In the letter dated August 26, 2014 the AIFA raised the major objection that endometrial biopsies are performed in patients who do not present particular pathologies or conditions requiring such invasive assessment in clinical practice, resulting in a disadvantageous benefit/risk ratio for the study. Though the endometrial biopsy remains the best option for the assessment of the endometrium, the measurement of endometrial thickness by means of transvaginal ultrasonography has been demonstrated to have good diagnostic accuracy and allows to limit the hysteroscopy examination only to suspicious cases. For this reason, the protocol will be amended to exclude the endometrial biopsies and to limit the efficacy assessment to the non-invasive endoscopic evaluation of endometrial thickness, as well as to the assessment of bleeding. Hysteroscopy and endometrial biopsies will therefore only be performed in those patients who, at the end of the treatment period, display endometrial thickness > 4 mm or recurrent bleeding, in agreement with clinical practice standards. Inclusion at screening will be based on endometrial thickness ≤ 4 mm as well as on medical history. As a consequence, analysis of estrogen and progesterone receptors in bioptic tissues has been deleted. In addition to the above, time windows for screening visit and follow-up have been extended to allow availability of results of diagnostic procedures and a mistake in the numbering of the weeks in the Overall Study Schedule has been corrected.

The inclusion criterion of menopause onset < 2 years appears to be too restrictive. In a reanalysis of data from the WHI study, age and time from last menses were significantly predictive of the occurrence of cardiovascular events and death. In the combined estrogen+progesterone arm, the odds ratio for coronary heart disease (CHD) was directly related to the time since menopause, with the hazard ratio for CHD in the hormone-treated versus placebo groups of 0.89 for <10 years, 1.22 for 10 to 19 years, and 1.71 for ≥20 years (Manson et al. 2003). In a further reanalysis by Rossouw et al for women with less than 10 years since menopause began, the hazard ratio for CHD (total mortality) was 0.76 (0.76), as compared to 1.10 (0.98) for 10 to 19 years, and 1.28 (1.14) for ≥20 years. International guidelines recognize that menopausal hormone therapy is the most effective treatment for vasomotor symptoms and other symptoms of the climacteric, with benefits more likely to outweigh risks for symptomatic women when therapy is started within 10 years after menopause onset. In consideration of the above, the study can be safely extended to women with menopause onset < 10 years, thus improving recruitment while maintaining the same benefit/risk ratio. In addition to the above, the study protocol foresees that a mammography is performed at screening if not already available within the last 6 months. As in the clinical practice, the availability of a breast ultrasound within 6 months is equally acceptable to the purpose of a safety assessment before starting the hormone replacement therapy. Due to some delay in the patients’ recruitment, the study duration will be prolonged until December 2015.