Influence of Peptide Bioregulators on Morphology of Parenchymatous Organs

Influence of peptide bioregulators on morphology of parenchymatous organs

TABLE OF CONTENTS

Introduction

Chapter 1. Ultrasound diagnosis. Method capacities

Chapter 2. Effect of Peptide Bioregulators on thyroid gland morphology

2.1. Summary on thyroid gland structure and functions

2.2. Thyroid gland disorders

2.3. Current diagnosis methods of thyroid gland disorders

2.4. Thyroid gland ultrasound diagnosis

2.5. Structural changes in the thyroid gland at peptide bioregulators

application

Chapter 3. Effect of peptide bioregulators on the prostatic gland morphology

3.1. Summary on the prostate structure and functions

3.2. Prostate age-related changes

3.3. Prostatic gland disorders

3.4. Current methods of diagnosis of the prostatic gland disorders

3.5. Prostatic gland ultrasound diagnosis

3.6. Structural changes in the prostatic gland at peptide bioregulators

application

Chapter 4. Effect of peptide bioregulators on morphology of other glandular

organs

4.1. Pineal gland (epiphysis)

4.1.1. Summary on the pineal gland structure and functions

4.1.2. Pineal gland disorders

4.1.3. Current diagnostic methods of pineal gland disorders

4.1.4. Structural changes in the pineal gland at peptide bioregulators

application

4.2. Pancreas

4.2.1. Summary on the pancreas structure and functions

4.2.2. Pancreas disorders

4.2.3. Current diagnostic methods of pancreas disorders

4.2.4. Pancreas ultrasound diagnosis

4.2.5. Structural changes in the pancreas at peptide bioregulators

application

4.3. Mammary gland (breast)

4.3.1. Summary on the breast structure and functions

4.3.2. Breast disorders

4.3.3. Current diagnosis methods of breast disorders

4.3.4. Breast ultrasound diagnosis

4.3.5. Structural changes in the breast at peptide

Conclusion

References

INTRODUCTION

Extension of human life span is the most important objective of modern science. With ageing body regulating functions deteriorate and are accompanied by the immunity disorders and development of age-related diseases [1, 2, 7, 21, 33, 35, 37]. The ageing process is characterized with a complex of alterations due to impairments in many body functions, diminution of adaptive capacities, progressive growth of abnormal alterations and death probability. The causes and mechanisms of ageing are not quite clear as yet. A great deal of theories were suggested to explain some or other ageing mechanisms [30, 34]. According to one of them ageing is caused by accumulation of pathologic alterations in the body, and the rate for such an accumulation might be influenced by genetic factors as well as by environmental conditions [11, 12]. An issue of health maintenance and longevity consists mainly in utilization of natural body reserve capacities. Therefore, issues regarding implementation of the very own body biological potential are still of current interest being key objectives for gerontology in general and geriatrics, in particular [47]. One of the priority trends of current research in gerontology is a concept of biological regulation (bioregulation) suggested and proved by V. Kh. Khavinson and V. G. Morozov [25, 26, 27]. The bioregulation as per up-to-date notions proceeds on several levels such as supracellular, intercellular, intracellular and molecular. The bioregulation mechanisms in spite of multilevel hierarchy perform a single task to coordinate processes of biosynthesis, interchanging and reproduction of genetic information. The bioregulation unites all control mechanisms in a pluricellular organism [50].

Multiplicity and complexity of the regulating processes suggest presence of universal mediators for information transmission to a cell. Such mediators are peptide bioregulators that exist in different tissues and reveal a wide range of biological activity. They participate in intercellular interactions by transmitting information recorded through corresponding amino acid sequence from one cell to another [5]. Another and not-the-least objective for gerontology is to pursue for new means of the ageing inhibition and life-span extension (the so-called geroprotectors). Development of new therapeutics based on endogenous physiologic active substances produced by a body is a novel approach for restitution of functions lost with ageing [8].

One of the recent discoveries consists in obtaining from animal organs and tissues of the peptide bioregulators, cytomedins [18]. Firstly the cytomedins were obtained from hypothalamic area of the cerebral cortex, pineal gland, thymus and vascular wall [25, 26]. Later peptides similar in origin and physical-chemical properties but different regarding functional activity were found in other body tissues, as well [23, 41, 42]. At present class of peptide bioregulators enumerates several dozens of known compounds and their number increases constantly. As per chemical composition they are complexes of polypeptides having molecular weight of 1000 to 10000 daltons. After experimental and clinical studies of cytomedins there appeared possibility for preventive and therapeutic application of peptide agents to enhance body resistance to impact of negative environmental factors. These researches admit development of new therapeutic agents containing peptide bioregulators of pineal gland (Epithalamin®), thymus (Thymalin®), prostate (Prostatilen®), brain cortex (Cortexin®), retina (Retinalamin®), etc. [23, 25, 26, 42].

