International Medical Conference Endometriosis 2025:
Endometriosis 2025: Your Mother Should Know, Your Doctor Should Know Better!
Keynote: A Neo-evolutionary Approach to the Secondary Prevention of Adenomyosis and Endometriosis - Paolo Vercellini, MD
Hello to everybody. I would like to thank Dr. Seckin, the organizer of this meeting. I am really honored to have been given a keynote lecture, and today I would like to propose you a neo evolutionary approach to the secondary apprehension of aosis and endometriosis. These are my financial competing interests. For the last, the past five years, I received money from Walter Kluber's for chapters and resource up to date, and I undertake both public and private gynecological practice. I would like to propose you an evolutionary view on the potential pathogenesis of adenomyosis and endometriosis is everything that I will tell you today. Definitively proven, no. Some pieces of the entire framework are demonstrated, definitively demonstrated, but it seems that the various pieces of the jigsaw puzzles fit together very well. And I would like to show you the what is our hypothesis and to share our view on this very frequent.
And as we know, very potentially severe disorder. In general, we must say that evolutionary medicine has received too little attention in the past year, whereas we know that several diseases originate from a so-called mismatch between the adaptation to ancient environment and the rapid changes of the living conditions, which create is called mismatch because selection and adaptation is a very long process. Therefore, if the living condition, the environment changes very rapidly in evolutionary terms and mismatch originates. Indeed, it's not only a matter of genetics and experts in the fields highlights that environmental and social factors may be as important as genetics. I would like to take you through what we believe. I say we, because I'm working with a group of people and when I talk, I talk also on behalf of my friends and colleagues such as Pagano and Ana. We worked together since decades and we share the same view and we believe that adenomyosis endometriosis may be a multi-step disorders that originates from evolutionary issues, as we will see.
First of all, we will talk about this so-called intrauterine estrogenic imprinting, which is a sort of imprinting that cells and tissue receives while during the intrauterine life. And this first hormonal experience, which might be dichotomized between high estrogen or high androgens or low estrogen, low androgens always in terms of ratio, estrogen to testosterone, estradiol to testosterone ratios may give an imprint to cells and tissues. And this first intrauterine experience may epigene genetically alter the set point for the lateral more response in mouths. This delayed response may be triggered by secondary or mono events such as typically the onset of puberty. Do we have direct evidence that women with endometriosis are exposed to a high estrogenic environment? No, not at the moment, but I believe that, or I hope that very soon direct data will be published on this topic, but we have at least two indirect demonstration.
One is the measurement of the so-called anogenital distance, and in particular the ano four kettle distance. The longer this distance, the higher in general testosterone or androgen exposure. The shorter this distance in general, the higher the estrogenic exposure. What does it happens in women with endometriosis? There are several studies published. This is a systematic review published in 20 2021, which demonstrate that women with endometriosis, especially those who have severe disease at a short anogenital distance compared with control without the disease, there is another indirect indicator of high estrogen intrauterine exposure in women who will develop endometriosis. And this is the so-called two to four D JIT ratio and is already determined that this ratio is determined, is established in Ute and is negatively related to prenatal testosterone, but positively related with prenatal estradiol exposure. This is a study from our group, a case control study for our group when we demonstrated that women with endometriosis have a higher two to four digit ratio with means higher intrauterine exposure or higher estrogen to hydrogen ratio exposure.
Interestingly, in this multinational study, very large population study, it has been demonstrated that women with higher estrogenic exposure have an early monarch compared with those with a low digit ratio. Even more interestingly, it has been demonstrated that women with a high two to four digit ratio had a higher number of children and the longer reproductive span. So overall it seems that women who were exposed to higher in a higher estrogenic environment in terro and then possibly will develop endometriosis are those who are more advantaged in terms of reproduction. This may be because they might have an earlier maturation of the hypothalamic pituitary ovarian axis, so early monarchy, more cycles and earlier development of secondary sexual characteristics. So we should always think in terms of ancestral life, we should think what happened in those small villages where people live with agriculture. And so as soon as a girl was ready for reproduction, usually after a few years they got pregnant ER crespi In Natalie Deans Dale, who are developmental biologists who have published much on endometriosis, embraced this view and they believe that an evolutionary mismatch is in play here because by this hypothesis, the high number of unexpected, evolutionary, unexpected number of ary menstruation between menarchy and pregnancy seeking my disadvantage for those women who were predisposed to achieve a pregnancy very soon sooner than their so-called mating competitors.
