**6. Concluding remarks ― The future**

Endometrial cancer is the fourth most common malignancy in women. Many women die each year of this potentially preventive disease. Uterine precancerous conditions and even early endometrioid cancer of the endometrium have a reasonably studied potential to respond to hormonal therapy. A growing body of evidence suggests that progestin therapy by means of local long-acting release of a potent progestin can promote early endometrial tumor regression and long-term remission.

only in 7 of 11 at 6 months and 6 of 8 at 12 months. [8] A significant reduction of the ERs and PRs expression observed during treatment with the LNG-IUS appears to be a marker for the strong antiproliferative effect of the hormone at the cellular level. Furthermore, as the treat‐

The most common source of endogenous unopposed estrogen is chronic anovulation which can be accompanied by either continued ovarian secretion of estradiol or conversion of circulating androstenedione and testosterone to estrone and estradiol, respectively, by aromatase in the adipocytes. Chronic anovulation is a feature of PCOS and is also a condition occurring frequently in the perimenopause. In all these women, whether they have a hyper‐ plastic condition due to exogenous or endogenous excess estrogen, direct delivery of LNG to the target cells of the endometrium using an intrauterine device will cause substantial histologic changes. The result is usually a very uniform suppression of the endometrium, regardless of the duration of treatment, the histologic picture being independent of the distance from the delivery system. [53] Intrauterine progestin delivery, particularly LNG, is therefore probably the most effective intervention in preventing endometrial proliferation because of the uniform suppression of the endometrium throughout the whole thickness of the mucosa caused by the high tissue concentrations of the locally applied hormone. With oral progestin therapy, a higher rate of residual hyperplasia, including complex and atypical hyperplasia, has been observed. [54] It has been demonstrated that the duration of the progestin adminis‐ tration is more important than the daily dose for prevention of endometrial hyperplasia. Again,

Over the past 5 to 10 years many reports on the management of atypical endometrial hyper‐ plasia and early cancer of the endometrium with LNG-IUS have been published. [56-63] Remissions were frequent, but also failures occurred. Some consider that at present there is no sufficient evidence because most studies were underpowered or contained a high proportion of patients lost to follow-up. [64] A meta-analysis and systematic review of the literature concludes that the available evidence suggests that treatment with oral or intrauterine progestin are of comparable effectiveness. The risk of progression during treatment is small, but longer follow-up is required. [65] As recently highlighted by Scarselli et al., who followed patients for over 15 years, LNG-IUS represents an option to treat hyperplasia and prevent endometrial carcinoma in at least 85% of patients. [66] Consistent with that study, in order to support stable regression over long periods of time, we recommend continued preventive LNG-IUS use on a life-long basis using a suitable LNG-IUS as the uterine cavity is often very small. Annual assessment of the endometrial thickness by ultrasound is probably sufficient

Endometrial cancer is the fourth most common malignancy in women. Many women die each year of this potentially preventive disease. Uterine precancerous conditions and even early endometrioid cancer of the endometrium have a reasonably studied potential to respond to

ment is continuous, compliance is not an issue.

190 Contemporary Gynecologic Practice

continuous intrauterine progestin delivery seems optimal. [55]

unless vaginal bleeding occurs.

