Menopausal Hormone Therapy, an Ever-Present Topic: A Pilot Survey about Women’s Experience and Medical Doctors’ Approach

Background and Objective: Menopause can be associated with many clinical manifestations: vasomotor symptoms, urogenital problems, and additional psychological disturbances, such as anxiety, mood changes, and sleep alterations. The prolonged lack of hormones also increases the risk of long-term consequences. Hormone Replacement Treatment (HRT) in menopause consists of the administration of estrogen, alone or associated to progesterone, to relieve these uncomfortable disturbances and to prevent the onset of other pathologic conditions. The aim of this study is to examine the prevalence of HRT use in a sample of menopausal women and their experience with menopause and HRT. This study also investigates the knowledge of general practitioners (GPs) and gynecologists about HRT and its prescription. Materials and Methods: We conducted a cross-sectional population survey on 126 women of 50–59 years in an industrial city in the North of Italy, Vercelli (Novara), in Eastern Piedmont. We also presented a questionnaire on the topic to 54 medical doctors (GPs and gynecologists) of the same area. Results: The prevalence of HRT use in our sample was 11.9%. In total, a good percentage of the users affirmed to be satisfied with HRT. Additionally, a minority of women reported being ideally against the use of replacement hormones, were advised against using HRT by doctors, and did not use it because of the fear of side effects. We found a positive association between patient education, health care attitude, and HRT usage. A significant number of women knew about HRT from the media, and most of them were not informed by a health professional. Despite this, the interviewed doctors considered their knowledge about HRT as ‘good’ and would recommend HRT: only 5.6% would not prescribe it. Conclusions: Our results highlight the need for information about HRT among patients and health professionals, along with the need for more effective communication, evaluation, and suggestion of treatment.


Introduction
Menopause is the less explored season of women's existence, in the literature and in everyday life.Scientifically, it results from the reduced secretion of estrogen and progesterone, which occurs as the finite store of ovarian follicles is depleted.Natural menopause is diagnosed after 12 months of amenorrhea [1,2].The onset is not an abrupt change but is preceded by a transition state, the perimenopause, characterized by the gradual loss of oocytes, altered responsiveness to gonadal steroid feedback, wide hormonal fluctuations, and irregular menstrual patterns [3].The menopause can be associated with many clinical manifestations: vasomotor symptoms; urogenital problems, such as vaginal dryness, Medicina 2024, 60, 774 2 of 24 itching, dyspareunia; and additional conditions, such as anxiety, mood changes, and sleep disturbances [4].The prolonged lack of estrogen also affects the bones and the cardiovascular system and increases the risk of long-term consequences, such as osteoporosis [5].
Hormone Replacement Treatment (HRT) in menopause consists of the administration of estrogen, alone or associated to progesterone, aiming to relieve these uncomfortable fluctuating symptoms and to prevent the onset of pathologic conditions [6].
The current scientific evidence indicates that wisely selected HRT is generally useful and rarely dangerous [7].Hormonal therapy is effective in the prevention of osteoporosis [8,9] and in the treatment of vulvovaginal atrophy [10]; it has also been shown to be the most effective treatment for vasomotor symptoms [11].
Nevertheless, the history of HRT has suffered many ups and downs.After a period of success at the end of the 20th century, when HRT seemed to be the answer to all women's problems, things changed after the publication of the first large-scale study on its collateral effects: the Women's Health Initiative (WHI) [12].The WHI study, published in 2002, raised concerns about HRT and the health risks observed in post-menopausal users older than 60 years and/or women who have been post-menopausal for more than 10 years.In those patients, the use of HRT was associated with an increased risk of incident and fatal breast cancer [12,13].The conclusion had an impressive mediatic resonance, although it was clearly based on some methodological inaccuracies.In fact, the enrolled women were asymptomatic, on average older than 60 years old, and frequently more than 10 years after the onset of menopause.These results struck the medical community, causing widespread distrust in HRT, with a dramatic drop in its prescription in the following years [14].
Subsequent follow-up of the studied cohorts and a comprehensive re-analysis of the data induced the elaboration of less catastrophic conclusions [15].
The history of HRT over the years has shown a trend with two peaks of utilization: a first rise in the 1960s and a second and higher increase in the years 1999-2000.After, there was a precipitous decline in HRT use in many countries [16], and this rate of utilization persists nowadays.The most prominent medical societies published numerous guidelines on the proper use and prescription of HRT, focusing mainly on adequate patient selection and route of administration.Apparently, this effort was not enough to settle the confusion among both health professionals and patients on the indications for HRT: a diffuse distrust and many uncertainties appear to persist among physicians [4,14,17].
The aim of this study is to examine the prevalence of HRT use in menopausal women living in a northern Italian city and women's experience with menopause and HRT.This study also investigates the knowledge about HRT of general practitioners (GPs) and gynecologists of the same geographic area, and their attitude toward its prescription.

