Introduction 

What are uterine fibroids? 

Uterine fibroids, also known as leiomyomas, are non-cancerous growths of the smooth muscle tissue of the uterus. They are sometimes conglomerate and multiple, and vary in size from tiny (comparable to a pinhead) to large, which may be many centimetres in diameter. Some submucous fibroids develop a stem and present as a polyp extending towards the cervix. 

Studies suggest that 2 out of 3 women and other people assigned female at birth (AFAB) develop at least one fibroid in their lifetime, especially if they are between 30 and 50 years of age.

What is uterine inflammation?

The exact mechanism of fibroid development is not fully understood, but is believed to be an interplay between many factors. Inflammation has been established as one of the factors that contributes to the development of fibroids, alongside genetic mechanisms, growth factors and hormones. 

Uterine inflammation can occur due to many reasons, ranging from infection of the inner lining (endometritis), to tissue damage caused by surgical procedures or intrauterine devices (IUDs).

Understanding the role of inflammation in fibroid development can aid in the early detection of underlying diseases based on signs of inflammation. Early detection facilitates early treatment against inflammation, thereby avoiding the need for advanced treatments such as surgeries.

Understanding uterine fibroids 

Types of fibroids 

Depending on the location, fibroids can be classified into submucosal, intramural, and subserosal. 

• Submucosal - fibroids located in the cavity of the uterus
• Intramural - fibroids within the uterine muscle
• Subserosal - fibroids on the outside surface of the uterus

If your doctor suspects a fibroid during clinical assessment, they will confirm its location with ultrasound imaging. 

Common symptoms 

Fibroids can be asymptomatic (e.g. when they are detected incidentally on an ultrasound scan) or can present with symptoms. Symptoms can be broadly defined in four main categories, based on the number, size and location of the fibroids. 

Menstrual disorders

Uterine fibroids commonly present with menstrual problems, particularly heavy menstrual bleeding (menorrhagia). This is more common in submucosal fibroids since they may make the uterus bulky and irregular, and may enlarge the cavity so that there is a greater area of endometrium to be shed at menstruation.

Pressure-related symptoms

The large fibroid can compress the adjacent structures, such as the bowel and bladder, resulting in constipation and frequent urination and urgency.

Abdominal distension

You may experience symptoms related purely to the size of the fibroid. This may be a feeling of dragging or pressure in the pelvis, or simply that of abdominal swelling and pain.

Fertility problems

Fibroid cells have a chronic inflammatory effect, which stimulates uterine muscle contraction, leading to implantation failure or recurrent miscarriage.

Risk factors

Fibroids are related to factors which increase their exposure to the body's natural oestrogen, and are divided into modifiable and non-modifiable risk factors. 

• Ethnicity - fibroids are also more common in black ethnicities than in Caucasian and Hispanic populations¹
• Age - fibroids develop during the reproductive years when oestrogen levels are the highest, with an increased risk present in women more than 30 years²
• Weight - a notable study has found that the risk of developing fibroids increases by 21% for every 10 kg weight gain, especially in women with a body fat percentage greater than 30%² 
• Family history - being a first-degree relative of affected women increases the risk of developing fibroids by 2.5 times² 

Understanding uterine inflammation 

Inflammation is a defence mechanism by the body in response to an infection, damaged tissue, or exposure to an external irritant or foreign substance. Inflammation works by activating various immune pathways, which release substances called cytokines and prostaglandins (chemicals which cause pain and swelling during the process of healing) and many other key inflammatory mediators.³

These substances work together to restore the function of the affected process or organ, which will manifest as symptoms of heat, redness, swelling, pain, and loss of function. 

However, all these signs will not be evident in inflammation involving internal organs like the uterus. Uterine inflammation may manifest as only pain and swelling or show no symptoms at all. Chronic uterine inflammation is particularly recognised as a crucial mediator in the formation, growth, and sustaining mechanisms of fibroids over time.

The link between fibroids and inflammation 

Since fibroids have not been identified in pre-pubertal girls and usually shrink at the time of menopause, it has long been assumed that they are dependent on the presence of the sex hormones oestrogen and progesterone. Much of the research has concentrated on this area, which has been exploited for the purposes of developing novel medical treatments for fibroids. 

Growth of fibroids is partly dependent on the ovarian hormones that act through receptors present on both fibroid and uterine muscle cells. It is also dependent on the fat stores in the body, which serve as a peripheral oestrogen storage that can be mobilised by converting androgen to oestrogen when required. This means that the higher the body fat percentage, the higher the peripheral oestrogen concentration, and the higher the oestrogen concentration, the higher the risk of fibroids. This link is attributed to having higher levels of oestrogen when you are overweight or obese. 

