
30%–80% as a function of infertility duration

31.  consumption of not more than one unit of alcohol per day
 maternal and paternal smoking
 caffeine consumption less then 250mg/day ( 2 cups)
 female body mass index ideally in the range 19–30
 Knowledge about fertile period
NICE 2012

32.  Guzick et al - retrospective review (45
studies) - average cycle fecundity of 1.3% to
4.1% in the untreated groups, which was
lower than most treatment
interventions.

33.  Benefit of expectant management in UI
 RCT comparing outcome after EM for 6 mths vs
immediate intervention concluded that initial EM for 6
months results in a considerable cost-saving without
jeopardizing the chances of having a child.

35.  Limited implementation of TEM
(Tailored Expectant Management)

36.  Overcome a subtle defect in ovulatory function
 Increasing the number of eggs
 Improve the monthly pregnancy rate by simply increasing the
number of oocytes available for fertilization and implantation.
 Increasing the density of motile sperm available to these
eggs

37. AGE & AMH,FSH AGE & AFC,FSH

38.  IGD Score ( Initial Gonadotrophin Dose)

39. score 0 1 2 3 4 5
AGE < 19 20-29 30 to 35 >35
BMI <19 19-22.5 22.6-28.5 28.6-35 >35
AMH >10 3.5-10 0.9-3.4 <0.9
AFC >20 10-20 5-10 3-5 1-2 0-1
Score Rec/Biosimiar Urinary
3 75 150
4-10 150 225
10-14 175 300
15 225 375

40.  29yr old, BMI 28,AFC 6,AMH 3ng/ml pt with
UI of 5yrs for Ovarian stimulation
 What dose to start for IUI or IVF
 Score..10…dose for IVF-150units
For
IUI..75units

41. Pt no IGD score No follicles No Eggs retrived
50 3 15-10 10-15
50 4-10 10-15 8- 10
50 10-14 5-7 4-5
50 > 14 2-3 1-2

42.  Do not offer oral ovarian stimulation agents (such
as clomifene citrate, anastrozole or letrozole) to
women with unexplained infertility
 Inform women with unexplained infertility that
clomifene citrate as a stand-alone treatment does
not increase the chances of a pregnancy or a live
birth
NICE 2012

43.  Overall effect of CC treatment is smaller and non
significant
 One additional pregnancy in 76 CC cycles compared
with untreated control cycles .
 The confidence interval includes infinity.
 ASRM 2006

44.  There was no evidence that clomiphene citrate was more
effective than no treatment or placebo for live birth or
clinical pregnancy per women when randomised with
IUI
Natural cycle
Without IUI but using hCG.

45.  No superiority between letrozole and CC for
inducing ovulation in women with unexplained
infertility before IUI.
Badawy et al Fertil Steril 2009
Barraso et al Fertil Steril 2006

46. CONCLUSIONS
In women with unexplained infertility, ovarian stimulation with
letrozole resulted in a significantly lower frequency of multiple
gestation but also a lower frequency of live birth, as compared
with gonadotropin but not as compared with clomi- phene.
(Funded by the National Institutes of Health and others;
ClinicalTrials.gov number, NCT01044862.)

47.  FSH/IUI is no better than expectant management when
the prognosis is good, but has a modest effect with more
than 3 years duration of infertility.
 There would be one additional pregnancy for every 11
cycles of FSH/IUI
Guzick et al., 1999
Steures et al., 2006
ESHRE capri 2009

48.  Multiple pregnancy rates including higher-order
multiples up to 40% have been reported in large
rétrospective studies (Gleicher et al., 2000; Turet al.,
2001; Fauser et al., 2005).

49.  Patients with unexplained infertility, who are
having regular unprotected sexual intercourse do
not routinely offer intrauterine insemination, either
with or without ovarian stimulation
NICE 2012

50.  Effect of IUI alone per cycle is small and only marginally
significant
 Average difference in pregnancy rates between IUI and
control groups was
7% per couple
3% per cycle

51.  A protocol that includes an average of three
IUI cycles led to a statistically significant effect.
 The magnitude of the benefit, however, is
modest: one additional pregnancy in 14 IUI
couples (95% CI: 8, 23) compared with control
couples (natural cycle).

