Alternatives to Hysterectomy for Dysfunctional Uterine Bleeding

Abstract

Hysterectomy is a major surgical procedure that is performed through conventional laparotomy, laparoscopy and robotic surgery, or through the vaginal route to avoid abdominal wall incisions. In certain situations, both the abdominal and vaginal routes are used in combination. Hysterectomy is indicated for malignancies of the uterus, uterine cervix, and ovaries; to reduce the risk of future malignancies and genital prolapse; and for dysfunctional uterine bleeding. Dysfunctional uterine bleeding is an aberration caused by hormonal imbalance that is not related to the normal menstrual cycle, with no clear etiology in most cases. Dysfunctional uterine bleeding can be treated medically or surgically. Medical treatment includes non-steroidal anti-inflammatory drugs, the combined oral contraceptive pills, progestogens, danazol, analogs of gonadotrophin-releasing hormone, and the anti-fibrinolytic tranexamic acid. Endometrial ablation and hysterectomy are common routine, low-risk surgical procedures for dysfunctional uterine bleeding but are associated with some comparatively rare serious complications, both operatively and post-operatively. All types of endometrial ablation and hysterectomy remain a mainstay of alternative options for patients where the medical approach proves to be ineffective or is associated with intolerable side effects.

1. Introduction

Dysfunctional uterine bleeding is an aberration bleeding that is not related to the normal menstrual cycle. The normal cycle is controlled by hormones that are produced in the right concentration at the right time of the menstrual cycle. Dysfunctional uterine bleeding occurs when the cycle’s hormones are imbalanced. In general, no clear etiology can be identified in most cases of dysfunctional uterine bleeding.

In the past, the broad term abnormal uterine bleeding was used to include various etiologies, causing changes in regularity and volume of the bleed, which have been present for 6 months or more, whereas dysfunctional uterine bleeding only covered ovulatory disorders.

Abnormal uterine bleeding, as defined by the Fédération International de Gynécologie et d’Obstétrique (FIGO), in 2011, included polyps, adenomyosis, leiomyomata, malignancy, hyperplasia, coagulopathy, ovulatory, endometrial, iatrogenic, and other unclassified disorders. The acronym PALM-COEIN was used to cover the causes of abnormal uterine bleeding. Bleeding associated with pregnancy was excluded.

Traditionally, various terms were used to describe abnormal uterine bleeding, such as menorrhagia for regular heavy menses, metrorrhagia for irregular menses, polymenorrhea for menses more frequent than every 21 days, and oligomenorrhea for menses that takes place every 35 days or more.

This chapter very briefly outlines hysterectomy and its most common complications, followed by alternatives that may be considered before embarking on this surgical option.

2. Hysterectomy

Hysterectomy is a major procedure that is performed through either the abdominal or vaginal route. Abdominally, the procedure is performed through conventional laparotomy, laparoscopic and robotic surgery. Vaginal hysterectomy avoids abdominal wall incisions. In certain situations, both the abdominal and vaginal routes are used in combination.

Hysterectomy is indicated for malignancies of the uterus, uterine cervix, and ovaries; to reduce the risk of future malignancies as in cases of BRCA mutations; and in Lynch syndrome. In addition, it is indicated for benign conditions that include genital prolapse and for dysfunctional uterine bleeding [1, 2].

Although hysterectomy is a common routine, low-risk surgical procedure, it is associated with some comparatively rare serious complications, both operatively and post-operatively.

3. Hysterectomy complications

The most common complications of hysterectomy may include infection in up to 13% of patients, venous thromboembolism in up to 12% of patients, and genitourinary and gastrointestinal tract injuries in up to 0.6% of patients [3, 4, 5].

Blood loss at hysterectomy is about 500 ml; vaginal cuff dehiscence occurs in up to 4% of patients; serious anesthetic complications such as neuropathy, allergy, and death occur in 0.00001% of cases of general anesthesia [3, 4, 5].

