ANALIZA KLINICZNYCH I SPOŁECZNYCH CZYNNIKÓW RYZYKA ZDROWIA REPRODUKCYJNEGO MĘŻCZYZN W WARUNKACH PRAKTYKI LEKARZA RODZINNEGO

Serhii Yu. Tsiporenko, Larysa F. Matyucha

Department of Family Medicine and Outpatient Clinical Care, National Medical Academy of Postgraduate Education
named after P. Shupyk, Kyiv, Ukraine

Abstract

Introduction: One of the important modern problems in the practice of a family doctor is the protection of reproductive health. Reproductive problems in marriage, including male infertility, are important components of demographic processes, therefore, attempts to resolve them are not only medical, but also social significance. Of all the physiological systems of man, for which the patterns of adaptation mechanisms are shown, the most “vulnerable” is the reproductive system, whose functioning depends on the set of exo- and endogenous influences. Unlike specific genital pathology, reproduction is more relevant to social processes, which is of great importance for the evaluation of reproductive risk.

The aim of this research was to investigate the medical and social risk factors of reproductive health of men, the study of seminal fluid in males with malnutrition, to establish the relationship between reproductive health disorders of men and their medical and social characteristics, taking into account altered parameters of sperm and individual forecasting of the development of this pathology.

Materials and methods: The study involved 388 men, of which 275 men in the main group had a reproductive disorder, the rest – 113 healthy men constituted a control group. All patients were subject to interview, clinical examination. A sperm analysis was conducted to determine the morphology of the sperm. Multi-factor regression analysis was used to construct models that describe the relationship between indicators characterizing the state of health and reproductive function of men with their medical, social characteristics and altered parameters of sperm.

Conclusions: In order to comprehensively evaluate the reproductive health of men, the medical, social characteristics and spermatological data should be included in the calculation of male reproductive health integral indicators. In the practice of a family doctor it is expedient to use prognostic models of reproductive health disorders for men not only with diagnostic but also for preventive purposes.

 

Wiad Lek 2018, 71, 2 cz. I, -290

 

INTRODUCTION

The issue of strengthening and preserving the health of people is the most important task for the governments of European countries today [1], while the responsibility for the health of the population relies on the medical sector, in particular on primary health care.

 According to WHO recommendations, primary prevention is the most cost-effective component in the process of controlling the health status of the population. It was WHO that recognized the need for states to prioritize disease prevention programs, which is to monitor the health of the population at the level of primary health care [2].

One of the important modern problems in the practice of a family doctor is the protection of reproductive health. Reproductive problems in marriage, including male infertility, are important components of demographic processes, therefore, attempts to resolve them are not only medical, but also social significance [3,4]. Of all the physiological systems of man, for which the patterns of adaptation mechanisms are shown, the most “vulnerable” is the reproductive system, whose functioning depends on the set of exo- and endogenous influences [5]. Unlike specific genital pathology, reproduction is more relevant to social processes, which is of great importance for the evaluation of reproductive risk [6]. Over the past 20 years there has been an increase in the proportion of male factor in the structure of the causes of infertility, which, according to statistics, accounts for 30 to 60% [7,8]. Data from researchers in different countries indicate a decrease in the volume and quality of sperm [9,10]. The urgency of the problem is also increasing due to the fact that men live and work in a modern society in conditions of economic, social, psychological tension, and are also more inclined to the most common addictions that are harmful to health [11]. All of the foregoing determines the relevance of the problem and necessitates the study of the features of male fertility violation in order to justify measures to reduce the risk of reproductive disorders in men.

THE AIM

The aim of the work was to investigate the medical and social risk factors of reproductive health of men, the study of seminal fluid in males with disturbed fertility, to establish the relationship between reproductive health disorders of men and their medical and social characteristics, taking into account altered parameters of sperm and individual forecasting development of this pathology.

