*2.2.3 Cyclic hormone replacement therapy using quarterly progestogen during 1 year or long cycle hormone replacement therapy*

By the year 1994, Ettinger B (USA) proposed a cyclic hormone regimen with quarterly progestogen instead of monthly, aiming endometrial protection from hyperplasia and cancer, fact that was accomplished by 10 mg/day of MPA for 14 days at every 3 months [71], and with gestodene 50 μg for the last 12 days of 84 days with continuously 17β E2 in different doses—1 or 2 mg/day, with 1 year duration in the Netherlands [72]. These studies reported less bleeding episodes, with longer duration, and similar high number of hyperplasia compared to baseline assessment. In the Nordic countries this type of MHT regimen is popular, and the Scandinavian study [73] with a duration of 4 years reported partially similar results, but they used norethindrone acetate at a dose of 1 mg/day, for 10 days associated to 17β E2 2 mg per day, reduced to 1 mg day during the last 6 days of each cycle of 12 weeks. They reported a higher rate of drop-out due to bleeding vs. monthly progestogen (P < 0.01), and hyperplasia incidence of 5.6% vs. 1% in the monthly group (P = 0.003), with 1 case of atypical hyperplasia, and 1 case of endometrial adenocarcinoma. The popularity of this regimen is correlated to the 2-fold elevation of endometrial cancer risk in Finland population, and the risk reduction after cessation of the regimen [74].

**65**

discontinuation.

**Table 2.**

multicenter study suggests [80].

*Endometrial Histology and Safety on Non-Oral Routes of Hormone Therapy...*

17β-estradiol gel 17β-estradiol emulsion 17β-estradiol spray

17β-estradiol ring 17β-estradiol tablet Estriol cream Estriol soft capsules

Levonorgoestrel

Progesterone

Conjugated equine estrogen cream

**Hormone Preparation** Transdermal estrogen 17β-estradiol patch

Vaginal estrogen 17β-estradiol cream

Transdermal progesterone/progestogens Norethindrone acetate

Progestin: intrauterine system Levonorgestrel

*Available non-oral estrogens and progesterone/progestogens for MHT.*

Besides these analyses, there is no proper study on non-oral administrated hormones, neither estrogens or progesterone/progestogen, because the Spanish study [75] assessing endometrial stability by the rate of amenorrhea and endometrial stimulation is monitoring the intermittent administration of 100 mg vaginal micronized progesterone to a patch delivering low-dose estradiol (25 μg/day). According to the Scandinavian data on hyperplasia and cancer risk [76, 77] in long cycle progesterone/ progestogen regimen the bleeding pattern is not sufficient for endometrial safety, being mandatory endometrial monitoring with ultrasound and biopsies (**Table 2**).

Vaginal progesterone Micronized progesterone—soft capsules, gel

*2.2.4 Uterine bleeding on hormone therapy: is it predictive for uterine histology?*

the incidence of breakthrough bleeding is high in the first 3–6 months.

Since many years it is considered that the bleeding pattern cannot be a good predictor for endometrial histology, and safety, but it is an exception with progesterone/progestogen withdrawal bleeding in the sequential regimens, after 3 to 6 cycles of therapy, and when it is a complete secretory transformation, the bleeding may be cyclic in the last 5 days of progesterone/progestogen, or in the first 6 days of the next cycle [79]. Hyperplasia is not predicted by regular bleeding on HT, as a

Women who start MHT from early stages of STRAW (−3 stage) may benefit from therapy with progesterone/progestogens, which balances their hormonal milieu, but starting replacement after 1 year amenorrhoea may induce the major disadvantage—the unpredictable bleeding and/or spotting, which are common in the early months of use, no matter what regimen is used. The unpredictability and persistence (in the short term) of bleeding and/or spotting is a common cause for

At the beginning of this century the Australian researchers [78] have presented 2 patterns for bleeding when on MHT: scheduled "withdrawal" bleeding, or unscheduled "breakthrough bleeding", usually for sequential, respectively for continuous combined regimen. Depending on the regimen, the endometrium may be proliferative, secretory, near atrophic or a mixed picture, and bleeding may occur from either an estrogen-dominated or a progestogen-dominated endometrium. When recommending continuous-combined regimen after a long duration of amenorrhea,

*DOI: http://dx.doi.org/10.5772/intechopen.89046*

*Endometrial Histology and Safety on Non-Oral Routes of Hormone Therapy... DOI: http://dx.doi.org/10.5772/intechopen.89046*


#### **Table 2.**

*Hormone Therapy and Replacement in Cancer and Aging-Related Diseases*

*2.2.2 Continuous combined estrogen-progesterone/progestogen therapy*

ous combined regimens 90% of women become bleed free.

back to a sequential regimen for at least another year.

can be doubled or duration increased to 21 days.

*year or long cycle hormone replacement therapy*

with regular withdrawal bleeding.