Hysterectomy may affect the blood supply to the ovaries that may predispose to menopausal symptoms, osteoporosis and ischemic heart disease, lower libido, depression, loss of reproductive capability, negative effect on femininity perception, and a mortality rate of up 1.6 per 1000 hysterectomies [3, 4, 5].

In a study that assessed the costs, hospital admission rates, and mortality of 376,246 total hysterectomies, the mortality rates were 0.26%, 0.09%, 0.07%, and 0.05% for supracervical, total abdominal, laparoscopic, and vaginal hysterectomies, respectively [6].

In the same study, total abdominal hysterectomy was financially the costliest of all types, followed by vaginal hysterectomy, supracervical abdominal hysterectomy, and laparoscopic hysterectomy. It was concluded that total abdominal hysterectomy had the highest overall financial cost [6].

4. Alternatives to hysterectomy

Dysfunctional uterine bleeding can be treated medically or surgically. Medical treatment includes non-steroidal anti-inflammatory drugs, the combined oral contraceptive pills, progestogens, the synthetic androgen danazol, analogs of gonadotrophin-releasing hormone (GnRH agonists), and the anti-fibrinolytic tranexamic acid.

5. Non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs reduce the levels of prostaglandins that may be elevated in cases of menorrhagia and dysmenorrhea.

In a metanalysis of nine randomized controled trials, where 759 women were included in the review, prostaglandins were higher in women with heavy menstrual bleeding and were reduced by the administration of non-steroidal anti-inflammatory drugs that were modestly effective compared to tranexamic acid, danazol, and levonorgestrel-releasing intrauterine system (LNG IUS). Those findings were based on a limited number of low- to moderate-quality trials [7].

Similar conclusions were made by a study of published Cochrane Reviews on heavy menstrual bleeding interventions in the Cochrane Database of Systematic Reviews [8].

6. Combined oral contraceptive pills

The combined oral contraceptive pill has various benefits that include the reduction of menstrual blood loss through the regular shedding of a thinner endometrium and the inhibition of ovulation [9].

In a search of the Menstrual Disorders and Subfertility Group trials register for all publications that describe randomized trials of oral contraceptive pills for the treatment of menorrhagia, there was no significant difference in menstrual blood loss between women treated with the oral contraceptive pill and a low dose of danazol, mefanamic acid, or naproxen [9].

A prospective study of 50 women that compared the efficacy and compliance of combined hormonal vaginal ring and oral contraceptive pill in patients with heavy menstrual bleeding suggested that the combined hormonal vaginal ring and oral contraceptive pill are very effective in the short-term therapy for heavy menstrual bleeding [10].

7. Progestogens

Regarding progestogens, a prospective observational cohort study found that medication therapy for women with heavy menstrual bleeding can be successfully implemented at primary care centers, with a low rate of surgery, in conjunction with an improvement in their quality of life [11].

Menorrhagia is a common indication for hysterectomy. Adenomyosis and endometriosis are common causes of menorrhagia and pelvic pain in women of reproductive age; therefore, progestogens could be considered as an alternative to hysterectomy.

In this context, a study aimed at evaluating the effects of etonogestrel implants on pelvic pain and menorrhagia in patients that had not completed their families, thus requiring long-acting reversible contraception and being sufferers from adenomyosis or endometriosis. One hundred women with adenomyosis or endometriosis received etonogestrel implants and were followed-up for 24 months. Of these, 74 women completed the 24-month follow-up. There was a significant decrease in pelvic pain and menstrual blood loss [12].

It was concluded that etonogestrel implants were effective in reducing pelvic pain and menstrual flow in women with adenomyosis or endometriosis [12].

8. Danazol

Danazol was synthesized in 1963 and was introduced for medical use in 1971 [13, 14, 15]. The mechanism of action of danazol is complex. It acts as a weak androgen, a functional antiestrogen, an anabolic steroid, a weak antigonadotropin, a weak progestogen, and a weak steroidogenesis inhibitor [16, 17, 18, 19, 20, 21, 22, 23].

