Submucosal Fibroids – Causes, Symptoms, Treatment

Submucosal Fibroids are the most common type, located in the muscle beneath the endometrium of the uterus and distort the uterine cavity; even small lesions in this location may lead to bleeding and infertility. A pedunculated lesion within the cavity is termed an intracavitary fibroid and can be passed through the cervix.

Uterine Fibroids are the most common benign tumor affecting women. Fibroids originate from uterine smooth muscle cells (myometrium) whose growth is primarily dependent on the levels of circulating estrogen. Fibroids can either present as an asymptomatic incidental finding on imaging, or symptomatically. Common symptoms include abnormal uterine bleeding, pelvic pain, disruption of surrounding pelvic structures(bowel and bladder), and back pain. Uterine fibroids typically are seen in three significant locations: subserosal (outside the uterus), intramural (inside the myometrium), and submucosal (Inside the uterine cavity). They can further be broken down to pedunculated or not. Fibroids are classically diagnosed by physical exam and ultrasound imaging, which carries a high sensitivity for this pathology. Fibroids continue to be the leading indication for hysterectomy. [rx]

Uterine fibroids, also known as uterine leiomyomas or fibroids, are benign smooth muscle tumors of the uterus. Most women have no symptoms while others may have painful or heavy periods. If large enough, they may push on the bladder causing a frequent need to urinate. They may also cause pain during sex or lower back pain.^[rx][rx] A woman can have one uterine fibroid or many. Occasionally, fibroids may make it difficult to become pregnant, although this is uncommon.^[rx]

Types of Uterine Fibroids

Growth and location are the main factors that determine if a fibroid leads to symptoms and problems.^[6] A small lesion can be symptomatic if located within the uterine cavity while a large lesion on the outside of the uterus may go unnoticed. Different locations are classified as follows:

• Intramural fibroids are located within the muscular wall of the uterus. Unless they are large, they may be asymptomatic. Intramural fibroids begin as small nodules in the muscular wall of the uterus. With time, intramural fibroids may expand inwards, causing distortion and elongation of the uterine cavity.
• Subserosal fibroids  – are located on the surface of the uterus. They can also grow outward from the surface and remain attached by a small piece of tissue and then are called pedunculated fibroids.^[rx]
• Submucosal fibroids – are most common type, located in the muscle beneath the endometrium of the uterus and distort the uterine cavity; even small lesions in this location may lead to bleeding and infertility. A pedunculated lesion within the cavity is termed an intracavitary fibroid and can be passed through the cervix.
• Cervical fibroids – are located in the wall of the cervix (neck of the uterus). Rarely, fibroids are found in the supporting structures (round ligament, broad ligament, or uterosacral ligament) of the uterus that also contain smooth muscle tissue.

Fibroids may be single or multiple. Most fibroids start in the muscular wall of the uterus. With further growth, some lesions may develop towards the outside of the uterus or towards the internal cavity. Secondary changes that may develop within fibroids are hemorrhage, necrosis, calcification, and cystic changes. They tend to calcify after menopause.^[rx]

If the uterus contains too many to count, it is referred to as diffuse uterine leiomyomatosis.

Extrauterine fibroids of uterine origin, metastatic fibroids

Fibroids of uterine origin located in other parts of the body, sometimes also called parasitic myomas have been historically extremely rare, but are now diagnosed with increasing frequency. They may be related or identical to metastasizing leiomyoma.

They are in most cases still hormone dependent but may cause life-threatening complications when they appear in distant organs. Some sources suggest that a substantial share of the cases may be late complications of surgeries such as myomectomy or hysterectomy. Particularly laparoscopic myomectomy using a morcellator has been associated with an increased risk of this complication.^[rx][rx][rx]

There are a number of rare conditions in which fibroids metastasize. They still grow in a benign fashion, but can be dangerous depending on their location.^[rx]

• In leiomyoma with vascular invasion – an ordinary-appearing fibroid invades into a vessel but there is no risk of recurrence.
• In intravenous leiomyomatosis – leiomyomata grow in veins with uterine fibroids as their source. Involvement of the heart can be fatal.
• In benign metastasizing leiomyoma – leiomyomata grow in more distant sites such as the lungs and lymph nodes. The source is not entirely clear. Pulmonary involvement can be fatal.
• In disseminated intraperitoneal leiomyomatosis – leiomyomata grow diffusely on the peritoneal and omental surfaces, with uterine fibroids as their source. This can simulate a malignant tumor but behaves benignly.