Last years among the agents of bioregulation therapy another new class of therapeutics generally named as cytamins and being biologically active nucleoprotein complexes extracted from animal organs and tissues appeared. The said medicines relate to parapharmaceuticals and can effectively restore altered functions in organs they were extracted from [22, 43].

Normalizing effect of peptide bioregulators on the functions of various organs and tissues was found. One can note one of the mechanisms of <> activity of peptides, namely, participation of cytomedins in regulation of cell proliferation and differentiation, as well as capacity of the self-regulation regarding the number and functional activity of cell elements in population [18, 27]. Therefore, one can suggest that peptide bioregulators might affect tissue morphology restituting their altered structure.

To prove the aforementioned mechanism of action for the peptide agents the clinical study of influence of cytomedins and cytamins on normalization in structure of abnormally altered tissues in parenchymatous organs.

Chapter 1 - ULTRASOUND DIAGNOSIS METHOD CAPACITIES

Among the most topical problems in the modern medicine there stands out the search for such a method of intrinsic organ visualisation that would provide a sufficiently informative, evident, fast and patient-friendly demonstration of the target organs in their normal state and pathologic morphology alterations. We applied one of the radiation diagnosis methods, namely, ultrasound diagnosis (USD).

The USD method presents a number of advantages: it is non-invasive, painless and easily tolerable for the patient, which is very important for any sick person and, especially, for elderly patients. Elimination of ionised irradiation is another USD advantage over the rest of radiation diagnosis techniques. There-upon, USD is virtually unlimited in its application in the patient, i. e. multiple monitoring examinations of the process development are feasible. Providing double-dimension image of the studied organ USD, at the same time, is fast (often used as a screening examination), portable (possible to be used at home, on a trip, etc.), relatively economic (USD costs several times less than, for instance, X-ray examination). USD does not require any special preparation of the patient and has no contraindications, thus allowing immediate examination of various organs [6].

Another reason for using USD is its adequacy for the set objectives. Majority of the target organs are quite accessible for ultrasound. In particular, it refers to the thyroid gland, liver, kidneys, adrenal glands, pancreas, prostate and ovaries. Unfortunately, such structures as the pineal gland, cerebral cortex, vessels are impossible to be assessed by ultrasound. In these cases we used computed (CT) and magnetic resonance tomography (MRT).

We would like to give a brief review of the biophysic basics for obtaining an image by ultrasound.

Ultrasound oscillations appear due to the so-called piezo-effect. In case of the quartz plate deformation, an electric potential appears on its surface. On the other hand, if an electric charge is delivered to the quartz plate its dimensions change. If an alternating voltage with a particular ultrasound frequency is taken to the piezo-element the latter would vibrate with the similar frequency emitting an ultrasound. The piezo-element can interchangeably be both receiver and transmitter of the ultrasound oscillations. One or several suchlike elements mounted in a protective housing along with electric contacts are called an acoustic transformer, transducer or probe. It is an obligatory part for any diagnosis ultrasound device.

Sound spreads in a medium as waves of particular oscillation frequency. In the international system of units (SI) one Hertz (Hz) is taken as a unit of oscillatory motion frequency and equals 1 oscillation per second; 1000 oscillations equal 1 kilohertz (kHz) and 1 000 000 — 1 megahertz (MHz). In medicine audible sound (suggestion, music therapy, etc.), as well as the ultrasound with frequency of 1 to 20 MHz is normally used.

An important role for forming <> width and impulse duration is played by wave-length. The oscillatory motion frequency and the wave-length are of important practical value: the higher the frequency is, the shorter the wave-length is. Application of high-frequency transmitters provides improved exposure of small details in the examined object at little depth, and vice versa.

Acoustic or wave impedance is taken as a characteristic for any elastic medium (including body tissues as well). Changes in the medium elasticity or density alter acoustic impedance. It means that at the medium boundary the sound energy is partially reflected and, furthermore, the larger the difference of acoustic impedance between two media is, the larger the amount of energy would be reflected from the boundary between them.

A boundary between tissues and air is a complete reflector; therefore, lungs or gastrointestinal tract filled with gas cannot be examined by the ultrasonography. Due to the same reason, to provide penetration of the ultrasound wave into the human tissues between the probe surface and skin, one must put a contact medium, i. e. special gel. On the other hand, to conduct intravenous artificial contrasting of heart cavities the so-called <> comprising small carbon dioxide bubbles is applied.

Medical ultrasound diagnosis equipment allows to obtain three types of images, namely, A, B and M. The A-type image is single-dimensional being a single space coordinate along direction of the sound beam spreading. Time is indicated at the X-axis, and the signal amplitude — at the Y-axis. The B-type image is a double-dimensional one of an <> layer obtained at grayscale mode. The less the echo intensity is, the darker the corresponding image part on the screen is, and vice versa. Nowadays the B-type imaging is mainly used in the abdominal sonography. The M-type imaging is based on Doppler's effect: while a sound source is approaching to an observer, its frequency increases, and at moving away it diminishes. The said principle and imaging type are primary for echocardiography. Basing on the data obtained by M-scanning heart biometric indices (amplitude and speed of motion of cardiac structures, etc.) can be calculated.