MATERIALS AND METHODS

The study was conducted on the basis of the Department of Family Medicine and Outpatient and Clinical Care of the NMAPE named after P. Shupyk in the period of 2013-2016. All men (388 people, of which 275 men in the main group had reproductive impairment, the remaining 113 healthy men were control group) who participated in the study confirmed in writing the informed consent of the patients. After that, interviewing men was conducted. The wives of patients have previously undergone a comprehensive study and are considered to be fertile. The questionnaire consisted of passport and anamnestic parts, and also contained questions reflecting the presence of harmful habits, harmful factors of production, qualitative and quantitative characteristics of nutrition of patients. All patients were examined clinically, including examination and palpation of the penis, gut and prostate gland. All patients gave semen for analysis. On the eve of delivery the analysis should not have occurred ejaculation for 4-5 days. Semen analysis was performed half an hour after ejaculation and according to WHO guidelines [12]. Calculated the concentration of sperm, pH of the semen, the content of leukocytes and their populations (granulocytes, macrophages, lymphocytes), the number of actively mobile and weakly mobile sperm (category A + B). To determine the morphology used staining for Papanicolaou. Based on micrometry, the following variants of the sperm morphotype were distinguished [13]: – Macrosomatic – sperm length greater than 60 μm; – microsomatic – the sperm length is less than 50 μm; – Hypoacrosomal – the ratio of length of the nucleus to the length of the head of the sperm more than 0.6; – Hyperhallow – the ratio of length of the tail to the length of the head of the sperm is less than 10.0; – Round-leafed – the ratio of the width of the head of the sperm to its length more than 0.7.
To form a generalized assessment of violations of reproductive health of men, an integral index was calculated that allows a comprehensive assessment of the state of reproductive health of a man taking into account individual components and their significance. At the same time criterion χ2 was used for checking the indicators for normal distribution. Calculated median, lower and upper quartiles, confidence intervals. To compare the indicators, the criterion χ2, the two-sided critical region, was used. To analyze the presence and the strength of the relationship, the Kendal correlation coefficient τ was calculated. Multivariate regression analysis was used to construct models that describe the relationship between indicators that characterize the state of health and reproductive function of men with their medical and social characteristics and altered parameters of sperm.
Statistical analysis of the material was carried out using standard methods using the MS Excel XP application package.

RESULTS AND DISCUSSION

The analysis showed that among men with reproductive health disorders predominate persons aged 30 and over (62.8%), infertility (41.8%), children from the present wife (28.6%) who are had a history of prostatitis (54.83%), had sexually transmitted diseases (56.9%), had abnormalities in the genital organs (3.4%), had genital traumatic lesions (71.2%) 12,4%), the body mass index is more than 29,5 (24,7%), with the average material security (41,7%), evaluate their housing and living conditions as “good” (42.7%), with a state of nervous overcrowding (24.7%), with a sleep time of 6-7 hours (72.6%), smoking (67.1%) , who use alcohol (67.9%), evaluate their health as “satisfactory” (69.5%), eat 3 times a day (48.4%) who had the first sexual contact at the age of 16-18 years (39.6%), 2-4 sexual partners during life (24.7%), sexual contacts 1-3 times a week (48.7%), erectile dysfunction (24.2%), orgasm disorders ( 27.4%), assessed their sexual power as “sufficient” (39.0%).

According to the results of the research, among the patients in the main group, men with fertility disorders (115 men – infertile men) and survived fertility (160 men – fertilemen) were identified.
The study of subpopulations of leukocytes in the examined male in the semen is demonstrated in Table I.