Causes of Uterine Fibroids

The exact pathophysiology behind the development of uterine fibroids is unclear.[rx] Research suggests that the starting event for fibroid development begins with a single uterine smooth muscle cell(myometrium), which is then followed by deviations from the normal signaling pathways of cellular division.[rx] Fibroids are considered to be estrogen-dependent tumors, and there is evidence showing that leiomyomas overexpress certain estrogen and progesterone receptors when compared to normal surrounding myometrium.[rx]

Fibroids are a result of the inappropriate growth of uterine smooth muscle tissue or myometrium. Their growth is dependent on estrogen and progesterone levels. The underlying pathophysiology is uncertain.

• Genetic changes – Many fibroids contain changes in genes that differ from those in normal uterine muscle cells.
  Hormones – Estrogen and progesterone, two hormones that stimulate development of the uterine lining during each menstrual cycle in preparation for pregnancy, appear to promote the growth of fibroids. Fibroids contain more estrogen and progesterone receptors than normal uterine muscle cells do. Fibroids tend to shrink after menopause due to a decrease in hormone production.
• Other growth factors – Substances that help the body maintain tissues, such as insulin-like growth factor, may affect fibroid growth.
• Extracellular matrix (ECM) – ECM is the material that makes cells stick together, like mortar between bricks. ECM is increased in fibroids and makes them fibrous. ECM also stores growth factors and causes biologic changes in the cells themselves.
• Fibroids can grow
  • In the muscle wall of the uterus (myometrial)
  • Just under the surface of the uterine lining (submucosal)
  • Just under the outside lining of the uterus (subserosal)
  • On a long stalk on the outside the uterus or inside the uterus (pedunculated)

Fibroids are more common in the following groups of women

• Black women: Fibroids are two to three times more common in black women – but the exact reason is not known.
• Women who have never been pregnant.
• Women whose mother or sister has had fibroids.
• Women who are very overweight. But it’s not clear whether the extra weight itself is the cause.

Fibroids are less common in these women

• Women who have had several children.
• Women who have used birth control pills for several years.

It’s not clear whether there’s a link between your diet and the development of fibroids.

Symptoms of Uterine Fibroids

Many women who have fibroids don’t have any symptoms. In those that do, symptoms can be influenced by the location, size and number of fibroids.

In women who have symptoms, the most common signs and symptoms of uterine fibroids include

• Heavy menstrual bleeding
• Menstrual periods lasting more than a week
• Pelvic pressure or pain
• Heavy bleeding (which can be heavy enough to cause anemia) or painful periods
• Feeling of fullness in the pelvic area (lower stomach area)
• Enlargement of the lower abdomen
• Frequent urination
• Pain during sex
• Bleeding between periods
• Heavy bleeding during your period, sometimes with blood clots
• Periods that may last longer than normal
• Needing to urinate more often
• Pelvic cramping or pain with periods
• Feeling fullness or pressure in your lower belly
• Pain during intercourse
• Complications during pregnancy and labor, including a six-time greater risk of cesarean section
• Reproductive problems, such as infertility, which is very rare
• Frequent urination
• Difficulty emptying the bladder
• Constipation
• Backache or leg pains

Rarely, a fibroid can cause acute pain when it outgrows its blood supply, and begins to die.

Fibroids are generally classified by their location. Intramural fibroids grow within the muscular uterine wall. Submucosal fibroids bulge into the uterine cavity. Subserosal fibroids project to the outside of the uterus.

Diagnosis of Uterine Fibroids

History and Physical

• History and physical exam include a thorough menstrual history to determine the timing, quantity, and any potential aggravating factors for the abnormal bleeding. Common presenting symptoms include metrorrhagia, menorrhagia, or a combination of the two. Less common presenting symptoms include dyspareunia, pelvic pain, bowel problems, urinary symptoms, or signs and symptoms related to anemia. Most of the less frequent symptoms are a reflection of the mass effect produced by leiomyomas on surrounding structures. Patients may also be completely asymptomatic with an incidental finding of fibroids on imaging.
• A speculum exam with a bimanual exam should be performed to rule out any vaginal or cervical pathology, as well as assess the size, and shape of the female reproductive organs. A large asymmetric uterus felt upon the exam is indicative of fibroids. Finally, consider evaluating for conjunctival pallor and thyroid pathology to identify potential secondary symptoms or causes of abnormal bleeding.

