For many people, the hardest part of unexplained infertility is not just the delay in getting pregnant but the uncertainty, and Dr Elias Tsakos, FRCOG, Medical Director of Embryoclinic, framed that uncertainty as something that should be narrowed step by step rather than accepted too quickly.
Hosted by: Dr Shabana Bora, MBBS, MRCOG, Consultant Gynaecologist, Fertility Specialist & Co-founder of ALMA Fertility, UK.
The label can sound final, but it is actually conditional. Unexplained infertility, also called idiopathic infertility, means that after investigations to a certain level, no factor has been identified as the cause of infertility in the couple or in the single woman. That “certain level” matters, because the scope of testing is not the same everywhere. It depends on where a patient is in the world and whether care is being delivered in a public, NHS, or private setting.
That distinction helps explain why some patients feel they have been told everything is normal while still suspecting that more could be explored. A normal first round of tests does not necessarily mean every relevant issue has been ruled out. It may simply mean the standard initial workup has not found an answer yet.
At age 35, with a clear history and a normal baseline examination, the starting point is not an immediate rush to invasive procedures. The first steps are a detailed ultrasound scan and blood tests, including AMH and a general hormonal panel. Thyroid testing is part of that early workup because latent thyroid issues are common.
This is also where a common blind spot appears: the assumption that a healthy-looking male partner is unlikely to be part of the picture. Male assessment should be included from the beginning, even in a young, healthy, and fit partner. In practical terms, that means the initial appointment, semen analysis, tubal testing, and ultrasound can cover about 80% to 90% of possible fertility factors.
For patients, that number is reassuring and frustrating at the same time. It suggests that a careful early workup can answer a great deal, but it also leaves room for problems that are less obvious and require more targeted testing.
A routine gynecologic scan is not always enough. A high-resolution three-dimensional ultrasound scan can identify structural anomalies, congenital anomalies, endometriosis, fibroids, and cancer-related issues that may be missed on standard imaging. Congenital uterine anomalies, in particular, are often overlooked on routine scans.
Among the abnormalities discussed most often is a heart-shaped uterus, also described as a septate or bicornuate uterus, or more broadly as an abnormal uterine shape or size. These findings matter because they can change the next steps in investigation and treatment. The same is true for myoma and fibroids: they are common, and most do not require surgery or carry major clinical significance, but their size, shape, location, and fertility implications need to be assessed accurately rather than assumed.
This is one reason patients who have already been told that their scans are normal may still benefit from more specialised imaging. “Normal” can depend on how closely someone was looking and what kind of scan was used.
If the initial history, ultrasound, and blood tests are normal, the next step is usually a tubal test. Many patients want this done at the first visit because they are looking for a quicker diagnosis, and that reflects a broader shift in fertility care: people are often less willing to wait through months of uncertainty when a blocked tube or another tubal issue could change the entire treatment plan.
At Embryoclinic, office-based ultrasound-guided tubal tests have largely replaced the standard X-ray hysterosalpingogram, or HSG. The group compared older X-ray HSG with HyCoSy and HyFoSy ultrasound-based tubal tests and found that HIFOSI was probably superior for the initial investigation of a young couple in the first few months or first year of trying.
For patients, the larger point is that tubal testing is no longer automatically synonymous with older X-ray methods. In the right setting, ultrasound-based options may offer a more useful first look.
A normal semen analysis can be falsely reassuring. Male-factor investigation should go beyond semen parameters alone because sperm may appear normal or near normal while other problems are still present. After semen analysis, further assessment may include microbiological assessment, oxidative stress testing, and DNA fragmentation evaluation.
That broader view extends to Y microdeletions, hormonal balance, vitamin D levels, and metabolic factors. Overweight men with metabolic syndrome, abnormal metabolic parameters, insulin resistance, or inflammation may have affected sperm quality and altered sperm behavior in IVF. Sperm quality, in this framework, reflects the overall health of the male rather than just a single lab result.
That can be a difficult message, but it is also a useful one. It shifts the conversation away from a narrow pass-fail test and toward a fuller assessment of factors that may affect both natural conception and IVF outcomes.
Patients often worry that if no answer has been found, the next step must be a more invasive procedure. But hysteroscopy and laparoscopy are not routine early tests for a young couple with otherwise normal findings. They are reserved for cases where there is a reason to do them, such as an abnormal scan or an abnormal tubal test.
That approach keeps the investigation focused and avoids turning “unexplained” into a reason for automatic escalation. Noninvasive tools, especially ultrasound, tubal testing, and deeper male-factor evaluation, remain the preferred route unless something specific points elsewhere.
