Benefits and risks of hormonal replacement therapy

Corresponding author: Mihaela Plotogea E-mail: nicole_plotogea@yahoo.co.uk ABSTRACT Menopause, defined as the permanent cessation of menstruation resulting from the loss of the ovarian function, has gradually become a fundamental health concern. Menopause hormonal replacement therapies (HRT) were initially developed with the purpose to alleviate the estrogen deficiency induced symptoms. Currently, HRT is approved by the FDA (Food and Drug Association) for four indications: bothersome vasomotor symptoms (VMS); prevention of bone loss; hypoestrogenism caused by hypogonadism, castration, or premature ovarian failure and genitourinary symptoms. For patients younger than 60 years or within the first 10 years from menopause onset and without contraindications, the benefit-risk ratio should be favorable for treatment of VMS and for preventing bone loss and related fractures. For women who initiate HRT more than 10 / 20 years from menopause onset (or aged 60 years or older), the benefit-risk balance seems to be less favorable than for younger patients because of greater absolute risks of cardiovascular disease, stroke and VTE. Even though the management of menopausal symptoms through pharmacological and cognitive-behavioral therapy improves quality of life of affected women in the short term, there is a need for the development of strat¬egies to modify menopausal health risks, in the long term.


INTRODUCTION
Menopause, defined as the permanent cessation of menstruation resulting from the loss of the ovarian function, has gradually become a fundamental health concern through the last decades [1][2][3]. Women longevity is increasing worldwide, by 2050, the world's female population aged 50 years and older being believed that will total 1.6 billion [4] and with a life expectancy greater than 80 years, women can live around 30 years after menopause [5].
As ovarian function declines, estradiol production falls to a small fraction of premenopausal levels and in his place the predominant estrogen becomes estrone, which has approximately one tenth the potency of estradiol. Cessation of ovarian function also implies a marked reduction of progesterone secretion [3].
Menopause hormonal replacement therapies (HRT) were initially developed with the purpose to alleviate the estrogen deficiency induced symptoms [5]. According to current practices, the use of HRT has extended, and it is taken into consideration even for different cultural or minority populations of women, including women with hypogonadism, early menopause, primary ovarian insufficiency, surgical menopause, for prevention of bone loss, cognition and mood issues, for women older than 65 years of age, and in observational studies for heart disease prevention [6][7][8][9].
Unfortunately, HRT along with benefits has proven to have risks as well, so, the initiation and the choosing of a regimen (chemical compound/-s and doses) should be carefully weighted and be also dictated by tolerance in the attempt to ensure compliance [1,5].
The optimal duration of HRT remains an unsolved issue and must be decided after taking into account the initial indication and the benefit-risk balance, which is specific to each patient. Continuation of HRT is also conditioned by the benefit-risk balance, which must be assessed regularly, and also by the evolution of symptoms when HRT is interrupted [5].
After stopping HRT, medical follow-up is necessary and should be adapted to the clinical situation of each woman in regard to her gynecological and cardiovascular risk factors [1,7,10].