As is evident from the results of the study, patients with impaired fertility (Group I) were characterized by a significant reduction in the number of monocytes / macrophages (12.54 ± 0.93, p <0.01) as compared to fertile men (group II) and control group, and with normative indicators. Fluctuations in the number of monocytes / macrophages in fertile males (group II) were within the limits of normative indicators. At the same time, the number of lymphocytes had a reverse trend to a significant increase (14,12 ± 0,53, p <0,01) in patients of Group I compared with the second group and with normative indicators. Such imbalance of monocytes / macrophages and lymphocytes in the infertile men in seminal plasma suggests the presence of intimate mechanisms of disorder of spermatogenesis and the participation of the immune system in this process. The literature states that the effect of white blood cells on the function of sperm depends on the dominance of subtypes of leukocytes [14,15].
       During micrometry, differences in the variants of sperm morphotypes in patients of both groups of men with reproductive impairment were found (Table II).

Specifics of morphotypes of spermatozoa are caused by dysfunction of different levels of their formation and ripening. Obviously, the presence of macrosomatic sperm is due to the lack of the mitotic division of the spermatogonium, the extension of the phase of their growth, during which they, sharply increasing in size, turn into spermatocytes of the first order, which are further transformed into macrosomatic spermatozoa [13]. The microsomatousmorphotype is probably due to the reduction of the spermatocyte growth period due to the premature formation of stress peptides. Hypoakrosomiya, obviously, is connected with the fact that during the differentiation of gametes, while the formation of haploid sperm cell occurs a consistent phase transformation of the structure of the nucleus and cytoplasmic elements, which ends with the final formation of acrosomes and “packaging” of nuclear chromatin, which manifests itself in a single-modal relationship between the nucleus and the acrosome . Therefore, the violation of this ratio can be associated with dysfunction at the level of differentiation. Hypercapitatedmorphotype, as is known, is characterized by morphological signs of insufficient maturity of spermatozoa, namely: residual protoplasia, cytoplasmic drop and shortening of the tail. In the case of dysfunctional hypofertility, they are practically not observed. This can be explained by the fact that maturation of the sperm in the testicle’s appendix occurs in several stages. First, there is a transition to external nutrition (loss of protoplasms and droplets), then the immune coating (mimicry) changes and, finally, anticapacitate properties are acquired – the phase of final maturation of the sperm, during which there is an acrosome seal, which, in fact, determines the ratio between the lengths of the head and the tail. At the last stage of the finding in the appendage of the testicle, the spermatozoa undergo selection – the inferior ones are labeled with ubiquitin and, as a rule, phagocytes. Thus, dysfunctional hypofertility makes itself felt at the last stages of maturation, which manifests itself as a hypercapitatedmorphotype of sperm. As can be seen from Table II, the normosomatic variant in patients of group I was observed in 42 cases, while in patients of group ІІ – in 115 cases (difference of fate is statistically significant at р <0,001). Consequently, infertile patients, despite the normal amount and mobility of sperm, remain morphofunctional changes, which, obviously, determine the fertilizing potential of the male.

In the study of the correlation relationships, it was found that in the first group of patients there is a correlation between the presence of morphological changes in sperm and an imbalance of subpopulations of sperm. Thus, in the group of patients with elevated levels of lymphocytes, a positive correlation was observed with the microsomal morphotype of the spermograms, the Kendal correlation coefficient τ = +0.34 (the correlation coefficient is different from 0 at the level of p <0.01). Negative correlation relationship was established between the level of monocytes / macrophages and hypercapitatedmorphotype of spermograms, τ = -0.51 (the correlation coefficient is different from 0 at the level of p <0.01).

The obtained correlation relations indicate that white blood cells take direct part in the spermatogenesis at all its stages, and changes in the disproportion of leukocyte populations lead to a disturbance in the concentration of products of their metabolism, and hence to changes in the microenvironment of generative cells. Obviously, the surplus of certain cytokines and a number of other biologically active compounds that release activated lymphocytes shorten the growth period of spermatocytes, the manifestation of which is the microsomal morphotype. At the same time, a decrease in the concentration of products of metabolism of monocytes / macrophages is accompanied by insufficient maturation of sperm, defective gametes are not eliminated in full by macrophages. This, probably, can also be explained by the presence of a negative correlation between the high level of hypercapitated sperm and the number of monocytes / macrophages. Negative influence on the processes of maturation is carried out and increased levels of granulocytes.