Diagnosis ultrasound devices are normally furnished with a set of probes with various radiation frequencies. The probe frequency characteristics significantly alter the quality of the obtained acoustic image. For instance, preferable frequency for examination of the patients with excessive body weight is about 2.5 MHz; organs close to the body surface are better to be insonified using the probe with a frequency of about 7 MHz, and to study the eye structures high-frequency transducers (up to 10 MHz) are used.

Finally, in many cases sonography can and must be considered as preferable, first-choice and major diagnostic method. The given technique often provides all information required at the given clinical situation making unnecessary application of other, more expensive, effort-consuming, aggressive and costly ones [4].

Chapter 2 - EFFECT OF PEPTIDE BIOREGULATORS ON THYROID GLAND MORPHOLOGY

2.1. SUMMARY ON THYROID GLAND STRUCTURE AND FUNCTIONS

Thyroid gland /glandula thyroidea (PNA) [38]/ is a non-pair endocrine gland. Its main function is synthesis and incretion in blood and lymph of hormones regulating tissue growth, development, proliferation, differentiation and body metabolism. This U-shape gland is located in front and at the sides of the trachea and comprises two lobes with different measurements. Generally, the gland right and left lobes are connected with an isthmus. The dimensions of each lobe are: lengthwise — up to 5-8 cm, width — up to 2-4 cm and thickness — up to 1-2.5 cm. During pubescent period the thyroid gland is enlarged, and its size diminishes in the elderly.

The thyroid gland is of histological structure typical for endocrine glands: there are no excretory ducts and every functional unit is closely connected with the vascular system. The thyroid gland structural unit is a follicle, that is a round or slightly oval close vesicle with the wall covered with secretory (follicular) epithelium, i. e. thyrocyte. Thyrocytes produce thyroid hormones (thyroxin — T4 and triiodothyronine — T3), as well as thyreoglobulin. The latter is the main colloid constituent filling the follicular space. Simultaneously the thyroid gland produces thyreoalbumin. Normal ratio of thyreoglobulin to thyreoalbumin is about 9 : 1. In disorders associated with thyroid gland parenchyma proliferation, its goitrous transformation and adenoma development thyreoalbumin production increases, and the latter, in case of thyroid malignancy, might even excess thyreoglobulin synthesis.

Beside the follicles, in the thyroid gland interfollicular (extra-follicular) islands formed by cells with a typical thyrocyte-like structure are defined. Interfollicular islands are of importance for regeneration of the thyroid gland if the latter considerably impaired and entire follicles are destroyed.

Hypophysial thyrotropic hormone is considered to be the specific thyroid gland stimulator. In its turn, thyrotropic hypophysial function is activated by thyroliberin produced in the hypothalamus. Therefore, hypothalamic impairment causes similar decline in the thyroid gland functioning as hypophysectomy. This can be defined as transadenohypophysial regulation.

In its turn, the thyroid hormones inhibit the hypophysial thyrotropic function, i. e. the relationship between the functional thyroid gland activity and the hypophysial thyrotropic function intensity is a negative back-feed system that keeps fluctuations of the thyroid gland activity within the normal physiologic bounds.

The thyroid hormones are necessary for normal functioning of the central nervous system. Content of the thyroid hormones in children at the age of 1 to 15 years does not change considerably. However, with ageing the thyroxin-binding globulin and thyroxin levels decrease and triiodothyronine content increases.

The thyroid gland functional activity remains stable for a long time. Only in the elderly people atrophic alterations in the gland parenchyma are observed. They are associated with inconsiderable decrease of basal metabolism though there are signs of the thyroid gland activity growth that can be considered as compensatory reaction counteracting oxidative processes exacerbation in the tissues of a senescent organism [48].

2.2. THYROID GLAND DISORDERS

Both birth defects and alterations in the thyroid gland are rare. Primarily, the thyroid gland disorders are accompanied by signs of increased (thyrotoxicosis) or inhibited (hypothyrosis) function. However, some disorders of the thyroid gland function can have no clinical manifestation (euthyroid state).

The most wide-spread thyroid gland disorder is endemic goiter found in geographic regions with the shortage of natural iodine supply. In the course of the disease the thyroid gland enlarges though, in the majority of cases, without alteration in its function. Its hyperfunctioning bringing forth abnormal metabolism and development of various disturbances in different organs and systems is called <>. The following types are distinguished: diffuse, nodular and mixed toxic goiter. Diminished activity of the thyroid gland (hypothyrosis) emerges as a result of impairment in the gland, hypophysis or hypothalamus. The following types of the thyroid gland inflammatory disorders (thyroidites) can be distinguished: acute, subacute and chronic.

