1. Introduction

Currently, there has been a steady increase in thyroid disease. Their prevalence reaches 20%, and in endemic goiter regions this figure exceeds 50%. Over the past five years, in economically developed countries, the absolute increase in newly diagnosed thyroid diseases was 51% among women and 16.7% among men [3,4]. Diseases of the thyroid gland mainly affect women; their frequency in the female population is 5-20 times higher than in men. In addition, the prevalence of most thyroid diseases increases with age. In the Republic of Uzbekistan, the situation does not differ from global trends. Since our country is an endemic region for iodine deficiency, the average prevalence of endemic goiter is approximately 10–15%, and in some regions it reaches 40% [2]. Therefore, thyroid diseases such as hypothyroidism, autoimmune thyroiditis, nodular goiter and cancer are most common in postmenopausal women and older women.

However, in this group of patients, difficulties in diagnosing the condition are noted, because symptoms such as anxiety, palpitations, sweating, weight gain and insomnia are common for thyroid dysfunction and ovarian steroid insufficiency. Additional problems in making a diagnosis arise due to the interpretation of the results of tests of the functional state of the thyroid gland: according to many observations, the concentrations of serum TSH, thyroxine (T4) and tri-iodothyronine (T3) depend on age, concomitant diseases and the treatment performed. Despite the fact that the functional state of the thyroid gland has a significant effect on cardiovascular risk, cognitive function, disability, and life expectancy, there is no consensus among world medical associations on methods for screening thyroid dysfunction in postmenopausal women [1,3]. Physiological changes in the thyroid gland accompany age-related aging of the body. According to morphological studies, “the thyroid epithelium undergoes degenerative processes that lead to its flattening, the size of the thyroid gland follicles decreases, while the connective tissue and lymphoid tissue proliferate.” As a result, the size of the thyroid gland can decrease with age. The ability of the thyroid gland to absorb iodine is reduced, in the elderly, the absorption capacity of the thyroid gland becomes 40% lower than in women aged 30 years. The daily production of the main thyroid hormone T4 decreases by 20 μg, but at the same time its metabolism slows down due to a decrease in the activity of 5'-deiodinase-I. As a result, the half-life of T4 lengthens from 8 to 9.3 days, and the concentration of T4 in serum does not change over time. Daily production of T3 decreases by 10 μg in women, and with age, the concentration of T3 in serum decreases significantly. Studies evaluating the hypothalamic-pituitary-thyroid system demonstrate various patterns of pituitary function: persistent or decreased ability to secrete TSH after various influences [5].

2. Relevance of the Problem

Hypothyroidism, especially its subclinical form, is one of the most common endocrinopathies. It affects women 7-10 times more often than men, and its age increases with age. According to a Wickham poll, the incidence of elevated TSH is about 7.6% in the general female population, but in women over 70 years old it will increase to 17%. The risk of developing hypothyroidism is 1.4 / 1000 / year in women aged 18-24 years, 6.7 / 1000 / year in women aged 65-74 years and 14/1000 / year in women aged 75-80 years [6,8].

The most common cause of hypothyroidism is chronic autoimmune thyroiditis (syn. Hashimoto thyroiditis), previous treatment with radioiodine and surgery for benign or malignant thyroid diseases, external exposure to radiation from malignant tumors of the head and neck, and several drugs such as lithium, amiodarone, interferon, and inhibitors tyrosine kinases.

Typical symptoms of manifest hypothyroidism are dry skin, poor memory, slow thinking, drowsiness, fatigue, muscle cramps, a feeling of cold, a hoarse voice, general swelling and constipation. In the blood there is an increased level of TSH in serum, a decrease in free T4. All of them reduce the quality of life and performance. Hypothyroidism, which causes hypertension, heart failure, an unfavorable lipid profile, insulin resistance and endothelial dysfunction, creates an increased risk of developing atherosclerosis, cardiovascular disease, type 2 diabetes, cognitive impairment, depression and mortality.

Symptoms of subclinical hypothyroidism can be very scarce (for example, higher fatigue, drier skin and weight gain) or even absent. In the blood, an elevated serum TSH level is determined, free T4 in the normal range.

In subclinical hypothyroidism, the risk of cardiovascular disease, heart failure, and cardiovascular mortality appears to be associated with TSH values of ≥ 10 mIU / L and with an age of up to 65 years. Several observations have documented not only the absence of cardiovascular risk, impaired cognitive function and mortality among the population aged 65–70 years, but also the protective role of subclinical hypothyroidism in elderly and longer survival [10–12].

