Cover Story

The future of fibroid therapy

By Elizabeth A. Stewart, MD, and Adriana Faur, MD

While medical and surgical treatment are the mainstaysof therapy today, advances in molecular biology and genetics promise todramatically change the ob/gyn's approach to these common tumors.

Uterine leiomyomas, also known as myomas or fibroids, are an importantpart of every gynecologist's practice. Traditionally fibroids are viewedas a surgical disease and thus, hysterectomies, myomectomies, and an ever-increasingarray of minimally invasive techniques are used to relieve the symptomscaused by myomas.

Research regarding the effects of the steroid hormones estrogen and progesteroneled to a new view of leiomyomas: that of steroid-hormone responsive neoplasms(Figure 1). This work opened the way for medical treatments based on themanipulation of steroid hormones, such as the use of GnRH agonist. Newerdrugs may make treatment of fibroids based on hormonal manipulation saferand more effective.

Current research on the basic biology of leiomyoma cells (Figure 2),as well as the normal myometrium from which it arises, will also lead tonew treatments. These future treatments may improve hormonal therapy orprovide entirely new ways of treating myomas. Viewing fibroids as tumorswith abnormal blood vessels, or as a genetic disease, may lead to radicallydifferent approaches to these tumors in the future.

The present: fibroids and surgery

Uterine leiomyomas are the most common pelvic tumors in women, with aclinical incidence of 20% to 25%. They are benign smooth-muscle tumors ofthe uterus and cause a variety of symptoms for women, which lead them toseek surgical therapy including hysterectomy, and alternatives to hysterectomyincluding myomectomy. As alternatives to hysterectomy become more popular,the limitation of conservative surgical therapy becomes evident: Althoughsurgical therapy is very successful in treating the symptoms caused by theleiomyomas present at that time, it does not affect the underlying diseaseprocess. New myomas continue to form and may cause additional symptoms andeven the need for additional surgery. Studies have indicated that up to51% of women will have fibroids visible on transvaginal ultrasound 5 yearsafter an abdominal myomectomy, and that the risk of having a second surgeryappears to be between 15% and 26%.^1,2 Thus, although surgicaltherapy is effective in the short term, the long-term results are less satisfactory.

The present: medical treatment

Medical treatment for leiomyomas is also currently an option. All currentmedical treatment for leiomyomas is based on the understanding that theseare steroid-responsive tumors. This concept grew out of a body of researchthat demonstrated that leiomyomas were affected by the steroid hormonesestrogen and progesterone and that there were differences in their behaviorcompared to normal myometrium. For example, the concentration of estradiolwas found to be significantly higher in myomas than in normal myometrium,and the conversion of the more potent estradiol to the weaker estrone significantlylower in myomas.^3,4 Similar biochemical, pathologic, and clinicalevidence supports the role of progestins in leiomyoma growth.⁵ Thus,since the gonadal steroid hormones estrogen and progesterone differentiallyaffect leiomyomas, medications that manipulate the levels of steroid hormonesare treatment options for leiomyomas.

GnRH agonists are widely used to treat uterine fibroids. GnRH agonistscreate a hypogonadotropic hypogonadal environment, termed a "medicalmenopause" because of the extreme suppression of both estrogen andprogesterone. This withdrawal of steroid hormones results in two major endpointsthat are useful in the treatment of myomas: induction of amenorrhea, whichthereby controls bleeding and secondly a significant reduction in uterinesize in most women, which in turn controls bulk-related symptoms. Thesetwo benefits have been demonstrated in a number of studies.⁶

Although it is effective, GnRH-agonist therapy has three important limitations.⁶First and most important, this therapy affects all estrogen-dependent tissuesand thus causes significant hypoestrogenic symptoms. Although symptoms suchas hot flashes and sleep disturbance can significantly limit patient acceptanceof the therapy, it is the effect on bone, that limits the duration of itsuse and can lead to osteoporosis. Second, upon discontinuation of therapy,there is rapid regrowth of the uterus, often to a size above pretreatmentlevels. Finally, in a small proportion of women, vaginal hemorrhage canbe precipitated by this therapy.