BENEFITS OF HORMONAL REPLACEMENT THERAPIES (HRT)
The most frequent reason for prescribing HRTusually involving estrogen (E) with / without a progestin (P) -is to treat the plethora of vasomotor, somatic and psychologic symptoms related to estrogen deficiency that represents the menopausal syndrome [7,11].
Currently, HRT is approved by FDA (Food and Drug Association) for the following four indications: bothersome vasomotor symptoms (VMS); prevention of bone loss; hypoestrogenism caused by hypogonadism, castration, or premature ovarian failure and genitourinary symptoms [6,7,12].
Central nervous system related symptoms appear as a consequence of the neurobiochemical changes occurring after ovarian failure, and include VMS, anxiety, migraine, sleep disturbances, depression and changes in cognitive performance [13]. Fatigue, insomnia, loss of concentration, anxiety, irritability and depression appear in 30 to 40% of patients, the menopausal transition being a very favorable period for the onset of depressive symptoms [13]. Some reports state that sleep disturbances (particularly nocturnal awakenings) are major complaints in the case of up to 60% of menopausal women [13][14][15].
Vasomotor instability, manifests through hot flashes / flushes, this being the most common symptom, that can start years before the actual menopause. When ovarian endocrine function declines, about 75% of women begin to experience episodes of extreme heat sensation that starts unexpectedly and can last from 30 seconds to 5 minutes [13]. They are many times accompanied by other vasomotor manifestations like palpitations, headaches, dizziness, diaphoresis, nausea and night sweats [2].
In the absence of HRT, VMS will manifest for more than a year in 85% of affected women, whereas in 25% to 50% may continue for more than 5 years [3]. In most cases, hot flushes are infrequent and mild, but some women report symptoms so disturbing that they result in severe insomnia or nervousness that interfere with their social / professional functioning [3].
Women who undergo surgical menopause may experience even more frequent and intense hot flashes than the ones going through natural menopause, especially in the first 6 months after surgery [2].
HRT has been shown in double-blind RCTs to relieve hot flashes and is approved as first-line therapy for relief of menopause symptoms in appropriate candidates. [6,16]. Research has shown also marked improvements in affective symptoms or general well-being and quality of life with HRT [3].
Urogenital atrophy usually translates into genitourinary syndrome of menopause (GSM) the affection that includes the symptoms and signs resulting from the effect of estrogen deficiency on the female genitourinary tract. GSM is highly prevalent, and it affects according to various studies 27 to 84% of postmenopausal women [17,18].
The most apparent changes affect the vaginal mucosa, which's thickness and rugae decrease. Also, the glycogen production falls leading to a more alkaline vaginal pH with a more friable mucosa. Blood flow and vaginal lubrication also diminish. Women are also less likely to have a Lactobacillus-dominant vaginal flora, this also affecting the vaginal pH [17]. All these changes will usually lead to vaginal dryness, pruritus, dyspareunia, sometimes bleeding, increased risk of infection and intercourse discomfort with loss of sexual interest [2]. Low estrogen levels also lead to atrophy of the urethra and trigone of the bladder and the pubococcygeal muscle, changes that may cause symptoms of urethritis, cystitis, and urge / stress incontinence [3].
HRT has been shown in RCTs to effectively restore genitourinary tract anatomy, reduce vaginal pH, increase vaginal mucosa thickness, and successfully treat symptoms of GSM [6].
Commonly used regimens include low-dose vaginal estrogens, vaginal DHEA inserts and oral ospemifene [6]. Transdermal and oral HRT are effective options in the case of women with moderate to severe dyspareunia and concurrent VMS. Symptom alleviation may take 1 to 3 months, and continued therapy is generally necessary because symptoms usually recur on cessation of therapy [17].
Osteoporosis is a serious condition, often debilitating, consisting of a reduction in bone mass that compromises the biomechanical integrity of the skeleton leading to an increased risk for fractures. Current statistics sustain that 40% of women worldwide will experience an osteoporosis-related fracture by age 70, while, by age 80, 15% will have sustained a hip fracture [3,12].
The rapid loss of bone mass that occurs in response to estrogen depletion may start a year before menopause, so it is not necessary for a patient to be postmenopausal to receive estrogen. She only needs to present irregular periods and menopausal symptoms. One way to establish the onset of menopause is to measure serum follicle-stimulating hormone level annually, starting at age 50, and when its value becomes greater than 40 IU/ml, it is time to begin HRT [3,12].
HRT was proven in double-blind RCTs to prevent bone loss and, when administered for a period of minimum 5 years early in the climacteric, to reduce osteoporosis related hip and wrist fractures by 50% and vertebral crush fractures by 80% [3]. Also, in the Women's Health Initiative (WHI) landmark study (16,000 postmenopausal women; mean age 64; daily conjugated equine estrogens / CEE 0.625 mg plus medroxyprogesterone acetate / MDPA 2.5 mg) HRT was found to reduce fractures in postmenopausal women [6,12,19].
Cardiovascular disease prevention used to be an indication for HRT, but over time studies showed contradictory information and, even though a clear consensus has not been reached, this is not an FDA approved indication for HRT. The WHI study (16.000 postmenopausal women; mean age 64) assessed CEE 0.625 mg daily with MDPA 2.5 mg daily and found that EP HRT increased the risk for cardiovascular events [10,19].

