**1. Introduction: update on the importance of the hormone treatment in perimenopausal women—non-oral routes of hormone therapy**

The menopausal transition is associated with profound dynamic and critical changes of the reproductive tract, and in the hypothalamic-pituitary-ovarian axis, which have been well chronicled and matched with concomitant symptoms regarding the characteristics of menstrual cycle—the most important parameter in the new criteria of STRAW +10 (2012), which starts with the irregularities from stage-3b/-3a in the late reproductive age [1, 2], and of all other organs and tissues of the women's body, biology and psychology through this time of life. There are ethnic differences in symptoms and hormones that may reflect either basic biologic variations in hormone receptors and actions or the different social milieus that women in different ethnic groups experience [3]. The highly prevalent menopausal symptoms are sufficiently bothersome to drive almost 90% of women to seek out their healthcare provider for advice on how to cope with it. Current medical management of perimenopause should include screening for general health maintenance, avoidance of weight gain—a very important parameter for endometrial health—and a holistic approach to symptoms (**Figure 1**).

Menopausal hormone therapy (MHT) is indicated for the treatment of vasomotor symptoms and menopausal genitourinary syndrome caused by hypoestrogenism. MHT helps in the prevention of osteoporosis, colorectal cancer, type 2 diabetes mellitus, and possibly coronary heart disease (CHD), and Alzheimer's disease if started early in the perimenopause or early postmenopause—+1a/+1b (STRAW +10) in the "window of opportunity," with a positive effect on quality of life and reduction of global mortality.

The initial and quick publication of the results of Women's Health Initiative (WHI) (2002) led to confusion and fear regarding medical recommendations and women's use of MHT in conjunction with CHD, stroke, and venous thromboembolism, metabolic disorders, breast cancer, cognitive and mood disorders, and general


#### **Figure 1.**

*The stages of reproductive aging workshop +10 staging system for reproductive aging in women (adapted from Ref. [1]).*

**57**

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

mortality [4]. The analyze of risks of endometrial and colon cancer proved their reduction by MHT in postmenopausal women, being proven by the reduction of

Timing of therapy is time since menopause, being more important than women's age. When the benefits are higher than risks, as was proven by previous observational studies, animal models, and new RCT—as Kronos Early Estrogen Prevention Study, Early Versus Late Intervention Trial With Estradiol, Estrogen and Thromboembolism Risk, at near 10 years from the premature closure of both arms of WHI (2002, 2004), when on recorded the "end of an era". The personalized recommendations of MHT, or tailoring the use of MHT to appropriate candidates, with the ultimate goal of developing a personalized risk/benefit prediction model must take into account clinical and genetic factors, "patient-centered" outcomes as

**1.1 Non-oral versus oral route for hormone therapy administration: advantages** 

Oral HT was and still may be the most commonly used route of administration in the USA and all over the world. Evidence suggests that oral delivery may lead to some undesirable physiologic effects caused by significant gut and hepatic metabolism. After closure of the estro-progestogen arm of the WHI (2002), some researchers admitted that not all estrogens and progestogens are alike, and alternative drugs, doses, and delivery systems may exhibit better safety profiles than CEE/MPA (with co-multiple and complex studies of the WHI), with no loss of efficacy [5, 6]. The next subchapters will present the transdermal/percutaneous route for estrogens, the vaginal route for micronized progesterone, and the intrauterine systems with levonorgestrel/progesterone for recommendation in menopause transition—early and late perimenopause and early postmenopause from the road of menopause [2]. The best regimen, formula, and dosage—the lowest efficient estrogen dose—will give the opportunity to medical staff to stratify the individual risks and to personal-

Transdermal/percutaneous drug delivery may mitigate some of the undesirable physiologic effects caused by significant gut and hepatic metabolism of oral HT, which still may be the most commonly used route of administration for MHT in the USA and many other countries. Active systems deliver therapeutics noninvasively across intact skin by means of an electric potential (electrotransport) [8], ensuring rapid onset and termination of action, self-administration, and attainment of therapeutic hormone levels with low daily doses, with the disadvantage of the variable intra- and interindividual percutaneous absorption and skin irritation in

The used estrogen is 17-β-estradiol, and women from European countries (Austria, Belgium, France, Germany, Italy, Romania, Spain, Switzerland, the Netherland, and the UK), and Canada used it during the twentieth century's last decade. It is available in multiple formulations—matrix, patches (25, 50 μg/day), and non-patches, as topical gel (hydroalcoholic gel containing 0.06% or 0.1% 17β-E2), spray, emulsion, and lotion [9] and recently in the technology of micellar nanoparticles with their unique physical and chemical properties which enable

The pharmacokinetic and pharmacodynamic differences between oral and non-oral routes of administration give to medical staff new therapeutic

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

sense of well-being, and/or quality of life.