Danazol may be prescribed in cases for endometriosis, fibrocystic breast disease, hereditary angioedema, and other conditions [16, 17, 18, 19, 20, 21, 22, 23].

Danazol has been shown to be effective in controlling symptomatic primary menorrhagia [24]. It has to be noted that the use of danazol may be associated with some unacceptable masculinizing side effects such as acne, excessive hair growth, breast atrophy, hot flashes, voice deepening, mood changes, and other long-term side effects [17, 25].

9. Gonadotrophin-releasing hormone analogs

The analogs of gonadotrophin-releasing hormone could be utilized as one of the approaches for the medical management of dysfunctional uterine bleeding. Gonadotrophin-releasing hormone modulators exert their action through their effect on the secretion of the gonadotropins, follicle-stimulating hormone and luteinizing hormone [26, 27, 28, 29, 30, 31, 32].

This action, in turn, suppresses the function of the ovaries and their hormone production of sex steroids, including that of estrogen and progesterone, with subsequent endometrial atrophy and improvement of hemoglobin levels [26, 27, 28, 29, 30, 31, 32].

Add-back therapy may be considered in cases of long-term use of gonadotrophin-releasing hormone analogs to prevent adverse effects on bone density and vasomotor symptoms without nullifying gonadotrophin-releasing hormone analogs’ therapeutic effect.

A combination of both estrogen and progestin or progestin only have been prescribed as add-back therapy with gonadotrophin-releasing hormone analogs. Norethindrone acetate has been used as add-back therapy, as this unique progestin has both estrogenic and androgenic properties, that have been shown to be effective in reducing gonadotrophin-releasing hormone analogs’ side effects [33, 34].

10. The anti-fibrinolytic tranexamic acid

The anti-fibrinolytic tranexamic acid exerts its effect by blocking lysine binding sites on plasminogen. This prevents plasmin from acting with lysine residues that affects the fibrin polymer, thus resulting in fibrin degradation in a reversible manner.

In a review that focused on the efficacy and safety of tranexamic acid in the treatment of idiopathic heavy menstrual bleeding, it was found that tranexamic acid was an effective therapy for heavy menstrual bleeding. It reduced menstrual blood loss by up to 60%, being significantly more effective than placebo, nonsteroidal anti-inflammatory drugs, oral cyclical luteal phase progestins, or oral etamsylate [35].

Adverse effects of tranexamic acid are infrequent, with no evidence of an increase in thrombotic events that are related to its use [35].

An active thromboembolic disease or a history of thrombosis or thromboembolism or thrombophilia are considered contraindications for its use [35].

11. Levonorgestrel-releasing intrauterine system

Regarding the utility of the levonorgestrel-releasing intrauterine system in the treatment of dysfunctional uterine bleeding and dysmenorrhea, a thorough and critical overview of previously published research found that that the insertion of a levonorgestrel-releasing intrauterine system was an effective modality in the long term [36].

The original idea for the insertion of a progestogen-releasing device inside the uterus was to utilize it as a long-term contraceptive method. The early devices were associated with unacceptable rates of ectopic pregnancies in cases of contraception failure. On the other hand, it was soon discovered that the system had other useful therapeutic applications, especially for the non-surgical treatment of dysfunctional uterine bleeding [36, 37, 38, 39].

Furthermore, levonorgestrel-releasing intrauterine system (LNG-IUS) use in dysfunctional uterine bleeding and dysmenorrhea improves the quality of life, not only by the reduction of menstrual blood loss better than other medical therapies but also by reducing the extent of dysmenorrhea and pelvic pain. In addition, another benefit for some patients is the fact that the system is able to induce amenorrhea, thus eliminating heavy menstrual bleeding and associated dysmenorrhea in women of all ages, especially when contraception is required [39, 40, 41, 42].

