Hormone Replacement Therapy: Is It Always Necessary in Natural and Surgical Menopause?

Abstract

The aim of this paper is to delve into the multifaceted effects of hormone replacement therapy (HRT) in postmenopausal women, elucidating its therapeutic benefits and potential risks. HRT demonstrates efficacy in alleviating genitourinary and vasomotor symptoms, enhancing sleep, mitigating myalgias, addressing skin issues, bolstering emotional well-being, improving joint health, and enhancing overall quality of life. Moreover, HRT exerts a positive influence on bone density, thereby reducing the incidence of osteoporotic fractures. However, we also scrutinize the associated risks, including heightened susceptibility to cardiovascular disease, breast cancer, ovarian cancer, and thromboembolic events. The administration method and dosage of hormones emerge as pivotal factors in modulating these risks. Furthermore, we explore the impact of genetic factors on thromboembolic events in women undergoing oral estrogen therapy. Additionally, considerations regarding the duration of HRT treatment are discussed, with annual reassessment advocated, albeit lacking consensus on optimal treatment duration. We also examine the implications of oophorectomy, delineating potential hormonal dysfunction post-hysterectomy and its ramifications. Moreover, we investigate the cardiovascular and lipid profile effects of ovarian conservation post-hysterectomy, suggesting potential advantages over oophorectomy. In conclusion, this is a comprehensive overview of both the benefits and risks entailed in HRT utilization among postmenopausal women, thereby facilitating informed decision-making in clinical practice.

1. Introduction

In 2030, as per projections from the World Health Organization, the number of women aged 50 years and above is anticipated to exceed 1.5 billion. Although a woman’s menopausal period is characterized by a lack of estrogen, it is expected that her healthy and productive life will continue for at least another 30 years [1, 2]. The large and constantly growing population of peri- and post-menopausal women has contributed to the fact that the treatment of menopause-related symptoms and disorders is an important socio-economic and scientific parameter in industrialized countries with a perspective of its development in developing countries as well [1, 2]. The primary reasons for implementing this treatment include addressing vasomotor symptoms, complications arising from the atrophy of the genitourinary system, preventing osteoporosis and cardiovascular diseases, and managing ovarian failure in women of reproductive age, presenting as early menopause, and menopause. Contraindications include a history of breast cancer, ovarian cancer, or uterine cancer, as well as a history of thromboembolic events, untreated high blood pressure, liver disease, and pregnancy or the desire to become pregnant. Similar to any medication, hormone replacement therapy (HRT) has the potential to induce side effects. However, these side effects typically subside within 3 months of initiating the treatment. Common side effects include breast tenderness, headaches, malaise, abdominal pain, and vaginal bleeding [1, 2].

2. Effects of hormone replacement therapy

Hormone replacement therapy (HRT) continues to be the most effective therapeutic approach for addressing genitourinary symptoms in postmenopausal women, and it is also highly effective in managing vasomotor symptoms [3, 4]. At the same time, it has a beneficial effect and improves other types of disorders related to menopause, such as sleep disorders, myalgias, skin problems, emotional disorders, and joint disorders, and also improves the quality of life of patients but also their sexual issues (Tables 1 and 2) [3, 4]. Furthermore, the beneficial effects of HRT include the reduction of the incidence rate of colon cancer [5], diabetes mellitus, insulin resistance [3], as well as lipids and metabolic syndrome, with the oral administration of preparations. Nevertheless, one drawback of this method is the potential elevation of blood pressure. Despite this, it is not a contraindication for administration, as blood pressure is typically regulated prior to the initial treatment. As reported by Palacios et al. [6], there is a positive response from some progestogens in improving blood pressure, while Henderson [7] reports that there is a positive effect of HRT, at the onset of menopause, and on cognitive function, although it is an issue that remains to be investigated. However, when there is a pre-existing cognitive impairment in older women, then the effect of HRT ceases to be beneficial and instead may worsen the condition [7, 8]. At the same time, it has been reported by some researchers that the administration of HRT at the onset of menopause may reduce the incidence of Alzheimer’s disease [8].