**and disadvantages**

ize the MHT indications [7].

some patients, when women use patches.

transport of substances directly into the skin [10, 11].

*1.1.1 Transdermal/percutaneous and nasal routes for estrogens*

colon cancer by HT in postmenopausal women.

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

mortality [4]. The analyze of risks of endometrial and colon cancer proved their reduction by MHT in postmenopausal women, being proven by the reduction of colon cancer by HT in postmenopausal women.

Timing of therapy is time since menopause, being more important than women's age. When the benefits are higher than risks, as was proven by previous observational studies, animal models, and new RCT—as Kronos Early Estrogen Prevention Study, Early Versus Late Intervention Trial With Estradiol, Estrogen and Thromboembolism Risk, at near 10 years from the premature closure of both arms of WHI (2002, 2004), when on recorded the "end of an era". The personalized recommendations of MHT, or tailoring the use of MHT to appropriate candidates, with the ultimate goal of developing a personalized risk/benefit prediction model must take into account clinical and genetic factors, "patient-centered" outcomes as sense of well-being, and/or quality of life.

## **1.1 Non-oral versus oral route for hormone therapy administration: advantages and disadvantages**

Oral HT was and still may be the most commonly used route of administration in the USA and all over the world. Evidence suggests that oral delivery may lead to some undesirable physiologic effects caused by significant gut and hepatic metabolism.

After closure of the estro-progestogen arm of the WHI (2002), some researchers admitted that not all estrogens and progestogens are alike, and alternative drugs, doses, and delivery systems may exhibit better safety profiles than CEE/MPA (with co-multiple and complex studies of the WHI), with no loss of efficacy [5, 6]. The next subchapters will present the transdermal/percutaneous route for estrogens, the vaginal route for micronized progesterone, and the intrauterine systems with levonorgestrel/progesterone for recommendation in menopause transition—early and late perimenopause and early postmenopause from the road of menopause [2]. The best regimen, formula, and dosage—the lowest efficient estrogen dose—will give the opportunity to medical staff to stratify the individual risks and to personalize the MHT indications [7].

### *1.1.1 Transdermal/percutaneous and nasal routes for estrogens*

Transdermal/percutaneous drug delivery may mitigate some of the undesirable physiologic effects caused by significant gut and hepatic metabolism of oral HT, which still may be the most commonly used route of administration for MHT in the USA and many other countries. Active systems deliver therapeutics noninvasively across intact skin by means of an electric potential (electrotransport) [8], ensuring rapid onset and termination of action, self-administration, and attainment of therapeutic hormone levels with low daily doses, with the disadvantage of the variable intra- and interindividual percutaneous absorption and skin irritation in some patients, when women use patches.

The used estrogen is 17-β-estradiol, and women from European countries (Austria, Belgium, France, Germany, Italy, Romania, Spain, Switzerland, the Netherland, and the UK), and Canada used it during the twentieth century's last decade. It is available in multiple formulations—matrix, patches (25, 50 μg/day), and non-patches, as topical gel (hydroalcoholic gel containing 0.06% or 0.1% 17β-E2), spray, emulsion, and lotion [9] and recently in the technology of micellar nanoparticles with their unique physical and chemical properties which enable transport of substances directly into the skin [10, 11].

