**2.2 Regimens of MHT: uterine bleeding on perimenopausal/menopausal hormone therapy**

The chapter will discuss MHT with non-oral administrated natural estrogens which are available for perimenopausal and postmenopausal women, in comparison to oral available drugs, including contraceptive pills, among which there are some with natural estrogens, as are the estrogens in MHT. The history of MHT describes three types of MHT systemic regimens with estrogens and progesterone/progestogens for women with intact uterus, and only one systemic regimen with natural estrogens in hysterectomized women. Exogenous hormones are influencing endometrial cycle, and may also influence uterine volume, fibroid growth, polyps, endometriosis, and the development of cervical adenocarcinomas [50]. Progesterone/progestogens are mandatory for endometrial protection, as it is known since long time. Regarding endometrial safety one must discuss the characteristic of uterine bleed which appears in conjunction to the type of regimen, and the medical staff must counsel patients.

#### *2.2.1 Sequential combined estrogen-progesterone/progestogen therapy*

The sequential/cyclic administration of HT has minimum 10 days of progesterone/progestogen, more safe is 12–14 days. In this regimen both hormones are oral or non-oral administrated, or only one is on a non-oral route. If the last menstrual period occurred less than 1 year prior to starting MHT, a sequential combined regimen should be started, i.e. continuous estrogen with progesterone/progestogen for 12–14 days per month [29]. Thereby reducing the risk of endometrial hyperplasia. The patients will have a monthly withdrawal bleed with this regimen, which usually starts from the 11th day of progesterone/progestogen when this administration is for 10 days [69], and the endometrial thickness at transvaginal sonography

(during the progestin administration) is higher than 4 mm at least in the first year of use [70]. Prescription of cyclic transdermal/percutaneous E2, and the sequential addition of natural progesterone or a synthetic progestogen induces artificial cycles with regular withdrawal bleeding.

## *2.2.2 Continuous combined estrogen-progesterone/progestogen therapy*

Both hormones are administered oral or non-oral, or only one is non-oral. These regimens are increasingly used early in postmenopausal women, and the large long term Medical Research Council randomized controlled trial on HT, the Women's International Study of Long Duration Estrogen after the Menopause, and the WHI study in the USA are based on this type of oral treatment, being accepted also for women with endometrial hyperplasia without atypia. This type of regimen is discussed after a minimum 6 [69] to 12 months of sequential MHT [29] or 1 year after the last menstrual period (2 years in women with premature ovarian insufficiency). Women who wish to avoid a monthly withdrawal bleed may attempt a switch to a continuous combined regimen, which aims to give bleed-free MHT. This will minimize also the risk of endometrial hyperplasia, as it was previously discussed. There may be some erratic bleeding to begin with, but on persistence with continuous combined regimens 90% of women become bleed free.

British Menopause Society [20] has some recommendation for some special situations with uterine bleeding on continuous combined HT, as follows:

