**2. Endometrial safety on MHT: history, regimens, endometrial assessment, and endometrial histology during MHT**

### **2.1 History**

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

complete secretory changes, in the majority of treated cases.

levels, but the endometrial secretory transformation is incomplete [40].

**Recommended doses of micronized progesterone for endometrial protection in MHT**

*Comparison of oral and vaginal route, and dosages of P4 administration for endometrial safety.*

Vaginal Sequential 45mg/day or continuous

combined 100mg/day

**Route Dose Safe use/month and total duration of use** Oral 200mg/day 12–14 days/month up to 5 years Transdermal — Does not provide endometrial protection

> 10 days/month or every other day for up to 3–5 years (off-label use)

or anti-mineralocorticoid effects.

of MPA continuously for 6 weeks or cyclically for 3 months (2 weeks per month), these

Available progestins—progesterone/progestogens—differ largely in their hormonal pattern, and, in addition to their progestogenic and antiestrogenic actions on the endometrium, they can exert androgenic, antiandrogenic, glucocorticoid, and/

Oral progesterone (P4) formulations exist but with a very low bioavailability (<10%) because of rapid intestinal and liver metabolism. After oral administration of P4, low circulating concentrations of P4 contrast with the high concentrations of its metabolites, notably 5α-reduced metabolites which are known sources of neuropsychological effects [34], reconsidered actually for neuroprotection. The micronization of the P4 molecule provides an optimal bioavailability, which depends both on the size of the P4 particles in suspension and on the nature of the oily excipient [35]. The vaginal route for micronized P4 was proposed since many years ago [36], but the new hypothesis regarding the higher endometrial P4 levels than that obtained after intravenous administration was presented by [37], being considered an opportunity for MHT. This phenomenon of preferential uterine distribution after vaginal administration was named "first uterine pass effect" [38], or "uterine specificity of vaginal progesterone" [39]. Although the serum P4 concentration is often low or "up-physiological", the endometrium shows clear and

The proposed mechanisms for explanation were done after many experimental and clinical studies: direct diffusion through tissue, intracervical aspiration, absorption into the portal venous system, or lymphatic circulatory system, and countercurrent vascular exchange with diffusion from utero-vaginal veins/lymph vessels to the arteries—all these mechanisms to concur in various extents to the "uterine specificity of vaginal progesterone." Nasal administration of P4 is inducing comparative serum

Previous studies showed that P4 absorption from the vagina is dependent on the formulation used and on the estrogen treatment [41]. The micronization of P4 is very important, and the oral micronized progesterone capsules were re-directed to be used vaginally [42]. Micronized P4 has a more selective effect on PRs and results in less interaction with androgenic and mineral-corticoid receptors compared with other progestogens. The previous administration of estrogens to vaginal micronized P4—100 mg/200 mg—is sustaining endometrial secretory effect compared with many other more potent progestogens. Recent evidence suggests that MHT regimens containing micronized P4 can minimize the metabolic impact and reduce the risk of thromboembolism and side effects associated with progestogens [29]. There are considerable debates about whether and at which dosage micronized P4 provides effective endometrial protection if applied orally, vaginally, or

being the two regimens most widely used during the years 1990–2000 [33].

**60**

**Table 1.**

*Adapted from Ref. [44].*

The review of climacteric symptom alleviation in the medical literature shows that the attempts are approximately 100 years old, starting with ovarian extracts, but in time it was demonstrated the ovarian responsibility for endometrial growth up to adenocarcinomas, as in ovarian transplantation [46] or in estrogen secreting ovarian tumors [47–49], cited by Van Gorp and Neven [50]. Long time it was a minimal knowledge on the real estrogen dose per day to correct the menopausal estrogen insufficiency, and on the imposed dose of progesterone to balance endometrial estrogen induced proliferation [51], for prevention of endometrial hyperplasia and cancer [52, 53]. After observational, cohort, and animal studies were designed large prospective RCTs, as it was WHI with 2 arms, closed early than it was intended initially. After a proper WHI patient reanalysis, new perspectives were discovered for the medical communities of medical staff and women.