Laboratory studies

• The initial evaluation should include a beta-human chorionic gonadotropin test to rule out pregnancy, CBC, TSH, and a prolactin level to evaluate for the non-structural causes in the differential. Include an endometrial biopsy for women over 35.
• The International Federation of Gynecology and Obstetrics (FIGO) has developed a classification system that allows for the determination of the extent of invasion into the endometrial cavity. The FIGO scale ranges from 0 to 8, with the lower number indicating closer proximity to the endometrium[rx][rx].
• If bleeding is the predominant symptom and there is a concern for anemia or other sequelae of recurrent blood loss, a complete blood count (CBC) is indicated. Further evaluation of blood work should include a thyroid-stimulating hormone level to rule out thyroid disease as the cause of abnormal bleeding if the index of suspicion is low for leiomyomata as the etiology [rx].

Radiologic studies

• Transvaginal ultrasound – is the gold standard for imaging uterine fibroids. It has a sensitivity of around 90 to 99% for the detection of uterine fibroids. Ultrasound can improve with the use of saline-infused sonography, which helps increase the sensitivity for the detection of subserosal and intramural fibromas.[rx][rx] Fibroid appearance is as a firm, well-circumscribed, hypoechoic mass. On ultrasound, tend to have a variable amount of shadowing, and calcifications or necrosis may distort the echogenicity.[rx]
• Ultrasound – Ultrasounds use sound waves to take a picture of your uterus. A technician will place a device either in your vagina or on your abdomen to get the images. Then your doctor can see if you have fibroids and where and how large they are.
• Lab tests – Your doctor may want you to have blood tests to help figure out why you have fibroids. Your complete blood count (CBC) can help them decide whether you have anemia (low levels of red blood cells) or other bleeding disorders.
• Magnetic resonance imaging (MRI) – If your doctor needs more information after you have an ultrasound, you may also have an MRI. MRIs show more detailed images of fibroids and can help doctors decide the best treatment. Your doctor may also suggest an MRI if you have a large uterus or are close to menopause.
• Hysterosonography – In this test, a technician pushes saline into your uterine cavity to make it larger. This helps them see fibroids that are growing into your uterus (submucosal fibroids) and the lining of your uterus. This is useful if you’re trying to get pregnant or have heavy periods.
• Hysterosalpingography – If your doctor needs to see if your fallopian tubes are blocked, you might have a hysterosalpingography. Your doctor uses dye to highlight your uterus and fallopian tubes on an X-ray to help see these areas better.
• Hysteroscopy – is where the physician uses a hysteroscope to visualize the inside of the uterus. This imaging modality allows for better visualization of fibroids inside the uterine cavity. This method allows for the direct removal of intrauterine growths during the procedure.
• Electric Magnetic Resonance Imaging MRI – has the benefit of providing a better picture of the number, size, vascular supply, and boundaries of the fibroids as they relate to the pelvis. Nevertheless, it is unnecessary for a routine diagnosis when fibroids are suspected. It has not been shown to differentiate leiomyosarcoma from leiomyoma.[rx]
• Hysterosalpingography – is a special X-ray test. It may detect abnormal changes in the size and shape of the uterus and fallopian tubes.
• Sonohysterography – is a test in which fluid is put into the uterus through the cervix. Ultrasonography is then used to show the inside of the uterus. The fluid provides a clear picture of the uterine lining.
• Laparoscopy – uses a slender device (the laparoscope) to help your health care professional see the inside of the abdomen. It is inserted through a small cut just below or through the navel. Fibroids on the outside of the uterus can be seen with the laparoscope.

Treatment of Uterine Fibroids

While deciding on treatment options for uterine fibroids, the patient’s age, presenting symptoms, and desire for fertility preservation all merit consideration. The locations and size of the fibroids will both determine the available treatment options.[rx] Management options can be broken down into three categories starting at surveillance with progression to medical management or surgical therapy with increasing severity of symptoms.

Surveillance – This is the preferred method in women with asymptomatic fibroids. The current recommendations do not require serial imaging when following these patients.[rx]  Most fibroids do not require treatment unless they are causing symptoms. After menopause, fibroids shrink, and it is unusual for them to cause problems.

Symptomatic uterine fibroids can be treated by

• medication to control symptoms (i.e., symptomatic management)
• medication aimed at shrinking tumors
• ultrasound fibroid destruction
• myomectomy or radiofrequency ablation
• hysterectomy
• uterine artery embolization

In those who have symptoms, uterine artery embolization and surgical options have similar outcomes with respect to satisfaction.^[rx]

Medical Management

Primarily revolves around decreasing the severity of bleeding and pain symptoms.

