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Clinical Manifestations of Uterine Fibroids

Uterine fibroids (leiomyoma) is a benign neoplasm in the muscular layer of the uterus, which occurs in 20-25% of women of reproductive age.

In 25-50% of women, uterine fibroids have clinical manifestations. The symptoms of leiomyoma largely depend on the size. Among the symptoms of uterine fibroids:

  • heavy menstruation;
  • pelvic pain;
  • abnormal uterine bleeding;
  • infertility;
  • complicated pregnancy.

Unlike normal cells of the muscular layer of the uterus (myometrium), fibroid cells multiply uncontrollably. In myoma, blood vessels grow, and the production of fibronectin and collagen, components of connective tissue, increases. All these factors contribute to the growth of fibroids.

Leiomyoma cells are sensitive to ovarian hormones – estrogen and progesterone. Therefore, the growth of fibroids decreases during menopause or when the ovaries are removed.

Treatment Methods

Symptomatic leiomyoma is treated with hormonal drugs, surgically, or by limiting the blood flow of fibroids:

  • Myomectomy – surgical removal of fibroids with preservation of the uterine body and fertility. However, 42-55% of patients develop a new fibroid after a myomectomy. In addition, complications during pregnancy are possible.
  • Hysterectomy – surgical removal of the uterus. The procedure makes the patient sterile.
  • Uterine artery embolization (UAE) – restriction of leiomyoma blood flow. Reproductive function is preserved. Possible side effects include damage to the ovaries and the re-growth of fibroids.
  • Progestins (with or without estrogens) – were used to treat bleeding associated with leiomyoma. Although progestin treatment is often associated with a short-term reduction in bleeding, in the long term, progestins increase the size of leiomyoma.
  • Gonadotropin-releasing hormone (GnRH) antagonists – inhibit the production of pituitary hormones that affect the ovaries. As a result, the level of estrogens and progesterone sharply decreases. The lack of estrogens and progesterone leads to an initial decrease in leiomyoma volume by 50%, stabilizing after about 3 months of continuous therapy without further improvement. After treatment discontinuation, leiomyomas often quickly grow back, so GnRH antagonists require long-term use. However, long-term use is associated with significant side effects due to a lack of estrogens. Side effects include hot flashes, osteoporosis, and vulvovaginal atrophy. Therefore, GnRH antagonists are often used only to prepare for the surgical removal of fibroids.

Hormone therapy suppresses the growth of uterine fibroids only during the period of taking medications. After discontinuation of administration, fibroids resume growth. In addition, hormone therapy is incompatible with reproductive function.

In some cases, drug therapy is preferable to surgical treatment. However, due to the problems associated with hormone therapy, scientists have focused on developing non-hormonal treatments for leiomyomas. Among the potentially effective means is interferon-alpha.

Antitumor Effect of Interferon

Interferon (IFN) has an antitumor and antiviral effect. IFN activates macrophages and natural killers that destroy the tumor.

Interferon suppresses cell proliferation by blocking protein synthesis. In addition, interferon suppresses the action of the main fibroblast growth factor bFGF – a protein that stimulates cell division and the formation of new blood vessels.

In uterine fibroids, synthesis and release of transforming growth factor TGF-β – protein increases, stimulating tumor growth and enhancing metabolism. Excessive synthesis of TGF-β leads to the proliferation of connective tissue in the uterine fibroids. Interferon suppresses the synthesis of TGF-β.

In addition, interferon suppresses the synthesis of collagen, which also resists the proliferation of connective tissue.

Interferon-Alpha Suppresses The Division of Uterine Fibroids Cells

Scientists at Harvard Medical School investigated how interferon-alpha affects the growth of uterine fibroids. In this laboratory study, scientists used leiomyoma, myometrium, and endometrial tissues obtained during a planned hysterectomy from five premenopausal patients with symptomatic uterine fibroids. The patients did not receive any hormonal or drug therapy.

