A genetic predisposition: from speculation to opinion to 'fact' without any data (Part II)

In my last blog post I presented the ‘evidence’ (or lack thereof) on which the theory of a genetic/constitutional predisposition for Asherman's syndrome was based. To recap the gist of these observations which pass for proof:

a) some women develop a severe form of IUA after undergoing the ‘same’ traumatic procedures as others who do not acquire AS, and 

b) some women respond more ‘favourably’ to treatment than others who suffer from recurrent adhesions. 

Before deconstructing these observations, the most obvious argument against a genetic basis is the lack of familial clustering of the ‘pathology’. Assuming a polygenic mode of inheritance (as opposed to a Mendelian one) it would be expected that those with a first degree relative with Asherman’s syndrome would have a higher risk of  developing AS than those without a close relative who has the condition. I have yet to read a study of identical twins with Asherman’s syndrome, let alone any study showing the sisters or daughters of patients having a higher risk. In over a century since its first report, there is no evidence of familial clustering to lend support to this theory. Nor is there any evidence that women with scarring defects (eg. keloids) or connective tissue disorders (Marfan’s syndrome, Ehlers-Danlos syndrome) are more prone to AS as one might expect. 

How can trauma be quantified when surgery is blind?

As for the ‘evidence’ above, with regards to a), what proof is there that the women who develop severe IUA actually underwent the exact same trauma as those who did not acquire it? This is a an unfounded statement given differences in doctor’s skill, technique and more importantly, the mis- or under-diagnosis of AS and the blind nature of D&Cs- the number one cause of AS. The problem with bind surgery is that one relies on guess work and instinct to not scrape too deeply. ‘Too deeply’ can be one millimeter too much. How is it possible to detect this difference when not even an ultrasound is used during the procedure? Even with visualization it is not possible to tell where the functional endometrium ends and the basal endometrium begins. However, techniques which utilize visualization for intrauterine surgery (i.e. hysteroscopy) are inherently less risky with regards to instrumental injury because they allow the surgeon to only scrape/dissect/remove parts of the endometrium which need to be treated thus sparing underlying and adjacent tissue from potential injury. Furthermore, each woman has a different anatomy, and different location of retained products of conception. Some have retroverted uteri, others have Mullerian malformations, and the shape, widths and lengths of uteri vary enough between women to be a significant factor with regards to acquiring an injury during a blind procedure. A D&C consists of blindly scraping away the top layer of the endometrium (the functional layer) which can vary in thickness between women but is often not thicker than a few millimeters in most parts. It is simply impossible for a clinician or midwife to know whether they have scraped into the basal endometrium, particularly when no visual guidance is used. 

In summary, the above argument is akin to saying that not all smokers develop lung cancer therefore lung cancer is not caused by cigarettes. Why not theorize that those who develop lung cancer have a genetic predisposition instead? (Note: this comment was intended to highlight the absurdity of believing that cigarette smoking does not cause lung cancer, and hence the absurdity of believing that the fact that all women who have D&Cs do not acquire Asherman's syndrome proves that the condition is not caused by D&Cs but is instead genetic. I later learned that the famous statistician RA Fisher actually theorized half a century ago that people who are genetically predisposed to lung cancer are also genetically predisposed to becoming smokers. Of course this theory was refuted by a study of monozygotic twins versus dizygotic twins who were discordant for cigarette smoking, and it turns out,  lung cancer risk. This example points out how easily theories can be taken seriously just because an expert, or in this case, a genius put it forth, and that experts too have biases which affect their views (he smoked and was a consultant for the tobacco industry!). These theories, will not hold up against evidence from well-designed studies, but until these are done, they impede medical progress).

Recurrence depends on initial severity and treatment methods

With respect to the second part of the argument, the fact that some women respond more ‘favourably’ to treatment than others who suffer from recurrent adhesions can be rationally explained in other ways.