The thyroid gland tumours are often found along with enhanced hypophysis function that causes proliferation of the thyroid epithelium. The hypophysis thyrotropic function can be stimulated by alimentary iodine shortage, antithyroid agents, ionised radiation, hormonal disorders. There are benign and malignant tumours. Among the benign formations adenomas reveal the greatest incidence (16% of all nodular thyroid swellings). They can be single or multiple (multisite nodular goiter). As per the histologic structure, the following adenoma types are defined: trabecular (embryonal), tubular (fetal), microfollicular and macrofollicular (colloid). Still, fibromas, tetratomas, paragangliomas, hemangiomas, lipomas and miomas are rarely registered. The first place among malignant thyroid tumours (90% of all neoplasms) is taken by cancer. Such non-epithelial tumours as sarcoma, malignant lymphoma, hemangoendothelioma, malignant teratoma are rare in the thyroid gland.

2.3. CURRENT DIAGNOSIS METHODS OF THYROID GLAND DISORDERS

Methods of examination of the patients with thyroid gland disorders include clinical examination, methods for evaluation of the gland function and structure. The clinical examination comprises case taking and objective data (assessment of skin, subcutaneous fat, hair, nervousmuscular and cardiovascular systems, gastrointestinal tract). The thyroid function is estimated by indirect and specific methods. The indirect methods (examination of basal, fat and protein metabolism, state of nervousmuscular and cardiovascular systems) are based on investigation of the organism physiologic functions influenced by the thyroid hormones. Indices obtained by these methods are not specific to the thyroid gland disorders as other diseases might cause similar alterations. The specific diagnosis methods for the thyroid gland functional state include blood tests for the thyroid hormones and iodine metabolism.

The methods for the structure assessment are based mainly on radiation examination (conventional roentgenography, radionuclide examination, sonography, CT and MRT) and needle biopsy. Below the method of ultrasound diagnosis for the thyroid gland disorders is described.

2.4. THYROID GLAND ULTRASOUND DIAGNOSIS

The thyroid gland USD provides highly accurate assessment of the gland position, form and dimensions, structure, surface profile, state of surrounding tissues. It should also be stated that nowadays the sonography appears to be the most optimal diagnosis method allowing fast, informative and painless evaluation of the thyroid gland morphology [49].

To conduct the most effective sonographic examination it is desirable to use high-frequency probes of 5 to 7.5 MHz giving resolution of 3 —1 mm. During the examination the patient is in horizontal position on his/her back, with the head slightly inclined backwards. Such position is comfortable for the patient and does not cause any negative effect.

The normal thyroid gland at transversal scanning looks as a homogenous U-shape formation with medium echogeneity and fine-grained structure covering the trachea. Outside the side lobes there are round echo-negative zones — vessels: common carotids and jugular veins. In front of the gland there are hypoechogenic stripe-like structures — neck muscles. Inside each lobe there is a non-homogenous oval formation — the trachea (Fig. 1).

Transversal sonogram of the normal thyroid gland

Fig. 1. Transversal sonogram of the normal thyroid gland: 1 — neck vessels, 2 — right gland lobe, 3 — muscles, 4 — trachea, 5 — left gland lobe

USD of the normal gland gives the following dimensions: width of each lobes from the tracheal wall to outward gland border — up to 2-2.5 cm; the lobe length (front-back dimension) — of about 2 cm, and the maximal isthmic length is of about 0.6 cm. At the examination it is advisable to scan in multiple plans providing more detailed examination and structure assessment from all angles (sections) of the gland. The gland lobe length at longitudinal section can reach 5-6 cm.

Pathologic alterations in the gland at the sonography are exhibited with dimensional transformation (changes in the size and form) and local or diffuse echostructure rebuilding.

Changes in the size and form without any structural alterations are mostly found in the patients with endemic goiter. The gland is evenly enlarged owing to both lobes of the isthmus with a form more resembling a large oval.

Changes in the size and form with any structural alterations appear in case of diffuse goiter with or without nodes. If there are no nodes, along with enlargement one can note non-homogeneity of the sonographic structure in its parenchyma — normal tissue sites alternates with hyperechogenic inclusions, zones of rarefaction (diminished sonographic density).

Local parenchymatous reconstitution of the thyroid gland (with or without dimensional changes) is determined mainly with benign (adenomas, cysts) and malignant (cancer) neoplasms. Various adenomas (nodular goiter) are oval or round formations with distinct smooth profile. Inner structure of the gland is mostly homogenous, its sonographic density is decreased but, however, the latter can be equal to surrounding tissues or, more seldom, have increased echogeneity. A characteristic feature consists in the presence of hypoechogenic rim (<>) of about I-2 mm width that is an image of a well-formed capsule, edged out lobes, blood and lymph vessels. Heterogeneity of the node inner structure is caused by degenerative processes as cyst-like cavities of irregular shape or presence of denser wall inclusions in the echo-negative node. Sometimes little calcified formations of high echogeneity can be found in the adenomatous node.