But if this interval between menarchy and pregnancy seeking is too long, that evolutionary advantage may translate in a disadvantage and in an increased risk of developing adenomyosis and endometriosis. Until 100 of years ago, menarchy a mean age agent Menarchy was 16 years now is 12, 12.5 mean number of children when five six now is one to mean number of duration of breastfeeding was two even three years now is fourth six months exclusive breastfeeding and the mean number of menstruation between menarchy and 25 years, years of age. And we'll see why Cy was about 50 ovulatory menstruation now is three times that number and the mean number of menstruation during the interval between menarchy and the first full-term pregnancy was just 20 about crops, 20 O three cycles. Now this number is 10 times higher. Why 25 years? Because the incident of diagnosed endometriosis, so new diagnosed cases of endometriosis rise sharply at about 55 years.
However, we know very well that this very well known diagnostic delay that even today is reported to be between six and eight years with some peak at about 11, 12 years. But they say that the main delay is between six and eight years. So if we consider that the incidents occurred rises sharply at 25 years and we have a delay of six 80 years, we should imagine that the roots of endometriosis is during the adolescence, during the early postmenstrual ears. And we must be grateful to Professor Roger and Valentine Short and to Professor Marilyn Rain free, which are very famous, very productive developmental biologists, which focused on these aspects, which is a somewhat dismissed aspect in the pathogenesis of endometriosis. Because if we believe really that endometriosis derives from menstruation, we should focus also on the probability of developing the disease from based on the number of menstruation. And Rainey wonder whether monthly administration is an genic disorder of our modern western society that leads to diseases like breast cancer, endometrial cancer, ovarian cancer. This is demonstrated, this is effect n potentially to endometriosis.
So the transition prolonged the men area to prolonged cycling may be particularly detrimental for a susceptible subset of individuals, young women with a genetic profile that would once in those ancestral environment have ensure the highest likelihood of reproduction in trade transmission. But today in our environment, they are more prone to develop adenomyosis and endometriosis. Let's have a look at the pathogenic modalities through which all these ovary menstruation may lead to adenomyosis and endometriosis, whereas the in tri terrain estrogen exposure could be seen as, let's say from an oncological point of view as the initiation phase. This could be seen considered as the progression phase. And first of all is adenomyosis frequent in adolescent, in girls, young women. We conducted a systematic review with the meta-analysis and we observed that there are several available studies on this issue. Unfortunately, five out of six are from Italy. So generally IT ability is obviously limited. However, we see that in symptomatic, in symptomatic women with dysmenorrhea and heavy menstrual bleeding, one in five has ultra sonographic evidence of adenomyosis.
The percentage is slightly less than 20% in ace, so from in to 20 years, but is 30% between 20. In the 20 to 25 stratum of age menstruation means bleeding. Bleeding means iron and iron may lead to the development of adenomyosis and endometriosis. So let's say sort of progression, we know that two thirds of young women, ace with pelvic pain who undergo end laparoscopy for chronic pelvic pain symptoms have endometriosis. So both aosis and endometriosis are very frequent, much more frequent that previously bleed ly stop thought in symptomatic ace. But we also know that in these girls with adenomyosis, we have so-called the so-called hyper and DYS peristalsis, an old concept advanced by Lion Decker and colleagues. We know that the uterus has a peristaltic pattern which changes through the cycles because it's the contractions. Peristalsis has a directionality, which is from the service to the fundus in the follicular phase to facilitate spermatozoa ascension toward the tubes, followed by phase of relative quiescence after ovulation to facilitate implantation of the blasts, then followed by waves or peristaltic waves from the fundus to the surface to facilitate expulsion of the mastro material.
But we see that in this review of the literature in the recently published review of the literature, we see that women with endometriosis have a frequency or uterine contraction, but more importantly they have a DYS peristalsis, so a high risk of retrograde contraction. So from the surface to the fundus, even in the menstrual phase. And this we believe might facilitate retrograde menstruation. So it might be that hypothesis is that adenomyosis might be assisted disease, but might also be another disease with endometriosis being the daughter disease because aosis creates the condition to increase retrograde administration. And indeed, the risk of developing endometriosis in adolescence and young women with adenomyosis is more over three times higher than controls. Iron generally is, let's say roci are when they're not in excess, are phagocetized by pelvic macrophages. However, when there is too much blood in the pelvis, too many cytes, the scavenging protective mechanism of pelvic macrophages are overwhelmed and free iron is free floating in the pelvis.