Firstly, it is not surprising that some women need more than one hysteroscopic adhesiolysis surgeries than others, depending on severity. This has been known for many years and reported in the literature. The more damage incurred on the endometrium, the higher the rate of IUA recurrence, and the more surgeries needed for correction, although at some point, damage is too great to allow for endometrial regeneration resulting in recurrent adhesions or fibrotic endometrium.

Another important point to consider is that hysteroscopy was not used for diagnosis or treatment when the observation about treatment outcomes was made. Asherman’s syndrome was still ‘treated’ with blind D&C, the same procedure which is responsible for most cases of AS. This would understandably result in inconsistent outcomes. The absence of accurate diagnosis (and hence classification) in those days also distorted the correlation between severity and outcome. A patient with seemingly severe AS presenting with total amenorrhea may ‘inexplicably’ have had a better outcome after surgery than someone with supposedly less severe AS who had some menstrual flow. We now know that amenorrhea is not always due to severe and widespread adhesions. It can be due to cervical adhesions alone. As the rest of the uterus may be intact in such cases, the reproductive prognosis is better than a patient who has deep adhesions in part of her uterus but no outflow obstruction (and thus has menstrual bleeding, albeit reduced flow). 

With regards to treatment, estrogen therapy was not carried out as part of post surgical therapy in the past. It is generally accepted that estrogen supplementation plays an important role in the prevention of adhesion recurrence following surgery/adhesioloysis by stimulating endometrial regeneration. Thus in the absence of hysteroscopic adhesiolysis, uterine stents and estrogen therapy, more severe cases were less treatable than they are today. 

It is well known that the functional endometrium is regenerated from the underlying basal endometrial layer. As a simple analogy, imagine the lining of the uterus as a lawn. The grass seeds would be the stem cells from which the grass grew with the addition of water (i.e. estrogen). The functional layer would be the grass, and the roots would be the basal endometrium. If someone came along to trim the lawn (i.e. D&C) and accidentally dug out the roots of the grass, the grass would regrow after watering only in the areas where there were either some residual roots, or seeds. Imagining that the seeds are in a slightly deeper layer of soil (for the purpose of this analogy), if the gardener dug very deeply so that even the seeds were removed, no amount of watering would regrow the grass. This could happen in a patch of grass or the whole lawn. In this simple analogy the bald patches would be endometrial sclerosis (unstuck Asherman’s), but adhesions would result if two bald patches came into contact with eachother in the uterus.

More recently, the presence of endometrial stem cells at the myometrial junction was reported. These should be able to transform into endometrial stem cells with the right stimulation. The discovery of the existence of endometrial stem cells could explain why in some cases an apparently denuded endometrium (ie.no visible endometrium) will regenerate while in other cases it will not. Or why some women have recurring adhesions while others do not. This would explain why estrogen therapy after hysteroscopic adhesiolysis can in some cases stimulate the regerenation of endometrium while other cases of IUA are recurrent no matter the dose of estrogen therapy and the length of uterine barrier therapy. Endometrium is what keeps the myometrial layer of the uterus from adhering to opposing walls of the uterus. Once again, it is imposible to observe with the naked eye whether stem cells have been removed by curettage or not which would give rise to ‘paradoxical’ outcomes between patients with the ‘same’ severity of injury. In addition, differences in methods for dissecting adhesions can account for differing outcomes. Mechanical methods for adhesion dissection may also be preferable to methods which utilize thermal energy as the latter may damage adjacent tissue.

A modern perspective on an old problem

Authors need to re-evaluate the validity of assumptions, speculations and theories made in publications written when conditions and standards differed greatly to those of today, taking into consideration medical progress.   Although older papers are still important and interesting to read, they need to be interpreted carefully and in the context of limitations in medical technology and critical thinking, lower standards needed for proof and gaps in scientific understanding at the time they were written. Blind repetition of theories cited from papers that were published decades ago without any questioning is simply archaic, unrigorous and unscientific. If there is a case for a genetic or constitutional basis for AS, data from well designed studies would be more persuasive than citing theories which lack any experimental support of any kind. In what seems to be a recurring theme in AS, absence of evidence may not be evidence of absence, but by today’s standards in medicine only presence of evidence is evidence of presence.

