The Role of Hormone Replacement Therapy in Women’s Health

Introduction

As life expectancy increases, the number of older people is growing. According to the World Health Organization, the average life expectancy of women will reach 85 years by 2031. Thus, women will spend almost one-third of their lives after menopause, making it important to ensure that menopause becomes another natural and high-quality stage of every woman's life.

Menopause is a physiological period in every woman's life, occurring at an average age of 51.3 years. It represents a major transition in the female body, during which reduced production of estrogen and progesterone may cause various symptoms that impair a woman's quality of life.

The female sex hormones estrogen and progesterone are produced mainly by ovarian follicles. The maximum number of follicles is present in the fetal ovaries while still in the mother's womb. At birth, the number of follicles is already lower, and follicular reserves subsequently decline continuously. At around 50 years of age, ovarian function gradually diminishes, and the balance and synthesis of secreted hormones become disrupted. Ovulation occurs less frequently or ceases altogether, meaning that the corpus luteum, which produces progesterone, no longer forms, resulting in reduced progesterone levels in the body. Estrogens continue to be produced, creating a relative excess of estrogen. This results in irregular menstruation and dysfunctional bleeding.

Early menopausal symptoms often appear during the premenopausal period. These include vasomotor symptoms such as hot flashes, sweating (especially at night), palpitations, headaches, dizziness, tinnitus, chills, bloating, and fluctuations in blood pressure. Psychological symptoms may also occur, including depressed mood, anxiety, increased irritability, mood swings, insomnia or drowsiness, lack of energy, and decreased libido.

During this period, women and the specialists treating them often do not associate these psychological complaints with approaching menopause, and sedatives or antidepressants may therefore be prescribed. To improve diagnosis and help women, the 2013 recommendations of the British Menopause Society state that general practitioners should counsel women around the age of 50 on health and healthy lifestyle issues and develop an individualized healthcare plan for menopause and the subsequent period, thereby helping to ensure a longer and healthier life. The recommendations emphasize that the greatest opportunity for prevention is at the onset of menopause.

The British Menopause Society recommendations state that even short-term use of hormone replacement therapy (HRT) during early menopause improves mood and alleviates symptoms of depression (possibly through a so-called domino effect resulting from the resolution of vegetative symptoms, as well as through a direct antidepressant effect). Psychiatric consultation is recommended for women with depression or when no improvement is observed with HRT.

Over the years, follicular reserves become depleted and progressively less estrogen is produced. Through the feedback mechanism, the pituitary gland therefore secretes increasing amounts of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Even when stimulated, the ovaries no longer secrete sex hormones (estrogens and progesterone), and menopause begins.

On average, 3–5 years after the onset of menopause, intermediate symptoms develop, including urogenital disorders such as vaginal dryness, itching, painful sexual intercourse, vaginal prolapse, frequent and painful urination, recurrent urinary tract infections, and urinary incontinence. Due to connective tissue atrophy and impaired collagen synthesis, hair begins to fall out, nails become brittle, the skin becomes thinner and drier, and bone and joint pain develops. Late menopausal symptoms include osteoporosis, cardiovascular diseases, and senile dementia.

Every woman experiences the post-reproductive period individually. Since the main cause of the symptoms described above is a deficiency of sex hormones, the most effective treatment for improving a woman's quality of life would be HRT—estrogen (E) and estrogen/progestin (E/P) preparations intended to reduce symptoms caused by estrogen deficiency.

Contemporary Approach to HRT

In 2002, the Women's Health Initiative Study conducted a study examining the effectiveness of HRT during the postmenopausal period. Two groups of participants were distinguished: one received a combination of conjugated estrogens (CE) and medroxyprogesterone acetate (MPA), while the other received CE alone. It was found that the group receiving the CE and MPA combination had an increased risk of breast cancer, cardiovascular disease, and deep vein thrombosis; therefore, the study in this group was discontinued. In the other group, which received CE alone, the study was continued. No increase in breast cancer risk was observed in this group, and a cardioprotective effect of treatment was also noted.

Unfortunately, after the initial results of this study were published, physicians stopped prescribing HRT, and various dietary supplements, phytoestrogens, and soy preparations were used to alleviate postmenopausal symptoms. Later, after the study results were reanalyzed, factors that may have contributed to the negative findings were identified. These included the older age of women when HRT was initiated (mean age 63 years), a postmenopausal period lasting more than 10 years, an excessively high dose of CE, and the inappropriate choice of the progestogen MPA.