Since leiomyomas are chronic or recurrent in nature, it would be advantageousto modify therapy to allow more prolonged treatment or retreatment. Severalgroups have addressed this problem by adding hormone replacement therapy(HRT) or "add-back" regimens to GnRH-agonist therapy to make itmore acceptable in terms of bone loss and other adverse effects. The idealHRT regimen would prevent symptomatic side effects, prevent bone loss, causeno significant adverse effects of its own, and not affect the clinical efficacyof the GnRH agonist.

Some of the earliest attempts at add-back therapy used medroxyprogesteroneacetate on the hypothesis that estrogen was the important hormone governingleiomyoma growth. Both studies showed that progestin started simultaneousto the GnRH therapy inhibited the decrease in uterine and leiomyoma volumeseen with GnRH-agonist therapy alone.^7,8

Further studies using a GnRH agonist with low-dose add-back estrogenand progestin (equivalent to levels used for menopausal replacement) havedemonstrated that this approach retards bone resorption and decreases hypoestrogenicsymptoms without causing myoma growth. Studies have documented the efficacyof this treatment for up to 2 years.⁹ Thus GnRH agonist withadd-back estrogen and progesterone therapy is one of the most frequentlystudied medical therapies.

The future: innovative add-back

GnRH agonist with tibolone add-back is a newer alternative for medicaltreatment. A synthetic steroid that exhibits estrogenic, progestational,and androgenic activity, tibolone has been widely used outside the UnitedStates for the treatment of menopausal symptoms. It appears to prevent postmenopausalbone loss and reduce vasomotor symptoms without causing significant endometrialor breast stimulation. Tibolone appears to provide the advantage of a decreasedincidence of bleeding at the start of therapy.¹⁰

Among postmenopausal women with myomas, those receiving tibolone weremore likely to become amenorrheic with the drug than with more conventionalHRT.¹¹ A study of premenopausal women receiving tibolone withGnRH agonist for the treatment of symptomatic fibroids did show that therewas no inhibition of uterine shrinkage with preservation of bone density,symptomatic improvement, and improvement in lipid profiles compared to GnRHagonist with placebo treatment.¹² This might make long-term GnRH-agonisttherapy more acceptable to women with myomas.

The future: antagonists and receptor blockers

There are several new therapies based on the manipulation of steroidhormone levels that may be useful in the future for treating leiomyomas.First, GnRH antagonists have been shown in small studies to produce equivalentlevels of amenorrhea and uterine shrinkage to that seen with GnRH agonist.^13,14There are two clear advantages to GnRH-antagonist therapy compared to GnRHagonist. First, the initial increase in estrogen seen with agonist therapyis eliminated, and thus women are less likely to get an estrogen-withdrawalbleed early in treatment. Secondly, the rapid shrinkage, seen over approximately2 weeks, is a major advantage, especially when preoperative therapy is needed.

In addition to decreasing peripheral hormone levels through a centralaction on GnRH, estrogen or progesterone antagonists may provide a differentroute to block hormone action peripherally. Mifepristone, also know as RU-486,is a steroidogenic molecule that acts in most circumstances as a progesteroneantagonist. In pilot studies, RU-486 has been shown to be effective in causingequivalent uterine shrinkage and rates of amenorrhea to that seen with GnRH-agonisttherapy.^15,16 The advantage of mifepristone is that normal levelsof estradiol are maintained and thus the symptoms of therapy are less andthe impact on bone is minimized.¹⁵ Estrogen antagonists may alsobe useful, although there is currently no available data in this area.

The future: growth factor therapy

Many scientific studies have suggested that the effects of steroid hormonesare mediated through the local production of growth factors, small peptidehormones that act locally on many cellular processes. Therefore, by lookingfor differences in growth factor expression between leiomyomas and normalmyometrium, we may better understand the process by which leiomyomas growand cause symptoms. Although a number of growth factors are expressed differentiallyin leiomyomas and normal myometrium, one factor appears central to the pathogenesisof uterine leiomyomas: basic fibroblastic growth factor (bFGF). bFGF isa factor important in the formation of new blood vessels, termed angiogenesis,and thus provides a new way of thinking about fibroid treatment.