This claim was further supported by scientists who found that the fibroid cells grew faster when they were placed near fat cells in a tightly regulated in vitro environment, especially when exposed to an inflammatory substance called tumour necrosis factor-alpha (TNF-α).⁴

Fibroids as a source of inflammation

Interestingly, inflammation can be both the cause and outcome of fibroids. If the condition causing acute inflammation is not resolved, the inflammation may become chronic, favouring tumour onset and development. Once the fibroid growth occurs, it will secrete cytokines such as interleukin-6 (IL-6) and TNF-α, which will maintain low-intensity chronic inflammation. These molecules promote scarring of tissue, abnormal tissue and blood vessel formation, all of which help to maintain the growth of fibroids.³ This is not only useful for the development of fibroids but also contributes to the symptoms such as heavy menstrual bleeding and pelvic pain. 

Clinical implications and health consequences 

Impact on fertility and pregnancy outcomes 

Even though the exact mechanism behind the fertility-altering effect of fibroids is unclear, it is often assumed that fibroids cause infertility since the chance of pregnancy increases after treating or removing them. 

Intramural and subserosal fibroids also cause mechanical disruption in the endometrial-myometrial junction, leading to the release of inflammatory cells called macrophages, and uterine natural killer cells from the myometrial lining of the junction. This can hinder embryo implantation, leading to pregnancy failure and recurrent miscarriages.⁵ Miscarriages are usually more common in women and other people AFAB with fibroids located in the lower segment of the uterus than in the body of the uterus.⁶ 

It is also worth noting that symptoms produced by chronic low-grade uterine inflammation can also overlap with other conditions, such as endometriosis and adenomyosis. 

Current and emerging treatments targeting inflammation 

Conventional treatments

Women and people AFAB with asymptomatic uterine fibroids do not require any active treatment except for periodic monitoring of the fibroid size and any associated symptoms. 

The treatment modalities depend on: 

• The size of the fibroids 
• The fertility wish of the person
• Pregnancy status 
• Complications and other health conditions 
• Symptomatic status and many other factors 

The treatment of fibroids has historically been surgery. The two main methods are:

• Hysterectomy - removal of the uterus with the fibroids 
• Myomectomy - conserving the uterus while removing only the fibroids 

Recently, there has been a shift of emphasis on gynaecological practice towards medical therapies. However, medical treatments do not cure the problem but are designed to bring symptomatic relief.

Anti-inflammatory agents

Since inflammation is one of the main mechanisms behind the symptoms related to fibroids, nonsteroidal anti-inflammatory drugs (NSAIDs) are given to counter this effect. NSAIDs decrease excessive bleeding and pain by reducing the synthesis of inflammatory mediators secreted by the endometrium. NSAIDs mainly aim towards achieving symptomatic relief, rather than shrinking the fibroids.

Hormonal therapies with anti-inflammatory effects

he most established medical option is gonadotropin-releasing hormone agonists (GnRH), which work by acting on GnRH receptors in the pituitary gland, thereby affecting GnRH levels.⁷ This will ultimately decrease the release of ovarian hormones and cause fibroid shrinkage, over a course of 3 months. 

This is also used prior to surgery due to its fibroid shrinking effect, which will facilitate surgeons to remove the fibroid with greater ease. GnRH agonists are usually given by monthly depot injections as the most convenient option, although other methods of administration, such as the nasal spray, are available as well. 

Surgical treatment

Surgical treatment of fibroids is mainly determined by fertility wishes. It is also recommended if the fibroid is causing symptoms which have a significant impact on daily activities, or when its location is causing issues with fertility. 

The curative option for women not seeking to preserve their fertility or keep their uterus is hysterectomy, while myomectomy is an option for those wishing to maintain fertility. Myomectomy procedure involves the removal of the fibroids via an open surgery, via a laparoscopic or a hysteroscopic procedure.

Holistic approaches

Currently, potential therapies such as vitamin D and green tea extract have been gaining recognition as anti-inflammatory compounds effective against fibroids.⁷

These alternative approaches, together with adequate exercise, managing stress and maintaining a healthy lifestyle, help decrease inflammation and mitigate symptoms. However, it is important that the treatment choice you receive is tailored to you based on underlying inflammation and fibroid status, since the effectiveness of these approaches is yet to be researched. 

Summary 

The “vicious cycle” of inflammation fostering fibroid growth, and fibroids sustaining local inflammation is an important concept which gives more insight into managing both issues more effectively. Understanding inflammation as a promoter of fibroid growth also helps doctors to look beyond just the fibroids and on a deeper level towards the root causes. This supports a more inflammation-focused treatment approach, which may help improve the quality of life, particularly in women preferring more holistic options.