Unexplained infertility usually refers to a diagnosis (or lack of diagnosis) made in couples in whom all the standard investigations such as tests of ovulation, tubal patency and semen analysis are normal.

Incidence 10-30% (ASRM 2006)

For the infertile couple, a ‘diagnosis’ of unexplained infertility may be very frustrating and is often interpreted by them as meaning that if there is no explanation for the cause of infertility, there is, therefore, no effective treatment.

The basic evaluation should provide evidence of ovulation, adequate sperm production and patency of fallopian tubes.{asrm2006}

The prognosis is worse when the duration of infertility exceeds 3 years and the female partner is >35 years of age (Collins et al.,1995).

Prognostic factors related to a higher cumulative pregnancy rate are duration of infertility less than 2 years, a previous pregnancy in the same relationship and female age <30 years.

Causes for unexplained infertility:

Ovarian and endocrine factors:

  • Abnormal Follicle Growth
  • Luteinized unruptured follicle
  • Reduced GH secretion/Sensitivity
  • Cytologic Abnormalities in oocytes
  • Genetic abnormalities in oocytes
  • Antibodies to Zona pellucida

Cervical factors

  • Increased cell mediated immunity

Endometrial Factors

  • Abnormal secretion of endometrial proteins
  • Abnormal T cell & natural killer cell activity
  • Secretion of embryo toxic factors
  • Abnormalities in uterine perfusion

Tubal Factors

  • Abnormal peristalsis or cilia activity
  • Altered macrophage & immune activity

Peritoneal Factors

  • Altered Macrophage & immune activities
  • Mild Endometriosis
  • Anti Chlamydial Antibodies

Embryological factors

  • Poor quality
  • Reduced Progression to D5
  • Abnormal chromosomal complement

Male factors

  • Acrosome reaction

Oocyte binding and Zona penetration

  • Ultra structural abnormalities of head

Diagnosis: unexplained infertility is a diadnosis of exclusion.


Expectant mamgement

  • 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.

“Chance of spontaneous pregnancy with EM is low but never Zero.”

Ovulation induction with  CC

  • Enhances Fertility by
  • Correcting subtle Ovulatory dysfunction
  • Increasing the number of follicles (Balen 2003]


  • No better (inferior) LBR than EM (14% Vs 17%) Bhattacharya et al., 2008
  • Number of cycles needed under CC for one additional pregnancy was 40 compared with placebo.(ASRM 2006)
  • No evidence that CC was more effective than no TT or placebo for LBR or CPR Hughes et al 2010
  • Do not offer oral ovarian stimulation agents as there is no increase in pregnancy or live birth NICE,2013
  • Offer IVF after 2 years


  • 7% pregnancy rate


Significantly higher CPR in the group treated with hMG PR/cycle 8% (cc) and 25% (hMG). Echochard et al., 2000 Balasch

Oral Vs Injectable ovulation

Insufficient evidence to prefer either of the methods Cochrane database, Athaullah et al.,2009.

Letrozole + FSH

Improved response to FSH: lower FSH dose & higher number of mature follicles  Mitwally & Casper, 2003


  • No evidence of effect of IUI in the natural cycles compared with EM. Cochrane 2011
  • Though IUI has low success rate, it is not Ineffective.
  • It can be tried for 3-6 cycles as an empirical treatment.

Natural cycle IUI not RECOMMENDED!!!

  • CC(IUI) & Gn ( IUI) have similar pregnancy rates.

CC(IUI) is more cost effective


  • According to the guidelines of the ASRM 2006, laparoscopy should be performed in women with unexplained infertility or sign and symptoms of endometriosis or in whom reversible adhesive tubal disease is suspected.
  • If laparoscopy is performed in a patient with unexplained infertility and minimal/mild endometriosis is identified, we recommend ablation of endometriosis. Canadian Collaborative Group on Endometriosis



  • Most expensive but most successful Rx modality.

IVF/ICSI is Diagnostic and therapeutic

  • Poor quality embryos
  • Overcome Cervical factor abnormality
  • Sperm- Egg Interaction defects
  • Sperm-Egg transport defects.
  • Fertilization failure.
  • Cleavage abnormalities of embryos.


  • Conclusion: IVF may be associated with High LBR than EM, but there is insufficient evidence .
  • IVF may also be associated with higher LBR than unstimulated IUI.
  • In women pretreated with CC+IUI, IVF appears to be associated with higher birth rates than IUI+ Gns

Adverse events could not be assessed due to lack of evidence.


  • Patient tailored treatment depending upon the age, previous fertility and duration of infertility.
  • Treatment decided upon by the success rates, complications and cost effectiveness
  • Proper counseling is needed to prevent dropouts.
  • 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.