Nutraceuticals in fibroid management after ulipristal acetate administration: An observational study on patients’ compliance

On May 13, 2020, the Italian government Pharmaceutical Agency (AIFA) stopped ulipristal acetate (UPA) treatments for uterine fibroids (UFs), so patients shifted to other natural treatments. The authors tested the patients’ compliance with UF natural treatments.

on UF etiology focused on risk and stimulating factors, such as ethnicity and biological factors. Afro-American women are more likely than Caucasian women to develop such a formation, 4 and younger women show higher UF proliferation rates. 5 Other factors associated with UF development include genetics, 6 nulliparity, 7 and early menarche. 8 During their lifetime, more than 50% of women develop UFs, rising to 70% in perimenopausal women. 4 As a result, up to 70% of fertile women can develop UFs, even though more than 50% of women affected by UFs will never develop symptoms, 9 such as pelvic pain, menorrhagia, dysmenorrhea, anemia, infertility, and troublesome gestation. 2 Due to these severe symptoms, quality of life (QoL) must be considered as an important parameter to assess in women affected by UFs, in relation to therapy. The commonest approach in asymptomatic UF management is currently the "wait and see" method, monitoring UF growth and waiting for its spontaneous shrinking after menopause. 10 However, because of the burden of symptoms, symptomatic patients displaying UFs are usually scheduled for surgery. The estrogen-responsiveness of UFs frequently leads to their recurrence, making hysterectomy the only definitive surgical treatment. Other surgical approaches include myomectomy, uterine artery embolization, and high-frequency magnetic resonance-guided focused ultrasound surgery. 11 The most expensive and complex pharmaceutical treatments for UFs include gonadotropin-releasing hormone agonists and selective progesterone receptor modulators. Ulipristal acetate (UPA), a synthetic selective progesterone receptor modulators, 12 became one of the most widely used drugs in UF treatment. 13 It proved to be useful both in UF management and in pre-surgical treatment, for UF shrinkage and symptom improvement. 12 Nevertheless, important side effects were reported following UPA treatment, 14 the most life-threatening of which was liver failure. 15 Because of these serious adverse effects, on May 13, 2020, the Italian government Pharmaceutical Agency (AIFA) republished the note produced by the European Medicine Agency's Pharmacovigilance Risk Assessment Committee, recommending immediate suspension of UPA administration. 16,17 It therefore became necessary to search for alternative treatments, without the risk of side effects, especially in patients who had previously used UPA. Among these natural treatments, promising data emerged for epigallocatechin gallate (EGCG) and vitamin D3 administration, either alone 18,19 or in combination. 20 Studies showed that vitamin D3 was able to inhibit cell proliferation, so blocking growth, while EGCG displayed a UF shrinking activity. Porcaro et al. 20 reported that the combined treatment of EGCG plus vitamin D3 led to a significant reduction in the UF-related symptomatology, with a QoL improvement in patients undergoing this treatment. We, therefore, decided to evaluate the compliance of patients who were forced to stop UPA therapy and switch to another natural therapy such as EGCG plus vitamin D3, analyzing the QoL differences at the end of their 3 months of UPA treatment and after subsequent natural treatment.

| MATERIAL S AND ME THODS
A cohort of women undergoing UPA (Esmya ® ; Gedeon-Richter Company, Milan, Italy) administration for UF symptoms, was contacted by phone by their private gynecologists when the Pharmacovigilance Risk Assessment Committee recommended stopping the use of UPA. Patients were all checked in private clinics by their gynecologists and found to be healthy. Some women asked to switch UPA to other therapies, including natural ones, to continue a treatment against UFs, in accordance with common clinical practice. It was proposed to switch from Esmya (stopped after the first cycle of 3 months) to a natural therapy, containing EGCG The investigation on QoL after UPA and nutraceutical administration was carried out in private clinics, after informed consent had been signed by all patients spontaneously referred to the proposed study. As a result the study was carried out without Institutional Review Board or Ethics Committee approval.
The collected QoL data were analyzed and transformed into percentage scores as previously described. 21 The scores were then analyzed using paired Student's t test. A P value less than 0.05 was considered significant. Values are expressed as mean ± standard deviation. In this manuscript, UFs are classified with a number ranging from 1 to 3: 1 corresponding to UFs in the endometrial cavity; 2 being associated with intramural UFs; and 3 belong to serosal UFs.

| RE SULTS
Out of 39 patients attending the private clinic, a total of 30 Caucasian women participated in this data collection, with the following demographic data: mean age 35.9 ± 3.93 years, body mass index (calculated as weight in kilograms divided by the square of height in meters) of 23.63 ± 2.95 on average, mean parity 0.83 ± 0.87 children. The UF parameters were the following: mean number of UFs 1.53 ± 0.68 per woman, and UF diameter 5.65 ± 1.69 cm, with intramural UF as the most frequent type. Their data before starting UPA therapy are reported in Table 1.
Activity score at T0 was equal to 66.07% ±14.15%, but at T1 it had increased to 77.62% ±10.01% (P < 0.001). The score of energy and mood sub-group at T0 was equal to 70.12% ±12.07% on average, rising to 79.52% ±8.12% (P < 0.001). The control sub-group was the most improved, changing from 67.83% ±15.68% at T0 to 84.67% ±7.06% at T1 (P < 0.001). Self-consciousness scores were 77.22% ±12.93% at T0 and 89.72% ±9.71% at T1 (P < 0.001). Sexual function scored 80.00% ±18.74% at T0 and 91.25% ±12.35% (P = 0.0046) (Figure 2). No adverse effects were reported following UPA or EGCG plus vitamin D3 treatments.  30 and inhibiting proliferation of UFs. 19 In addition to all these effects against UFs and tumors, the combination of these molecules proved to reduce UF size and SS, so improving QoL. 20 Considering that Lukes et al. 23   The limits of the study are that it is observational, conducted over a short period of time and on a small sample size. Therefore, we would encourage further placebo-controlled, randomized, and double-blind studies on this subject, comparing UPA directly with the EGCG plus vitamin D3 combination, to validate these preliminary data.

ACK N OWLED G M ENTS
The authors thank the women who participated in this investigation.

CO N FLI C T S O F I NTE R E S T
The authors declare that they have no conflicts of interest and nothing to disclose. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

AUTH O R CO NTR I B UTI O N S
AT and SG contributed to the concept and design. All authors contributed to the acquisition of data. AT and GP contributed to the analysis or interpretation of data; AT, OD'O and ML drafted the article, and AT and SG provided critical revision for important intellectual content.