**6. Concluding remarks ― The future**

Conservative management with LNG-IUS of precancerous changes and early well differen‐ tiated endometrial cancer seems particularly promising in women who wish to preserve their fertility. It is emerging as an alternative to oral progestins as higher regression and lower hysterectomy rates for the treatment of complex and atypical hyperplasia are achieved with the device. LNG-IUS should, therefore, be the first-line primary prevention treat‐ ment. [67-75] However, conservative treatment carries an inherent oncologic risk as no correct staging is possible and the risk of missing a concurrent ovarian cancer cannot be neglected. Pre-treatment evaluation should include assessment for genetic conditions predisposing to cancer, such as Lynch syndrome. It is apparent that the ideal candidates for conservative cancer treatment are young women with grade 1, early stage endome‐ trioid endometrial cancer (T1) with no detectable myometrial invasion who are highly motivated to maintain their reproductive potential and understand and are willing to accept the risk associated with deviation from the established standard of care. [59, 76] Proges‐ tins rather than progesterone should be considered the ultimate tumor suppressors as they powerfully promote differentiation, cell cycle arrest and apoptosis, and reduce inflamma‐ tion and the invasion associated with metastasis. [37] Patients in whom the treatment fails should be evaluated by immunochemistry on endometrial biopsies as treatment failure is often caused by loss of PR expression. Clinical research is currently underway focusing on maintaining PR levels or identifying novel therapeutic approaches that restore PR expres‐ sion in tumors from which it has been lost. [38, 77] Failure could also occur simply due to the downward displacement of the hormone-releasing IUS causing less impact on areas away from the IUS. Proper distribution of the hormone to the deeper layers of the endometrium seems essential to achieve maximum impact.

As the lifetime risk of endometrial cancer in anovulating obese women is 15% or more, one could assume that many of these cancers could be prevented using LNG-IUS. We support such an approach together with others who believe that it could be successful provided that suitable LNG-releasing intrauterine delivery systems are used. The latter is important as the uterine cavities in women of any age are often small and even become smaller with the use of LNG-IUS. Side effects such as displacement, embedment and expulsion are not rare, leading to early discontinuation. [78] Leslie at al. hope that the following will be possible in the future: "As a profession, we should ask ourselves if we can not only treat, but prevent a substantial proportion of endometrial cancers with more liberal use of progestin-containing IUDs?" [79]

Apart from the emerging role of LNG-IUS for endometrial cancer prevention, as reviewed recently by Jóźwik et al. [80], the future might lead us to even more effective hormone-releasing IUDs. It was proposed that local delivery of other drugs such as mifepristone or ulipristal, with their strong antiprogestin activity and antiestrogenic effect at the endometrial level, may be more suitable than LNG to act as tumor suppressor. No studies with intrauterine delivery of these agents have been conducted so far. However, one example is worth mentioning which indicates the potential of these compounds: A 48-year old nulliparous woman was consulted by one of the authors (DW) in 2007 for bleeding problems. It was known that she suffered from multiple uterine leiomyomas which tended to increase in size significantly over the past years. A pipelle biopsy revealed atypical hyperplasia. On MRI, the uterus was increased in size with several leiomyomas, the largest being of 65 mm in diameter. A frameless mifepristonereleasing IUS was inserted on 20 January 2007. The first follow-up was done one month later. At that time, the patient mentioned some spotting and a repeat biopsy showed residual focal atypical hyperplasia. Three months after insertion, breakthrough bleeding stopped complete‐ ly, the diameter of the largest myoma was reduced to 33 mm and a histological specimen showed deficient endometrium without signs of atypia. All further follow-up examinations were uneventful with no abnormal bleeding. The patient was kept on this experimental mifepristone-releasing IUS for approximately 5 years. It was replaced by a LNG-IUS at the end of 2011 and, at annual check-ups, she has remained asymptomatic.

Finally, it is worth mentioning that several large epidemiological studies pointed out the potential of metformin as an anticancer drug. Metformin is an oral antidiabetic drug and is the first-line drug for the treatment of type 2 diabetes, in particular, in overweight and obese subjects with normal kidney function. It is used for the treatment of PCOS and has been investigated for other diseases where insulin resistance seems an important factor. Metformin acts by suppressing glucose production in the liver and has a vast safety track record. Preclin‐ ical and early clinical trials suggest a role for metformin in the prevention and treatment of cancer. Its potential is still unproven, but seems extremely promising. [81] Recently, a phase 2 study was designed in Australia combining LNG-IUS with oral metformin for the treatment of complex endometrial hyperplasia with atypia and grade 1 endometrial endometrioid adenocarcinoma. [82] Hopefully, this and other careful clinical studies will path a new approach to the prevention and treatment of early endometrial cancer.
