Characteristics of phenotypes (clinical variants) of polycystic ovary syndrome in women of reproductive age

The objective: on the basis of a comprehensive examination of women of reproductive age to establish the frequency of phenotypes (clinical variants) of polycystic ovary syndrome (PCOS). Materials and methods. 34 patients (main group) who complained of menstrual disorders and/or dermatopathies by recommendation of a dermatologist were examined. The control group is represented by 30 women without gynecological and somatic pathology. The mean age of women in the main group was 26,4±0,9 years and 29,1±0,9 years in the control group (p>0,05). The age of women in the study groups ranged from 18 to 35 years. Patients underwent a comprehensive examination to assess the severity of hirsutism and the severity of acne, as well as the body mass index was determined. All women underwent ultrasound examination in the dynamics and quantitative assessment of the concentration of hormones in the blood plasma, namely cortisol, thyroid-stimulating hormone, prolactin, free testosterone and its index, androstenedione, dehydroepiandrosterone sulfate, 17α-OH-progesterone, sex hormone binding globulin. Variation-statistical processing of the results was carried out using the program «STATISTICA 13». Results. The results of the conducted research show that 73,5% had menstrual irregularities, and 52,9% – infertility. Acne and hirsutism in every 3rd woman were combined and were diagnosed in 47,1% and 41,2% of women, respectively. Ultrasound signs of polycystic ovaries were found in 94,1% of patients according to the criteria for the diagnosis of PCOS, and in 88,2% – anovulation. According to the laboratory examination, hyperadrogenism was found in 55,9%, which is confirmed by statistically significant (p<0,05) predominance in the main group compared with the control group of androstenedione, free testosterone and its index. In addition, it should be noted statistically significant (p<0,05) higher levels of 17α-OH-progesterone and prolactin in the main group, but their indicators were within the reference values of the norm. Analyzing the frequency of phenotypes (clinical variants) of PCOS, it was found that phenotype A (classical) occurred in 32,4%. Phenotype B (incomplete classical) was diagnosed in 14,7%, and phenotype C (ovulatory) – only 8,8%. The most often, namely in 15 (44,1%) women with PCOS, the phenotype D (non-androgenic) was established. Conclusions. The results of the conducted research show that in women with PCOS clinical symptoms are characterized by menstrual dysfunction (73,5%), infertility (52,9%) and dermatopathies, namely acne (47,1%) and hirsutism (41,2%). According to the laboratory exanination, hyperadrogenism was found in 55,9%, which is confirmed by statistically significant (p<0,05) predominance in the main group compared with the control group of androstenedione, free testosterone and its index. Among the clinical variants of PCOS, the non-androgenic phenotype (phenotype D) was the most often diagnosed, the frequency of it was 44,1%. Classical (phenotype A) and incomplete classical (phenotype B) were found in 32,4% and 14,7%, respectively. It should be noted that only 8,8% of women with PCOS are diagnosed with phenotype C (ovulatory).


P olycystic ovary syndrome (PCOS) is a systemic pathology
in which all parts of the endocrine system are disrupted, not just ovarian function. PCOS occurs in women of all ages, from puberty to menopause, involving almost all systems of the body [11]. PCOS is a very common endocrine disorder among women of reproductive age and in the general population is observed in 6-15% of women [8]. PCOS should not be considered as only a gynecological syndrome, as it can later become a prerequisite for the development of diseases such as diabetes, thromboembolism, hyperplastic processes in the endometrium, as well as psychosomatic disorders [6]. Thus, it reduces the quality of life of patients with PCOS [16]. The syndrome is an interdisciplinary disease that combines reproductive dysfunction with multiple metabolic disorders. The reasons for the development of PCOS are ambiguous and are currently being discussed; it is known that up to 50% of women have the genetic nature of PCOS. [9].
Modern approaches to the diagnosis of PCOS are based on the assessment of clinical and laboratory manifestations of hyperandrogenism, ovulatory dysfunction and changes in the ultrasound characteristics of the ovaries [10]. Given the nature of the complaints, the doctors of the first contact with patients suffering from PCOS, first of all, are obstetrician-gynecologists and dermatologists, and the so-called latent manifestations of the pathology expand the range of specialists. PCOS is usually detected in the early reproductive period, its clinical manifestations are extremely variable and can include: MC disorders on the background of oligo-/ anovulation; infertility; polycystic ovaries according to the ultrasound; dermatopathies (acne, hirsutism, decreased hair growth in the scalp area); metabolic disorders: obesity, IR and, as a consequence, metabolic syndrome [7,8,17]. Patients with dermatopathies often turn to a dermatologist to solve this problem, so the doctor during the appointment should help the patient not only aesthetically, but also carefully get the medical history, examine the skin and, if necessary, refer to a specialist for further diagnosis, because the success in effectively help of women with PCOS is the joint work of a dermatologist, endocrinologist, gynecologist, etc. [6].
The main purpose of PCOS diagnosis is to determine the severity of clinical manifestations, the sources and pathogenesis of androgen hyperproduction, the impact on reproductive function, assessment of metabolic and cardiovascular risks [13]. A working group of experts from the National Institutes of Health (NIH) which was based on the methodology of evidence-based medicine (NIH Evidence-based Methodology Workshop), proposed to identify 4 phenotypes of PCOS (clinical variants). The 2018-year guideline «International evidence-based guideline for the assessment and management of polycystic ovary syndrome» confirmed the Rotterdam criteria and the relevance of determining clinical variants (phenotypes) of PCOS [2,8,9,14]. The selected phenotypic form affects the capacity of differential diagnosis, lifelong risks, fertility and, respectively, management of the disease [4,5]. That is why a differentiated approach to the examination of patients with different phenotypes of PCOS allows to personify the therapy of this disease and to determine a set of preventive measures to improve the quality of life of women of reproductive age [1,10].
The objective: on the basis of a comprehensive examination of women of reproductive age to establish the frequency of phenotypes (clinical variants) of polycystic ovary syndrome.