Symptoms of menopause	Frequency	Rate
Hot flashes, sweating	90	81.9
Discomfort	77.7	70.0
Sleep problems	80	72.7
Depressed mood	56	50.9
Irritability	76	69.1
Anxiety	70	63.6
Physical and mental exhaustion	94	85.4
Sexual problems	74	67.3
Bladder Problems	48	43.6
Gulf dryness	46	41.8
Joint and muscle discomfort	94	85.4

Table 1.

Frequency and rates of occurrence of menopausal symptoms among participants [3].

Hypothalamic	Hot flashes; Palpitations convulsions; Tingling sensation
Psychogenic	Nervousness headaches; Change of sexuality; Insomnias
Metabolic	Increased blood lipids osteoporosis; Myalgias urinary incontinence; Atrophic vaginitis

Table 2.

The clinical manifestations of menopause can be summarized in three categories based on their etiology: (a) hypothalamic, (b) psychogenic and (c) metabolic origin [4].

2.1 Postmenopausal osteoporosis

The positive effect of HRT in postmenopausal women in preventing bone loss has already been reported, as it reduces the rate of osteoporotic fractures, as well as the rate of spine and hip fractures, in patients who may be at low risk [9]. It also improves the bone density of postmenopausal women, even with small amounts of estrogen [10], which is why HRT is the main choice for the prevention of osteoporosis in postmenopausal women who experience more fractures and belong to the age range over 60 years. The same is true for women who experience menopause at a younger age [3]. However, when treatment is stopped, the protection in terms of bone density also stops, although it has been reported that some degree of protection still remains. Also, there is no reason to start HRT treatment in women over 60 simply to prevent fractures. HRT has long been known to significantly increase bone mineral density (BMD). In a meta-analysis of 57 trials (prevention and treatment trials) involving approximately 10,000 women, the combined results suggested that, on average, the change in BMD was significantly higher in the HRT group (both unopposed and unopposed estrogen) across all measurements. After 1 year, the HRT group showed an average increase in lumbar spine BMD of 5.4%, while the forearm and femoral neck also increased by 3.0% and 2.5%, respectively. After 2 years of treatment, the percentage change in favor of HRT increased by approximately 1.5% in all regions with increases of 6.8%, 4.5%, and 4.1% in the lumbar spine, forearm, and the femoral neck, respectively [11, 12]. HRT is also effective in preventing osteoporotic fractures. In a meta-analysis of 22 randomized trials, there was an overall 27% reduction favoring the HRT groups in nonvertebral fractures in a pooled analysis (RR = 0.73, 95% CI, 0.56–0.94, P = 0.02). Only for hip and wrist fractures did the effectiveness of HRT appear more impressive (RR = 0.60, 95% CI, 0.40–0.91, P = 0.02) [13]. In a randomized trial investigating the effects of tibolone on fractures, 254,538 women at risk of fracture were assigned to a placebo or tibolone group. Over a median treatment duration of 34 months, compared with the placebo group, vertebral fractures were 45% lower in the tibolone group, (RR = 0.55, 95% CI, 0.41 to 0.74, P < 0.001) and the nonvertebral fracture was reduced by 26% (RR = 0.74, 95% CI, 0.58 to 0.93, P = 0.01) [14]. It is worth noting that estrogen withdrawal leads to rapid bone loss, and within a year most of the previously increased BMD accumulated over 3–4 years is gone. In a randomized study, which included early postmenopausal women aged 55 years, HRT increased BMD by 5–6%. However, 4 years after stopping treatment there was a rapid decline in spine BMD of 7% in the HRT group. Another similar analysis showed that within 2 years hip fractures increased by 50% and after 5 years by 77%. It is therefore recommended that women who stop HRT choose other treatments to prevent osteoporosis [15]. However, it should be emphasized that estrogen is not considered a first-line option for fracture prevention [16, 17, 18].