Materials and Methods
This study was approved by the local Ethics Committee (protocol number AslVC.Med.18.01).We conducted a survey of 50-59-year-old women in Vercelli (Novara), an industrial city in the North of Italy with 170,000 inhabitants, located in Eastern Piedmont.At the conception of this study, the total number of women aged 50-59 years registered in this Local Health Unit was 13,767.
We planned a cross-sectional population survey on a random sample of this population, on the basis of a previous study [16].We conducted four rounds of phone calls in order to obtain 155 respondents willing to participate in the interview process.Out of these 155 individuals, 29 patients were excluded because failed to give correct contact information or to complete the questionnaire or for other reasons, resulting in a final sample size of 126 respondents (CONSORT flow chart, Figure 1).We also surveyed all GPs and gynecologists in the same area.
information or to complete the questionnaire or for other reasons, resulting in a final sample size of 126 respondents (CONSORT flow chart, Figure 1).We also surveyed all GPs and gynecologists in the same area.We extracted the addresses and telephone numcbers of the participants and sent a presentation letter of the phone interview to them.We administered the questionnaire from May to July 2018, through a Computer-Assisted Telephone Interview.All phone calls were made by a single researcher.We introduced all the questionnaires with a standard sentence, describing this study and informing about data protection and about the possibility of dropping out from this study at any time.
We designed the questionnaire on a model of those already validated and translated into Italian [16] (Appendix A).The questionnaire asked about menopausal status, women's attitude towards HRT, use of HRT, sources of information on menopause and HRT, and socio-economic status.The questionnaire was organized into sections.One of the main outcomes of this study was HRT use throughout life and at the time of the interview.
We also conducted a different survey by sending a questionnaire by email to all the 124 GPs and 29 gynecologists on the list of those practicing in the area (obtained from the local Medical Council).Questions were chosen based on L. Gao's study (2017) [18] to investigate their attitude to prescribing HRT and their knowledge about it (Appendix A).Doctors were previously informed about this study by a letter.
We tabulated the answers of women and doctors using Microsoft Excel 2011, in a pseudonymized way: a single researcher entered a code corresponding to each participant.We analyzed the sociodemographic, behavioral, and clinical characteristic distributions between HRT users and non-HRT users through Graph Pad 6.We tested binomial and categoric differences in study variables between the two groups using the Chi square test (or Fisher test as appropriate).We calculated differences in continuous variables between the two groups with a Student's t test.
The sample was obtained and evaluated by a single researcher.Since a response rate of 25% was expected, we extracted 620 subjects and contacted them until we finally reached 126 interviewed women (Figure 1).Our medical sample consisted of 54 doctors in total; 83.3% (n=45) were GPs and 16.7% (n=9) were gynecologists.

Results
In total, 101 interviewed women were in menopause.Twelve participants answered that were using or have used HRT in the past.The prevalence of HRT use in menopause We extracted the addresses and telephone numcbers of the participants and sent a presentation letter of the phone interview to them.We administered the questionnaire from May to July 2018, through a Computer-Assisted Telephone Interview.All phone calls were made by a single researcher.We introduced all the questionnaires with a standard sentence, describing this study and informing about data protection and about the possibility of dropping out from this study at any time.
We designed the questionnaire on a model of those already validated and translated into Italian [16] (Appendix A).The questionnaire asked about menopausal status, women's attitude towards HRT, use of HRT, sources of information on menopause and HRT, and socio-economic status.The questionnaire was organized into sections.One of the main outcomes of this study was HRT use throughout life and at the time of the interview.
We also conducted a different survey by sending a questionnaire by email to all the 124 GPs and 29 gynecologists on the list of those practicing in the area (obtained from the local Medical Council).Questions were chosen based on L. Gao's study (2017) [18] to investigate their attitude to prescribing HRT and their knowledge about it (Appendix A).Doctors were previously informed about this study by a letter.
We tabulated the answers of women and doctors using Microsoft Excel 2011, in a pseudonymized way: a single researcher entered a code corresponding to each participant.We analyzed the sociodemographic, behavioral, and clinical characteristic distributions between HRT users and non-HRT users through Graph Pad 6.We tested binomial and categoric differences in study variables between the two groups using the Chi square test (or Fisher test as appropriate).We calculated differences in continuous variables between the two groups with a Student's t test.
The sample was obtained and evaluated by a single researcher.Since a response rate of 25% was expected, we extracted 620 subjects and contacted them until we finally reached 126 interviewed women (Figure 1).Our medical sample consisted of 54 doctors in total; 83.3% (n = 45) were GPs and 16.7% (n = 9) were gynecologists.