Thyroid gland cyst is a echonegative formation of regular round or oval shape with distinct and even profile. Dorsal ultrasound enhancement can be noted behind the cyst. Often one can find in the gland parenchyma little (2-5 mm in diameter) echonegative cyst-like formations with very smooth and distinct profile that, according to some researchers [16], are centers of local follicular degeneration (focal hyperplasia, colloid degeneration). The said formations are likely to indicate signs of dysthyrosis.

Thyroid gland malignant tumours contribute a little to the morbidity structure and, generally, are rather rare. The highest oncologic alarm is related to solid and mixed solitary nodes. We should also indicate that nowadays there are no exact and reliable sonographic criteria for differentiation of benign and malignant thyroid gland formations. A range of important sonographic signs is somewhat incidental to both types of neoplasms. In some cases malignant tumours can fully reproduce the picture obtained for benign adenoma. Therefore, the sonographic data mostly allow to get a view on the anatomic structure only rather than on the impairment characteristics.

Reconstitution of the thyroid gland sonographic structure is observed also at chronic inflammations, thyroiditis. The most illustrative picture presents sites of irregular form, different sizes, diminished sonographic density and rarefactions against, the unchanged tissue background. The glandular parenchyma appear to be <>. Some researchers consider the hypoechogenic sites as manifestations of the gland stroma edema and lymphoplasmocytic infiltration [16]. Thus, USD as a very effective diagnostic method for external assessment of the thyroid gland is recommended for application at the first stage of examination in the patients with such disorders.

2.5. STRUCTURAL CHANGES IN THE THYROID GLAND AT PEPTIDE BIOREGULATORS APPLICATION

Our study objective was to assess the influence of peptide bioregulator. The complex included immunomodulating agent Thymalin, neuroendocrine system regulator Epithalamin and organotropic agent for the thyroid gland Thyramin on morphologic structure of the thyroid gland parenchyma in case of organic alterations.

Thyramin is a medicine of cytamin class used as a biologically active supplement. It was obtained from the cattle and pig thyroid gland. It comprises nucleoprotein complexes selectively affecting cells of the thyroid gland tissue.

There were examined and monitored 46 subjects at the age of 17 to 72 years with some thyroid gland disorders. Table 1 represents characteristics of the examined subjects and disorder type. Taking into account that in some subjects several types of the gland disorders occurred simultaneously, the total number of revealed nosologies exceeded the number of the patients and amounted to 63 cases.

Table 1

Characteristics of the examined subjects with various abnormal alterations in the thyroid gland

Disorder type (nosologic forms)

Number of cases

Male

Female

Age (years)

Mean age (X±m)

Focal colloid degeneration

26

I0

16

22-62

41.7±0.3

Adenomatous nodes

20

12

8

43-72

57.5±0.3

Chronic thyroidites

9

3

6

46-67

56.5±0.2

Cysts

8

4

4

33-41

37.4±0.1

Total:

63

29

34

22-72

The data given in Table 1 indicate that mostly in our study we noted signs of focal colloid degeneration (focal hyperplasia). The second frequency position is occupied by benign adenomas. The chronic thyroid gland inflammation and the cysts were relatively seldom.

Dysthyrosis (i. e. colloid degeneration of the thyroid gland) were equally found both in the younger patients and in the middle-aged subjects. The gland adenoma was revealed mainly in the middle-age and elderly subjects. Ratio of males to females was approximately equal with little prevalence of females. Multiple signs of disorders were noted in 17 subjects (37%).

29 patients were previously examined: they had revealed pathologic alterations in the thyroid gland and administered with conventional pharmacological agents. However, in none of 29 patients after the corresponding therapy the noted alterations disappeared or diminished. In 16 patients stabilization of the process was observed: the formation dimensions in the gland were the same; and in 13 subjects previously found focal formations enlarged.

17 patients were examined for the first time. Primary clinical examination comprised case taking, examination, blood test including hormone content. All patients underwent ultrasound examination, as main objective was to assess the gland parenchymatous structure. If indicated, the isotope scanning was applied to determine functional activity of the thyroid gland and noted nodular formations in it. To search for extraglandular spread of the pathologic formation MRT and CT were applied. In any of the examined patients no malignant neoplasms were found. Bioregulation therapy was administered as per the scheme developed at our Institute as treatment cycle dosing. Epithalamin and Thymalin were introduced intramuscularly, and Thyramin — orally.

The control group comprised 11 subjects at the age of 49 to 62 years (7 males and 4 females) with pathologic disorders in the thyroid gland similar to those of the main group found at primary examination. All the patients were monitored similarly. The control group subjects were not treated with bioregulation therapy. Basing on our examination and taking into account <> impact of regulating peptides, the first monitoring examination was made not earlier than in 4 - 5 months after the treatment onset. During the entire cycle of the bioregulation therapy subjects of both groups were not administered with any other therapeutics.