2.2 Coronary artery disease

In postmenopausal women, cardiovascular disease stands as the predominant cause of morbidity and mortality, as indicated by a WHO study. This study revealed that participants administered a combination of estrogen and progesterone exhibited a heightened risk of coronary heart disease (HR 1.29). Further analysis suggested that patient age at the initiation of hormone replacement therapy (HRT) and the duration since menopause played a role in this outcome [19]. According to Hodis [20], findings from studies such as those conducted by the Women’s Health Initiative (WHI) or the Nurses’ Health Study, along with a meta-analysis of 23 studies, indicated that administering either estrogen combined with progesterone or estrogen alone to women aged 50–59 reduced the likelihood of developing coronary heart disease. Similar observations were made in women under the age of 60, where the administration of raloxifene yielded comparable results [21]. Also, administration of estrogens reduced the incidence of coronary artery calcification in hysterectomized women aged 50–59 years who were screened by cardiac computed tomography [22]. Contrarily, adverse outcomes emerge when hormone replacement therapy (HRT) is administered 10–20 years post-menopause, particularly in women with pre-existing endothelial atherosclerosis, as it escalates the risk of coronary heart disease [23]. Postmenopausal women who already suffer from coronary heart disease and are older also face heightened concerns, while the beneficial effect of HRT is possible for most women who have a healthy endothelium, and are close to menopause, and are protected from cardiovascular diseases [23].

2.3 Breast cancer

While the specific causes of breast cancer remain unknown, certain predisposing factors include a sedentary lifestyle, obesity, and alcohol consumption. In assessing the relationship between breast cancer and hormone replacement therapy (HRT), it is crucial to consider and evaluate the risk rate in proportion to other predisposing factors [24]. As mentioned earlier, the administration of estrogen combined with progesterone has been associated with an increased risk of breast cancer [5]. Data from the Collaborative Group on Hormonal Factors in Breast Cancer reveals insights from a meta-analysis of 51 studies, highlighting the significance of treatment duration [25]. The findings indicate that women initiating HRT for the first time do not face an elevated risk of breast cancer, whereas the risk is heightened in those who had received HRT in previous years [26]. Probably, as reported by Fournier et al. [27], the type of progesterone administered also plays a role, i.e., if natural progesterone or dydrogesterone is administered, then the risk is reduced, compared to synthetic progesterone. Other studies have shown that the duration of treatment plays a role. Postmenopausal women who had undergone hysterectomies and received estrogen-only therapy had no or little risk of breast cancer after several years of treatment. The findings from the World Health Organization (WHO) and the Nurses’ Health Study indicate that the administration of estrogen for durations exceeding 7–15 years appears to carry a relatively small percentage of risk for breast cancer occurrence. Simultaneously, the WHO study revealed a slight reduction in risk [28, 29]. Notably, women with a history of hormone replacement therapy (HRT) demonstrated a significant reduction in risk. In the Collaborative Group on Hormonal Factors in Breast Cancer [30, 31] and Chen et al. [32] studies, it was observed that the incidence of breast cancer may increase after 5 years of treatment. However, the Nurses’ Health Study notes that this risk may appear after a longer period (15–20 years) of treatment.

Concerning the incidence of breast cancer in women exhibiting dense breasts on mammography, there is an elevated risk. The use of hormone replacement therapy (HRT) has been associated with an increase in breast density; however, it has not been conclusively established that this group of women faces a higher risk of breast cancer [3].

Additionally, compared to women who were diagnosed with breast cancer but did not take HRT, there was a comparatively reduced death rate in cases where the cancer was discovered in women who were already on HRT. This phenomenon may be attributed to early diagnosis, systematic follow-up, or the possibility that tumors in HRT-receiving individuals are less aggressive or exhibit a better response to treatment [30].

