Beyond Hysterectomy: Increasing Awareness of Uterine Fibroids and New Treatment Options

What bleeding patterns do you see when women who are ultimately diagnosed with uterine fibroids present at the clinic with abnormal menstrual bleeding?

The most common symptom of uterine fibroids is heavy menstrual bleeding. In a recent survey, approximately 60% of women diagnosed with uterine fibroids reported heavy menstrual bleeding.¹ Typically, the patient will say, “I’m bleeding heavily,” but when you go into more detail, the bleeding can take different forms. Some will say that they still have regular bleeding, more or less at the same time every month, but instead of what they consider normal, their bleeding is now much heavier. I’ve had women describe it as “hemorrhaging” or “soiling my clothes,” and others can quantify it by the number of tampons or sanitary pads that they use.

Over the years, clinician-scientists have tried to measure the normal range of menstrual bleeding. There is wide variation among women [in both the duration of menstruation and the amount of blood loss]. Up to 7 days of bleeding is within the normal range, and the total amount of blood loss is approximately 80 mL, which is roughly approximately 6 large spoonfuls. Anything greater than that is considered heavy bleeding.²  
 
Women with fibroids may have different bleeding patterns. Some women report prolonged duration of bleeding (37%), bleeding between periods (33%), frequent periods (28%), and/or irregular/unpredictable periods (36%); however, others even report light menstrual bleeding (11%), absent periods (14%), infrequent periods (17%), and/or shortened duration of menstrual bleeding (13%).¹ These women may say, “I had my period. I know this was my period, and then it stopped. But a few days later, I had another period.” They tend to have bleeding on and off throughout the month or sometimes during the whole month. If you quantify the total amount of all the bleedings, it can be quite a lot, and that is why many of these patients end up with anemia; one study reported that 35% of women with heavy or very heavy menstrual bleeding were anemic.³ These women are losing too much blood and too much iron, and their bodies cannot keep up. They often have anemia-related symptoms: fatigue, tiredness, headache, and lack of energy, among others. The normal hemoglobin level of a woman is typically between 12 and 16 g/dL. I have seen women living with one-quarter of that, 3 or 4 g/dL, which was remarkable. If a woman loses a lot of blood, then organs are going to start to suffer. Untreated iron-deficiency anemia can lead to  cardiac problems, such as arrhythmias and even heart failure, and those complications can have major health consequences.⁴

What are the challenges with diagnosing uterine fibroids?

This is a very important topic. There is a lack of awareness of uterine fibroids, and there are some cultural and social barriers.^5,6 Undiagnosed fibroids are a major issue because of the additional symptoms caused by the heavy bleeding. Many women normalize their heavy bleeding because it is a subjective assessment.^5,7 In interviews with 60 women diagnosed with uterine fibroids, 37% reported they did not seek an immediate diagnosis despite experiencing severe symptoms.⁵ Women are often told by their relatives that this [heavy or abnormal bleeding] is part of being a woman and that they should expect it and get used to it. Then, the person keeps bleeding heavily and may develop severe anemia. They have absolutely no energy and are tired all the time, but they do not know why. Sometimes they go through this for years until finally they read an article or someone encourages them to get this bleeding checked out.
 
So, there is a lot of this “normalization” and a lot of stigma.⁵ Sometimes a woman knows that she is bleeding heavily and even that she has fibroids, but she does not seek help.⁷ Some women believe that hysterectomy is the only treatment option, and if she does not want a hysterectomy, she does not seek help. It is important to increase awareness [about uterine fibroids and newer treatment options].⁶

How do you determine whether to pursue surgical vs nonsurgical treatment for uterine fibroids?

After we confirm the diagnosis with the appropriate pelvic examination and either transvaginal or transabdominal ultrasound, we start exploring treatment options. I start by talking with the patient about medical vs surgical treatment options or watchful waiting with monitoring. I always feel my job is to give the patient a lot of accurate medical information with the options and let her choose because I believe that the patient knows her situation, needs, and reproductive plans the best. We discuss all of that, but in the end, the final decision is hers. For women who would like to become pregnant, obviously a hysterectomy is not a viable option.
 
