Pharmacotherapy of endometrial hyperplasion

Pharmacotherapy of endometrial hyperplasia (EH) is a therapy, which use several types of drugs as a treatment option.

Most current guidelines recommend hormone therapies (including use of progestin, gonadotropin-releasing hormone (GnRH) or their combination and metformin) or surgical treatment (Pic. 1). The selection criteria for treatment options are based on patient age, health, the presence of cytologic-atypia and fertility status. 

Types of hyperplasia differ based on the characteristics of the cells found in the biopsy sample (Pic. 2). Patients with endometrial hyperplasia without atypia (there is 1% risk of uterine cancer) are treated conservatively through normalization of the menstrual cycles, whereas patients with atypical hyperplasia (29% of cases progress to uterine cancer and 17-59 % of cases have already coexistent uterine cancer) are treated surgically. EH without atypia responds well to progestins. Hormone therapy is also recommended for women whose general health prevents them from tolerating surgery due to coexisting medical conditions. However, women with atypical EH or persistent EH without atypia that are symptomatic (abnormal uterine bleeding) are treated with hysterectomy (surgical removal of uterus). 

Among women hoping for childbirth, EH treatment is challenging, demanding conservative treatment regardless of whether the hyperplasia is with or without atypia. 

Progesterone

Oral use of progestin, such as megestrol acetate (MA), and medroxyprogesterone acetate (MPA) is the most commonly used method with various regimens available for treatment of endometrial hyperplasia (EH). Nonetheless, the response rate is unsatisfactory, especially in atypical EH (approximately 70%). Progestin therapy may be continued or hysterectomy performed in cases of no response. 

Progestins can be given to patients via oral, intramuscular, micronized vaginal cream, or intrauterine devices. 

In recent years, the levonorgestrel-releasing intrauterine system (a intrauterine device that releases the hormone levonogestrel), and hysteroscopic resection (a procedure of removing the damaged tissue with the tube inserted through the cervix) of the cancer or hyperplastic area followed by oral or intrauterine progestogens have been demonstrated to be safe and effective alternatives.

The endometrium is highly sensitive to sex steroid hormones. Estrogens cause endometrial proliferation and progesterone inhibits this growth by converting the endometrium to its secretory stage to prepare the uterus for implantation. In relation to endometrial protection, progesterone is the key inhibitor of carcinogenesis (a development of cancer). The balance between the estrogen and progesterone activity during the menstrual cycle must be precisely maintained as an increase in the estrogen activity and/or a reduction in the antagonistic activity by progesterone will stimulate carcinogenesis (the formation of a cancer). 

The mode and duration of progestin treatment is essential to its success. EH usually shows a response after 10-week of dosing, but significant responses are commonly observed after 3-months of progestin therapy, with the median time to resolution being 6 months.

Gonadotropin-releasing hormone

The endometrium contains GnRH receptors and GnRH agonists can down-regulate GnRH receptors upon prolonged exposure. GnRH analogues suppress the hypothalamic pituitary-ovarian axis, thereby inhibiting estrogen production. Thus, GnRH analogues appear to have a direct anti-proliferative effect (tending to inhibit cell growth) on endometrial cells. This has led to exciting and promising new avenues for EH therapy. GnRH has been applied at a dose of 1 ampule intramuscularly every 28 days for 6 months to treat women with EH, with or without atypia. However, 25% of patients showed hyperplasia recurrence within 16-months of the completion of therapy. 

Accordingly, further study is needed to determine the usefulness of GnRH analogues before it can be recommended for clinical use in patients with atypical hyperplasia.

Methformin

Metformin is the most commonly used oral hypoglycaemic agent (a drug which lower glucose levels in the blood) in type 2 diabetes mellitus. It has also been linked to the reversal of endometrial hyperplasia and may therefore contribute to decreasing the prevalence of endometrial carcinoma without the fertility and side effect consequences of current therapies.

Oral progestins are associated with poor compliance (a degree to which a patient correctly follows medical advice) and systemic side effects (breast enlargement, headache, emotional lability, hot flashes, abdominal pain, joint pain) that may limit overall efficacy. 

Metformin has been applied in the treatment of type II diabetes mellitus for a long time. However, the antitumor effects of metformin have only been observed in recent years. Information about the relationship between metformin and edometrial hyperplasia is very limited. A large number of studies in vitro and in vivo are needed in the future to help us understand the mechanism of the effects of metformin on EH.

Historically, endometrial hyperplasia without atypia has been medically treated with oral progestogens (alone or in combination with oestrogen in polycystic ovary syndrome) or intrauterine progestogens, inhibiting oestrogen-driven cell growth and inducing withdrawal bleeds. This treatment provides the benefit of preserving fertility but is associated with side effects—in the short term, headaches, mood changes, acne or breast tenderness, and over the longer term, risk of a thromboembolic event (the blocking of a blood vessel by a particle that has broken away from a blood clot at its site of formation) or breast cancer. 

These longer term side effects can be mitigated by educating women on the symptoms of thromboembolic events and by ensuring that they attend regular breast cancer screening programmes. This approach has the effect of potentially hindering compliance, consequently producing a relatively high relapse rate. 

In women with atypia and in those who are resistant to progestogens, surgical hysterectomy is the treatment of choice.

Although there is no bona fide treatment for EH, most current guidelines recommend hormone therapies (including use of progestin, gonadotropin-releasing hormone (GnRH) or its analogues or their combination) or surgical treatment. Woman with atypical endometrial hyperplasia are treated with hysterectomy. If there is any medical conditions, which do not allow to perform surgery, hormone therapy is recommended. More conservative treatment is chosen in cases that the woman is in fertile age and wants to conceive.