So, diagnostically important is the determination of morphological changes in sperm and the determination of disproportion of leukocyte subpopulations in semen in the establishment of male infertility. This makes it possible to apply a differentiated approach both to the treatment of commonly used therapeutic agents and to differentiated immunotherapy. For a generalized assessment of the state of reproductive health of a man, taking into account a number of medical and social characteristics and parameters of the sperm, an integral index, which includes several components and allows to take into account the significance of each of them, was used.

The calculation of the integral index of the state of reproductive health of a man (SRHM INT) was carried out on the basis of the following formula [16]:

where N – the number of indicators characterizing the reproductive health of a man; – is the weight (significance) of the k-th indicator, which characterizes the reproductive health of a man;

– balance assessment of the k-th indicator of the state of reproductive health.

On the basis of expert opinion for the formation of the integral indicator, 8 (N = 8) components were chosen: age (SRH1); the number of children in the past (SRH2); frequency of sexual intercourse (SRH3); presence of pathological forms of sperm in sperm (SRH4); the presence of disproportion of leukocytes in the sperm (SRH5); presence of STDs in the past (SRH6); prostatitis in the history (SRH7); the body mass index is higher than 29.5 (SRH8).
To standardize for each indicator, a system of ballroom assessments (using a 10-point scale) has been developed.

Weight (meaningful) indicators were calculated according to the following formula:

WK = EЕkk=1NEEk,

where N – number of indicators included in the integral index; – the average value of expert estimates of the significance of the k-th indicator, which is included in the integral index.
The calculation results are presented in Table III.

To analyze the significance of medical and social risk factors for the development of male reproductive health disorders, the results of the comparison between the main and control groups according to Student’s t-criterion were used.

To predict reproductive health disorders in a man
on the basis of individual medical and social characteristics, regression models are constructed:

Model of reproductive health disorders in a man (MOD SRH):

reg = -0,161253+0,000293728* X₁₁+ 1,35782*X₁₂
-0,53901*X₁₃+0,39377*X₁₄+0,37451*X₁₅-0,73902*X₁₆+
+1,50112*X₁₇+1,29834*X₁₈

where

X₁₁ is the age of a man;

X₁₂ – body mass index;

X₁₃ – the presence of children in the past;

X₁₄ – pathological forms of spermatozoa;

X₁₅ – sperm disproportion in sperm;

X₁₆ – frequency of sexual contacts;

X₁₇– presence of chronic urological pathology;

X₁₈ – transferred STDs.

Scale for assessment: 0 – 0.30 – low probability of reproductive health disorders; 0.31 – 0.70 – average probability of reproductive health disorders; 0.71 – 1.00 – high probability of reproductive health disorders.

2. Model for assessing the health status of a man with reproductive health disorder (ASRH):

ASRH = 0,443291-0,00091232*Х₂₁+0,053290231*Х₂₂+
+0,00638728*X₂₃+0,146128*Х₂₄+0,0214523*Х₂₅+
+0,0421273*X₂₆-0,0294561*Х₂₇-0,0693471*Х₂₈,

where

X₂₁ – age of the patient;

Х₂₂ – education;

X₂₃ is the number of children;

Х₂₄ – material support;

Х₂₅ – working conditions;

Х₂₆ – drinking alcohol;

X₂₇– body mass index higher than 29.5;

Х₂₈ – violation of erectile function.

Scale for evaluation: 0-0,25 – unsatisfactory; 0,26-0,50 – satisfactory; 0.51-0.75 – good, 0.76-1.00 – excellent.