The post-WHI analysis [54] discovered a high incidence of endometrial cancer [55], specially an increase over time in women aged 50–74 years (with an annual percentage change, in 2004–2009: 2.8%; in 2005–2009: 3.3%; and 2006–2009: 4.2%) [56], parallel to the decrease in the use of FDA-approved estrogen plus progestogen HT and parallel to the increase of endometrial hyperplasia [57], and after the increasing usage of compounded bioidentical HT (CBHT) instead of pharmacological products [58, 59], even if CBHT are not approved by the FDA, because both hormone compounds lack of standard [type (estrogen: is E2 or E3), dosage, (under dosage), and underpotency (for progesterone)] [60].

The number of cases with hyperplasia/endometrial cancer analyzed in different studies was small, fact that gives us contradictory results on endometrial safety on MHT, and there are few analyses on non-oral MHT. The largest prospective study to date on over 700,000 women, Million Women Study [61], which had done information on HT, reported a 30% reduction in risk associated with continuous regimens (based on 73 cases), but other observational studies have shown either no association or increased risks with use of continuous regimens, and some studies showing evidence of a dose-response relation with increasing duration of use (≥10 years) or increasing progestin dose. Compared with never users of HT, the risk was: reduced with last use of continuous combined preparations [RR = 0.71 (95% CI 0.56–0.90); P = 0.005].

The "European Prospective Investigation Into Cancer and Nutrition" [62] analyzed the association of various types of HT with the risk of endometrial cancer among 115,474 postmenopausal women, during 1992–2000, and after a mean follow-up period of 9 years, 601 incident cases of endometrial cancer were identified. In comparison with never users of HT, risk of endometrial cancer was increased among current users of E-only HT, with (HR = 2.52, 95% CI: 1.77–3.57), and, to a lesser extent, E + P use (HR = 1.41, 95% CI: 1.08–1.83), although risks differed according to regimen, and type of progestin constituent. The finding of a strong increased risk of endometrial cancer with estrogen-only HT, and a weaker association with combined HT supports the hypothesis that progesterone/progestogens have an attenuating effect on endometrial cancer risk.

The North American large prospective "Diet and Health" Study of National Institutes of Health-AARP (NIH-AARP) [63] among 19,131 North American postmenopausal women reporting exclusive E plus progestogen use, between whom 176 cases developed endometrial cancer (RR = 0.88; 95% CI: 0.74–1.06), and the HRs for different regimens HT showed a little increase in comparison to the previous European Study. Long-duration (≥10 years) sequential E+ P (<15 days P/month) use was positively associated with risk (RR = 1.88; 95% CI: 1.36–2.60), whereas continuous E + P use (>25 days P/month) was associated with a decreased risk (RR = 0.64; 95% CI: 0.49–0.83). The American authors' opinion is that findings support the fact that specific used categories of E+P increase the endometrial cancer risk: specifically long durations of sequential progestogens, whereas decreased endometrial cancer risk was observed for users of short-duration continuous progestogens add to estrogen.

The National Institutes of Health-AARP Diet and Health Study cohort, which did the follow-up for endometrial cancer risk after WHI's premature closure, [64] did confirm a statistical reduction of endometrial cancer risk after continuous combined oral MHT for 5.6 years (RR = 0.85; 95% CI, 0.53–1.36), with normal endometrium at entry, and including women in the highest BMI groups; this review was done because the data were not clear after immediate publication of WHI (2002, 2004).