The pharmacokinetic and pharmacodynamic differences between oral and non-oral routes of administration give to medical staff new therapeutic

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

**1. Introduction: update on the importance of the hormone treatment in perimenopausal women—non-oral routes of hormone therapy**

The menopausal transition is associated with profound dynamic and critical changes of the reproductive tract, and in the hypothalamic-pituitary-ovarian axis, which have been well chronicled and matched with concomitant symptoms regarding the characteristics of menstrual cycle—the most important parameter in the new criteria of STRAW +10 (2012), which starts with the irregularities from stage-3b/-3a in the late reproductive age [1, 2], and of all other organs and tissues of the women's body, biology and psychology through this time of life. There are ethnic differences in symptoms and hormones that may reflect either basic biologic variations in hormone receptors and actions or the different social milieus that women in different ethnic groups experience [3]. The highly prevalent menopausal symptoms are sufficiently bothersome to drive almost 90% of women to seek out their healthcare provider for advice on how to cope with it. Current medical management of perimenopause should include screening for general health maintenance, avoidance of weight gain—a very important parameter for endometrial health—and a holistic approach to symptoms

Menopausal hormone therapy (MHT) is indicated for the treatment of vasomotor symptoms and menopausal genitourinary syndrome caused by hypoestrogenism. MHT helps in the prevention of osteoporosis, colorectal cancer, type 2 diabetes mellitus, and possibly coronary heart disease (CHD), and Alzheimer's disease if started early in the perimenopause or early postmenopause—+1a/+1b (STRAW +10) in the "window of opportunity," with a positive effect on quality of life and

The initial and quick publication of the results of Women's Health Initiative (WHI) (2002) led to confusion and fear regarding medical recommendations and women's use of MHT in conjunction with CHD, stroke, and venous thromboembolism, metabolic disorders, breast cancer, cognitive and mood disorders, and general

*The stages of reproductive aging workshop +10 staging system for reproductive aging in women (adapted from* 

**56**

**Figure 1.**

*Ref. [1]).*

(**Figure 1**).

reduction of global mortality.

perspectives for fewer health risks than oral therapy with estrogen, because only systemic therapy controls the moderate and severe climacteric syndrome, and associated to these data on must remember the large interindividual variability in the pharmacokinetics of estrogens. A dose-dependent effect explains why higher dose, longer duration, and residual endogenous estrogens are known risk factors to develop endometrial lesions and uterine bleeding with estrogens, and according to this pharmacokinetic condition, and to ovarian aging and continuous synthesis of endogenous estrogens, the actual recommendation is to use the lowest estrogen dose. The oral estrogens are converted to estrone (E1), and its conjugates, with less estrogenic activity than estradiol (E2), and the extensive metabolism of oral estrogens is inducing a higher ratio of E1 to E2 in the blood stream, which is opposite to the physiological levels in premenopausal women [12], and the formation of other metabolites from conjugated equine estrogens (CEE) used in the WHI was demonstrated to be antiestrogenic or may have unrecognized pharmacologic activity in the human body [13].

The transdermal/percutaneous and nasal administration of 17β E2 avoid the first-pass liver metabolism and the significant hepatic stimulation, without supraphysiologic concentrations in the liver. E2 is delivered directly, unmetabolized in the systemic circulation, and the estrogen doses are reduced in comparison to the oral formulation, maintaining a similar E2/E1 *ratio* to that of premenopausal women, by avoidance of gut and liver metabolism. Another peculiarity of transdermal/percutaneous route is the constant blood level of estrogens, without the peaks and troughs inherent to oral estrogens [14]. This quality is providing a more consistent blood level for the control of vasomotor symptoms and sleep disorders in perimenopause [15]. The lowest effective dose which covers treatment goals was considered to be 0.014–0.0375 mg transdermal/percutaneous 17β E2 patch, and 50 μg/day was the assessed dose in the majority of studies for sequential/cyclic regimens and 25 μg/day for continuous combined regimens.

The newest application method is the estradiol metered-dose transdermal spray (EMDTS) [16], which was proven to ensure a precise dosing, with the maximum of E2 concentration at 18–20 h after application (1 or 2 or 3 puffs), and a stable level of estradiol, estrone, and estrone sulfate on the 7th–8th day of application.

Lower HT doses generally have fewer side effects, as breast tenderness and uterine bleeding, and may have a more favorable benefit-risk *ratio* than standard doses [17]. The UK General Practice Research Database for a nested case-control study showed that the risk of stroke did not increased with low-dose transdermal estrogen (≤0.05 mg/day), but increased with oral therapies and higher transdermal doses [18]. The systemic benefits of transdermal estrogens are connected to their bioavailability and metabolic peculiarities—less pronounced effects on hepatic protein synthesis, such as markers of inflammation, coagulation, and fibrinolysis, to lower or no risk of deep vein thrombosis [19], stroke [20], and myocardial infarction, even in thrombophilic patients [21], and lower or no effects on steroid-binding proteins, but more favorable effects on triglycerides [22].