Nevertheless, when hormone replacement therapy (HRT) treatment is discontinued, research conducted by the Collaborative Group on Hormonal Factors in Breast Cancer [25] and Chlebowski et al. [26] indicates a decrease in the risk of women developing breast cancer. It is crucial to note that the timeframe for the development of breast cancer is extended, with a pre-cancerous stage requiring 5–10 years to progress into cancer [5]. Published findings on the risk of breast cancer associated with different types of hormone replacement therapy (HRT) display inconsistencies, and there is limited information on the long-term effects. Both published and unpublished evidence on these correlations were assessed in a 2019 pooling of epidemiological data by the Collaborative Group on Hormonal Factors in Breast Cancer, with a focus on pertinent randomized data. The primary analyses utilized individual participant data from all eligible prospective studies that had solicited information regarding the type and timing of HRT use. The main analyses were based on individuals with complete data. Studies were identified through a systematic search of multiple formal and informal sources, covering the period from January 1, 1992 to January 1, 2018. Current users were included up to 5 years (with a mean of 1–4 years) after their last HRT use. Logistic regression was employed to derive adjusted risk ratios (RRs), comparing specific groups of HRT users to those who had never used HRT. The findings showed that during follow-up, 108,647 postmenopausal women developed breast cancer at a mean age of 65 years (SD 7). A total of 55,575 (51%) had used HRT. Among women with complete data, the mean duration of HRT was 10 years (SD 6) in current users and 7 years (SD 6) in former users, and the mean age at menopause was 50 years (SD 5) and 50 years (SD 6) starting HRT (All forms of hormone replacement therapy (HRT), with the exception of vaginal estrogen, were linked to elevated risks of breast cancer. These risks showed a consistent rise with the duration of HRT use, and they were notably higher for preparations containing both estrogen and progestogen compared to those containing estrogen alone.

Among users, the risk was deemed excessive during the first 4 years, and it doubled in years 5–14. Specifically, during years 5–14, the consistent use of progestogen daily heightened the risk associated with estrogen-progestogen therapy, and this risk decreased when progestogen use was less frequent. For a specific HRT preparation, the risk ratios (RRs) during years 5–14 of current use were substantially higher for estrogen receptor-positive tumors compared to estrogen receptor-negative tumors. Moreover, these RRs were consistent across women initiating HRT at ages 40–44, 45–49, 50–54, and 55–59 years, but declined after age 60 or with the onset of menopausal symptoms (with a minor risk associated with estrogen-only HRT in women who were obese). After discontinuation of HRT, the excess risk persisted for more than 10 years. Its magnitude depends on the duration of previous use, with a slight excess after less than 1 year of HRT use [31]. According to the interpretation of the results, if these associations are primarily causal, then 5 years of hormone replacement therapy (HRT) starting at age 50 will increase the incidence of breast cancer in women of average weight in developed countries between the ages of 50 and 69. The estimated increases in breast cancer incidence are approximately one in 50 for daily users of estrogen-progestogen preparations, one in 70 for users of estrogen with intermittent progestogen preparations, and one in 200 for users of estrogen-only preparations. For a 10-year duration of HRT use, these excesses would be roughly twice as stated by the Collaborative Group on Hormonal Factors in Breast Cancer [31].

2.4 Ovarian cancer

A large number of studies [5, 32, 33] report that women taking HRT have a high risk of developing ovarian cancer, just as the risk is high for women taking estrogen, but it is an issue that is still in question, as the conclusions remain conflicting [32].

2.5 Strokes

Vascular strokes and the effect of HRT on them is an issue that is under study, regarding the rate of stroke, although studies so far have shown that most postmenopausal women are at high risk of having a stroke, a risk that decreases if the women’s age is under 60 Writing Group on behalf of Workshop Consensus Group [31, 34]. As reported by Rossouw et al. [19], it has been observed in the WHI study that there was a high incidence of stroke in the entire population (HR 1.32), which was found to be reduced in the age group of 50–59 years. The Nurses’ Health Study had the same result, which also found an increased risk of stroke, regardless of the age of the participants, while age was not an inhibitory factor for the subgroups of participants who received a small amount of doses estrogen and there was no increased risk of stroke in these women [35].

2.6 Thromboembolic events and pulmonary disease

Among the adverse effects of HRT are thromboembolic events, in which the probability of occurrence increases when the age of women exceeds 60 years, the risk is additionally linked to obesity and oral intake of estrogen, as opposed to when administration is conducted transdermally, where the risk is significantly diminished [36, 37, 38]. For this reason, transdermal administration is recommended for postmenopausal women who are at risk of thromboembolic events due to a history of thromboembolic disease or increased body weight. It is also pointed out that thromboembolic events also depend on the progesterone administered [37]. According to studies, thromboembolic events depend on genetic factors and occur when oral estrogens are administered (e.g., factor V Leiden, some CYP3A5 polymorphisms, G20210A mutation in the prothrombin gene) [38, 39].