IFN-alpha suppressed DNA synthesis in smooth muscle cells of leiomyoma and normal myometrium. At the same time, smooth muscle cells of leiomyoma showed greater sensitivity to the action of IFN-alpha.

bFGF stimulated the division of both normal myometrial cells and leiomyoma cells. The most significant response was in smooth muscle cells of normal myometrium. IFN-alpha suppressed the bFGF-stimulated increase in DNA synthesis in both cell types. However, leiomyoma cells reacted less to interferon.

The lower sensitivity of smooth muscle leiomyoma cells to exogenous bFGF may be because they produce more endogenous bFGF than normal myometrial cells, explaining why IFN-alpha is less effective at suppressing bFGF-stimulated DNA synthesis in smooth muscle cells of leiomyoma than normal myometrium cells.

The most extraordinary sensitivity to bFGF was shown by uterine stromal cells. IFN-alpha effectively suppressed bFGF-stimulated DNA synthesis in stromal cells.

At the same time, interferon-alpha did not affect the viability of cells.

Interferon-Alpha Triggers Apoptosis of Uterine Fibroids Cells

Type I interferon is involved in triggering apoptosis – programmed cell death. Two mechanisms of apoptosis:

  • External – signals from other cells activate cell death receptors.
  • Internal – the permeability of mitochondrial membranes increases, mitochondria release cytochrome, and cytochrome triggers the process of apoptosis.

Italian scientists have investigated how interferon-alpha affects gene expression in leiomyoma. For the study, the researchers used samples of the myometrium and leiomyoma of 29 premenopausal patients undergoing myomectomy or hysterectomy. The patients did not receive any drug therapy other than nonsteroidal anti-inflammatory drugs.

Unlike normal myometrium, the expression of TRAIL and IFI27 genes involved in apoptosis was suppressed in the leiomyoma. TRAIL triggers the external pathway of apoptosis, and IFI27 participates in the internal path. TRAIL and IFI27 are interferon-alpha-stimulated genes.

Low expression of TRAIL and IFI27 in leiomyoma cells leads to a decrease in cellular apoptosis, which promotes leiomyoma growth.

Interferon-alpha activated the expression of TRAIL and IFI27 in a dose-dependent manner in both normal myometrium and leiomyoma. IFN-alpha increased TRAIL expression significantly more in leiomyoma than in normal myometrium. On the contrary, in normal myometrium, IFN-alpha increased the expression of IFI27 considerably more than in leiomyoma cells.

In uterine fibroids, interferon-alpha activated the external pathway of apoptosis but did not trigger the internal path.

Treatment of Uterine Fibroids with Interferon-Alpha: A Clinical Case

Japanese doctors describe the case of a patient with chronic hepatitis C. A 42-year-old patient was admitted to the hospital with complaints of pain during menstruation. The examination showed that the uterus was enlarged to the size corresponding to the 12th week of pregnancy. Ultrasound and MRI revealed a 202 cm3 fibroid in the uterine wall.

Since the patient had active chronic hepatitis C, the doctors decided to treat her conservatively with interferon-alpha. 5 months after the end of interferon treatment, the volume of fibroids decreased markedly to 29 cm3. When the volume of fibroids decreased, the patient’s menstrual pains decreased.

Even though during and after treatment with interferon, the patient’s menstrual cycle was regular, fibroids irreversibly decreased. After 7 months after interferon treatment, fibroids fell to 22 cm3, and after 17 months – to 21 cm3.

Side effects included fever, leukocytopenia, and loss of appetite.

Conclusion

After surgical removal of uterine fibroids and hormonal treatment, fibroids often grow back. On the contrary, interferon irreversibly suppresses the growth of uterine fibroids and reduces their size.

Hormonal treatment is associated with severe side effects, including decreased fertility. Although interferon has temporary side effects, it does not suppress ovarian function. Therefore, interferon can become an alternative to surgical intervention for women with symptomatic uterine fibroids who want to preserve fertility.

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