Innovative Steroidal Therapies
Medical therapies that manipulate either estrogen or progesterone in an innovative way have been used for fibroid therapy. The most extensively studied is the progesterone-modulating drug mifepristone. Early studies used relatively high doses (25–50 mg a day) for relatively short exposures (up to several months). In these studies, mifepristone, like GnRH agonists, was very effective in the treatment of uterine fibroids and stopped menstrual periods in almost all women and caused substantial fibroid shrinkage of 30–60 percent. The major advantage of mifepristone over GnRH agonists is that with mifepristone treatment women maintained a low to normal level of estrogen. Thus, women had fewer symptoms such as hot flashes and should have high enough estrogen levels to maintain bone density.
The most troubling finding with mifepristone is that the endometrium had specific changes; the changes were not precancer-ous but were nonetheless worrisome. This concern stems from our understanding that progesterone is the major brake on the progres-sion of chronically estrogen-exposed endometrium to precancerous changes and cancer. Therefore drugs that block progesterone may make a woman more susceptible to this endometrial cancer. Subsequent studies with a lower dose (5 mg) suggest that these previously seen endometrial changes may be due to the higher dose and that relatively good control of fibroid symptoms can be achieved with lower doses. There was also concern with the higher doses (but not the lower doses) that mifepristone might interfere with the action of another class of important steroid hormones, the glucocorticoids, including the important stress hormone cortisol.
Although mifepristone is available in the United States, as with GnRH antagonists, the marketed doses make it difficult to provide effective treatment for uterine fibroids. The single marketed dose is 600 mg; to divide this dose into any of the previously tested doses of mifepristone requires a compounding pharmacy to make a specific formulation.
A newer generation of more selective progesterone-modulating compounds is under development; they are often termed progesterone receptor modulators (PRMs) or selective progesterone receptor modulators (SPRMs). The compound Asoprisnil (previously referred to as J867) has been used in clinical trials for uterine fibroids, but only prelimi-nary information is available about its efficacy. Additional PRMs are undergoing testing for the treatment of uterine fibroids, but results have not yet been reported in the scientific literature.
Although estrogen-modulating compounds have shown great effectiveness in animal models of fibroids, the results to date in women have been disappointing. The SERM raloxifene has been shown in small studies to be effective in treating postmenopausal women with fibroids and as a GnRH-agonist add-back regimen. Initial studies in premenopausal women with the standard dose of raloxifene used for menopausal hormone therapy showed no effectiveness; use of 3 times this standard dose did not cause fibroid or uterine shrinkage but did keep the fibroids from increasing in size over 3 months. This small benefit will have to be weighed against the risk of complications, since even the standard dose of raloxifene is associated with an increased risk of blood clots, or thrombosis. Finally, targeting the enzyme aromatase (which converts androgens to estrogens) may be an important therapy of the future. Aromatase inhibitors (blockers) are used in the treatment of hormonally responsive cancers, and scientific studies suggest they may be helpful in the treatment of gynecologic disease like endometriosis and fibroids.
Nonsteroidal Hormonal Therapies
All the drugs we currently use to treat fibroids manipulate estrogen or progesterone to achieve a therapeutic effect. This approach is based on the research showing that fibroids were different in biologic ways from normal myometrium: they had more receptors for estrogen or progesterone (or both), and they were more sensitive to potent estrogens and progestins. Understanding new elements of fibroid biology will likely lead to new treatments that approach fibroids in different ways. For example, if you start to think about fibroids as a disease of fibrosis or scar tissue rather than as a disease of steroid hormones, whole new targets for therapy develop. Although none of these treat-ments has been approved by the FDA yet, it is likely that these new treatment options will develop over the next decade.
Similar patterns have been seen in other diseases. Ulcer disease was once thought to be related only to stomach acid production. However, there is now good evidence that a particular bacteria (Helicobacter pylori) living in the stomach contribute to this disease process, so some ulcers can be treated with antibiotics and Pepto-Bismol. There are several hints that other biologic systems may be able to be manipulated to produce improvement in fibroid symptoms.
As we discussed earlier, the angiogenic growth factor called basic fibroblast growth factor (bFGF) appears to be important in the biology of fibroids. Interferon-α (alpha) and interferon-β (beta) are compounds that are known to interfere with bFGF in other biological systems. There was an unusual report from Japan of a woman who was treated with interferon-α for a totally separate disease (hepatitis-C). The doctors taking care of her noted that she had a very large fibroid prior to starting the therapy and that, after seventeen months of therapy, the fibroid had shrunk to approximately one-tenth its previous volume. The most interesting finding was that after only a short treatment with interferon the fibroid remained small for more than a year and a half. This is particularly interesting because interferons usually have a carry over effect; when used for the treatment of multiple sclerosis, a 6-month treatment can produce improvement of symptoms for more than a year.
A single report like this does not mean that the interferon was necessarily the cause of this change. For example, the interferon could have improved liver functions so that estrogen was processed differ ently. However, the results are striking enough that trying this type of therapy in women with fibroids may be useful.
Also, small studies from Italy suggest that interfering with the insulin-like growth factor (IGF) and growth hormone (GH) systems may be appropriate treatment for women with fibroids. Using a drug called lanoreotide for 3 months caused a reduction in uterine volume of approximately 24 percent; again, there were some carry over effects. Lanoreotide is a somatostatin-like drug (somatostatin is a natural hormone produced in the body) that is used to treat an excessive growth hormone disorder called acromegaly. It has orphan drug status in the United States and is not widely available. (An orphan drug is a drug developed under a 1983 act of Congress making it possible for drug companies to receive a tax reduction for developing drugs to treat rare diseases.)
Drugs that target fibrosis or fibrotic factors might also be useful in the treatment of fibroids. Compounds that have been tested in laboratory experiments include pirfenidone and halofuginone.
Signaling molecules, the molecules that transmit directions to the cell after a protein hormone binds to the cell surface (as discussed here: The endocrinology of the uterus), may also provide novel targets. Again, one particular molecule, peroxisome proliferator-activated receptor gamma (PPAR-γ) has been tested in laboratory experiments.
Gene therapy may also be an avenue for future treatments. Laboratory experiments suggest that cell-to-cell communication is so strong in fibroids that only a small percentage of cells need to be targeted to lead to substantial cell death with gene therapy.