DIET COMPOSITION FOR THE PREVENTION AND/OR THE TREATMENT OF ENDOMETRIAL HYPERPLASIA

Abstract

A diet composition for use in the prevention and/or the treatment of endometrial hyperplasia in a human subject is provided. It has a) a fasting mimicking diet component to be administered for a first period of time and providing less than 50% of the normal caloric intake of the subject with both protein restriction and sugar restriction; and b) a re-feeding diet component to be administered for a second time period, which provides 60-100% of the normal caloric intake of the subject, wherein the fasting mimicking diet component and the re-feeding diet component are administered over multiple cycles.

Claims

1. A method for preventing and/or treating endometrial hyperplasia in a human subject comprising: administering a fasting mimicking diet component for a first time period, said fasting mimicking diet component providing less than 50% of the normal caloric intake of the subject with both protein restriction and sugar restriction; and administering a re-feeding diet component for a second time period, said re-feeding diet component providing 60-100% of the normal caloric intake of the subject; wherein the fasting mimicking diet component and the re-feeding diet component are administered for multiple cycles.

2. The method of claim 1, wherein said first time period is from 2 days to 10 days, and said second time period is from 7 to 85 days.

3. The method according to claim 2, wherein said multiple cycles comprise an administration once a month for at least 2 months.

4. The method according to claim 2, wherein said fasting mimicking diet component provides the subject with 100-1160 kcal/day.

5. The method according to claim 4, wherein said fasting mimicking diet component provides the subject with a protein amount less than or equal to 36 g/day.

6. The method according to claim 3, wherein said fasting mimicking diet component comprises carbohydrates in such an amount as to provide no more than half of the calories provided by said diet component.

7. The method according to claim 2 any one of claims 1 6, wherein said fasting mimicking diet component provides the subject with 2-11 kcal/kg of body weight/day.

8. The method according to claim 7, wherein said fasting mimicking diet component provides the subject with proteins in an amount of 0.1-0.4 g/kg of body weight/day.

9. The method according to claim 4, wherein said fasting mimicking diet component comprises proteins in an amount that is less than 15% of the total calories provided by the fasting mimicking diet component.

10. The method according to claim 4, wherein said fasting mimicking diet component comprises sugars in an amount that is less than 15% of the total calories provided by the fasting mimicking diet component.

11. The method according to claim 4, wherein said first time period is 5 days and said fasting mimicking diet component provides the subject with 9 to 15 kcal/kg of body weight/day on day 1, and 6 to 10 kcal/kg of body weight/day for days 2 to 5.

12. The method according to claim 2, wherein said fasting mimicking diet component comprises at least 60% calories from fatty acids, 2-5% calories from glycerol and up to 5% calories from plant-based proteins and a maximum of 35% calories from carbohydrates.

13. The method according to claim 12, wherein said fasting mimicking diet component comprises complex carbohydrates from the group consisting of plant sources, preferably soy, rice and other grains.

14. The method according to claim 12, wherein at least 50% of the calories from fatty acids are from coconut oil and tree nuts, which comprise walnuts, macadamia nuts and/or almonds.

15. The method of claim 2, wherein said first time period is 5 days and said second time period is 25-26 days.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0050] FIG. 1A is a histogram showing the weight of the uterus of BALB/c mice, wherein the mice were subjected to normal diet, tamoxifen treatment and normal diet, fasting (water only), or tamoxifen treatment and fasting, respectively.

[0051] FIG. 1B is a histogram showing the weight of the uterus of BALB/c mice, wherein the mice were subjected to normal diet, tamoxifen treatment and normal diet, an FMD (ChemoLieve) or tamoxifen treatment+FMD (ChemoLieve).

[0052] FIG. 2 shows pictures of the uterus taken from the above BALB/c mice, subjected to the treatments set out in FIGS. 1A and 1B.

[0053] FIG. 3 presents pictures from histological analyses carried out on the uteri set out in FIG. 1C.

[0054] FIG. 4 is a diagram showing the Igfr1 mRNA quantification in the uteri of mice subjected to the treatments set out in FIGS. 1A and 1B.

[0055] FIG. 5 is a diagram showing Tff1 (an estrogen receptor target gene, ER) mRNA quantification in the uteri of mice subjected to the treatments set out in FIGS. 1A and 1B.

DETAILED DESCRIPTION

[0056] The invention relates to a diet composition as described above for the prevention and/or the treatment of endometrial hyperplasia. The diet composition is administered as described above to women at risk of developing endometrial hyperplasia (following HRT or tamoxifen intake, in the context of obesity or menstrual irregularitiesin the latter case, there is the indication for use of the diet composition particularly when the menstrual irregularities reflect a polycystic ovary syndrome) or with previously diagnosed endometrial hyperplasia. It is specified that the use of this diet composition does not exclude hysterectomy, in cases in which the presence of atypical hyperplasia requires it.

