To this day, there is still no medicine for dysmenorrhea.

Although in social concepts, dysmenorrhea is regarded as a common pain for women. Many women choose to endure or take painkillers to get through menstrual pain, and few people go to the doctor for this.

However, dysmenorrhea is not always harmless, and this tolerance may hide great hidden dangers.

Dysmenorrhea, especially severe dysmenorrhea, is likely to be a disease-endometriosis. Endometriosis is far more than just dysmenorrhea. It can not only invade surrounding tissues and other organs, causing complex symptoms, but also easily recur after treatment, and can only be relieved after menopause, bringing endless pain and torture to patients, and even called "immortal cancer".

Behind this, there are certainly many reasons. For example, wrong and rigid social concepts; for example, both patients and medical staff lack the awareness of early diagnosis and early treatment of endometriosis; most importantly, due to lack of money, lack of data and other reasons, pharmaceutical companies rarely set foot in this field, which has also led to a lack of effective treatment methods in clinical practice.

The situation of endometriosis may be just the tip of the iceberg among thousands of diseases, which is also the dark side of the prosperous scientific and technological progress.

And this complex situation is difficult to be completely reversed overnight.

However, we still keep looking forward to it. When more and more women realize that discomfort needs to be seen, and when endometriosis is gradually taken seriously, new changes will be born.

▍"Immortal Cancer"

Endometriosis is a disease caused by the growth of the endometrium out of its normal position.

Simply put, endometrial cells originally "live" on the mucosal layer in the uterine cavity, and undergo periodic changes under the regulation of estrogen and progesterone. It may fall off regularly and be mixed with menstrual blood and discharged from the body, or it may become a hotbed for the development of fertilized eggs.

However, some "rebellious" endometrium escapes from the uterine cavity and "sets up camp" in the pelvic peritoneum, ovaries, uterine surface, and uterosacral ligaments, causing a series of uncomfortable symptoms and adverse consequences.

As the most important clinical manifestation of endometriosis, dysmenorrhea is the body's distress signal.

Of course, endometriosis is far more than just dysmenorrhea. It can not only invade surrounding tissues and other organs, causing complex symptoms, but also easily recur after treatment, and can only be relieved after menopause. This wild growth, difficult to cure characteristics, and the pain and torture it brings to patients make it called "immortal cancer."

As a complex disease, endometriosis affects many women around the world. Epidemiological surveys show that about 10% of women of childbearing age suffer from endometriosis, and the number of patients worldwide may be close to or even exceed 200 million, and the number of patients in Asia exceeds the total of other continents.

The real data may be higher. The World Health Organization's endometriosis topic mentioned that the public and some medical staff in some areas lack awareness of early diagnosis and treatment of endometriosis. Many people think that dysmenorrhea and pelvic pain are normal processes that must be endured, thus delaying early medical treatment and treatment.

The same is true for patients. Insufficient attention to dysmenorrhea is also an important reason for the delayed diagnosis of endometriosis.

In addition, the delayed diagnosis of endometriosis is also related to its lack of effective non-invasive diagnostic methods. In the past, clinical diagnosis was usually only possible by directly observing the tissue in the uterus with the help of laparoscopic surgery. Although this method is regarded as the "gold standard" for the diagnosis of endometriosis, it will cause trauma and cost too much.

In addition, although ultrasound examination is also the main means of endometriosis examination, its accuracy is limited; another diagnostic method is gynecological examination (bimanual examination, trimanual examination), which can accurately identify endometriosis according to the location of the lesion, especially deep infiltrating endometriosis.

However, the results of the physical examination are closely related to the experience and examination skills of the physician, and not all doctors can master them proficiently.

▍Research on negative cycle

To date, there is no way to completely cure endometriosis, and all treatments are mostly aimed at controlling or relieving symptoms. The most common is taking painkillers and hormonal contraceptives to inhibit the development of lesions. In severe cases, surgery may be required to remove lesions caused by endometriosis, or even completely remove the uterus.

Usually, the large number of patients and the lack of treatments mean that the commercial prospects are broad, which often attracts the research and development layout of pharmaceutical companies. But this does not seem to be true for endometriosis.

On the one hand, it is not an easy task to develop drugs under any conditions. Especially when the disease is not well understood, the process will be more difficult.

To date, the pathogenesis of endometriosis has not been clarified.

There are some theories in the medical community that can partially explain the occurrence of endometriosis. The most popular theory is the implantation theory proposed by Sampson in 1927. The theory believes that the endometrium in the uterine cavity drifts to other parts and implants, forming the lesions of endometriosis.

Laparoscopy during the perimenstrual period found that 90% of women have retrograde menstruation, but only a small number of them develop endometriosis. This means that in addition to the migration of the endometrium, there may be other factors involved in the formation of lesions, such as gene mutations, changes in immune function, and abnormal endocrine signals.