3. HRT precautions

The hormone replacement therapy (HRT) formulations primarily consist of reproductive steroids, specifically estrogen, either in isolation (predominantly during the 1950s–1960s) or in conjunction with progestogens or androgens. The same category includes tibolone and phytoestrogens, while raloxifene is a non-steroidal substance [40, 41]. Estrogens are divided into two categories: natural and synthetic. Natural estrogens are mainly used in HRT preparations over synthetic estrogens due to fewer and less intense adverse effects, and this is because synthetics cause to a greater degree unwanted activation of liver enzymes. A special category is the conjugated estrogens derived from the urine of pregnant horses, with the main component estrone sulfate, secondary equilin sulfate, and 17a dihydroequilin sulfate. Equilin has a strong effect and is stored in adipose tissue, so it sometimes continues to work even after treatment is stopped [41, 42]. The term progestogen refers to all steroids used as a substitute for endogenous progesterone. These HRT preparations contain mainly synthetic progestogens belonging to two chemical classes, progesterone derivatives and nor-testosterone derivatives. Drospirenone is a new progestogen derivative of 17aspironolactone with antiandrogenic and antisaltocorticoid activity In particular, progesterone derivatives include dihydroprogesterone, medroxyprogesterone acetate (MPA), chlormadinone acetate (CMA), cyproterone acetate (CPA) and medrogestone, and 19nor testosterone derivatives include norethisterone, norgestimate, levonorgestrel, Lynestrenol, Gestodenis, Desogestrel and Dienogest [39]. The desirable actions of progestogens include the preservation and support of the endometrium after estrogenic influence, the antimitotic effect on the endometrium, and possibly some positive psychotropic effect. On the contrary, the side effects include a mild androgenic effect (more evident in testosterone derivatives) manifested as hirsutism and disturbance of lipid metabolism. The 19nor testosterone derivatives selectively bind the progesterone receptors with which they have a high degree of affinity, thus allowing the administration of a lower dosage, but at the same time, they also bind the androgen receptors. Finally, dienogest combines the advantages of 19nor-progestogens (high oral bioavailability, strong progesterone effect on the endometrium) with the corresponding ones of progesterone derivatives (antiandrogenic and antimitotic effect, moderate antigonadotropic effect). It is also not bound by endogenous proteins (SHBG-CBG). Finally, a special form of progestogen is drosperinone, which exhibits antisaltocorticoid, antiglucocorticoid, and antiandrogenic effects. The postmenopausal ovaries and adrenal glands are a source of androgen production. But with the passage of age, there is a drop in the level of circulating androgens by 50% with the greatest decrease (75%) concerning dehydroepiandrosterone (DHEA). On the contrary, at least 5 years must pass before the level of testosterone begins to fall. The combined administration of androgens and estrogens in postmenopausal patients is constantly gaining ground, especially in cases with previous oophorectomy.

The main advantages of the administration of androgens are the remission of vasomotor symptoms, the improvement of mental mood since androgens have a key role in the psychophysiology of women with significant interventions in (mental functions, emotions, and desire for sexual activity) as well as the improvement of sleep quality, the increased energy, and ability to deal with stress and the strong anabolic action.

Disadvantages of androgen administration include increased risk of cardiovascular disease (neutralization of potential beneficial effects of estrogen), reduction of HDL levels without substantial change in LDL counterparts, masculinization, and hirsutism (dose-dependent). A quite interesting substance with androgenic action is dehydroepiandrosterone and its divine derivative, which when administered causes a decrease in subcutaneous thickness and in general adipose tissue, an increase in muscle mass, and a decrease in plasma glucose levels. In addition, the presence of antimitotic activity has been established in experimental animals [43, 44].