A genetic predisposition: from speculation to opinion to 'fact' without any data (Part I)

The theory that Asherman’s syndrome has a ‘constitutional’ or ‘genetic’ basis has been making rounds for a while. It is time to critical appraise this idea with a view of our understanding of modern medicine.

From where did this theory originate and is there any evidence to support it? From my own thorough research of the literature on Asherman’s syndrome, having read most of the peer reviewed publications dating back to the early 60s, the first mention of the possibility of a hypothetical constitutional factor comes from a publication by Foix et al in 1966 (1). They write: (page 1028): "Besides the above-mentioned presidposing factors, there appears sometimes to be a constitutional element, for some of our patients treated for adhesions after each of several induced abortions, always developed new ones.” Thus they give no supporting references or evidence other than their own subjective observations.

Most reviews or studies mentioning this theory cite a review paper by Schenker and Margoliath in 1982 (2). In it they elaborate on the same ideas, citing a case series by Polishuk and Sadovsky in 1973 (3) as ‘support’. Schenker and Margoliath’s rationale was that:

a) some women develop a severe form of IUA after undergoing the ‘same’ traumatic procedures as others who do not acquire AS, and

b) some women respond more ‘favourably’ to treatment than others who suffer from recurrent adhesions.

They go further and conjecture that 28 women plucked from studies they compiled from the literature ‘may have possessed this predisposing factor, which might have been the reason for the development of IUA after normal delivery or following abortion without subsequent curettage, or even when lacking any attributable trauma.” This is a very bold, if not preposterous assertion to make about patients they have never examined or treated. Needless to say, diagnosis from a distance by third party observers is not a credible source of evidence.

The Polishuk and Sadovsky paper also fails to provide any proof. In fact, Polishuk and Sadovsky themselves never mentioned the idea of a genetic predisposition in their paper or set out to prove such a theory. Instead, they present a case series of 11 patients who have recurrent adhesions, one of three types of adhesions, they explain. Adhesions recurred in all cases after curettage for removal of adhesions or following abortion in a new pregnancy. They suggest that the patients in their study may have had extensive endometrial ‘repair’ i.e. fibrosis, where the endometrium is replaced by connective tissue, which they attempted to treat by removing it. Their understanding of cellular physiology, like their contemporaries, is incorrect but excusable given what was known at the the time it was written. They conclude that their treatment was not encouraging. It should not be surprising to doctors today that blind lysis using curettage is not a successful treatment for IUA or that the removal of fibrotic tissue does not result in endometrial regeneration. I will explain later...(Part II)

Since the speculation by Foix et al and later Schenker and Margoliath, numerous authors have subsequenty made it a habit to include this under etiology of AS, apparently without much thought. The theory also seems to have gained credibility with authors stating it as a fact rather than a hypothesis without any further ‘evidence’. The quality of referencing in many articles about Asherman’s syndrome is lacking. Some authors even cite other reviews which never made the speculation. Clearly, many authors simply copy references from other papers without ever reading the original article to confirm or verify what was actually written.

Back in 1948 Asherman himself seemed to have understood that the underlying cause of IUA are usually trauma from instrumentation (although severe infection, especially endometrial tuberculosis can also cause physical injury to the lining) when he named the condition ‘traumatic amenorrhea’ (4). Unfortunately, the medical community has since been trying to attribute other causes or factors necessary for its development (another example of this is ‘subclinical infection’) perhaps to redeem their dependence on blind curettage as a standard procedure, and also to compensate for their lack of understanding about cellular physiology and insight into the condition. The condition has also been renamed (or misnomered) ‘Asherman’s syndrome’ which distances it from an iatrogenic cause. The word ‘traumatic’ made some doctors feel uncomfortable (5):

(See Discussion Dr John Morton LA California): “The nomenclature also is objectionable. The “traumatic” part of the phrase indicates an iatrogenic lesion, which may not always be justified. (my edit: This is true, but many if not most cases are actually iatrogenic since surgery is involved).