The levonorgestrel-releasing intrauterine system may be prescribed for anticoagulated patients presenting with dysfunctional uterine bleeding. This approach is associated with a significant reduction in blood loss and an increase in hemoglobin level after less than 6 months of therapy [43].

It has to be noted that with the use of the levonorgestrel-releasing intrauterine system to treat dysfunctional uterine bleeding in patients on anticoagulants, some may experience no improvement, or even experience worsening of their original heavy menstrual blood loss to an unacceptable degree [44].

Glanzmann thrombasthenia is a rare, inherited blood coagulation disorder characterized by defects in the platelet membrane glycoproteins IIb/IIIA. Symptoms of this disorder usually include abnormal bleeding, which may be severe. Female patients with this condition are often troubled with heavy menstrual bleeding [45].

Some adolescents with Glanzmann thrombasthenia have issues with heavy menstrual bleeding beginning at menarche. In a report by Lu and Yang, levonorgestrel-releasing intrauterine system for treatment of heavy menstrual bleeding in adolescents with Glanzmann's thrombasthenia was shown to be associated with a significant reduction of menstrual blood loss along with an improved quality of life [45].

Levonorgestrel-releasing intrauterine system is a potential alternative to other modalities that include anti-fibrinolytics, nonsteroidal anti-inflammatory drugs, and hormonal therapies that are effective, but could be associated with poor compliance.

12. Endometrial ablation

Endometrial ablation is a minimally invasive surgical procedure for the treatment of the common problem of heavy menstrual bleeding. In general, menstruation totaling over 80 ml is considered heavy or excessive.

Several endometrial ablation devices have been approved for women with heavy menstrual bleeding due to benign causes provided that childbearing is complete.

Endometrial ablation device methodology includes heat energy created by heated gas, radiofrequency, free-flowing heated saline that circulates within the endometrial cavity, microwave energy, heated fluid within a balloon, heated water vapor that circulates within the uterus, and extreme cold treatment by nitrous oxide within balloons. All these devices are manipulated into the uterus using an appropriate hand piece.

Potential benefits of endometrial ablation include reduction in menstrual bleeding and improvement in the quality of life. On the other hand, side effects include cramping pain, vaginal discharge, bleeding, and spotting [46].

Late complications following endometrial ablation include post-ablation tubal sterilization syndrome and hematometra due to cervical stenosis [46].

Endometrial ablation does not protect women from future pregnancies. Pregnancy following ablation is hazardous for both the mother and fetus. Sterilization or contraception until menopause should be used. In addition, there may be future difficulty in diagnosing endometrial cancer due to the scarring of the endometrial cavity. Amenorrhea following treatment is not unusual [46].

Endometrial ablation is a more conservative alternative to all types of hysterectomy for dysfunctional uterine bleeding. It is less demanding financially and is associated with shorter hospital stay, but the original indication for its performance is not always resolved. Studies suggest that up to 25% of women undergoing endometrial ablation require further attention, in the form of medications, repeat ablation, or hysterectomy for unacceptable degrees of dysfunctional uterine bleeding [46].

Non-hormonal medications with or without hormonal therapy should be considered before trying more invasive treatments such as endometrial ablation or hysterectomy. Both the American College of Obstetricians and Gynecologists and the National Institute for Health and Care Excellence in the United Kingdom recommend medical therapy for the initial treatment of patients with excessive menstrual blood loss [47, 48].

Endometrial ablation modalities are now a second-line treatment choice after attempting medical therapy that fails for any reason, with the availability of a wide range of well-tested effective devices in use that directly deliver energy to the uterine endometrium. These modalities have demonstrated high levels of success with minimal complications when applied to appropriately selected patients [49, 50].

Hysterectomy remains a definitive surgical modality for patients with dysfunctional uterine bleeding. All types of hysterectomy are considered a mainstay of alternative options for patients where the medical approach proves to be ineffective or is associated with intolerable side effects [51].