Tibolone is a synthetic steroid derivative of 19-nor testosterone that exhibits simultaneous estrogenic, progesteronic, and androgenic effects. The degree of affinity for estrogens is small for tibolone as a whole and for the 3a and 3b hydroxy isomers, for progesterone and androgens, it is small for tibolone as a whole, moderate for the Δ4 isomer while there is no chemical affinity for the 3a and 3b hydroxy isomers. The advantages of the method include the reduction of climacteric vasomotor symptoms and estrogenic effect on bone tissue, the compensation of estrogenic action in the endometrium, and the improvement of the desire for sexual intercourse. Its disadvantages include the fact that the degree of its effect on other tissues especially on the breast is not yet known. Tibolone is administered in a daily dose of 2.5 mg for the relief of symptoms and the control of uterine bleeding [44]. Raloxifene and bazedoxifene are classified as selective estrogen receptor modulators (SERMS). Their action is both antagonistic and antagonistic to estrogen depending on the target tissue. In particular, it mimics the action of estrogen on bone tissue, the cardiovascular system, and lipid metabolism. This action is different from that of 17β estradiol and tamoxifen. They exhibit anti-estrogenic activity in the endometrium and have an inhibitory binding effect on estrogen receptors, antagonizing the estrogen-dependent proliferation of MCF-7 cells in breast tumors. Their advantages include the absence of mitotic activity in the breast and endometrium. Other advantages are the fact that they can be administered without progestogen to women with an intact uterus and act satisfactorily in the prevention of osteoporosis. Finally, they do not affect ovarian estrogen production and the hypothalamic-pituitary axis. Their disadvantages include the unsatisfactory treatment of climacteric symptoms and the occurrence of adverse effects such as hot flashes and leg cramps. In light of the aforementioned, they are the recommended course of action for preventing osteoporosis in patients at high risk of developing breast cancer as well as in those who experience bleeding or spotting during standard therapy [45, 46]. Phytoestrogens are plant components with estrogenic activity and potential positive therapeutic intervention in menopausal symptoms. The most well-known source of origin is vegetables, especially soy. According to epidemiological studies, they have a favorable effect on the remission of vasomotor symptoms. On the contrary, they are less effective in terms of their action in the atrophy of the genitourinary system. It has been reported that in women with mild and moderate symptoms and a contraindication to the application of HRT, the enrichment of the diet with foods rich in phytoestrogens may be beneficial. Finally, in the long term, soy may protect the cardiovascular system while, on the contrary, its effect on osteoporosis needs further investigation [47].

4. Ways of administration

The modes of administration for the specific formulations of hormone replacement therapy (HRT) are primarily twofold: oral and parenteral, with the latter further categorized into injectable transdermal and local methods.

Oral steroids are more common. Oral steroids, after being absorbed from the gastrointestinal tract, pass through the liver before entering the general circulation. This results in a small fraction (5%) of active substances entering the general circulation. Oral estrogens stimulate the production in the liver of substances with possible adverse effects such as coagulation factors and angiotensinogen, but they rapidly increase HDL and decrease LDL as a consequence of the first-pass effect [48]. The advantages include the possibility of daily interruption of treatment or reducing the dose in case of adverse effects or, conversely, the possibility of increasing the dose. It also allows the application of monotherapy or combined therapy through a wide variety of independent formulations. Parenteral therapy is available either for daily use or for longer periods of time (up to 6 months). Daily administration is used for rapid resolution of vasomotor symptoms after surgical removal of the ovaries. As with oral, it is possible to stop or reduce the dosage on a daily basis. Monthly or longer dosing has the disadvantage of losing the ability to stop immediately but offers the advantage of constant checks by the attending physician. Parenteral administration bypasses the first pass through the liver and does not stimulate hepatic metabolism [49]. Of the other types of parenteral administration, the subcutaneous implant maintains stable estrogen levels for approximately 6 months. It is more useful for women with good estrogen tolerance because it is not possible to stop treatment quickly. The transdermal patch is placed on the skin and gradually releases estrogen or estrogen and progesterone into the circulation. It is replaced every 3–7 days. During its stay on the skin, it releases steroid hormones at normal levels [50]. The local route is indicated for the treatment of atrophic disorders such as vaginitis and vulvitis. It mainly contains the biologically weaker estrogen, estriol. It is administered mainly in the form of a ring or suppository cream [51]. With regard to the types of HRT, the treatment is divided into monotherapy which includes a steroid, and combined treatment which mainly includes two types of steroid hormones. Estrogen monotherapy is only indicated in patients who have undergone hysterectomy Cyclic combination therapy, involving a treatment-free interval, closely mimics the hormonal profile of reproductive age. This approach is particularly popular in the pre- and peri-menopausal periods. The periodic addition of progestogen often results in breakthrough bleeding, occurring either during the progesterone phase or following both types of treatment, an effect not resisted by premenopausal women with regular menses. Moreover, women experiencing irregular cycles find benefit in the normalization of these cycles through progesterone. Conversely, some women initiating hormone replacement therapy (HRT) a few years after menopause may perceive the return of menstruation as a drawback, leading them to discontinue the treatment. Continuous combination therapy is utilized to enhance tolerance, reduce bleeding, or achieve complete amenorrhea, particularly in postmenopausal women. The uninterrupted administration of tibolone is also considered a viable solution for women who have been in a menopausal state for at least 1 year. Additionally, some propose the inclusion of progestogen for extended durations (3–6 months) with the aim of prolonging the period of menstruation-free intervals; however, it should be noted that there is no conclusive evidence documenting that this method provides protection to the endometrium [49, 50, 51].