3. Integral indicator of male reproductive health (IIRH):
IIRH= 4,023272 -0,0000536721*Х₃₁-0,314581*Х₃₂–0,0049278*Х₃₃+0,41907012*Х₃₄-0,59001237*Х₃₅–0,4433256*X₃₆-0,512789*Х₃₇-0,384512*Х₃₈
-0,2293522*Х₃₉,

where

Х₃₁ – the age of a man;

Х₃₂ – marital status; Х₃₃ – material support;

Х₃₄ – living and living conditions;

Х₃₅ – prostatitis in the history;

X₃₆– the first sexual contact;

Х₃₇ – the presence of bad habits;

Х₃₈ – nervous stress;

Х₃₉ – presence of STDs.

Scale for evaluation: 0-0.30 – low level; 0,31-0,70 – average level; 0.71-1.00 is a high level.

With the help of the constructed models, the prognosis of indicators characterizing the development of reproductive health disorders of men was carried out, taking into account the selected medical and social risk factors.
The constructed models were tested in 72 people. At the same time, 41 people were diagnosed with reproductive health problems. Table IV presents the results of the verification of the model for predicting the
development of reproductive health in men, from which it is evident that 62 out of 72 cases received the correct prognosis (the probability of correct prediction was 86.1%), with the development of reproductive health disorders was not predicted in six out of forty-one cases (14.6%). The average absolute error in the model of prediction of the state of health of men with reproductive function disorders was 0.13, and for the model of IIRH prediction – 0.83. The obtained results confirm the accuracy of the models, which is quite sufficient for application in practice.

CONCLUSIONS

1. It is important for the family doctor to take into account the following medical and social characteristics of the reproductive health of males: the age of patients over 30 years of age, the presence of children in the past, the presence of harmful habits and harmful factors of production, prostatitis and STDs in history.

2. Spermatometric studies are useful for the detection of morphological characteristics of spermatozoa and the establishment of infertility.

3. The presence of disproportion of leukocytes in sperm with the development of infertility indicates their influence on the intimate mechanisms of maturation of sperm.

4. In order to comprehensively assess the reproductive health of men, the medical, social and spermatological data should be included in the calculation of male reproductive health integral indicators.

5. In the practice of a family doctor it is expedient to use prognostic models of reproductive health disorders for men not only with diagnostic but also for preventive purposes.

REFERENCES

1. Voronenko YV, Boyko AI, Goyda NG et al. Dydaktychni technologii vykladannya pytan reproduktyvnogo zdoroviya. Kyiv. Knyga plus. 2011.

2. Goyda NG, Matyucha LF, Slabkyy VG et al. Optymizatsiya pervynnoyi medyko-sanitarnoyi dopomogy naselennyu Ukrayiny. Kyiv. 2010.

3. Gorpynchenko II. Muzhchina v XXI vyekye. Syeksologicheskiye i andrologicheskiye aspyekty. Zdorovye muzhchiny. 2012;4:15–18.

4. Stahl PJ, Stember DS, Goldstein M. Contemporary Management of Male Infertility. Ann Rev Med. 2012;63:525–540.

5. Ryngach NO. Pokrashchennya reproduktyvnogo zdoroviya naselennya yak napryam polipshennya umov realizatsii ditorodnoyi aktyvnosti. Medix antiaging. 2010;3:46–50.

6. Goyda NG, Bisyarin OY. Vykorystannya danych spetsialnogo sotsiologichnogo doslidzhennya yak instrumenta vplyvu na formuvannya i zberezhennya reproduktyvnogo zdoroviya Ukrainy. Zdoroviya natsii. 2011;2:82-89.

7. Tournaye H. Male factor infertility and ART. Asian J Androl. 2012;14 (1):103–108.

8. Gavrylyuk AM, Chopyak VV, Nakonechnyy AY, Kurpish M. Cholovichyy factor u patogenezi zhinochogo bezpliddya. Med Aspekty zdoroviya muzhchiny. 2011;8(49):5–12.

9. Povey AC, Stocks SJ. Epidemiology and trends in male subfertility. Hum Fertil (Camb). 2010;13 (4):182–188.

10. Shamrayev SN, Rutunskiy AI, Babyuk IA, Tsvyetkova PD. Sovryemennyye protivoryechiya otsenki sostoyaniya eyakulyata u muzhchin. Zdoroviye muzhchiny. 2012;4:19–23.