However, among women within 10 years after menopause who received the CE/MPA combination, there were fewer cases of cardiovascular disease (CVD) than in the placebo group. In the 50–59-year-old group, in which participants received CE alone, the number of CVD cases decreased by 50% compared with the placebo group.

A meta-analysis of 24 clinical trials showed that there were fewer cases of CVD among women younger than 60 years whose postmenopausal period had lasted less than 10 years and who were receiving HRT. This supports the cardioprotective effect of estrogens. The 2012 recommendations of the North American Menopause Society state that women who initiate estrogen therapy during the early menopausal period have a reduced risk of CVD and breast cancer.

In the Danish Osteoporosis Prevention Study, women were followed for 16 years, with HRT administered for 10 years: combination therapy was used in women with a uterus, while oral estradiol alone was used in women who had undergone hysterectomy. The study found a reduction in the number of cardiovascular disease cases and deaths compared with the control group, a reduced risk of stroke and breast cancer, and a slight increase in the number of cases of deep vein thrombosis.

Table 1. Estrogen and Progestogen Combinations for Cyclic Regimens

Product Name	Active Substance and Dose	Number of Tablets
Femoston®	E₂ 1 mg	14
	E₂ 1 mg + D 10 mg	14
Trisequens®	E₂ 2 mg	10
	E₂ + NETA 1 mg	12
	E₂ 1 mg	6

E₂ – 17β-estradiol; D – dydrogesterone; NETA – norethisterone acetate.

Table 2. Estrogen and Progestogen Combinations for Continuous Regimens

Product Name	Active Substance and Dose	Pack Size
Femoston conti®	E₂ 0.5 mg + D 2.5 mg	N28
Femoston conti®	E₂ 1 mg + D 5 mg	N28
Angeliq®	E₂ 1 mg + DSPR 2 mg	N28
Activelle®	E₂ 1 mg + NETA 0.5 mg	N28
Kliogest®	E₂ 2 mg + NETA 1 mg	N28

E₂ – 17β-estradiol; D – dydrogesterone; DSPR – drospirenone; NETA – norethisterone acetate.

The breast cancer risk associated with HRT is low. A statement from the International Menopause Society indicates fewer than 1 case per 1,000 women per year of use. The risk increases with postmenopausal obesity, low physical activity, or increased alcohol consumption. Healthy women younger than 60 years (within 10 years after menopause) should not be concerned about the safety of HRT, as the risk of breast cancer does not increase during the first 5–7 years of treatment. Micronized progesterone or dydrogesterone used with estradiol is associated with a more favorable breast cancer risk profile than synthetic progestogens. A conclusion from the U.S. Endocrine Society states that HRT does not increase the risk of breast cancer when used for 5 years or less.

Currently, there are no studies indicating that HRT influences the development of ovarian cancer or increases its risk. An important benefit of HRT in reducing the risk of colorectal cancer should also be noted. The risk of thromboembolic complications increases with oral HRT. The risk is highest during the first year of use. Before prescribing HRT, it is important to assess the woman's personal and family history of venous thromboembolism, obesity, and planned surgical treatment. If an increased risk is identified, transdermal estrogen preparations are selected, while the safer progestins—micronized progesterone or dydrogesterone—are preferred. HRT is not used for the primary or secondary prevention of stroke because it increases the risk of stroke in women older than 60 years.

HRT Regimens

If the last menstrual period occurred less than 1 year before the initiation of HRT, therapy is administered using a cyclic regimen, i.e., estrogens are administered continuously and progestogens for 12–14 days, after which bleeding occurs. It should be remembered that cyclic HRT used for more than 5 years slightly increases the risk of endometrial cancer.

Continuous HRT is used if the last menstrual period occurred more than 1 year previously or if a woman has been using cyclic hormone therapy for more than 1 year and wishes to switch to HRT without monthly bleeding. Continuous HRT is associated with a lower risk of endometrial cancer than that observed in the untreated population.

Femoston®

Femoston® is an HRT medicinal product containing micronized 17β-estradiol and dydrogesterone. Three different pharmaceutical formulations are available:

• Femoston® 1 mg/10 mg;
• Femoston conti® 1.0 mg/5.0 mg;
• Femoston conti® 0.5 mg/2.5 mg film-coated tablets.