Abnormal angiogenesis

In most organs, angiogenesis is a pathologic process; it is important,for example, in the pathogenesis of diabetic retinopathy and the growthof malignant tumors. In the uterus, however, angiogenesis is crucial toa nonpathologic process: menstruation. After every menstrual flow, new bloodvessels must be formed.

The concept that the arteries and veins are important in the pathogenesisof leiomyomas and leiomyoma-related menorrhagia dates back almost 100 years.¹⁷Injection of the blood vessels in the fibroid uterus showed an increasein the number of blood vessels and a dilation of the veins.¹⁷It is a recent idea, however, that molecules produced in or around fibroidscould be having an effect on blood vessel structure and function.¹⁸bFGF is a protein that can play that role: It promotes angiogenesis or theformation of new blood vessels through a number of mechanisms. It is alsoa potential candidate for a role in the pathogenesis of these smooth-muscle-celltumors since it causes smooth-muscle-cell growth.

Laboratory studies have shown that bFGF appears to be overproduced andstored in leiomyoma tissue.¹⁹ Additionally, a receptor for thismolecule is expressed at different times in the menstrual cycle in womenwho have fibroid-related bleeding compared with normal women.²⁰Thus, for women with leiomyoma-related bleeding, this factor or its receptormay be useful in targeting treatment.

One such treatment might be interferon-

or interferon-ß. Thesetwo classes of agents have been shown in a number of systems to oppose theactions of bFGF. Studies specifically in leiomyoma cells in culture haveshown interferon-

to decrease cellular proliferation.²¹ Althoughtrials in women have not been conducted, there is a case report of a womanwho received interferon for the treatment of hepatitis C and simultaneouslyhad dramatic shrinkage of a uterine leiomyoma.²² Most interesting,however, was the fact that in this report the shrinkage was sustained forup to 17 months after treatment, raising the possibility that treatmenteffects might be maintained after therapy is discontinued.²²

Genetic disease

The future will bring us an understanding of the leiomyoma at the geneticlevel. At least one gene has been identified that plays a role in myomas,and through in vitro work in mice, we are beginning to understand the propervectors needed to deliver gene therapy to these tumors.^23,24Understanding the genetic contribution to these tumors may also identifynew target molecules for therapy.

Conclusion

New research inevitably leads to new potential treatments. Molecularbiology and molecular genetics particular to uterine leiomyomas are beginningto uncover new potential targets for therapies. Newer therapies may dramaticallychange our approach to these common tumors in the future.

REFERENCES

1. Fedele L, Parazzini F, LuchiniL, et al. Recurrence of fibroids after myomectomy: a transvaginal ultrasonographicstudy. Hum Reprod. 1995;10:1795-1796.

2. Buttram VC Jr. Uterine leiomyomata--aetiology,symptomatology and management. Prog Clin Biol Res. 1986;225:275-296.

3. Otubu JA, Buttram VC, BeschNF, et al. Unconjugated steroids in leiomyomas and tumor-bearing myometrium.Am J Obstet Gynecol. 1982;143:130-133.

4. Yamamoto T, Takamori K,Okada H. Estrogen biosynthesis in leiomyoma and myometrium of the uterus.Horm Metab Res. 1984;16:678-679.

5. Rein MS, Barbieri RL, FriedmanAJ. Progesterone: a critical role in the pathogenesis of uterine myomas.Am J Obstet Gynecol. 1995;172:14-18.

6. Stewart EA, Friedman AJ.Steroidal treatment of myomas: preoperative and long-term medical therapy.Semin Reprod Endocrinol. 1992;10:344-357.

7. Carr BR, Marshburn PB, WeatherallPT, et al. An evaluation of the effect of gonadotropin-releasing hormoneanalogs and medroxyprogesterone acetate on uterine leiomyomata volume bymagnetic resonance imaging: a prospective, randomized, double blind, placebo-controlled,crossover trial. J Clin Endocrinol Metab. 1993;76:1217-1223.

8. Friedman AJ, Daly M, Juneau-NorcrossM, et al. A prospective, randomized trial of gonadotropin-releasing hormoneagonist plus estrogen-progestin or progestin "add-back" regimensfor women with leiomyomata uteri. J Clin Endocrinol Metab. 1993;76:1439-1445.