When no tubal factor or endometriosis is found and everything appears normal, treatment does not begin and end with IVF. IUI still has a role. It was described as a simpler and more natural assisted conception technique, though not as effective as IVF and likely to require a couple of cycles.
That tradeoff matters because treatment decisions are not only about the highest possible effectiveness. They are also about what kind of approach a couple prefers: a more effective treatment or a more natural one. In unexplained infertility, where there is no single correctable cause, those preferences can carry real weight.
If the decision is to move to IVF, expectations become more concrete. Dr Elias Tsakos said he would usually start with a reasonable dose rather than a massive dosage, expect six to eight good-quality eggs, usually perform ICSI, and aim for two to three good blastocysts. The plan would be to transfer one top-quality blastocyst and freeze the rest. In that kind of cycle, he would expect a very good outcome, with more than a 50% chance of transfer and a cumulative success of very near 90%.
A failed cycle can create pressure to overhaul the protocol immediately, but that is not the first move. The cycle should be reviewed step by step: oocyte yield, whether the stimulation produced the expected number of eggs, whether IVF or ICSI was used, whether the expected fertilisation rate was achieved, how embryos performed in culture, and whether the issue may have occurred at embryo transfer.
Just as striking is the emphasis on human factors. Who designed the stimulation protocol, who performed egg collection, who received the eggs, who carried out ICSI, and who performed embryo transfer may all matter. The most senior embryologist should ideally receive the eggs, perform ICSI, and handle the gametes in the incubation chambers, while embryo transfer should be done by the most senior person available in the department.
These are not glamorous changes, and they do not cost anything, but they may make the difference between success and failure. Even so, every cycle is different, and a repeat cycle can still produce a different result even with the same protocol and careful monitoring.
Unexplained infertility is often less a diagnosis than a reminder that fertility medicine depends on how deeply the search has gone. A careful pathway begins with high-quality imaging, hormonal testing, thyroid assessment, male-factor evaluation, and tubal testing, while holding back invasive procedures unless there is a clear reason. From there, treatment can still be individualised, whether that means trying IUI, moving to IVF, or considering dual stimulation to produce more eggs within a short period of time when the first stimulation does not yield enough.
For patients, the most useful takeaway may be that “everything is normal” should not end the conversation. It should prompt a more precise one about what has been checked, what has not, and which next step actually fits the evidence.
Unexplained infertility, or idiopathic infertility, means that with the investigations performed to a certain level, no factor has been identified to explain the infertility of the couple or the single woman. It is a broad term, and the extent of investigation depends on the setting, such as public, NHS, or private care.
If the history is entirely clear and the baseline examination is normal, start with a detailed ultrasound scan and one simple blood test panel. That panel should include AMH and may include a general hormonal panel, thyroid function testing, and a general blood panel. The male partner should also be assessed early, with a similar simple analysis test considered.
At that stage, do a tubal test. Many patients ask for this at the first visit because they want a quicker diagnosis, but a tubal test is more invasive than a transvaginal ultrasound scan.
Hysteroscopy and laparoscopy are not first-line tests at this stage. They should be reserved for later and only done for a reason, such as a finding on scan or a finding on the tubal test. The focus should also remain on the male factor, and semen analysis alone is not enough.
Yes. Male-factor infertility should be investigated earlier. Useful tools include evaluation for DNA fragmentation, Y microdeletions, oxidative stress, hormonal imbalance, vitamin D deficiency, and metabolic factors. It is also important to check for overweight, metabolic syndrome, insulin resistance, and inflammation, because these may affect sperm quality and sperm behaviour in IVF.
Review the cycle step by step rather than changing everything at once. Look at oocyte yield, whether the stimulation protocol was adequate, fertilisation yield, whether IVF or ICSI was used, embryo culture outcomes, blastocyst production, and the embryo transfer protocol. The human factor also matters, including who performed stimulation, retrieval, ICSI, gamete handling, and embryo transfer.
IUI should definitely be part of the discussion and should not be excluded. There is a place for IUI when everything looks normal, there is no evidence of tubal factor or endometriosis, and the male partner has been investigated to a certain degree. IUI is less effective than IVF and may require a couple of cycles, so the main decision depends on the couple’s preference.
In this situation, expect a good number of eggs, with an average of 6 to 8 good-quality eggs. If needed, dual stimulation can be considered in international patients. Start with a reasonable dose rather than a massive dose, and aim for effective stimulation rather than hyperstimulation.
ICSI would probably be used, with good fertilisation expected. The goal would be to create two to three good blastocysts, transfer one top-quality blastocyst if conditions are optimal, and freeze the rest. In this kind of cycle, expect more than a 50% chance of transfer and a cumulative success of very near 90%.