Femoston® 1 mg/10 mg is a low-dose cyclic HRT, i.e., estrogens are administered continuously and progestogens for 14 days. Bleeding occurs after their administration. Packs contain 28 tablets, taken continuously at a dose of 1 tablet daily. Each Femoston® tablet contains 1 mg of 17β-estradiol, and the last 14 tablets contain 10 mg of dydrogesterone. The preparation is prescribed if the last menstrual period occurred less than 1 year before the start of treatment. Femoston® is generally well tolerated. Adverse effects occur rarely and include headache, back pain, abdominal pain, breast pain, and increased sensitivity.

Continuous HRT is used if the last menstrual period occurred more than 1 year previously in menopausal women or more than 2 years previously in women with premature ovarian failure. Femoston® conti preparations belong to this category. Packs contain 28 tablets. Each tablet contains the same ratio of 17β-estradiol and dydrogesterone. The medication is taken daily at a dose of 1 tablet without interruption. It is indicated for women experiencing symptoms of estrogen deficiency or for the prevention of osteoporosis in women at increased risk of bone fractures who cannot tolerate or are contraindicated from using other medications intended for osteoporosis prevention. The protective effect on bone depends on the estrogen dose. Studies have shown that HRT administered during the perimenopausal period provides a long-lasting protective effect on bone for many years after treatment is discontinued.

Which dose of Femoston® conti should be selected—E2 1 mg + D 5 mg or E2 0.5 mg + D 2.5 mg? The general rule is that the optimal dose and duration of treatment should be individualized according to the severity of symptoms and the response to prescribed treatment.

Treatment is initiated with the lowest effective estrogen dose, i.e., with a preparation containing 1 mg of 17β-estradiol. If no menopausal symptoms have occurred for at least 6 months while taking Femoston® conti E2 1 mg + D 5 mg, the dose may be reduced to Femoston® conti E2 0.5 mg + D 2.5 mg. If symptoms persist for approximately 2–3 months while taking Femoston® conti E2 0.5 mg + D 2.5 mg, the dose should be increased to Femoston® conti E2 1 mg + D 5 mg. For many women, low estrogen doses of 1 mg are sufficient to relieve symptoms. Very low estradiol doses of 0.5 mg are effective in controlling subjective symptoms and maintaining bone mineral density in postmenopausal women.

Scientific studies have shown that even with the lowest Femoston® conti dose of 0.5 mg/2.5 mg, a statistically significant reduction in moderate and severe hot flashes compared with placebo is observed as early as week 4.

The dydrogesterone contained in Femoston® is associated with a more favorable breast cancer risk profile than synthetic progestogens, as stated by the International Menopause Society. Femoston® should not be prescribed to women diagnosed with breast or endometrial cancer, unexplained genital bleeding, previous or current venous thromboembolic disease (deep vein thrombosis, pulmonary embolism), known thrombophilic disorders, recent arterial thromboembolic disease, acute liver disease, porphyria, or allergy to the active substance.

Key Points

• HRT is the most effective treatment for vasomotor symptoms and urogenital atrophy.
• Other menopause-related symptoms, including joint and muscle pain, mood changes, and sexual dysfunction, may improve with HRT.
• Every woman should decide for herself whether to use HRT based on comprehensive, evidence-based information provided by her physician.
• The HRT preparation, dose, route of administration, and duration should be individualized.
• If HRT must be initiated in women older than 60 years, the lowest doses should be used, preferably transdermally, and it is not recommended for the prevention of bone fractures or coronary heart disease.
• The public should be aware that the increased risk of breast cancer associated with HRT is considerably lower than that associated with other lifestyle factors linked to the development of breast cancer, such as obesity and alcohol consumption.
• Regarding the benefit-risk ratio: the benefit is greater when treatment is initiated as soon as possible after menopause; HRT has a clear benefit for women with premature ovarian failure and should be continued until the average age of menopause; the benefit-risk ratio should be assessed annually; if symptoms persist after 5 years of HRT use, the benefits of continued treatment outweigh the risks.

Authors:
Ieva Užringytė, Department of Obstetrics and Gynecology, Faculty of Medicine, Vilnius University
Indrė Juzelskytė, Department of Obstetrics and Gynecology, Faculty of Medicine, Vilnius University
Assoc. Prof. Žana Bumbulienė, Department of Obstetrics and Gynecology, Faculty of Medicine, Vilnius University

GINEKOLOGIJOS AKTUALIJOS, supplement to the journal INTERNISTAS, 2016, No. 1