One recent, large observational cohort study of postmenopausal women (45, 112 cases hormone treated, with a mean duration of 5.5 years of HT use) made a multiple statistic comparison of clinical outcomes among users of oral and transdermal estrogen (CEE or E2) therapy, with or without progestogen, in the Women's Health Initiative Observational Study on Menopause [23], and confirmed all the benefits of non-oral estrogens and their beneficial effect on the global index events (GIE) (defined as the time to the earliest of CHD, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death from any cause) and stratified the results by duration of HT usage (mean 5.5 years),

**59**

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

age at time of HT initiation (<60 years, 60–69 years, and ≥ 70 years), years since

The fear of breast cancer is counterbalanced by transdermal estrogens and vaginal micronized progesterone, a fact demonstrated by the figures of the large observational French study E3N Cohort, which showed a small increase in the risk of breast cancer (HR: 1.31; 95% CI: 1.15–1.48), after 5 years of use, but the risk was no longer statistically significant following discontinuation of MHT (HR: 1.15; 95%

Low-dose vaginal estrogen preparations as cream, suppositories, and pessaries are recommended for long-term use in symptomatic women as required, and all topical estrogen preparations have been shown to be effective in this context. There is no requirement to combine them with systemic progestogen treatment for endometrial protection, as low-dose or ultralow-dose (10 μg vaginal 17β-estradiol tablets) [25, 26] estrogen preparations do not result in significant systemic absorption, and the risk of endometrial hyperplasia and cancer is low. After 52 weeks of such treatment, a case with hyperplasia without atypia and a case with endometrial adenocarcinoma was discovered, which was considered to be previous to the 17β-E2 vaginal treatment [25]. When the estrogen is estriol—a weak estrogen, with low potency to the estrogen nuclear receptor—the endometrial and breasts' risks are null [27].

The British Menopause Society considers that it is safe to recommend only 1-year use of vaginal estrogens, and the clinicians are advised to use the lowest effective dose for symptoms' control and to counsel women regarding this [28, 29]. A vaginal ring that delivers a large dose of estrogen to the whole body may be an option for HT in hysterectomized women; vaginal rings more often deliver low doses and are

The addition of a progestin (progesterone/progestogen) has only one indication: endometrial protection and endometrial safety during MHT—the prevention of hyperplasia and cancer. Progesterone, the native hormone produced by the corpus luteum during the luteal phase of the menstrual cycle, is the unique option when one seeks "physiological" hormone replacement therapy. The pure progesterone was synthesized in large amount from the plant diosgenin by the chemist Russell Marker in 1940 [30]. Depending on its chemical structure, a progestogen can either enhance (e.g. hot flushes, gonadotropin release, breast epithelial proliferation, and bone mineral density) or antagonize (e.g. endometrium, arterial wall, lipid metabolism, hepatic protein synthesis, and mood) the effects of the estrogen component [31]. Progesterone/ progestogens have gene effects on estrogen receptors' synthesis downregulation and metabolic effects on rising levels of the enzyme 17-hydroxysteroid dehydrogenase, which transforms E2 to E1—sulfate, a weak estrogen—and these effects mean the arrest of endometrial glandular cell proliferation, cell differentiation, and secretory activity, and stroma decidualization. Actually, it is very well known that progestins protect the endometrium by inducing secretory transformation within the endometrial glands and stroma decidualization, and their capacity to restore to the normal endometrium without signs of differentiation or secretion is assessed after minimum 6 days and daily administration for 3–6 months in the conditions of hyperplasia [32]. These facts were assessed regarding oral compounds such as MPA, levonorgestrel, and norethisterone during the last two decades of the twentieth century, and less with vaginal/ transdermal route of administration. Hyperplasia was reverted by the administration

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

CI: 0.93–1.42) [24].

*1.1.2 Low-dose vaginal estrogens*

considered topical therapy.