MATERIALS AND METHODS
The main group of the research included 34 patients who complained of menstrual irregularities and/or dermatopathies by recommendation of a dermatologist. The control group is represented by 30 women without gynecological and somatic pathology. The mean age of women in the main group was 26,4±0,9 years and 29,1±0,9 years in the control group (p>0,05). The age of women in the study groups ranged from 18 to 35 years.
In order to establish the diagnostic criteria that characterize PCOS, a comprehensive clinical and laboratory examination and ultrasound in the dynamics. Quantitative assessment of the concentration of hormones in blood plasma was performed by enzyme-linked immunosorbent assay to determine the level of cortisol -C (μg/DL), thyroid-stimulating hormone -TSH (μIU/ ml), prolactin -Pr (ng/ml), free testosterone -Tf (pg/ml) and its index (%), androstenedione -An (ng/ml), dehydroepiandrosterone sulfate -DHEA-S (μg/dl) and 17-α-OH-progesterone -17-OHP (ng/ml), sex hormone binding globulin -SHBG (nmol/l). The research was performed on the third-fifth day of the menstrual cycle. Due to the fact that HA can be formed in hypothyroidism, hyperprolactinemia and adrenal dysfunction, women with relevant pathology were not included in the study group. Criteria for the diagnosis of PCOS are the presence of at least 2 of the 3 criteria: excessive activity or secretion of androgens (clinical and/or biochemical signs of HA); oligo-/ anovulation; polycystic ovaries according to ultrasound of the pelvic organs (visualization of at least 12 follicles with a diameter of 2-9 mm in at least one ovary) [8].
Each woman was interviewed about the feasibility of additional research methods and consent was obtained. The research matches the modern requirements of moral and ethical norms regarding the rules of ICH/GCP, the Declaration of Helsinki (1964), the Council of Europe Conference on Human Rights and Biomedicine, as well as the provisions of legislative acts of Ukraine.
Variation-statistical processing of results was carried out using licensed standard packages of applications of multidimensional statistical analysis «STATISTICA 13».

RESULTS
According to the gynecological anamnesis, 73,5% of women indicated menstrual irregularities and 52,9% -infertility (Pic. 1). Clinical manifestations of menstrual dysfunction included, in particular, oligo-/ amenorrhea. According to the ultrasound examination, 94,1% of patients had ultrasound signs of polycystic ovaries according to the criteria for the diagnosis of PCOS. The vast majority of women in the main group, namely 88,2%, have anovulation.
Obesity is often accompanied by PCOS and is an additional significant factor in the formation of metabolic disorders and the subsequent development of serious complications [3]. 3 (8,8%) women were diagnosed with grade I-II obesity and 4 women, which amounted to 11,8%, were overweight.
Clinical manifestations of hyperandrogenism of women with PCOS are acne, hirsutism (enhanced hair growth in women of the male type -in androgen-dependent areas), seborrhea, androgenic alopecia (baldness by male type), virilization (roughening of the voice, hypotrophy of the mammary glands, android body structure), etc. [8].
According to laboratory examination, it was found that among women of the main group androstenedione levels were increased by more than half, namely in 19 (55,9%). However, according to the assessment of the level of Tf and its index, an increase of these indicators was found only in 2 (5,9%) and 5 (14,7%) women, respectively. It should be noted that 62,5% of women with acne had elevated androgen levels. Differential diagnosis of HA in order to exclude other diseases primarily involves the exclusion of diseases The results of the assessment of the concentration of hormones in the blood of women in the study groups  of thyroid gland, hyperprolactinemia and non-classical forms of congenital dysfunction of the adrenal cortex [8,12]. Therefore, for the purpose of differential diagnosis in all patients with suspected PCOS, it is necessary to determine the level of prolactin, 17-OH-progesterone, thyroid-stimulating hormone, T4 free, antibodies to thyroglobulin, antibodies to peroxidase to exclude thyroid pathology [15]. The main criterion for the diagnosis of non-classical form of congenital adrenal dysfunction is an increase the level of 17-OH-progesterone and in some cases to confirm this diagnosis, genetic research methods can be used [8,18]. The results of the assessment of the concentration of hormones in the blood of women in the study groups are presented in table. Statistically significant (p<0,05) predominance in the main group compared with the control group was established by the level of An, Tf and its index, as well as 17-OHP and Pr. However, about 17-OHP and Pr, their indicators were within the reference values of the norm in all women in the study groups.
Free and total testosterone are known to have relatively low sensitivity, and among the most informative indicators in the diagnosis of HA, according to the recommendations of the European Endocrine Society (ESS), are the free testosterone index and androstenedione. It should be noted that the study of androgen levels is an auxiliary method for diagnosis and in any case should not be used as the main criterion or substitute for clinical diagnosis of PCOS [8].