(…)

Dr Jones (closing):It is true that the term “traumatic” is not wholly satisfactory, but it is the term most frequently used in current literature to describe the abnormality under discussion. H W Jones Jr has suggested that the term “postcurettage atresia of the endometrial cavity” is more descriptive, and this may avoid the iatrogenic connotation of the word “traumatic”.

(…)

Thus, there must be an inflammatory factor in the etiology of intrauterine adhesions (my edit: Trauma to the tissue causes inflammation-not to be confused with infection). Parenthetically this too underlines Dr Morton’s objection to the term ‘traumatic’.”

I won’t go into why the above reasoning is incorrect here, my point was to display the obvious discomfort doctors felt in acknowledging an iatrogenic etiology, which probably contributed to its eventual name change as well as the reason why the medical community is so willing to accommodate other unproven causes of Asherman’s syndrome. It’s as if the mentality with regards to Asherman’s syndrome is caught in a time warp where principles of modern medicine such as using modern techniques, well designed studies, objectivie interpretation of data and the requirement of evidence have been temporarily waived.

Although it is natural to consider the possibility that any condition may have a genetic basis, a current understanding of adhesions, the advent of hysteroscopy and techniques to view inside the uterus, a century of observations and plain common sense suggest that such an explanation is not only based on speculation and flawed thinking, and cannot obscure the lack of even the weakest level of research evidence (eg. a case study) exists to support it. Next time I will explain exactly why.

We know now that adhesions (whether intra unterine or intra abdominal) are not a pathological response: they are a normal physiological response to injury adjacent mucosa. Adhesions are only pathological in the sense that they can lead to pathologies such as infertility, bowel obstruction and pain, depending on their location. They are the end result of normal wound healing, of which inflammation (not to be confused with infection) is an inherent process. They occur very commonly in intraabdominal surgery because there is no regenerative layer unlike the uterus which is lined with a regenerative endometrium. Yet no intraabdominal surgeon has attempted to label the condition as ‘genetic’ or ‘constitutional. However, not surprisingly, the endometrium will not regenerate if it is entirely removed, which should not occur during curettage, but which may happen unintentionally due to the blind nature of the procedure. The situation in the uterus then becomes analogous to that in the peritoneum, and adhesion formation ensues.

Lastly, with regards to Polishuk and Sadovsky’s paper, if anything, these cases should highlight the dangers of blind curettage as a method of treating Asherman’s syndrome and miscarriage, the latter particularly in women who have had Asherman’s syndrome. It would appear that endometrial damage leading to AS predisposes to further adhesions probably by facilitating injury, even after previous treatment to restore an open cavity. This is consistent with the observation that even after corrective surgery, women who have a history of Asherman’s syndrome are at an increased risk of specific obstetric complications. It is therefore of no surprise that the common underlying characteristic of these complications is a defective utero-placental interface.

REFERENCES

1.  Foix A, Bruno RO, Davison T, Baltasar L. The pathology of postcurettage intrauterine adhesions. Am J Obst & Gynec.1966; 96(7):1027-33.
2. Schenker JG, Margoliath EJ. Intrauterine adhesions: an updated appraisal. 1982; 37(5):593-610.
3. Polishuk WZ, Sadovsky E. A syndrome of recurrent intrauterine adhesions. Am J Obstet Gynecol 1975 151-8.
4. Asherman J, Amenorrhoea traumatic (Atretica). J Obstet Gynecol 1948; Br Emp 55:23.
5. Jones W. Traumatic Intrauterine adhesion; a report of 8 cases with emphasis on therapy. Am J Obstet & Gynec 1964; 89(3):304-13.

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