Subclinical progression to open hypothyroidism is about 2.6% per year and can double in cases with a positive T-TPO or TSH> 10 mIU / L. Spontaneous remission of subclinical hypothyroidism was also observed, affecting up to 37-46% of patients over 65 years of age during 2-4 years of follow-up [8].

The treatment of hypothyroidism in postmenopausal women depends on several conditions: the presence of symptoms, the severity of hypothyroidism, the coexisting risk of cardiovascular disease, and the patient's age. With overt hypothyroidism, treatment with L-thyroxine is always recommended. In patients with cardiovascular risk and advanced age, the initial dose should be low: 25 mcg daily and slowly increasing every 2-4 weeks with an additional 12.5-25 mcg L-thyroxine per day. Women taking hormone replacement therapy need higher doses of L-thyroxine because of the larger capacity of the main blood transporter based on thyroxin - TBG (thyroxine-limiting globulin). The treatment of subclinical hypothyroidism is a matter of debate. According to the recommendations of the European Thyroid Association, in patients with subclinical hypothyroidism and age <65-70 years, L-thyroxine therapy should be established in the presence of symptoms or TSH ≥ 10 mIU / L. In a population older than 70 years and TSH ≥ 10 mIU / L, therapy may be considered if there are symptoms of hypothyroidism or cardiovascular risk. In patients> 70 years of age and TSH <10 mIU / L, observation and TFT should be performed every six months [7].

According to other authors, L-thyroxine should be used even with slightly increased TSH in serum <5 mIU / L, if there is a cardiovascular risk (cardiac diastolic failure, diastolic hypertension, diabetes mellitus, unfavorable lipid profile, nicotinism), goiter, antiperoxidase antibodies (a-TPO) and ultrasound scanning of the thyroid gland in accordance with chronic lymphocytic inflammation [6]. When L-thyroxine therapy is introduced, the target TSH depends on the patient's age and is recommended: 0.5-2.0 mIU / L in young people, 1.0-3.0 mIU / L in patients aged 50 years and 2-5 mIU / l in patients aged 70-80 years [7].

In a recent double-blind, randomized, placebo-controlled study of 737 adults who were at least 65 years old (average 74.4 years) and who persisted with subclinical hypothyroidism (TSH levels from 4.60 to 19.99 mIU / L , free thyroxine level in the control range), no obvious benefits in symptom relief were obtained within one year of observation [8]. In a retrospective study evaluating the effect of L-thyroxine therapy for subclinical hypothyroidism on cardiovascular risk and mortality, the only positive effect was observed in a population aged 40–70 years old and was even harmful for people over 80 years old [9].

It should be remembered that long-term therapy with L-thyroxine, leading to a decrease in TSH levels, is associated with an increased risk of atrial fibrillation and acute coronary heart disease.

3. Purpose of Research

The purpose of our study is to study the features of the course of menopause in women with thyroid diseases and the possibility of drug correction using menopausal hormone therapy.

4. Material and Methods of Research

In accordance with the goal of the study, 166 postmenopausal women with thyroid diseases and 80 women without its pathology were examined.

The main groups included women with thyroid pathology: autoimmune thyroiditis or diffuse-nodular non-toxic goiter; natural menopause (at least a year after the last menstruation); complaints of symptoms of menopausal syndrome; Consent to the use of MHT to relieve menopausal symptoms.

Exclusion criteria were: decompensated hypothyroidism; diabetes mellitus and impaired carbohydrate tolerance; vaginal bleeding of unknown origin; a history of thrombosis and thromboembolism; severe extragenital pathology; estrogen-dependent tumors; malignant neoplasms at present or in history.

The research program included a clinical and laboratory study, which included taking an anamnesis, anthropometry, determining the parameters of the blood lipid spectrum, biochemical parameters of the liver and blood coagulation system, ultrasound examination of the pelvic organs, mammography. All women underwent thyroid examination, including palpation, ultrasound, immunological and hormonal studies. The diagnosis of diffuse-nodular non-toxic goiter was established only after ultrasound confirmation of the presence of nodular formations and comparison of the thyroid gland volume with WHO standards obtained in regions with adequate iodine supply.

Autoimmune thyroiditis was confirmed by an increase in the level of antithyroid autoantibodies to peroxidase and thyroglobulin in the blood serum, an increased thyroid density during palpation, and a change in the echogenicity of the thyroid gland during ultrasound examination [6].

Patient complaints were clarified in detail, the age of the appearance of thyroid disease, the duration of the course of the disease and the duration of taking thyroid drugs, heredity (the presence of thyroid diseases in blood relatives), the presence of concomitant pathology.