Patient P., 50 years old. Thyroid gland sonograms

Fig. 2. Patient P., 50 years old. Thyroid gland sonograms.

a — right lobe, cross section, b — left lobe, cross section, c — left lobe, longitudinal section.

In the right lobe (a) round formation: the node (bold arrow) ≈ 8 mm in diameter with heterogeneous inner structure. In the left lobe (b, c) — hypoechogenic

formation: the node, ≈ 23x19x18 mm (marked by arrows)

Patient P., 50 years old. The thyroid gland sonograms in 4.5 months

Fig. 3. Patient P., 50 years old. The thyroid gland sonograms in 4.5 months after the first USD: a — right lobe, cross section,b — left lobe, cross section, c — left lobe, longitudinal section.

At the sonogram the right lobe node (a) without any significant changes (bold arrow). In the left lobe (b, c) tissue formation ≈ 14x10x8 mm (marked by arrows)almost isoechogenic with the gland parenchyma that the previous large node in this lobe turned into

Here are some clinical cases.

Patient P., 50 years old — the patient first applied on 26.01.99. She complained of diminished working capacity, impaired memory, higher irritability, fatigue and sleep disorders. At clinical examination were found no considerable alterations in the functional state of various organs and systems were registered. T3 blood content was 3.384 nmole/l (norm — 1.0— 3.0 nmole/l), the T4 one did not exceed the normal limits. At USD the following pathologic changes in the thyroid gland were noted: in the right lobe - a node of about 8 mm in diameter, in the left lobe — a node of 23x19x18 mm (Fig. 2). The patient was subject to bioregulation therapy. In 4.5 months (04.06.99) the monitoring examination was made. USD exhibited that the right lobe node did not change significantly whilst the left lobe node decreased two-fold and its tissue structure became close to normal (Fig. 3). Blood content of the thyroid hormones corresponded to the normal values. Subjectively the patient felt considerably better, noted improvements in mood and sleep.

Patient M., 39 years old

Fig. 4. Patient M., 39 years old. The right lobe thyroid gland sonograms at cross (a) and longitudinal (b) sections.

Found node is marked by arrow

Patient. M., 39 years old

Fig. 5. Patient. M., 39 years old. The thyroid gland sonograms in 10 months after the first USD. Same sections.

The right lobe node decreased (≈ 1.5 — 2 mm in diameter)

Patient M., 39 years old. The patient first applied on 25.03.99. On sonography in the right lobe of the thyroid gland a hypoechogenic node of 5 mm in diameter was found (Fig. 4). Content of the thyroid hormones in blood was within the physiologic range. The bioregulation therapy was applied. Repeated examination was made in 10 months (17.01.2000) after the primary one and showed the following at USD: the previously observed node in the right lobe of the thyroid gland decreased considerably and its diameter was about 1.5 —2 mm (Fig. 5).

Patient. N., 48 years old

Fig. 6. Patient. N., 48 years old. Cross-section sonograms of the right (a) and left (b) lobes of the thyroid gland.

In the right lobe (a) a round node about 5x3 mm with heterogeneous inner structure (bold arrow). In the left lobe (b) small hypoechogenic sites of about 2— 3 mm in diameter (arrows)

Patient N. 48 years old, in 5 months

Fig. 7. Patient N. 48 years old, in 5 months after the primary USD examination. Same gland sections. Echogenicity of the right lobe of the thyroid gland (a) slightly increased and its structure became more homogenous (bold arrow). in the left lobe (b)

one of the small nodes disappeared. Another node is marked by arrow

Patient. N., 48 years old

Fig. 8. Patient N., 48 years old. The thyroid gland sonograms in 7.5 months after the primary USD: a — right lobe, b — left lobe, cross-section.

The right lobe node size (a) decreased (arrow). In the left lobe (b) the nodes are not determined

Patient N., 48 years old. The patient first applied on 22.10.98. The patient complained of periodic headache, more considerable fatigue, causeless weakness, irritability, sleep disorders, mood lability. The thyroid gland USD showed small nodular formations in both lobes (Fig. 6). Peptide bioregulators therapy was administered. In 5 months (15.03.99) the patient was examined again: the right lobe node had the same size, but its structure became more homogenous and <>. One of the small sites in the left lobe disappeared (Fig. 7). Subsequent monitoring in 7.5 months (08.06.99) after the primary examination showed diminution in the size and further restoration of the right lobe node and no nodes in the left one (Fig. 8). The patient's state improved: headaches were less often, fatigue and irritability decrease, sleep was restored.

After the treatment with peptide bioregulators USD visible positive results were noted in 39 cases out of 63 constituting 62%. In other 24 cases (38%) no pronounced changes in the thyroid gland structure were found, comparing to the initial stage. However, in none of the 24 cases negative development was registered.