*1.1.3 Vaginal versus oral route for progesterone*

menopause, body mass index (BMI), and ethnicity.

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

age at time of HT initiation (<60 years, 60–69 years, and ≥ 70 years), years since menopause, body mass index (BMI), and ethnicity.

The fear of breast cancer is counterbalanced by transdermal estrogens and vaginal micronized progesterone, a fact demonstrated by the figures of the large observational French study E3N Cohort, which showed a small increase in the risk of breast cancer (HR: 1.31; 95% CI: 1.15–1.48), after 5 years of use, but the risk was no longer statistically significant following discontinuation of MHT (HR: 1.15; 95% CI: 0.93–1.42) [24].

#### *1.1.2 Low-dose vaginal estrogens*

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

perspectives for fewer health risks than oral therapy with estrogen, because only systemic therapy controls the moderate and severe climacteric syndrome, and associated to these data on must remember the large interindividual variability in the pharmacokinetics of estrogens. A dose-dependent effect explains why higher dose, longer duration, and residual endogenous estrogens are known risk factors to develop endometrial lesions and uterine bleeding with estrogens, and according to this pharmacokinetic condition, and to ovarian aging and continuous synthesis of endogenous estrogens, the actual recommendation is to use the lowest estrogen dose. The oral estrogens are converted to estrone (E1), and its conjugates, with less estrogenic activity than estradiol (E2), and the extensive metabolism of oral estrogens is inducing a higher ratio of E1 to E2 in the blood stream, which is opposite to the physiological levels in premenopausal women [12], and the formation of other metabolites from conjugated equine estrogens (CEE) used in the WHI was demonstrated to be antiestrogenic or may have unrecognized pharmacologic activity in the

The transdermal/percutaneous and nasal administration of 17β E2 avoid the first-pass liver metabolism and the significant hepatic stimulation, without supraphysiologic concentrations in the liver. E2 is delivered directly, unmetabolized in the systemic circulation, and the estrogen doses are reduced in comparison to the oral formulation, maintaining a similar E2/E1 *ratio* to that of premenopausal women, by avoidance of gut and liver metabolism. Another peculiarity of transdermal/percutaneous route is the constant blood level of estrogens, without the peaks and troughs inherent to oral estrogens [14]. This quality is providing a more consistent blood level for the control of vasomotor symptoms and sleep disorders in perimenopause [15]. The lowest effective dose which covers treatment goals was considered to be 0.014–0.0375 mg transdermal/percutaneous 17β E2 patch, and 50 μg/day was the assessed dose in the majority of studies for sequential/cyclic regimens and 25 μg/day

The newest application method is the estradiol metered-dose transdermal spray (EMDTS) [16], which was proven to ensure a precise dosing, with the maximum of E2 concentration at 18–20 h after application (1 or 2 or 3 puffs), and a stable level of estradiol, estrone, and estrone sulfate on the 7th–8th day of

Lower HT doses generally have fewer side effects, as breast tenderness and uterine bleeding, and may have a more favorable benefit-risk *ratio* than standard doses [17]. The UK General Practice Research Database for a nested case-control study showed that the risk of stroke did not increased with low-dose transdermal estrogen (≤0.05 mg/day), but increased with oral therapies and higher transdermal doses [18]. The systemic benefits of transdermal estrogens are connected to their bioavailability and metabolic peculiarities—less pronounced effects on hepatic protein synthesis, such as markers of inflammation, coagulation, and fibrinolysis, to lower or no risk of deep vein thrombosis [19], stroke [20], and myocardial infarction, even in thrombophilic patients [21], and lower or no effects on steroid-binding

One recent, large observational cohort study of postmenopausal women (45, 112 cases hormone treated, with a mean duration of 5.5 years of HT use) made a multiple statistic comparison of clinical outcomes among users of oral and transdermal estrogen (CEE or E2) therapy, with or without progestogen, in the Women's Health Initiative Observational Study on Menopause [23], and confirmed all the benefits of non-oral estrogens and their beneficial effect on the global index events (GIE) (defined as the time to the earliest of CHD, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death from any cause) and stratified the results by duration of HT usage (mean 5.5 years),

proteins, but more favorable effects on triglycerides [22].

**58**

human body [13].

application.

for continuous combined regimens.