RISKS ASSOCIATED TO HRT Endometrial adenocarcinoma
Available data show that the use of unopposed estrogen therapy invariably leads to adenomatous endometrial hyperplasia, a presumed neoplasia precursor, and that it associates a fourfold to tenfold increased risk of endometrial adenocarcinoma in postmenopausal women, this increase being related to dosage and duration of treatment [5,6,19].
It has been demonstrated that adding a P to E-HRT markedly reduces the development of endometrial hyperplasia, being able to even cause regression of preexisting hyperplasia at higher doses [3]. Limited data suggest that the risk of endometrial cancer depends also on the type of P used, indicating that natural progesterone offers a diminished protection compare to dydrogesterone and other synthetic progestatives [5].
Given the above, it is now standard practice to add a P whenever E-HRT is given to a woman with an intact uterus [2,3,5,19].

Breast cancer
There appears to be a growing consensus that short-term E-HRT does not associate an increased breast cancer risk. However, giving that a few studies with small numbers of long-term E users have showed a modest increase in risk, the long-term use (>15 years) is still open to debate [3,20,21].
The risk of breast cancer seems to be greater when opting for EP than for E alone [5,21,22], although the preferential use of progesterone / dihydrogesterone may limit the additional risk for HRT related breast cancer, at least when the duration of treatment doesn't exceed 5 to 7 years [5]. Available data seem to suggest that there is even a slight diminution of risk with the use of CEE compared to placebo [22].
In addition, the type of P appears to influence the risk of EP-HRT related breast cancer, as there are 4 European cohort studies that report a lower risk for women using progesterone or dydrogesterone compared to combinations including other synthetic progestatives when treated for 5 years or less [5,20,[23][24][25]. It is noteworthy that the WHI study, found that EP-HRT increased the risk for breast cancer [19].

Venous thromboembolism (VTE)
Clinical data shows no increase in the risk of VTE for postmenopausal women using oral E-HRP [3]. On the other hand, women using EP-HRT have twoto-five-fold higher risk for the development of VTE than nonusers [19,[26][27][28].
The Heart and Estrogen/progestin Replacement Study (HERS) which assessed the administration of daily oral CEE 0.625 mg combined with MDPA 2.5 mg in 2,763 women with coronary artery disease (mean age 67 years) found that HRT users had a twofold increased risk of developing VTE (OR 2.08; 95% CI: 1.28-3.40) and pulmonary embolism (OR 2.86; 95% CI: 1.13-7.26). HERS does not contain data about estrogen-only and transdermal HRT preparations [19,27].
Great caution should be exercised in recommending HRT to women who are at risk for vascular thrombosis or embolism. In the presence of these disorders, HRT should be interrupted. Transdermal E, however, may be used by patients with history of thromboembolic disease giving that it associates less hepatic production of clotting factors and theoretically implies less risk of thromboembolic disease [2,26].

Hypertension
Hypertension doesn't seem to be caused by postmenopausal HRT according to most available data, and it has been suggested that the therapy may even have a beneficial effect. But, given the occasional reports of marked, idiosyncratic hypertension attributed to E-HRT, blood pressure should be monitored shortly after initiation of therapy and periodically after [3,26].

Glucose tolerance
Estrogen improves carbohydrate metabolism, and this may be why many women with diabetes tolerate glucose better with E-HRT than without it. On the other hand, P seem to counteract this effect and decrease glucose tolerance. However, the doses used in HRT are lower than with combined oral contraceptives, and glucose tolerance deterioration rarely occurs as a result of EP-HRT [3,26].

EVALUATING THE INDIVIDUAL RISKS AND BENEFITS OF HRT
One way to evaluate HRT risks and benefits balance is to consider the change in life expectancy / mortality among patients. Available data suggest that EP-HRT decreases by 211 per 100,000 women, the total annual mortality among patients aged 65 to 74 years [3].
HRT must be individualized, by taking into account evidence-based treatment goals, patient's age, time since menopause, personal health risks and preferences in order to decide therapy initiation / continuation, and the balance of potential benefits and risks of HRT versus nonhormonal therapies [6].
For patients younger than 60 years or who are within the first 10 years from menopause onset and are without contraindications, the benefit-risk ratio should be favorable for treatment of VMS and for preventing bone loss and related fractures. Longer duration treatment may be more beneficial for E-HRT than for EP-HRT, based on the WHI RCTs. For women who initiate HRT more than 10 / 20 years from menopause onset (or when aged 60 years or older), the benefit-risk balance seems to be less favorable than for younger patients because of greater absolute risks of cardiovascular disease, stroke and VTE [6,26].