In other words, even if some theories seem reasonable, they still cannot explain many problems, which makes the cause of endometriosis still unclear, and it is naturally difficult to take corresponding preventive and therapeutic measures based on the cause.

On the other hand, information deficit is the key reason for the lack of related drug research and development.

Researchers sometimes use biobanks - medical and biological data collected from tissues, blood and DNA samples - to identify molecular markers of diseases or develop effective diagnostic methods. If collected by government-funded projects, the data are usually published or provided to scientists, providing a starting point for drug research.

However, according to Baburek and Joseph Nassif, associate professor and clinician of obstetrics and gynecology at Baylor College of Medicine, this resource is very limited in endometriosis. Of course, change is happening, and the United States is trying to create a database for all patients with endometriosis.

In fact, this lack of information is deeply rooted. In the late 1990s, the FDA also recommended excluding women of childbearing age from participating in phase 1 and phase 2 clinical trials, even if they were using contraceptives. These policies were enacted in response to birth defects caused by the drug thalidomide.

A 1993 law requires the inclusion of women and minorities in clinical research funded by the National Institutes of Health, but the effect of blocking women from participating in trials continues to this day.

A 2022 study found that women accounted for 41% of participants in phase 1 to 3 trials of drugs and medical devices conducted in the United States between 2016 and 2019. Compared with the proportion of women in the total patient population in some diseases such as heart disease and mental disorders, women are far less represented in clinical participation.

These research gaps, and the lack of clinical information and resources they can cause, ultimately put girls and women at a "huge disadvantage."

This puts things in a negative cycle, and people know little about this disease despite its prevalence.

▍Pharmaceutical companies’ retreat

Of course, the root of everything may point to money. Endometriosis research is very underfunded, and pharmaceutical companies rarely get involved in this field.

In fact, women’s health is still underfunded compared with other areas of drug development. An analysis of research supported by the National Institutes of Health found that diseases that primarily affect men received more funding. Diseases that primarily affect women who receive investment are usually in the field of oncology, such as breast and ovarian cancer, and reproductive medicine.

Data from Silicon Valley Bank show that in 2019, the United States and Europe invested $122 billion in 3,225 biopharmaceutical transactions, of which only $1.3 billion was invested in women’s health biopharmaceutical companies.

Lack of funds is the main reason why biotechnology companies stop studying candidate drugs or prioritize other projects.

At the same time, the huge unmet clinical needs, which are not proportional to the final commercial returns, also greatly affect the enthusiasm of pharmaceutical companies to invest.

Lupron Depot, a hormone therapy originally approved for the treatment of prostate cancer, is approved in the United States for the control of pain associated with endometriosis.

The FDA has approved two other products for endometriosis pain management in the past decade: AbbVie's Orilissa in 2018 and Pfizer and partner Myovant Sciences' Myfembree in 2022.

However, these drugs are expensive, with Orilissa and Myfembree costing more than $1,000 per month at their respective list prices. They also fail to address the disease at its root and can only be used for a maximum of two years due to the potential for reduced bone density.

As a result, sales of Orilissa and Myfembree have not been ideal. Among them, three years after Orilissa was approved, AbbVie tried to sell the women's health unit where the drug was located, but the deal did not materialize. Sales of the drug are no longer reported separately, but are aggregated with "other key products" in AbbVie's financial reports.

The last time AbbVie reported net income for Orilissa was in fiscal 2021, when its U.S. sales were $139 million.

Even big pharmaceutical companies have had to turn to other areas for returns: Bayer, once a major player in women's health, said last year it would shift its focus from women's health to immunology, rare diseases and neurology.

Bayer has long sold a hormone drug called Visanne for the treatment of endometriosis-related pain. It has also worked with researchers in the United States and the United Kingdom to help identify inflammatory genes that may be associated with endometriosis. A Bayer spokesman said that while the discovery seemed to point to possible non-hormonal drug targets, further research "ultimately did not advance development."

According to Reuters, the reason is that Bayer's overall work in women's health "did not meet expectations."

▍Summary

The situation of endometriosis may be just the tip of the iceberg among thousands of diseases.

After all, the human body is a mysterious and complex organization, and the lack of relevant disease mechanisms and clinical data has made us still lack understanding of many diseases, which is also the dark side of the prosperity of scientific and technological progress.

Coupled with the inherent and wrong social cognition of diseases, it will further hinder new changes.

However, we still have to keep looking forward. Setbacks and risks have always been common in the development of new drugs, which will not change the trend of new drugs moving forward. Groundbreaking research is often a technical trigger point, leading to the explosive growth of new drug research.

Whether it is endometriosis or other diseases that are in urgent need of new treatments, they are waiting for such a trigger point.