Parallel to these data, the "European Prospective Investigation Into Cancer and Nutrition" shows a strong association of risk among women who were older, leaner, or had ever smoked cigarettes [62], and the North American studies show an increased risk for sequential E + P only among thin-to-normal weight women (BMI < 25 kg/m2 ; RR = 2.53) [63]. California Teachers Study [65] reports that continuous-combined MHT was confined to thinner women (BMI < 25 kg/m<sup>2</sup> ) (P for interaction: 0.03), and among heavier women (BMI ≥ 25 kg/m2 ), use of continuous-combined EPT was associated with a statistically nonsignificant reduction in risk, fact that is different from what was assumed in normal weight women. The association between endometrial cancer risk in continuous-combined MHT users to patients' BMI is correlated to women's lower endogenous estrogen levels, suggesting that menopausal hormones and obesity increase endometrial cancer through common etiologic pathways, as was recently considered that a BMI ≥ 25 kg/m2 is increasing the rate of recurrence in patients hormonally treated for complex hyperplasia/carcinoma (P = 0.0004, OR 0.4; 95% CI: 0.3–0.6), or early stage carcinoma (P = 0.0000, OR 0.3; 95% CI: 0.2–0.6) [66] (**Figure 2**).

Healthy lifestyle index including diet, alcohol consumption, physical activity, body mass index, cigarette smoking, is recently correlated to endometrial cancer risk in Canada [67] and USA [68], and higher scores reflecting a healthier behavior of postmenopausal women are associated to reduction of endometrial cancer risk of various intensity according to the degree of type 1 cancer differentiation. Each unit increase in the HLI score was associated with 3% and 5% reductions in risk of postmenopausal endometrial cancer risk (HR 0.95; 95% CI: 0.90–0.99). The American

**63**

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

HLI showed that after a median follow-up of 17.9 years there were 1435 endometrial cancer cases, and women in the highest quintile of the HLI score had a lower risk of overall, type I, well-differentiated, moderately differentiated, poorly differentiated, and localized endometrial cancer than those in the lowest quintile [for quintile 5 vs. quintile 1, HR = 0.61 (95% CI: 0.51, 0.72), HR = 0.60 (95% CI: 0.49, 0.72), HR = 0.66 (95% CI: 0.46, 0.96), HR = 0.69 (95% CI: 0.52, 0.90), HR = 0.49 (95%

*Hazard ratios (HRs) for risk of endometrial carcinoma (black squares) according to use of menopausal hormone therapy (HT), by recruitment center and age, European Prospective Investigation into Cancer and Nutrition, 1992–2006. The size of each square is inversely proportional to the variance of the logarithm of the relative risk. HRs were adjusted for body mass index, parity, age at menopause, and oral contraceptive use.* 

*Bars, 95% confidence interval (CI). Adapted from Ref. [62]. Permission of Oxford Publishers.*

CI: 0.34, 0.72), and HR = 0.61 (95% CI: 0.50, 0.74), respectively].

*2.2.1 Sequential combined estrogen-progesterone/progestogen therapy*

**hormone therapy**

**Figure 2.**

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

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.

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

*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*

#### **Figure 2.**

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

gens have an attenuating effect on endometrial cancer risk.

The "European Prospective Investigation Into Cancer and Nutrition" [62] analyzed the association of various types of HT with the risk of endometrial cancer among 115,474 postmenopausal women, during 1992–2000, and after a mean follow-up period of 9 years, 601 incident cases of endometrial cancer were identified. In comparison with never users of HT, risk of endometrial cancer was increased among current users of E-only HT, with (HR = 2.52, 95% CI: 1.77–3.57), and, to a lesser extent, E + P use (HR = 1.41, 95% CI: 1.08–1.83), although risks differed according to regimen, and type of progestin constituent. The finding of a strong increased risk of endometrial cancer with estrogen-only HT, and a weaker association with combined HT supports the hypothesis that progesterone/progesto-