Low-dose vaginal estrogen preparations as cream, suppositories, and pessaries are recommended for long-term use in symptomatic women as required, and all topical estrogen preparations have been shown to be effective in this context. There is no requirement to combine them with systemic progestogen treatment for endometrial protection, as low-dose or ultralow-dose (10 μg vaginal 17β-estradiol tablets) [25, 26] estrogen preparations do not result in significant systemic absorption, and the risk of endometrial hyperplasia and cancer is low. After 52 weeks of such treatment, a case with hyperplasia without atypia and a case with endometrial adenocarcinoma was discovered, which was considered to be previous to the 17β-E2 vaginal treatment [25]. When the estrogen is estriol—a weak estrogen, with low potency to the estrogen nuclear receptor—the endometrial and breasts' risks are null [27].

The British Menopause Society considers that it is safe to recommend only 1-year use of vaginal estrogens, and the clinicians are advised to use the lowest effective dose for symptoms' control and to counsel women regarding this [28, 29]. A vaginal ring that delivers a large dose of estrogen to the whole body may be an option for HT in hysterectomized women; vaginal rings more often deliver low doses and are considered topical therapy.

#### *1.1.3 Vaginal versus oral route for progesterone*

The addition of a progestin (progesterone/progestogen) has only one indication: endometrial protection and endometrial safety during MHT—the prevention of hyperplasia and cancer. Progesterone, the native hormone produced by the corpus luteum during the luteal phase of the menstrual cycle, is the unique option when one seeks "physiological" hormone replacement therapy. The pure progesterone was synthesized in large amount from the plant diosgenin by the chemist Russell Marker in 1940 [30]. Depending on its chemical structure, a progestogen can either enhance (e.g. hot flushes, gonadotropin release, breast epithelial proliferation, and bone mineral density) or antagonize (e.g. endometrium, arterial wall, lipid metabolism, hepatic protein synthesis, and mood) the effects of the estrogen component [31]. Progesterone/ progestogens have gene effects on estrogen receptors' synthesis downregulation and metabolic effects on rising levels of the enzyme 17-hydroxysteroid dehydrogenase, which transforms E2 to E1—sulfate, a weak estrogen—and these effects mean the arrest of endometrial glandular cell proliferation, cell differentiation, and secretory activity, and stroma decidualization. Actually, it is very well known that progestins protect the endometrium by inducing secretory transformation within the endometrial glands and stroma decidualization, and their capacity to restore to the normal endometrium without signs of differentiation or secretion is assessed after minimum 6 days and daily administration for 3–6 months in the conditions of hyperplasia [32]. These facts were assessed regarding oral compounds such as MPA, levonorgestrel, and norethisterone during the last two decades of the twentieth century, and less with vaginal/ transdermal route of administration. Hyperplasia was reverted by the administration

of MPA continuously for 6 weeks or cyclically for 3 months (2 weeks per month), these being the two regimens most widely used during the years 1990–2000 [33].

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/ or anti-mineralocorticoid effects.

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 complete secretory changes, in the majority of treated cases.

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

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


**61**

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

transdermally [43]. Stute P at al. [44] are presenting the international expert panel recommendations on MHT containing micronized P4, based on their systematic review of the actions of micronized P4 on the endometrium. **Table 1** presents the comparison of daily dose, number of days imposed for endometrial protection, and

The medicated intrauterine systems with levonorgestrel or with P4, actually accepted by many menopause societies, are minimizing systemic progestogenic side effects by direct release of progestogen/progesterone into the endometrial cavity and directly opposing the estrogens—natural or from HT. It is presented an endometrial protection which is equivalent to that provided by systemic continuous progestogen administration, and superior to sequential progestogen regimen [45].

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

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

dosage), and underpotency (for progesterone)] [60].

(95% CI 0.56–0.90); P = 0.005].

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

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

time duration of safety use.

**2.1 History**

*1.1.4 Medicated intrauterine systems*

#### **Table 1.**

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

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

transdermally [43]. Stute P at al. [44] are presenting the international expert panel recommendations on MHT containing micronized P4, based on their systematic review of the actions of micronized P4 on the endometrium. **Table 1** presents the comparison of daily dose, number of days imposed for endometrial protection, and time duration of safety use.