In the control group comprising 11 subjects at repeated USD in 4.5 — 7 months there was found an enlargement of abnormal formations in 5 patients (4 males and 1 females), in 6 patients (3 males and 3 females) no changes were noted. There was not observed restoration or improvement in the gland morphology in any of the control group patients.

The USD-visible positive results of the bioregulating peptides impact on the thyroid gland parenchyma can be distributed in the following three groups: 1) abnormal alterations fully vanished; 2) abnormal alterations diminished (in size or number); 3) tissue with abnormal alterations restored to normal partially. Number of cases for each group and disorder is given in Table 2. The highest efficacy of the bioregulation therapy is observed in the patients with adenomatous nodes: 17 cases out of 20 (85%). The 2nd place in number of cases with the gland morphologic structure improvements is occupied by degeneration sites: 14 cases out of 26 (53.8%); then — cysts (4 cases out of 8 (50%)) and chronic inflammation (4 cases out of 9 (44.4%)).

Table 2

Distribution of the number of cases with observed thyroid gland disorders depending on the disease type and obtained positive results

Distribution of the number of cases with observed thyroid gland disorders depending on the disease type and obtained positive results

Thus, normalising influence of the developed peptide bioregulators complex on abnormally altered thyroid gland tissue is mostly manifested in the patients with various adenomatous nodes. Furthermore, as the studies showed, reparation proceeded both in large and small foci. Restoration of the normal glandular tissue was not significantly affected by the type of the node inner structure: no matter whether it was hyperechogenic (solid) formation or had decreased sonographic density (cyst-like).

There was found a significant coherence (P < 0.05) of positive impact of the regulatory peptides on the thyroid gland morphology and patient's age (Table 3). As it is demonstrated in Table 3, the best results were obtained in the patients of 40 to 60 years old. Such age distribution suggests that in younger subjects, due to satisfactory reserves of their own regulatory peptides, the treatment is less effective. In elderly persons lower treatment efficacy can be presumably explained by significantly lowered reserves of endogenous peptide regulators whilst dosing of exogenous ones is insufficient to compensate for the shortage.

Table 3

Dependence of the bioregulation therapy efficacy on the patient's age

Patient's age

(years)

Effect exhibition

Number of cases

31-40

+

4

41-50

+++

15

51-60

+++

18

61-70

++

5

>70

+

4

The obtained data indicate that the optimal combination of the peptide bioregulators such as immunocorrecting agent Thymalin, neuroendocrine system regulator Epithalamin and organotropic agent for the thyroid gland Thyramin — has a restoring activity on the abnormally altered tissue of the thyroid gland. Thus; the complex can be recommended as a preventive and therapeutic agent in organic thyroid gland disorders in middle-age, elderly and senile persons.

Chapter 3 - EFFECT OF PEPTIDE BIOREGULATORS ON THE PROSTATIC GLAND MORPHOLOGY

3.1. SUMMARY ON THE PROSTATE STRUCTURE AND FUNCTIONS

Prostate /prostata (PNA) [38]/ is one of the male genital system glands. It is located in the low-front third of the small pelvis, under the urinary bladder between the pubic joint and the rectum. Anatomically, the prostate is a non-pair, chestnut-like structure. In the gland the apex turned down to the urogenital triangle and the base with wide, inflected surface turned to the urinary bladder can be distinguished. The prostate has two surfaces — anterior, located behind the lower department of the pubic joint, and posterior, turned to the rectum. There are also two lobes, the right and the left, between which, on the posterior prostate surface a non-distinct groove is located. Microscopic examination cannot show division of the prostate into the right and left parts. Prostatic part of the urethra penetrates through the gland (from the base to the apex). It is situated on the medium plane, closer to the gland anterior surface (Fig. 9).

The prostate dimensions considerably differ depending on the age and constitutional peculiarities. In adult males its length is about 2.5 — 4.2 cm, width — 2.2 — 5 cm, thickness — 1.7 — 3 cm. The gland weighs about 17 to 28 g.

The prostate comprises a glandular body constituting 1/2 to 3/4 of its size and a prostatic muscle. The glandular body consists of 20 —50 separate tubular-alveolar pear-shaped or cuneal glands and each of them has its own duct. These ducts merge and open on the posterior wall of the prostatic urethra.

Prostate gland sketch

Fig. 9. Prostate gland sketch:a — general view (frontal), b — sagittal section: 1 — prostatic utricle,>2 — gland lobe (right), 3 — seminal vesicle (right), 4 — anterior surface, 5 — gland base, 6 — middle lobe, 7 — urethra, 8 — isthmus, 9 — lower surface, 10 — gland apex

The glandular lobules are linked together by connective tissue comprising elastic fibers and strong smooth muscular bundles constituting the orbicular prostate muscle that causes secretion discharge at contraction.