And this is a very toxic event because free iron generates reactive oxygen species, which is associated with damages to cells and tissues and even DNA. So too much iron means oxidative stress, which is already very well demonstrated. So in synthesis, we must we very quickly through this hypothesis. So a subset of genetically sub susceptible women may expose their fats to a high intra relatively high estrogenic environment with a pro estrogenic imprinting, which translate in a postnatal hyper estrogenic phenotype, which means early monarchy, regular cycles, abundant flows, which means early readiness for reproduction. But with the advent of the post-industrial reproductive patterns, decreased number of term pregnancy, decreased duration of ex breastfeeding, so decreased periods of amenorrhea and increased number of repetitive of volatile menstruation, intrauterine iron, excess development of adenomyosis because of repetitive tissue injury and repair, increased retrograde menstruation, pelvic iron access. Pelvic iron access means we have given too much emphasis probably to endometrial fragments which are transported in the pelvic cavity in too little attention to blood to erythrocytes.
Too much free iron means meso damage means the nude extracellular matrix which is ready for implantation of refluxed endometrial cells and development of endometriosis. Certainly we have other factors exposure to endocrin disrupting chemicals which can add in several steps. So in the intrauterine life, in the develop aosis and endometriosis, and we have a recent hype on pelvic infections as a potential origin of endo materials, a potential cause. We consider that the presence of blood and iron constitute favorable condition for bacteria grow because blood is an excellent palu for bacteria grow. Not only, but we must not forget that one of the evolutionary mechanism to antagonize bacteria grow was iron sequestration. But if there is a lot of iron flee in the pelvis, of course this mechanism does not function.
We have observed that adenomyosis and endometriosis are very frequent, even in adolescence and young women. So we must try to diagnose timely. This for the early disease form. And a number of authoritative authors, which have also received the award from the endometriosis foundation in past years have demonstrated that it's not accessory to perform, a laparoscopy to diagnose, to have a working diagnosis of endometriosis. And indeed there are very well known symptoms and signs which must suggest we must induce to make a presumptive diagnosis of adenomyosis and endometriosis even in adulation. Superficial peritoneal endometriosis, which can be difficult to demonstrate with imaging and even with magnetic resonance should be systematically suspected in all ace and young women with severe dysmenorrhea, heavy menstrual bleeding and pelvic pain symptoms regardless of non-invasive test results, even if they are negative. Also because symptomatic young patients should always be treated to improve their quality of life, can we prevent progression of these disorders?
Secondary prevention aims to reduce the impact of disease or injury that has already occurred. This is done by detecting and treated disease or injury as soon as possible to heart as low is progressed. We know that if untreated adenomyosis is progressive in one third of women compared with almost half of those treated or mono, the same is through for so-called deep infiltrating endometriosis, which is progressive in without hormonal treat any more than one woman out of five. And the risk of progression is almost half in those who are hormonally treated. And there is also a direct effect on lesions with almost one third of volume reduction under treatment, which are the potential, the tradeoffs of treating these young women. These A lesions, certainly part of them will experience adverse effects, adverse events. However, when treated with very low dose oral contraceptives or progestogen, including intrauterine device releasing leave or gere, if we do not suggest, indicate secondary prevention by suppressing of atory administrations, what are the potential harms of letting these diseases progress?
Increased risk of menorrhagia dysmenorrhea endometriosis in case of aosis, infertility miscarriage. So also potential effect not only on fertility and on pain, but also on the obstetric outcome, increased risk of miscarriage, preeclampsia, intrauterine growth restriction, placenta premia, placenta preta, placenta previous, especially in women with deep infiltrating endometriosis and therefore in case of hemorrhage at cesarean delivery, increased risk of hysterectomy. So these are all the risk that should be explained to parents of ACE with a diagnosis of early onset adenomyosis and endometriosis. In conclusion, yes, we had a dream. We might have dream because the goal is to intercept adenomyosis and endometriosis as early as possible because if we can stop these diseases, many patients would no longer be faced with advanced disease without the known and potentially dramatic sequelae. The hypothesis that we in this occasion propose to you is to test weather changing the approach to endometriosis management from treating anatomic complications to preventing an atomic complication is clinically effective and cost effective.
We don't know at the moment, but meanwhile, long-term menstrual suppression would improve quality of life anyway. And I would like to conclude my presentation, remembering the words of two very famous investigators. One is Mamud fatal who wrote a few years ago that while the modern woman now makes much less use of reproductive potential, the evolved system machine edited from our ancestors continues incessantly to function. Innovo is proposedly released every month. The endometrial continues to be exposed to cyclic or Mona exposure. Roger Valentine Short, who many, many years ago already wrote that we should try to recapture while civilization has destroyed. That is the ability to keep the ovaries and the reproductive tract. In a state of Ians where a production is not desired. Women may be physiologically ill adapted to spend the greater part of their reproductive lives having an endless succession succession of mess cycle. Thank you. Thank you very much.