[0057] The finding that animals treated for four weeks with tamoxifen (a drug which induces endometrial hyperplasia acting as a partial ER agonist at uterus level) show an increase in uterus weight (see FIGS. 1A and B), an increase in the size of the uterus itself (FIG. 2) and a histological pattern of uterine hyperplasia (FIG. 3), supports the importance of the invention. However, mice subjected to fasting cycles (only water for 48 h) or an FMD (ChemoLieve of L-Nutra) and concurrent tamoxifen treatment did not develop any of these effects (FIGS. 1-3).

[0058] In particular, in the experiments set out in FIGS. 1-5, 6-8 weeks old BALB/c mice were used, which were randomly distributed to one of six groups (five mice per treatment group): control (normal diet); tamoxifen (normal diet with tamoxifen, given at a dosage of 30 mg/kg/day by gastric gavage); fasting (only water for 48 h once a week); FMD (ChemoLieve; 72 h once a week); fasting+tamoxifen; FMD+tamoxifen. After five weeks of treatment, the mice were sacrificed and the taken uteri were weighed (FIGS. 1A and 1B), photographed (FIG. 2), fixed for subsequent histological analysis (FIG. 3), or subjected to flash freezing and subsequently used for the RNA extraction and the Igfr1 and Tff1 mRNA quantification (FIGS. 4, 5).

[0059] Both fasting and fasting mimicking diet (FMD) were found to have reduced uterus weight and prevented the tamoxifen-induced uterus weight increase (FIGS. 1, 2). Prevention of tamoxifen-induced endometrial hyperplasia by fasting was promptly confirmed by histology (FIG. 3).

[0060] Previous studies suggested a role for the Igf-1 growth factor-activated signaling cascade in making endometrial cells sensitive to the mitogenic effects of estrogens or, plausibly, of tamoxifen (which acts primarily as a partial estrogen receptor agonist in endometrium) (Eritja N, Mirantes C, Llobet D, Yeramian A, Bergada L, Dosil M A, Domingo M, Matias-Guiu X, Dolcet X: Long-term estradiol exposure is a direct mitogen for insulin/EGF-primed endometrial cells and drives PTEN loss-induced hyperplasic growth. The American Journal of pathology 2013, 183(1):277-287).

[0061] It is interesting to note that, in the experiments conducted, an Igf-1 receptor mRNA downregulation (Igf1R) was detected in the uteri of mice which were fasted or subjected to FMD during tamoxifen treatment (FIG. 4). This suggests that fasting may downregulate the Igf-1-induced signaling and that this effect may be one of the mechanisms by which fasting itself or FMD protect against tamoxifen-induced endometrial hyperplasia. In response to fasting or FMD used alone or in combination with tamoxifen, very low levels of Tff1mRNA were also measured in the uteri of mice and this indicates that the estrogen receptor (ER) activity, which precisely controls Tff1 expression, is blocked by fasting or FMD. This aspect, i.e. blocking the ER function by fasting or FMD, could represent a further mechanism underlying the countering of endometrial hyperplasia by these dietary measures.

[0062] Both fasting and FMD cycles were well tolerated, causing a transient weight loss that was subsequently readily recovered by the animals between cycles.

[0063] Overall, the above experimental results clearly demonstrate the capability of fasting or FMD to prevent or treat endometrial hyperplasia.

[0064] The main advantages of the invention lie in the possibility of preventing a side effect, which is annoying and heavily affecting the quality of life of women undergoing tamoxifen or HRT therapy. The onset of uterine hyperplasia may in fact lead to bleeding and, even when it is asymptomatic, involves the burden of careful clinical or ultrasound monitoring and sometimes invasive biopsy investigations.

[0065] Periodic cycles of a FMD with the diet composition according to the invention during tamoxifen therapy or HRT, or when obesity or menstrual irregularities are present in the context of a polycystic ovarian syndrome might represent a sufficient approach for preventing uterine hyperplasia thus significantly improving the quality of life of patients as well as reducing the risk of developing endometrial cancer.

[0066] Compared to the use of caloric restriction for the prevention or the treatment of endometrial hyperplasia, the use of FMD cycles would have the advantage of allowing a normal diet between cycles and avoiding the side effects of caloric restriction itself (e.g. weight loss, hunger, hypothermia, reduced wounds healing capability). Prevention of uterine hyperplasia by FMD in women taking tamoxifen would also allow not to interrupt the tamoxifen therapy, thus continuing to benefit from the antineoplastic activity of this drug for the entire period of time in which the intake thereof is recommended. In these women, this would have the additional advantage of increasing the antineoplastic activity of tamoxifen itself, which would likely result in an improvement of the prognosis of the patients themselves (in this regard see Italian Patent Application No. 102016000017036 of the same Applicants).

[0067] In the cases of women diagnosed with uterine hyperplasia (i.e. in the presence of an already developed uterine hyperplasia), FMD cycles with the diet composition according to the invention could be prescribed with therapeutic purpose, allowing to avoid the topical or systemic use of progestogens and the adverse effects that these drugs can cause (e.g. bleeding).