Until recently, the medical treatment options were very limited; thus, we tended to go to surgery quite quickly. The US Food and Drug Administration (FDA) approved the first oral treatment for [heavy menstrual bleeding associated with] fibroids, Oriahnn^TM (elagolix, estradiol, and norethindrone acetate capsules; elagolix capsules), just months ago.⁸ I was an investigator for the ELARIS UF-2 clinical trials. Even though I’m a surgeon, I strongly believe in trying medical treatment first. If we can avoid surgery altogether, that’s better.

What were the main findings that led to the FDA approval of elagolix with hormonal add-back therapy?

We conducted 2 large phase 3 studies (funded by AbbVie; Elaris UF-1 and Elaris UF-2, ClinicalTrials.gov Identifiers: NCT02654054 and NCT02691494), which included a total of 790 patients.⁹ About 68% of those were African American; I was very pleased with that because fibroids are more common in women of color, including African American women and Hispanic women.⁶ These were randomized, placebo-controlled studies. Patients received elagolix, with or without hormonal add-back therapy (estradiol, and norethindrone acetate), or placebo every day for 6 months, and we evaluated the bleeding and the size of the fibroid in addition to other assessments, including safety and quality of life. The results were published in January 2020 in the New England Journal of Medicine.
 
Elagolix with hormonal add-back therapy successfully controlled bleeding in approximately 75% of women, which is fantastic. We never had anything even close to that before. At the end of the 6 months, compared with baseline, bleeding was decreased by approximately 90%.⁹ After 6 months, we did an extension study (Elaris UF-EXTEND) for an additional 6 months, and the percentage of women with successfully controlled bleeding rose to nearly 90%.¹⁰ For safety, elagolix with hormonal add-back therapy was very well tolerated. There was slight increase in the number of women who had hot flushes compared with placebo. Those patients said the hot flushes were very mild, and they did not discontinue the study. The remainder of the side effects were similar between the treatment arms.⁹

How will the FDA approval of elagolix with hormonal add-back therapy affect the treatment landscape?

Previously, we had few medical treatment options with oral administration; most of them have not been thoroughly evaluated in well-designed clinical studies nor are they approved by the FDA for the treatment of fibroids. Most of these off-label strategies use the progestin hormone. These treatments make the lining of the uterus thinner and, in some cases, help decrease the bleeding temporarily.¹¹ They usually fail after a few months and might not even work from the beginning. Also, they do nothing for the fibroid itself and sometimes even make the fibroid grow. I’m very excited now that elagolix with hormonal add-back therapy has gone through the appropriate studies and secured FDA approval.
 
Oriahnn has very different active ingredients. It uses elagolix, which works centrally on the pituitary gland. It inhibits ovulation and the production of estrogen and progesterone in the ovary; these hormones are responsible for the growth of the fibroid. Thus, with this treatment, the fibroid gradually becomes inactive, and it can no longer make the uterine lining bleed more.⁹
 
However, when we inhibit ovulation, women sometimes have some side effects that are similar to the changes that happen when women go through menopause. With elagolix alone, you will have side effects such as hot flushes, night sweats, and vaginal dryness. For extended treatment periods, the bone also starts to lose some of its strength due to decreased bone mineral density, which estrogen helps maintain. Thus, to obtain the benefit of elagolix and alleviate the side effects, the team advising AbbVie, the company that produces elagolix, including myself, decided to add a small amount of estradiol and norethindrone acetate into the tablet. This allows you to decrease and control the bleeding while limiting the side effects.⁹
 
It is very encouraging, and I’m already using Oriahnn in my practice. I believe that Oriahnn should be the first-line treatment for women who have fibroids and heavy menstrual bleeding (unless the patient for some reason prefers another treatment option).

Are there other medical treatment options being developed?

I’ve been working in the fibroid field during the past 20 years or so — my entire professional career. I have been saying in many venues that women should have multiple options. I am very glad that more attention is being given to fibroid treatment options.
 