5. Modus and duration of administration

Typically, the initial prescription spans 3 months, with a subsequent course extending to 6 months of administration. Remission of vasomotor symptoms is observed after a few weeks of satisfactory treatment. The pace of improvement in urogenital symptoms is gradual, as it necessitates approximately 6 months for the estrogenization of the vagina to take effect. Finally, a reassessment of the effectiveness of the therapeutic treatment is required on an annual basis [49]. There is no agreement regarding the duration of the therapeutic treatment. Some argue that it should be applied until symptoms subside. Usually, a treatment of 3–5 years is sufficient for the complete remission of the symptoms without excluding the relapse upon interruption, in which case a repetition of the treatment is necessary. Relapse is inevitable with regard to the symptoms of urogenital atrophy. Discontinuation of treatment without medical consent is often due to events that occur during this period at the woman’s age, such as retirement or the occurrence of breast cancer in a relative or friend. However, in any case, for the continuation of the treatment for a long period of time, the possible slightly increased risk of breast cancer and thromboembolic events should be taken into account. The modern opinion regarding hormone replacement therapy is that it should be given to perimenopausal and early menopausal women without contraindications and after systematic information about the possible risks and benefits. It is not recommended to start the treatment after the age of 60. In women with early menopause <40 years or early menopause <45 years, it is recommended to administer replacement with sex hormones until the age of 51 for the treatment of vasomotor symptoms, and for the prevention of osteoporosis and cardiovascular diseases [49].

6. Surgical menopause

The frequency of oophorectomy varies depending on the age of the woman and the indication for which the operation is performed. Oophorectomy is performed in 75% of women with cancer or precancerous conditions [50], and in 52% with benign diseases during abdominal surgery, while only in 20% when access is vaginal. There is no unanimity on the necessity of oophorectomy and on its indications in benign diseases. In many cases, the decision is arbitrary and based on some age limit. An important role in these decisions must be played by the woman’s desire for balanced information about the benefits and harms of ovarian conservation. Although this seems commonplace, in reality, women are affected by counseling, which is usually lacking. It is typical in one paper that 20% of women who have undergone oophorectomy during hysterectomy did not know that the ovaries have been removed [51]. In general, hysterectomy with oophorectomy is more commonly performed in women with a lower educational level, obesity, and nulliparous women [52].