Results
In total, 101 interviewed women were in menopause.Twelve participants answered that were using or have used HRT in the past.The prevalence of HRT use in menopause was 11.9%, and the used formulations were 58.3% estrogens + progestinic, 33.3% Tibolone, and 16.7% estrogens + bazedoxifene (SERM), during a variable period of years.The average age at which the patients started assuming HRT was 49.1 years old (Table 1).Ninety-three women were aware of HRT, while thirty-three women were not informed about it (Table 1).In total, 41.7% of the users affirmed that they are satisfied with hormonal replacement therapy; 75.0% would recommend the treatment to a friend, while the remaining 25.0% would not, and 16.7% reported that they are unsatisfied with the treatment.
Table 1 shows the reasons why they did not choose HRT: most patients (38.3%) reported not having such intrusive symptoms and not needing any medical treatment, 23.5% of women reported being ideally against the use of replacement hormones, 8.6% of women were advised against using it by doctors, and 2.5% do not use HRT because afraid of the side effects.
Interestingly, of the 126 interviewed women, 73.8% reported knowing about the use of HRT: 92.1% of these patients were in menopause.A significant number of women who knew about HRT (31.2%) have received information about menopause from the media (TV, newspapers, radio, etc.), and most of them did not receive the information from a health professional: 50.5% have never received information from an expert (Table 2).Table 2 describes which categories are most likely to receive information about HRT.Women who had some health issues before menopause (p = 0.074), patients whit regular interaction with the GP (p = 0.014; 5.4 appointments/year vs. 3.1 appointments/year), and women familiar with breast cancer (p = 0.019) were more informed about HRT.
Patients who usually have intake of vitamin D appeared to be more updated about HRT than the non-users (51.1% vs. 28.1%,p = 0.038).There is no difference in the two groups regarding the use of complementary medicines (Table 2).
Table 3 shows the results of the interview presented to the 54 doctors.The gender distribution was equal.The physicians generally considered their knowledge about HRT as 'good' (96.3%).
In total, 75.9% would recommend HRT: 18.5% (n = 10) would prefer to first discuss the case with a colleague, and only 5.6% (n = 3) would not recommend it.
In most cases (75.9%), physicians prescribed oral treatment, and less frequently, transdermic (24.1%) or local assumption (27.8%).In total, 55.6% prescribed alternative options to HRT, such as Phytotherapy.In total, 94.3% believed that HRT could be the most efficient treatment for the management of menopausal symptoms, and 100% believed that the general female population should receive more information on the positive aspects of hormonal therapy.Furthermore, 96.3% also answered that health workers should be more informed.
Regarding the WHI study, 67.9% affirmed that the study did not have any influence on clinical decisions, 28.6% that they prescribed HRT with more caution after the study results, and only one doctor (3.6%) did not recommend HRT due to the study.