The North American large prospective "Diet and Health" Study of National Institutes of Health-AARP (NIH-AARP) [63] among 19,131 North American postmenopausal women reporting exclusive E plus progestogen use, between whom 176 cases developed endometrial cancer (RR = 0.88; 95% CI: 0.74–1.06), and the HRs for different regimens HT showed a little increase in comparison to the previous European Study. Long-duration (≥10 years) sequential E+ P (<15 days P/month) use was positively associated with risk (RR = 1.88; 95% CI: 1.36–2.60), whereas continuous E + P use (>25 days P/month) was associated with a decreased risk (RR = 0.64; 95% CI: 0.49–0.83). The American authors' opinion is that findings support the fact that specific used categories of E+P increase the endometrial cancer risk: specifically long durations of sequential progestogens, whereas decreased endometrial cancer risk was observed for users of short-duration continuous progestogens add to estrogen. The National Institutes of Health-AARP Diet and Health Study cohort, which did the follow-up for endometrial cancer risk after WHI's premature closure, [64] did confirm a statistical reduction of endometrial cancer risk after continuous combined oral MHT for 5.6 years (RR = 0.85; 95% CI, 0.53–1.36), with normal endometrium at entry, and including women in the highest BMI groups; this review was done because the data were not clear after immediate publication of WHI

Parallel to these data, the "European Prospective Investigation Into Cancer and Nutrition" shows a strong association of risk among women who were older, leaner, or had ever smoked cigarettes [62], and the North American studies show an increased risk for sequential E + P only among thin-to-normal weight women

continuous-combined MHT was confined to thinner women (BMI < 25 kg/m<sup>2</sup>

tinuous-combined EPT was associated with a statistically nonsignificant reduction in risk, fact that is different from what was assumed in normal weight women. The association between endometrial cancer risk in continuous-combined MHT users to patients' BMI is correlated to women's lower endogenous estrogen levels, suggesting that menopausal hormones and obesity increase endometrial cancer through common etiologic pathways, as was recently considered that a BMI ≥ 25 kg/m2

increasing the rate of recurrence in patients hormonally treated for complex hyperplasia/carcinoma (P = 0.0004, OR 0.4; 95% CI: 0.3–0.6), or early stage carcinoma

Healthy lifestyle index including diet, alcohol consumption, physical activity, body mass index, cigarette smoking, is recently correlated to endometrial cancer risk in Canada [67] and USA [68], and higher scores reflecting a healthier behavior of postmenopausal women are associated to reduction of endometrial cancer risk of various intensity according to the degree of type 1 cancer differentiation. Each unit increase in the HLI score was associated with 3% and 5% reductions in risk of postmenopausal endometrial cancer risk (HR 0.95; 95% CI: 0.90–0.99). The American

for interaction: 0.03), and among heavier women (BMI ≥ 25 kg/m2

(P = 0.0000, OR 0.3; 95% CI: 0.2–0.6) [66] (**Figure 2**).

; RR = 2.53) [63]. California Teachers Study [65] reports that

) (P

is

), use of con-

**62**

(2002, 2004).

(BMI < 25 kg/m2

*Hazard ratios (HRs) for risk of endometrial carcinoma (black squares) according to use of menopausal hormone therapy (HT), by recruitment center and age, European Prospective Investigation into Cancer and Nutrition, 1992–2006. The size of each square is inversely proportional to the variance of the logarithm of the relative risk. HRs were adjusted for body mass index, parity, age at menopause, and oral contraceptive use. Bars, 95% confidence interval (CI). Adapted from Ref. [62]. Permission of Oxford Publishers.*

HLI showed that after a median follow-up of 17.9 years there were 1435 endometrial cancer cases, and women in the highest quintile of the HLI score had a lower risk of overall, type I, well-differentiated, moderately differentiated, poorly differentiated, and localized endometrial cancer than those in the lowest quintile [for quintile 5 vs. quintile 1, HR = 0.61 (95% CI: 0.51, 0.72), HR = 0.60 (95% CI: 0.49, 0.72), HR = 0.66 (95% CI: 0.46, 0.96), HR = 0.69 (95% CI: 0.52, 0.90), HR = 0.49 (95% CI: 0.34, 0.72), and HR = 0.61 (95% CI: 0.50, 0.74), respectively].