AVAILABLE HRT REGIMENS
Various treatment regimens are used to provide HRT (Table 1).
For patients that do not need endometrial protection, current recommendation is to use unopposed estrogen, so daily E-HRT is the most common method for hysterectomized women [3]. In non-hysterectomized women, HRT include both estrogens and progesterone, the latter having the purpose to counteract the negative impact the estrogen has on endometrial proliferation [1,5,7].
The estrogens most commonly used are micronized 17b-estradiol, CEE (synthetic conjugated estrogens) and ethinylestradiol. CEE are isolated from the urine of pregnant mares and consist of estrone sulfate (less potent than estradiol) and a mixture of more than 10 minor components of different active forms of estrogens (weak E agonists). CEE and estradiol are rapidly metabolized into less potent estrogens like estrone [6].
Some patients who use EP-HRT complain of severe side effects, like migraines, headaches or dysphoria, that persist even when changing the P or the dosage. Unopposed E with careful monitoring Including annual endometrial biopsy may be an option in their case [2,29]. HRT may be given on a cyclic schedule: an E for 25 days and a P added on days 1-12 / 14-25. Another option is to give E daily, and a P added for the first 12 days of the month. The progestin supplementation has a (considered by some) major disadvantage represented by the vaginal bleeding occurring after P withdrawal in as many as 97% of patients until age 60, and 60% of patients older than 65 years. Many women are reluctant to the returning of the menses, considering them "unnatural" after menopause and this can make them hesitant to start / continue HRT. Thus, it is important to inform them about the protective effect of P against endometrial adenocarcinoma and also to underline the fact that withdrawal menses are usually light, free of dysmenorrhea, of short duration (3-4 days) and predictable, regular withdrawal bleeding generally oc-curring shortly after the P is stopped. A bleeding occurring before P is withdrawn usually indicates that the dosage should be increased, while a bleeding starting more than 4 days after P withdrawal must be investigated. For women taking EP-HRT, an endometrial biopsy is warrant only if unexpected, prolonged or excessive bleeding occurs [3,29].
Continuous daily administration of both E and P in another quite popular alternative with the advantage of achieving amenorrhea in approximately 60% of patients within 4 to 6 months. Most women using this regimen eventually achieve endometrial atrophy. Patients must be informed that frequent and unpredictable bleeding is not unusual during the first months of this therapy. Because of this bleeding, an endometrial biopsy should be to obtain (to rule out hyperplasia) prior to initiating HRT [2].
Usually, it is recommended to opt for 17b-estradiol or estradiol valerate in association with progesterone or dydrogesterone [5]. The combination of low-dose CEE / bazedoxifene may be an option for menopausal women intolerant or having contraindications to P [1].
Practitioners should use an appropriate HRT regimen (pharmacologic substance type, dose, combination, administration route and treatment duration to achieve clinical objectives, and also make periodic reassessment of the eventual changes in a woman health status, and anticipated risks, benefits [6].

CONCLUSIONS
HRT can prevent some estrogen deprivation related health issues and should be recommended to most menopausal women in order to preserve their vitality and good health giving that, in most cases, more than one third of their lives is postmenopausal. HRT has proven very effective in the treatment of VMS and GSM and also to prevent bone loss and related fractures.
HRT implies risks that should be carefully weighted and individualized for each woman as these risks differ depending on type, dose, route of administration, duration of treatment, initiation moment and the need for a progestative, and periodic reevaluation of risk-benefits balance is mandatory.
Even though the management of menopausal symptoms through pharmacological and cognitive-behavioral therapy improves quality of life of affected women in the short term, there is a need for the development of strategies to modify menopausal health risks, in the long term.