Discussion
Several longitudinal studies have investigated the prevalence of HRT use in menopause during the last decades.In the Nurses' Health Study, it was reported that 15.8% of women used HRT during a 14-year observed period (1980)(1981)(1982)(1983)(1984)(1985)(1986)(1987)(1988)(1989)(1990)(1991)(1992)(1993)(1994) [19].In a Japanese study, the proportion of all the participants who had used HRT was 13.8% [20].In a cohort study in Denmark, only 28.4% of the participants used HRT from 1995 to 2010 [21].The proportion of women aged more than 54 years old who started HRT from 1990 to 2001 was 16.8%, and the proportion of women who started HRT at more than 55 years of age was 9.0% in a survey conducted in 2003 [22,23].
In Italy, only 4.0-7.0% of menopausal women use HRT: between these patients, most were gynecologists or gynecologists' wives.It is a rare case in medicine in which doctors use a therapy more than patients [24].
In our survey, the proportion of women who used HRT is 11.9%, while only 3.0% were using it at the time of the survey, similarly to other Western industrialized countries.
In 2016, the International Menopause Society also recommended that the duration of HRT should not be limited, and that the long-term user rate has to be increased [25].
In total, 41.7% of the participants of our study affirmed to be satisfied with hormonal replacement therapy, and 75.0%would recommend the treatment to a friend, while the remaining 25.0% would not, and 16.7% reported that they were unsatisfied with the treatment.
Of the 126 interviewed women, 73.8% affirmed that they know about the use of HRT: most of these patients were in menopause.In the literature, many studies confirm a variety of sources of information about menopause and HRT (e.g., healthcare providers, medical surveys, professional societies or hospitals, internet, TV, magazines, and friends and family) [26][27][28].Unfortunately, a study published by Hamid et al. showed that most women had poor knowledge regarding menopause: 35.0% did not use treatments to relieve symptoms, and only 27.0% had good knowledge about HRT [27].
Chinese women, on the other hand, who were found to have good knowledge about menopause but poor knowledge about HRT, think that menopausal symptoms should not be treated [28].Also, for most of our interviewed patients (38.3%), non-HRT users reported having symptoms that were not intrusive enough to justify the drug therapy.
The EMPOWER study, conducted on 1858 post-menopausal women, reported that concern about side effects is one of the main reasons for not using hormonal products [29].In our results, only 2.5% do not use HRT because of the fear of side effects, and 23.5% of women affirmed being ideally against the use of replacement hormones.
Other works reported that most patients discontinued HRT after the WHI study publication because of the fear of side effects, even if they realize that HRT can alleviate disturbing symptoms [30].In our research, doctors recommended not using HRT only to 8.6% of the interviewed women: our results could be considered encouraging data, assimilable to the great possibility of receiving information in an alternative, conscious, and independent way.
In fact, we have found a positive association between patient education, health care attitude, and HRT usage.We observed higher assumption of HRT in case of more informed patients-about their health in general or for previous comorbidities-correlated to work occupation, and with better socio-economic status.
Women appreciate being listened to and being informed about the possible approaches and about the risks and the effects of each treatment option on their quality of life.
It is also important to stress that the effect of the education about HRT adherence was long-term rather than temporary [31].
This may be correlated with factors such as access to care, recognized risk for disease, health control, confidence levels, and other medical reasons [32].It may also be possible that women with a higher socio-economic status have access to better health services.HRT was used 12.3 times more in university hospitals and 5.4 times more in private hospitals, when compared to public hospitals [32].
Consultation with doctors, GPs or gynecologists, is fundamental for the patient in the choice of HRT.In clinical practice, many specialists would theoretically favorably prescribe HRT, but very often they do not believe that this would be their responsibility [33].
In our study, 94.3% believe that HRT is the most efficient treatment for the management of menopausal symptoms, and 100.0%believe that the female population should receive more information on the positive aspects of hormonal therapy.In total, 96.3% of doctors also think that health workers should be more informed.
Moreover, in our sample, physicians generally considered their knowledge about HRT as 'good' (96.3%), and 75.9% would recommend HRT: only 18.5% would prefer to first discuss the case with a colleague, and only 5.6% would not recommend it.This is probably due to the evolution of studies and to the generational changes in the sample of health professionals, temporally less connected to the WHI study.In fact, 67.9% of them affirmed that this research did not have any influence on their clinical decisions.
GPs are officially in charge of patients' integral wellness, and they are strategical actors in the promotion of a healthy lifestyle and preventive topics.In comparison to gynecologists, their comfort level in providing counseling regarding the risks, benefits, and alternatives to vaginal estrogen is not so strong, and this could be a knowledge gap [34].
Beyond this, as highlighted in our data, many factors seem to affect HRT usage.In fact, medical influence, place of residence, age, occupation, stipulation of a health insurance, concerns about the side effects, overall knowledge surrounding HRT, partner's job, advice and influence of neighborhoods, and the hospital they applied for have been identified as factors affecting the rate of HRT in the performed analyses [32].
Our results could be useful to highlight the need for information about HRT among patients and health professionals, along with the need for more effective communication, evaluation, and suggestion of treatment.
Despite the interesting insights that our survey provides, we intend to underline some limitations, such as the sample size of HRT users, to be implemented in future studies: we expected an even higher patient response rate.Our research has the objective of being a pilot source of information describing women's and doctors' attitude to HRT.Our survey does not aim to define static conclusions on the subject but wants to trigger a possible dialogue on a very important topic for women's health.
Another limitation is the lack of further analysis in the case of surgical menopause.Moreover, our attention was focused on an industrial populated Italian area, and the results could be different in poorer and less educated region of the world.

Conclusions
Our data support the need for successful communication and shared decision making, allowing patients and medical professionals to work together and to consider the best scientific evidence for health care decisions.
Our study does not aim to define rigid conclusions but wants to trigger a possibility of discussion on a very important topic for women's health: this survey is a preliminary descriptive analysis of patients' and doctors' attitude to HRT.
In particular for menopausal patients, doctors have the task of sharing medical evidence, including information about the benefits and risks of HRT.They should also be conscious of potential prejudices and make efforts to minimize the impact of them.

Table 1 .
Menopause and HRT in our population sample (main results).
GP = General Practitioner.• 81 women know about HRT and not use the therapy.* More than one possible answer.

Table 2 .
Variables of HRT users: informed versus not-informed women (main results).
• 77 patients in menopause.# 24 patients currently in menopause.* More than one possible answer.

Table 3 .
Doctors' answers to the questionnaire regarding HRT (main results).
GP = General Practitioner.• 30 doctors answered yes.* More than one possible answer.