(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

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 continu-

British Menopause Society [20] has some recommendation for some special

• If breakthrough bleeding occurs following the switch to continuous combined HRT and does not settle after 3–6 months, then the woman can be switched

• If bleeding is heavy or erratic on a sequential regimen, the dose of progestogen

• Persistent bleeding problems beyond 6 months warrant investigation with

By the year 1994, Ettinger B (USA) proposed a cyclic hormone regimen with quarterly progestogen instead of monthly, aiming endometrial protection from hyperplasia and cancer, fact that was accomplished by 10 mg/day of MPA for 14 days at every 3 months [71], and with gestodene 50 μg for the last 12 days of 84 days with continuously 17β E2 in different doses—1 or 2 mg/day, with 1 year duration in the Netherlands [72]. These studies reported less bleeding episodes, with longer duration, and similar high number of hyperplasia compared to baseline assessment. In the Nordic countries this type of MHT regimen is popular, and the Scandinavian study [73] with a duration of 4 years reported partially similar results, but they used norethindrone acetate at a dose of 1 mg/day, for 10 days associated to 17β E2 2 mg per day, reduced to 1 mg day during the last 6 days of each cycle of 12 weeks. They reported a higher rate of drop-out due to bleeding vs. monthly progestogen (P < 0.01), and hyperplasia incidence of 5.6% vs. 1% in the monthly group (P = 0.003), with 1 case of atypical hyperplasia, and 1 case of endometrial adenocarcinoma. The popularity of this regimen is correlated to the 2-fold elevation of endometrial cancer risk in Finland population, and the risk reduction after

ultrasound scan, and endometrial biopsy if clinically indicated.

*2.2.3 Cyclic hormone replacement therapy using quarterly progestogen during 1* 

situations with uterine bleeding on continuous combined HT, as follows:

**64**

cessation of the regimen [74].

*Available non-oral estrogens and progesterone/progestogens for MHT.*

Besides these analyses, there is no proper study on non-oral administrated hormones, neither estrogens or progesterone/progestogen, because the Spanish study [75] assessing endometrial stability by the rate of amenorrhea and endometrial stimulation is monitoring the intermittent administration of 100 mg vaginal micronized progesterone to a patch delivering low-dose estradiol (25 μg/day). According to the Scandinavian data on hyperplasia and cancer risk [76, 77] in long cycle progesterone/ progestogen regimen the bleeding pattern is not sufficient for endometrial safety, being mandatory endometrial monitoring with ultrasound and biopsies (**Table 2**).

## *2.2.4 Uterine bleeding on hormone therapy: is it predictive for uterine histology?*

Women who start MHT from early stages of STRAW (−3 stage) may benefit from therapy with progesterone/progestogens, which balances their hormonal milieu, but starting replacement after 1 year amenorrhoea may induce the major disadvantage—the unpredictable bleeding and/or spotting, which are common in the early months of use, no matter what regimen is used. The unpredictability and persistence (in the short term) of bleeding and/or spotting is a common cause for discontinuation.

At the beginning of this century the Australian researchers [78] have presented 2 patterns for bleeding when on MHT: scheduled "withdrawal" bleeding, or unscheduled "breakthrough bleeding", usually for sequential, respectively for continuous combined regimen. Depending on the regimen, the endometrium may be proliferative, secretory, near atrophic or a mixed picture, and bleeding may occur from either an estrogen-dominated or a progestogen-dominated endometrium. When recommending continuous-combined regimen after a long duration of amenorrhea, the incidence of breakthrough bleeding is high in the first 3–6 months.

Since many years it is considered that the bleeding pattern cannot be a good predictor for endometrial histology, and safety, but it is an exception with progesterone/progestogen withdrawal bleeding in the sequential regimens, after 3 to 6 cycles of therapy, and when it is a complete secretory transformation, the bleeding may be cyclic in the last 5 days of progesterone/progestogen, or in the first 6 days of the next cycle [79]. Hyperplasia is not predicted by regular bleeding on HT, as a multicenter study suggests [80].

The variations of endometrial answers to transdermal estrogen and vaginal micronized progesterone are reduced in comparison to HT oral route, according to more stable transdermal/percutaneous estrogen serum levels, and progesterone uterine first pass. When the bleeding pattern is observed comparative to endometrial histology, the patients with proliferative histologic pattern are bleeding early than the patients with secretory transformation [81].

An Italian prospective study [82] evaluated and compared uterine bleeding in 100 early postmenopausal women (12–36 months after last mensis) on a sequential regimen with both hormones administered non-oral, *versus* the same regimen with oral natural progesterone (NP). All groups were treated with transdermal 17β-E2 50 μg/day, and the NP was 100 mg or 200 mg per day from the 14th day to the 25th day of each 28-day cycle. After 12 cycles of treatment, no significant differences were observed in endometrial thickness between groups, suggesting that all treatments are effective in balancing the estradiol effects on endometrium. Regarding bleeding control, patients in the group with sequential vaginal NP showed a higher number of episodes of regular bleeding than patients in groups with oral NP, and fewer episodes of spotting. Authors' conclusion was that transdermal estrogen combined with vaginal 100 mg micronized NP from the 14th day to the 25th day of each 28-days cycle leads to a good cycle control, and provides excellent patient satisfaction without serious side-effects. The better control of bleeding was associated with a higher treatment compliance in patients who received vaginal NP, with a larger percentage of women completing the study. The authors recommend to start treatment with the lower dose of NP (100 mg/day) to avoid the risk of amenorrhea with 200 mg/day.

An Italian study which is considered with the longest duration—3 years, has prospectively evaluated the bleeding/amenorrhea in 30 postmenopausal women treated with continuous transdermal E2 gel and every-other-day vaginal micronized progesterone in capsules [42]. They report that 4 (13%) of 30 patients withdrew from the study because of bleeding (3 for heavy bleeding and 1 for repeated spotting), and an higher incidence of amenorrhea (82%) than commonly reported (70%) with oral compounds [83].