• Gonadotropin-releasing hormone (GnRH) agonists. Medications called GnRH agonists treat fibroids by blocking the production of estrogen and progesterone, putting you into a temporary menopause-like state. As a result, menstruation stops, fibroids shrink and anemia often improves. GnRH agonists include leuprolide (Lupron, Eligard, others), goserelin (Zoladex) and triptorelin (Trelstar, Triptodur Kit). Many women have significant hot flashes while using GnRH agonists. GnRH agonists typically are used for no more than three to six months because symptoms return when the medication is stopped and long-term use can cause loss of bone. Your doctor may prescribe a GnRH agonist to shrink the size of your fibroids before a planned surgery or to help transition you to menopause.
• Progestin-releasing intrauterine device (IUD). A progestin-releasing IUD can relieve heavy bleeding caused by fibroids. A progestin-releasing IUD provides symptom relief only and doesn’t shrink fibroids or make them disappear. It also prevents pregnancy.
• Tranexamic acid (Lysteda, Cyklokapron). This nonhormonal medication is taken to ease heavy menstrual periods. It’s taken only on heavy bleeding days. Tranexamic acid improves blood clotting and is used to reduce heavy menstrual bleeding and to minimize postoperative blood loss. Tranexamic acid is a derivative of the amino acid, lysine.  This medication is a reversible inhibitor of lysine receptor sites on plasminogen that, when bound, prevent fibrin degradation and functionally stabilize clot formation [rx].
• Selective estrogen receptor modulators –  bind to estrogen receptors to mimic or block estrogen activity, and have differential effects across tissue types (e.g., bone, brain, liver). Tamoxifen was introduced to block estrogen action in the treatment of breast cancer, but has estrogen–like effects on the uterus. Raloxifene has estrogen-like effects on bone, but anti-estrogen effects in the breast and uterus. It is used to treat osteoporosis and prevent breast cancer, and reduce fibroid size.
• Hormonal contraceptives – This treatment group includes oral contraceptive pills (OCP) and the levonorgestrel intrauterine device(IUD). OCPs are common options in the management of abnormal uterine bleeding related to symptomatic fibroids. However, there is only limited data showing their effectiveness in uterine fibroids, and larger randomized controlled trials are necessary.[rx][rx][rx] The levonorgestrel IUD is currently the recommended hormonal therapy for symptomatic fibroids due to the lack of systemic effects and low side effect profile.[rx] Caution should is necessary when treating fibroids that distort the intrauterine cavity as they can lead to a higher rate of expulsion.
• GnRH Agonist (leuprolide) – This method works by acting on the pituitary gland to decrease gonadal hormone production, thus decreasing the hormone-stimulated growth of the fibroid. A study by Friedman et al. showed a decrease in uterine size by 45% at 24 weeks of treatment on a GnRH agonist with a return to pretreatment size 24 weeks after cessation.[rx] Long-term therapy with a GnRH agonist has also been shown to result in statistically significant bone loss. Because of this and its relatively short-term effect, the American College of Obstetricians and Gynecologists (ACOG) has recommended that it’s use be limited to 6 months or less.[rx][rx][rx] Leuprolide is most effective when used as a pre-surgical therapy for symptomatic fibroids.[rx]
• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) – Anti-inflammatories have been shown to decrease prostaglandin levels, which are elevated in women with heavy menstrual bleeding and are responsible for the painful cramping experienced in menstruation. They have not been shown to decrease the size of the fibroids.[rx]
• Levonorgestrel intrauterine devices –  are effective in limiting menstrual blood flow and improving other symptoms. Side effects are typically few as the levonorgestrel (a progestin) is released in low concentration locally.^[rx] While most levongestrel-IUD studies concentrated on treatment of women without fibroids a few reported good results specifically for women with fibroids including a substantial regression of fibroids.^[rx][rx]
• Cabergoline – in a moderate and well-tolerated dose has been shown in two studies to shrink fibroids effectively. The mechanism of action responsible for how cabergoline shrinks fibroids is unclear.^[rx]
• Ulipristal acetate – is a synthetic selective progesterone receptor modulator (SPRM) that has tentative evidence to support its use for presurgical treatment of fibroids with low side-effects.^[rx] Long-term UPA-treated fibroids have shown volume reduction of about 70%.^[rx] In some cases UPA alone is used to relieve symptoms without surgery.^[rx]
• Danazol – is an effective treatment to shrink fibroids and control symptoms. Its use is limited by unpleasant side effects. Mechanism of action is thought to be antiestrogenic effects. Recent experience indicates that safety and side effect profile can be improved by more cautious dosing.^[rx]
• Progesterone antagonists – such as mifepristone have been tested, there is evidence that it relieves some symptoms and improves quality of life but because of adverse histological changes that have been observed in several trials it can not be currently recommended outside of research setting.^[rx][rx] Fibroid growth has recurred after antiprogestin treatment was stopped.^[rx]
• Aromatase inhibitors – have been used experimentally to reduce fibroids. The effect is believed to be due partially by lowering systemic estrogen levels and partially by inhibiting locally overexpressed aromatase in fibroids.^[rx] However, fibroid growth has recurred after treatment was stopped.^[rx] Experience from experimental aromatase inhibitor treatment of endometriosis indicates that aromatase inhibitors might be particularly useful in combination with a progestogenic ovulation inhibitor.

Other potential medical therapies include aromatase inhibitors, and selective estrogen receptor modulators (SERM), such as raloxifene or tamoxifen. There is little evidence supporting the use of these medications in the treatment for symptomatic uterine fibroids.[rx] Tranexamic acid has been approved for the treatment of abnormal and heavy uterine bleeding but has not been approved or shown to decrease the disease burden in uterine fibroids.[rx][rx]

Surgical Therapy

• Endometrial Ablation – It offers an alternative to surgery in patients whose primary complaint is heavy or abnormal bleeding. There is a larger risk of a failed procedure with submucosal fibroids because they cause disruption of the uterine cavity and can prevent proper cauterization of the entire endometrium.
• Uterine Artery Embolization – A minimally invasive approach for those who wish to preserve fertility. This technique works by decreasing the total blood supply to the uterus, thereby decreasing the flow to the fibroids and minimizing bleeding symptoms. The procedure has been shown effective in controlling menorrhagia. However, according to De La Cruz et al., only limited studies show the effects on fertility preservation with this technique. [rx]
• Myomectomy – An invasive surgical option for those who desire fertility preservation. There is no large randomized controlled trial showing that myomectomy can improve fertility for patients.[rx][rx] Furthermore, the outcome is highly dependent on the location and size of the fibroid.[rx][rx] Nevertheless, it can be an effective treatment option in those wishing to avoid hysterectomy.
• Hysterectomy – Hysterectomy was the classical method of treating fibroids. Although it is now recommended only as last option, fibroids are still the leading cause of hysterectomies in the US.
• Endometrial ablation – Endometrial ablation can be used if the fibroids are only within the uterus and not intramural and relatively small. High failure and recurrence rates are expected in the presence of larger or intramural fibroids.

There are three types of myomectomy

• In a hysteroscopic myomectomy (also called transcervical resection) – the fibroid can be removed by either the use of a resectoscope, an endoscopic instrument inserted through the vagina and cervix that can use high-frequency electrical energy to cut tissue, or a similar device.
• A laparoscopic – myomectomy is done through a small incision near the navel. The physician uses a laparoscope and surgical instruments to remove the fibroids. Studies have suggested that laparoscopic myomectomy leads to lower morbidity rates and faster recovery than does laparotomic myomectomy.^[53]
• A laparotomic – myomectomy (also known as an open or abdominal myomectomy) is the most invasive surgical procedure to remove fibroids. The physician makes an incision in the abdominal wall and removes the fibroids from the uterus. Laparoscopic myomectomy has less pain and shorter time in hospital than open surgery.^[rx]

Other procedures

Radiofrequency ablation is a minimally invasive treatments for fibroids.^[rx] In this technique the fibroid is shrunk by inserting a needle-like device into the fibroid through the abdomen and heating it with radio-frequency (RF) electrical energy to cause necrosis of cells. The treatment is a potential option for women who have fibroids, have completed child-bearing and want to avoid a hysterectomy.

• MRI guided focused ultrasound surgery – This treatment option utilizes MRI and ultrasound waves to focus on the fibroid, resulting in cauterization. As a relatively new treatment, there is not enough clinical evidence to support its long term effectiveness at this time.
• Hysterectomy – Remains the definitive treatment for fibroids.
• Myolysis – A needle is inserted into the fibroids, usually guided by laparoscopy, and electric current or freezing is used to destroy the fibroids.
• Uterine Fibroid Embolization (UFE), or Uterine Artery Embolization (UAE) – A thin tube is thread into the blood vessels that supply blood to the fibroid. Then, tiny plastic or gel particles are injected into the blood vessels. This blocks the blood supply to the fibroid, causing it to shrink. UFE can be an outpatient or inpatient procedure. Complications, including early menopause, are uncommon but can occur. Studies suggest fibroids are not likely to grow back after UFE, but more long-term research is needed. Not all fibroids can be treated with UFE. The best candidates for UFE are women who:
  • Have fibroids that are causing heavy bleeding
  • Have fibroids that are causing pain or pressing on the bladder or rectum
  • Don’t want to have a hysterectomy
  • Don’t want to have children in the future