I’m aware of 2 other medications that are still going through their clinical research evaluations and do not yet have FDA approval. The first is called relugolix (funded by Myovant; ClinicalTrials.gov Identifier: NCT03049735). Phase 3 studies have been completed, and the results were also very encouraging; my understanding is that they will seek FDA approval soon. The other medication is linzagolix (funded by ObsEva; ClinicalTrials.gov Identifier: NCT03070951). Phase 3 studies are being completed, and it seems very effective as well. Hopefully in the near future, there will be several medical treatment options available for our patients.

Have there been any recent advances in the surgical treatment of uterine fibroids?

Robotic myomectomy is probably the newest development on the surgical side. In robotic myomectomy, which is very similar to laparoscopic or minimally invasive surgery, the robot gives us more flexibility, and the suturing is easier. We do encourage surgeons to use minimally invasive techniques with more cases where they might have done open myomectomy before.
 
The Q&A was edited for clarity and length.

Disclosure

Ayman Al-Hendy, MD, PhD, disclosed the following relationships: AbbVie: Consultant/Advisory Board; Allergan: Consultant/Advisory Board; Bayer: Consultant/Advisory Board; MD Stem Cells: Consultant/Advisory Board; Myovant: Consultant/Advisory Board.

References

1. Zimmermann A, Bernuit D, Gerlinger C, Schaefers M, Geppert K. Prevalence, symptoms and management of uterine fibroids: An international internet-based survey of 21,746 women. BMC Womens Health. 2012;12:6. doi:10.1186/1472-6874-12-6
2. Reed BG, Carr BR. The normal menstrual cycle and the control of ovulation. MDText.com, Inc. http://www.ncbi.nlm.nih.gov/pubmed/25905282. Accessed September 26, 2020.
3. Fuldeore MJ, Soliman AM. Patient-reported prevalence and symptomatic burden of uterine fibroids among women in the United States: Findings from a cross-sectional survey analysis. Int J Womens Health. 2017;9:403-411. doi:10.2147/IJWH.S133212
4. National Heart, Lung, and Blood Institute. Iron-deficiency anemia. https://www.nhlbi.nih.gov/health-topics/iron-deficiency-anemia. Accessed September 26, 2020.
5. Ghant MS, Sengoba KS, Vogelzang R, Lawson AK, Marsh EE. An altered perception of normal: understanding causes for treatment delay in women with symptomatic uterine fibroids. J Women’s Heal. 2016;25(8):846-852. doi:10.1089/jwh.2015.5531
6. Al-Hendy A, Myers ER, Stewart E. Uterine fibroids: burden and unmet medical need. Semin Reprod Med. 2017;35(6):473-480. doi:10.1055/s-0037-1607264
7. Bernardi LA, Ghant MS, Andrade C, Recht H, Marsh EE. The association between subjective assessment of menstrual bleeding and measures of iron deficiency anemia in premenopausal African-American women: across-sectional study. BMC Womens Health. 2016;16(1):50. doi:10.1186/s12905-016-0329-z
8. U.S. Food and Drug Administration. FDA approves new option to treat heavy menstrual bleeding associated with fibroids in women. https://www.fda.gov/news-events/press-announcements/fda-approves-new-option-treat-heavy-menstrual-bleeding-associated-fibroids-women. Accessed September 26, 2020.
9. Schlaff WD, Ackerman RT, Al-Hendy A, et al. Elagolix for heavy menstrual bleeding in women with uterine fibroids. N Engl J Med. 2020;382(4):328-340. doi:10.1056/NEJMoa1904351
10. Simon JA, Al-Hendy A, Archer DF, et al. Elagolix treatment for up to 12 months in women with heavy menstrual bleeding and uterine leiomyomas. Obstet Gynecol. 2020;135(6):1313-1326. doi:10.1097/AOG.0000000000003869
11. Farris M, Bastianelli C, Rosato E, Brosens I, Benagiano G. Uterine fibroids: an update on current and emerging medical treatment options. Ther Clin Risk Manag. 2019;15:157-178. doi:10.2147/TCRM.S147318
 
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