9. Friedman AJ, Daly M, Juneau-NorcrossM, et al. Long-term medical therapy for leiomyomata uteri: a prospective,randomized study of leuprolide acetate depot plus either oestrogen-progestinor progestin 'add-back' for 2 years. Hum Reprod. 1994;9:1618-1625.

10. Hammar M, Christau S, Nathorst-BoosJ, et al. A double-blind, randomised trial comparing the effects of tiboloneand continuous combined hormone replacement therapy in postmenopausal womenwith menopausal symptoms. Br J Obstet Gynaecol. 1998;105:904-911.

11. de Aloysio D, Altieri P,Penacchioni P, et al. Bleeding patterns in recent postmenopausal outpatientswith uterine myomas: comparison between two regimens of HRT. Maturitas.1998;29:261-264.

12. Palomba S, Affinito P,Tommaselli GA, et al. A clinical trial of the effects of tibolone administeredwith gonadotropin-releasing hormone analogues for the treatment of uterineleiomyomata. Fertil Steril. 1998;70:111-118.

13. Kettel LM, Murphy AA, MoralesAJ, et al. Rapid regression of uterine leiomyomas in response to daily administrationof gonadotropin-releasing hormone antagonist. Fertil Steril. 1993;60:642-646.

14. Felberbaum RE, Germer U,Ludwig M, et al. Treatment of uterine fibroids with a slow-release formulationof the gonadotrophin releasing hormone antagonist Cetrorelix. Hum Reprod.1998;13:1660-1668.

15. Murphy AA, Kettel LM, MoralesAJ, et al. Regression of uterine leiomyomata in response to the antiprogesteroneRU-486. J Clin Endocrinol Metab. 1993;76:513-517.

16. Murphy AA, Morales AJ,Kettel LM, et al. Regression of uterine leiomyomata to the antiprogesteroneRU486: dose- response effect. Fertil Steril. 1995;64:187-190.

17. Sampson JA. The blood supplyof uterine myomata. Surg Gynecol Obstet. 1912;14:215-230.

18. Stewart EA, Nowak RA. Leiomyoma-relatedbleeding: a classic hypothesis updated for the molecular era. Hum ReprodUpdate. 1996;2:295-306.

19. Mangrulkar RS, Ono M, IshikawaM, et al. Isolation and characterization of heparin-binding growth factorsin human leiomyomas and normal myometrium. Biol Reprod. 1995;53:636-646.

20. Anania CA, Stewart EA,Quade BJ, et al. Expression of the fibroblast growth factor receptor inwomen with leiomyomas and abnormal uterine bleeding. Mol Hum Reprod.1997;3:685-691.

21. Lee BS, Stewart EA, SahakianM, et al. Interferon-alpha is a potent inhibitor of basic fibroblast growthfactor-stimulated cell proliferation in human uterine cells. Am J ReprodImmunol. 1998;40:19-25.

22. Minakuchi K, Kawamura N,Tsujimura A, et al. Remarkable and persistent shrinkage of uterine leiomyomaassociated with interferon alfa treatment for hepatitis. Lancet.1999;353:2127-2128.

23. Schoenberg Fejzo M, AsharHR, Krauter KS, et al. Translocation breakpoints upstream of the HMGIC genein uterine leiomyomata suggest dysregulation of this gene by a mechanismdifferent from that in lipomas. Genes Chromosomes Cancer. 1996;17:1-6.

24. Niu H, Simari RD, ZimmermannEM, et al. Nonviral vector-mediated thymidine kinase gene transfer and ganciclovirtreatment in leiomyoma cells. Obstet Gynecol. 1998;91:735-740.

Dr. Stewart is Clinical Director, Center for Uterine Fibroids, Departmentof Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, Mass.,and Assistant Professor of Obstetrics, Gynecology, and Reproductive Biologyat Harvard Medical School. Dr. Faur is formerly the research coordinatorat the Center for Uterine Fibroids and is currently a resident in Obstetricsand Gynecology at Henry Ford Hospital, Detroit, Mich.

Dr. Stewart serves as a consultant to TAP pharmaceuticals.

Elizabeth Stewart, Adriana Faur. Cover Story: The future of fibroid therapy.

Contemporary Ob/Gyn

2000;7:26-38.