52.  IUI in a natural cycle with expectant management showed no
evidence of increased live births
 Six trials where IUI was compared with TI, both in stimulated
cycles, there was evidence of an increased chance of
pregnancy after IUI (six RCTs, 517 women: OR 1.68, 95% CI
1.13 to 2.50).
bhattacharya et al BJM2009, snick et al HR 2008

53.  Prospective, randomized, controlled trial and meta
analysis of the literature.
 After COH randomly assigned to, IUI and FSP
 patients with unexplained infertility had a statistically
higher pregnancy rate with fallopian sperm perfusion (odds
ratio, 4.1; confidence interval, 1.1–16.4)

54.  No of patients who became pregnant
FSP – 27%
IUI – 8%
 It may be that the large volume of inseminate
washes out tubal obstructions or some factor
that is deleterious to fertilization

55. Meta-analysis of randomized controlled trials
 Double IUI - 13.6% clinical pregnancies
 Single IUI - 14.4% clinical pregnancies
 There was no significant difference between the single and
double IUI groups in the probability for clinical pregnancy
Polyzos et al 2010, fert ster

56.  Advise women with unexplained infertility who are
having regular unprotected sexual intercourse to
try to conceive for a total of 2 years (including up to
1 year before investigation) before IVF will be
considered. [new 2012]
 NICE 2012

57.  ART Vs Expected Management
Pregnancy rate per woman or couple
associated with a single cycle of IVF was
significantly higher than with expectant
management (P = 0.04).
› Hugh et al (HR 2004)

59.  No significant increase in multiple
pregnancies with IVF when compared to
IUI+SO.
 However
 Effectiveness of IVF relative to expectant
management, clomiphene citrate and IUI
alone remains unproven.

60. Randomized controlled trial
 conventional treatment
 Three cycles of CC/IUI,
 Three cycles of FSH/IUI,
 up to six cycles of IVF
If fails
If fails
Acceleraed treatment
Three cycles of CC/IUI,
If fails
up to six cycles of IVF

61. Per cycle pregnancy rates for CC/IUI, FSH/IUI, and IVF were 7.6%, 9.8%,
and 30.7%, respectively.

62. Time (mths) conventional (%) Accelerated (%)
6 31.9 43.2
9 43.8 54.7
12 55.4 65.4
Compared with conventional infertility t/t an accelerated approach to
IVF that starts with CC/IUI, but eliminates gonadotropin/IUI, results in a
shorter time to pregnancy, with fewer treatment cycles, and at a
suggested cost savings

63.  Couples should undergo a semen analysis, ovulation testing, assessment
of ovarian reserve, and imaging to assess for tubal and uterine factors
before a diagnosis of unexplained infertility is made.
 The principal treatments for unexplained infertility include expectant
observation with timed intercourse and lifestyle changes, clomiphene
citrate and intrauterine insemination (IUI), controlled ovarian
hyperstimulation with IUI, and in vitro fertilization (IVF).
 Although expectant management is associated with the lowest cost, it
results in the lowest cycle fecundity rates. It may provide an option for a
couple with unexplained infertility in whom the female partner is young
and the problem of oocyte depletion is not an immediate concern.

64.  The most expensive, but also most successful
treatment of unexplained infertility consists of the
spectrum of assisted reproductive technology
including IVF, with or without intracytoplasmic
sperm injection. IVF is the treatment of choice for
unexplained infertility when the less costly, but also
less successful treatment modalities have failed.
 The optimal treatment strategy needs to be based
on individual patient characteristics such as age,
treatment efficacy, side-effect profile such as
multiple pregnancy, and cost considerations.

65.  Depression or history of depression were significantly
higher in women with unexplained infertility than in the
control group (Meller et al, 2002).
 Unexplained infertility: prolonged & mutual agony &
sexual dysfunction.
 Recognition of the cause of infertility: acceptance of
childlessness & return to normal sexual behavior.

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