When collecting a gynecological history, the time of the onset of menopause, the duration of menopause, the treatment of MHT, gynecological diseases, previous pregnancy and childbirth were clarified. The severity of menopausal syndrome was evaluated by calculating the Cooperman menopausal index [3]. All women underwent examination and palpation of the mammary glands, examination by a gynecologist, cytological examination of a smear from the surface of the cervix and cervical canal. Of the instrumental methods of research, ultrasound examination (ultrasound) of the pelvis, thyroid gland, mammography, dual-energy X-ray absorptiometry (DXA) in three zones was performed. MHT was recommended for women of the main group in order to relieve menopausal symptoms.

After 12 months of taking hormonal preparations, the women studied underwent an anthropometric, clinical and laboratory examination of biochemical and hormonal blood parameters, a gynecologist's examination, cytological examination, pelvic and thyroid ultrasound, and mammography.

All 246 women included in the study were divided into three groups. The main group included 166 women who were divided into two subgroups. The first subgroup consisted of 106 women with diffuse-nodular non-toxic goiter who did not receive potassium iodide therapy and thyroxine preparations. The second subgroup included 60 women with AIT in whom hypothyroidism was compensated before starting treatment for MHT. The duration of thyroxine administration ranged from 6 months to 3 years in a daily dose of 50 μg to 100 μg, while the target TSH level was in the range of normal values. All women of the main group were treated with a low-dose estrogen-progestogen drug containing 1 mg of 17β estradiol in combination with 5 mg of dydrogesterone in monophasic mode for 12 months once a day. The monophasic MHT regimen prevents the proliferative effect on the endometrium and mammary glands [2,11].

5. Results and Discussion

The average age of the patients in the examined groups was 46.7 + 4.01 years in the main group, while in the comparison group 48.2 + 5.11 years. The age range is 40-54 years, the duration of postmenopause in both groups did not exceed 2 years.

Our studies have revealed that women with hypothyroidism were more likely to have late puberty compared with women with unchanged thyroid status. Late puberty in thyroid pathology in women with menopausal syndrome was observed in 41.37% of cases, and with its unchanged condition - in 32.3%. The average age of menarche was 14 + 1.01 and 14 + 1.33, respectively, compared with the control group - 12 + 1.3 years (p <0.05).

Analysis of the generative function of patients showed that almost all women had a history of pregnancy, childbirth and abortion.

Menstrual irregularities during puberty and during the reproductive period were observed in women with hypothyroidism (52.5%) and AIT (54.5%), while in women from the control group, the course of the menstrual cycle was significantly favorable.

A study of the features of the course of pregnancies and childbirth revealed the presence of their complications in (32.5%) and (25%) women of the main group compared with the control group.

An analysis of the reproductive history showed that with an increase in the birth rate, the number of women with endemic goiter with hypothyroidism increases. So, out of 166 women with thyroid pathology with multiple births (3 or more births) there were 76, and out of 40 women in the control group only 14. Based on this, it can be assumed that frequent births can contribute to the appearance of thyroid pathology, which affects the further function of the reproductive system and the timing of its extinction.

The onset of menopause in all examined was determined retrospectively. Women with of hypothyroidism accounted for the age from 44 to 52.9 years, and in patients with AIT, the age of menopause was in the range from 42 to 55 years. The average age of menopause was 46.15 ± 0.35 and 48.55 ± 0.72 years, respectively. Compared to control, menopause in women with thyroid disease started earlier.

The menopausal period ranged from one year to four years. When analyzing such parameters as BMI and the OT / OB ratio, in patients with of hypothyroidism and AIT, there were no significant differences from similar indicators of women without thyroid pathology. The body mass index (BMI) in patients with thyroid diseases at the time of inclusion in the study averaged 30.01 ± 1.56 and did not differ from women in the control group (30.53 ± 1.17). In the examined patients of the main group, the ratio of waist to hip circumference (OT / OB) averaged 0.86 ± 0.01, a similar indicator was obtained in the control group of women, which averaged 0.83 ± 0.02.

Most often, women complained of such manifestations of menopausal syndrome (MS), as increased sweating, heartbeat at rest, hot flashes, sleep disorders. Hot flashes were observed in 62% of patients with of hypothyroidism and 71% of patients with AIT. Psychoemotional manifestations in the form of increased excitability, tearfulness, fatigue were observed in different groups of symptoms in 70-80% of patients.

The degree of severity of individual symptoms of pathological climacteria was evaluated in points, which were used to calculate the modified menopausal index (MMI). In women with of hypothyroidism and AIT, manifestations of pathological climacteria were observed, mainly of moderate and mild severity. In the subgroup of patients with AIT, a moderate degree of climacteric disorders prevailed in contrast to patients with of hypothyroidism. Meanwhile, the control group was characterized by mild climacteric disorders.