11. Fisher JR, Hammarberg K. Psychological and social aspects of infertility in men: an overview of the evidence and implications for psychologically informed clinical care and future research. Asian J Androl. 2012;4 (1):121–129.

12. WHO laboratory manual for the examination of human sperm and semen-cervical mucus interaction. WHO, 4-th edn. Cambridge university press. 1999.

13. Dyemchenko AN. Disfunktsionalnaya hipofertilnost u muzhchin, novyeyshyye podchody k yeyo klassifikatsii, diagnostiky i terapii. Novosti myeditciny I farmatsii. 2004;13:16-18.

14. Syemyonov AV, Sotnikova NY. Narusheniye sootnosheniya subpopulatsiy limfotsytov v eyakulyate pri besplodii u muzhchin. Meditsinskaya Immunologiya. 2007;9 (1): 91-96.

15. Arata de Bellabarba G, Tortolero I, Villarroel Vet al. Nonsperm cells in human semen and their relationship with semen parameters. Arch Androl. 2000;45:131 –136.

16. Chernyshova ML, Lyebyedyev VV, Osmanov EM, Chernyshov AV. Modelirovaniye I prognozirovaniye riska besplodiya u muzhchin I puti sovyershenstvovaniya myeditsinskoy pomoshchi muzhchinam s narusheniyami reproduktivnogo zdoroviya. Saratov. Indigo-IT. 2010.

ADDRESS FOR CORRESPONDENCE

Serhii Yu. Tsiporenko

22 Svoboda av., 04215 Kyiv, Ukraine

tel. +380506498131

e-mail. tsiporenko@ukr.net

Received: 20.02.2018

Accepted: 10.04.2018

Table I. Subpopulations of leukocytes in semen.

Subpopulation
of leukocytes,
%

Average score (according to Wolff et al.)

Infertile Men (Me ± m (Confidence Intervals))

Fertile Men (Me ± m (Confidence Intervals))

Control group (Me ± m (confidence intervals))

granulocytes

50-60

61,56±2,01*

[57,56;74,84]

49,56±1,53

[46,75;58,14]

49,44±1,65

[47,73;57,59]

monocytes /
macrophages

20-30

12,54±0,93**

[10,45;12,88]

19,10±0,98

[17,64;21,97]

19,05±0,87

[17,54;23,67]

lymphocytes

5-10

14,12±0,53**

[12,34;14,34]

9,09±0,42

[8,11;9,45]

8,12±0,34

[7,36;11,02]

Note: The probability of the difference between the indices is calculated between the groups of indicators and the norm at P <0.05 – *; at P <0.01 – **.

Table II. Variants of sperm morphotypes.

Morphotypes of sperm

Number of cases

Infertile men
(Group I)

Fertile men
(Group I)

Healthy men
(control group)

Macrosomatic

9

8

2

Microsomatic

28

17

3

Hypoacrosmic

6

7

1

Hypecapitated

30

18

2

Normosomatic

42

115

105

Table III. Significance of the components of the integral index of the state of reproductive health of men

Characteristic

Significance (weight)

Rank

Age

0,2346

1

The number of children in the past

0,2097

2

Frequency of sexual contacts

0,0929

6

Pathological forms of sperm

0,1507

3

Disproportion of leukocytes in sperm

0,1035

5

Presence of STDs in history

0,1167

4

Prostatitis in the history

0,0727

7

The body mass index is above 29.5

0,0192

8

Table IV. Results of verification of the prognostic model of development of reproductive health disorders in a man

Groups

The probability of reproductive function is predicted

>50 %

≤50 %

With a violation of fertility (n=41)

35 men

(85,36%)

6 men

(14,64%)

Without disturbance of fertility (n=31)

4 men

(12,90%)

27 men

(87,10%)