6.1 Hormone replacement therapy after hysterectomy

Before deciding to remove functioning ovaries, there should be ways to replenish their function for long periods of time without health consequences. It is a fact that young women, even after the preservation of the ovaries in hysterectomy, often experience hot flashes and other symptoms of estrogen deficiency that are not related to the hormonal picture [53], while others (up to 50%) tolerate the ovarian failure caused by salpingo-oophorectomy relatively well. Sometimes, while preserving the ovaries, replacement therapy is not given and their insufficiency is not recognized, resulting in unwanted cardiovascular effects [54, 55, 56]. The existing preparations with conjugated estrogens, estradiol, and various types of progesterone are far from the normal secretion of the ovary, although they substitute to a large extent at the cost of some risks. These include thromboembolic disease, cholecystopathies, and to a lesser extent the risk of breast cancer. Hypertension may occur during the administration of hormone replacement and it may be necessary to stop it. The most serious practical problem is non-compliance with chronic treatment. Speroff et al. [57], in a review of the literature, observed that adherence to treatment ranged from 31% to 89% at baseline and, after 5 years, varied between 13% and 71%. If a woman who undergoes oophorectomy at age 35 does not adhere to the treatment, it is estimated that she may experience a reduction in life expectancy by 1.4 years. However, the absence of hysterectomy bleeding and the variety of formulations help with compliance. Woodman and Read [58] reported compliance up to 84.3% at 4 years, but in 64.5% they had to change the initial formulation. The surgeon should resist the temptation to remove the ovaries in a menstruating woman. Such a decision, as technically easy as it may seem, has significant implications for her overall health. Arbitrary age limits cannot justify such an act unless the woman is at or approaching menopause. The patient’s opinion will be mainly taken into account after being informed about the benefits and risks of ovarian reserve in combination with her history. Factors to be considered are infertility, infertility, hereditary risk of cancer, risk factors for cardiovascular disease or osteoporosis, carcinophobia, views on hormone replacement, and its psychological background. After all, the art of medicine is to adapt the patient’s needs and desires to what is best for maintaining his health. HRT is effective in preventing bone loss associated with menopause. HRT reduces the incidence of all (osteoporosis-related) fractures, including spine and hip fractures, even in low-risk patients. Even with lower doses of estrogen, most women have improvements in bone mineral density, even though the reduction in bone loss is dose-dependent [50, 51, 56]. When it comes to women who are younger than 60 years old and have entered early menopause, hormone replacement therapy (HRT) is the recommended initial course of treatment for preventing osteoporosis. After treatment is stopped, HRT’s protective effect on bone mineral density decreases, albeit in certain situations some protection endures. It is not advised to begin HRT treatment after the age of 60 in order to prevent fractures alone. Age has a major impact on how safe HRT is. Recent data and a re-evaluation of older studies indicate that, for the majority of women, hormone replacement therapy (HRT), when initiated within a few years of menopause and with clear indications, tends to offer more benefits than risks. An important observation that should be explained to women, is that HRT reduces mortality (by about 30%) when administered to women <60 years of age, perhaps because of protection against coronary heart disease. The decision to initiate a woman’s HRT must be individualized. The actual opinion regarding hormone replacement therapy Timbolone, a phytoestrogen, is that it should be administered to perimenopausal and early menopausal women without contraindications and after systematic information about potential risks and benefits. It is not recommended to start treatment after the age of 60. In women with premature menopause <40 years old, it is recommended to administer replacement with sex hormones until the age of 51 years for the treatment of vasomotor symptoms, and for the prevention of osteoporosis and cardiovascular diseases [56]. The increase in life expectancy up to 82 years, results in a woman living about 30 years with problems appearing during menopause. The significant decrease in ovarian estrogens is responsible for the appearance of changes in many organ systems and in general in the life of the menopausal woman. This reduction, in addition to the annoying symptoms that afflict the woman when she enters the climacteric period, is also responsible for “asymptomatic”—insidious effects that affect many organ systems, such as the vagina, uterus, urethra, urethra bladder, breast, skin, heart and blood vessels. It is understood that, with such an effect on this multitude of organ systems, the possibility of dangerous conditions for the health and quality of life of the menopausal woman is increased. In Western societies, the quality of life in menopause is considered an inalienable right and necessity, as a result, in recent decades, research has been carried out that examines the range and severity of the symptoms that accompany it. The necessity—and subsequently the appropriateness—of the various therapeutic methods that have been developed has become a dominant issue of disagreement. Health professionals must be informed about the developments in the field of menopause and contribute to the improvement of the quality of life of menopausal women.