In the study we observed a more severe manifestations of climacteric syndrome in women with compensated hypothyroidism compared to women with diffusely non-toxic goiter in the euthyroid state and women without thyroid pathology.

During the treatment of 1 mg of estradiol with 5 mg of didrogesterone in patients with diffusely non-toxic goiter during the first two months of taking the drug, the following side effects were observed: 3 women – nausea, 4 women-headache, 2 women – tendency to edema, 10 women – mastalgia and 7 women – menstrual bleeding. After 6 months of MGT administration, the incidence of side effects decreased: 6 women retained mastalgia, 3 women had emotional lability and 2 women had menstrual-like spotting.

All women showed significant positive changes in menopausal disorders after treatment. The patients noted a significant decrease or disappearance of such neurovegetative manifestations of CS as sweating, palpitations at rest, intolerance to high temperature. There was an improvement in mood, reduction of irritability, tearfulness, normalization of sleep in 80% of women. In many patients, the hot flashes, the feeling of heat and the attacks of suffocation at night have disappeared. The decrease in the severity of manifestations of pathological climacteria was reflected in the decrease in the value of modified menopausal index (MMI).

It should be noted that the treatment did not adversely affect the results of the gynecological examination (sizes of myomatous nodes, cytological examination of smears from the cervix and cervical canal) and mammographic examination in patients with thyroid diseases.

The examined women showed an increase in free-T3 and free-T4 levels in the blood after 12 months of MHT. In the group of patients with hypothyroidism, there was an increase in the level of free-T3 from 5.62±0.23 to 6.08±0.24 nmol/l and free-T4 from 15.16±0.16 to 16.35±0.18 nmol/l (p<0.01), and in the group of patients with AIT – an increase in the level of free-T4 from 15.25±16.43 nmol/l and free-T3 from 5.21±2.1 to 5.93±0.23 nmol/l (p<0.01). There was no significant change in serum TSH levels in the two subgroups. Indications for changes in doses of thyroid drugs in any patient with hypothyroidism on the background of MHT treatment were not revealed. According to many authors, an increase in free-T3 and free-T4 levels with preserved TSH levels is typical for women with hypothyroidism on the background of MHT treatment [9]. A slight increase in free-T3 and free-T4 levels, which does not lead to a change in TSH levels, is probably an adaptation to MHT and may be adaptive [7]. However, there is work indicating that the use of estrogens in combination with Progestogens in women with compensated hypothyroidism requires increased doses of thyroid drugs to preserve euthyroidism. These allegations relate to drugs with a high content of hormones, including mainly equine estrogens. This is probably due to the dose-dependent effect of estrogens, which increases the synthesis of TSH in the liver and increases the level of total T4 and total T3 in the blood [14]. The results obtained in our work indicate that the intake of low-dose estrogen-gestagenic drugs containing natural estrogens and progestins in their composition does not significantly affect the functional activity of the thyroid gland.

During treatment in women with AIT revealed a decrease in the titer of antibodies to thyroperoxidase and thyroglobulin (p<0.05). Previously, in some studies, the stimulating effect of estrogens on the production of antibodies to thyroperoxidase was noted [18]. The results indicating a decrease in the titer of antithyroid autoantibodies to the thyroid gland in patients with AIT on the background of treatment with sex steroids were obtained in a number of other studies [12,17].

6. Conclusions

In menopausal women with altered thyroid status, especially when hypofunction of the thyroid gland (hypothyroidism) there is a significant mismatch of activities of hypothalamic structures in the regulation of gonadotropic pituitary function, which can be one of the factors contributing to the pathological symptoms of menopause, climacteric syndrome.

Thus, the use of systemic combined menopausal hormone therapy in women with thyroid pathology does not affect the volume, growth of nodules and thyroid function. In women with compensated hypothyroidism, the administration of this low-dose MHT does not increase the need for thyroid drugs and reduces the production of antithyroid autoantibodies. The obtained results justify the safety of low-dose estrogen-gestagen therapy in postmenopausal women with diffuse nodular nontoxic goiter and autoimmune thyroiditis.

Our study shows the safety of menopausal hormone therapy in women with thyroid disease, containing in its composition 1 mg 17β estradiol+ 5 mg didrogesterone (Conti). These doses of the drug reduce the manifestations of climacteric syndrome, do not have a clinically significant effect on the coagulation and fibrinolytic potentials of the blood, the structure and functional state of the thyroid gland and contribute to the growth of mass density of bone tissue. In the future, the study of this group of patients using low and ultra-low doses of estradiol undoubtedly represents a significant scientific and practical importance.