The connective tissue intercalations cover and surround separate lobule and the entire gland. Radiating from the colliculus seminalis region they divide the prostate into separate parts where three main groups of the glands are distinguished. Close around the prostatic urethra there are periurethral glands located between the mucous and muscular urethral layers, each of them having a separate opening into the urethra. Behind the periurethral group a concentric layer of submucosal glands can be found.

The prostate gland is supplied with blood from the medial hemorrhoidal, common pudendal and, mainly, inferior vesical arteries that come to the gland in small branches forming extended network of external anastomosing arteries on its surface. From the latter, along the prostate discharging ducts, the small arteries go inside forming a rich capillary network basketing the prostatic glandules. The prostate veins are numerous. Through anastomosing, they form a vesicalprostatic plexus receiving blood not only from the prostate but also from the seminal vesicles, testicular ducts and urinary bladder.

The seminary vesicles are sack-shape structures of the testicular ducts. They are located between the anterior surface of the rectal ampoule and posterior surface of the urinary bladder. Each seminary vesicle has the following size: length — about 3.5 cm, width — about 1.5 — 2 cm, and thickness — about 1 — 1.5 cm.

Lower animals do not have the prostate gland and, evolutionally, it appears only in mammals. The fact that its anatomic differentiation as an organ is attributed only to the higher species of this class, suggests significance of the prostate not only for the urogenital system but also for the entire organism functioning. By the pubertal period, the prostate is fully matured as an organ. The prostate secretion supports motion and vitality of spermatozoids improving their resistance to different negative impacts, for instance, to lowered temperature. At the same time, many researchers relate the prostate to endocrine organs considering spermine produced by the gland epithelium as the basis of the increte. Spermine can not only stimulate sexual functions but also boost general metabolism and support energetics of the entire organism.

The prostate diseases and, especially, its loss were noted to cause significant reconstitution entailing various disorders including general prostration, a range of neuralgias, stenocardiac attacks, melancholy and severe mental alterations [55, 57].

Increased prostate function is associated with such general signs as loss of subcutaneous fat layer, enhanced neuromuscular excitability, breath rate acceleration, higher blood pressure, pulse rate decrease, whereas diminished function is attributed to asthenia and melancholy. Basing on these observations, many clinicians call it <>, taking into account importance of the prostate for the organisms [19].

Considering the structure and function of the prostate gland, we cannot omit the issue of age-related changes and, therefore, of man's ageing.

Climacteric is a general biological process tightly connected with the organism ageing. Anyway, it is impossible to explain such complex biological phenomenon as ageing with one reason, for instance, atrophy of genital glands, autotoxication, cell metabolism alteration, etc. On some ontogenesis stages there are organs and systems with the lowest resistance to destructive influence of time on the human organism that should be considered as locus minoris resistentiae regarding to primary ageing processes.

On the other hand, the organism ageing is manifested not only in diminished intensity of metabolic processes and functional extinction of some organs and systems but also in forming of complex adaptive mechanisms. Therefore, from the point of view of clinical gerontology and geriatrics, the life time from 40 to 60 years is especially important because at this time the organism undergoes the most significant changes.

Functional status of the genital glands altered with age influences considerably man's organism vitality. The male genital glands do not abruptly stop functioning, however, their incretive activity decreasing with years. With age blood flow from the spermatic glands becomes less rich with testosterone and the excretion of androgen with urine certainly decreases.

Ageing starting from the early ontogenesis stages proceeds irregularly. Slow and often unregistered functional, structural and behavioral alterations can be changed with time with a peculiar <> that is notably exhibited at climacteric. Intensive, non-coordinated age-related reconstruction of the body neurohumoral medium at this time can cause alterations outbounding physiologic limits and bringing forth various disorders.

3.2. PROSTATE AGE-RELATED CHANGES

Age-related changes in such endocrine glands as hypophysis and testicles affect the prostate state. The prostate becomes an indicator of changes in the hypophysis-gonadal system including the age-related ones.

The age-related changes in the prostate have been studied for a long time. In the ancient manuscripts there are described ageing disorders in elderly men reminding the prostate adenoma by the clinical picture. Later the opinion that the prostate gland in all elderly men is enlarged to some extent was widespread. However, afterwards, the data indicated that the age-related changes of the prostate morphologic structure were manifested either in enlarged weight and size or in structural atrophy and diminished weight [44]. Nevertheless, in a half of the examined men after 60 the gland is enlarged.

The prostate hyperplasia occurs in the old age when some alterations in the organism neurohumoral status caused by shifts in the functional state of the central and vegetative nervous systems and disordered gonadohypophysial balance and functions of other endocrine glands appear in men against the background of the genital gland dysfunction. Naturally, one can conclude that the prostate functional status changes in the old age are manifestations of virile climacteric period caused by altered hormone balance.

Now rich experimental and clinical material is gathered indicating the influence of endocrine factors on the functional state of the prostate and allowing to state that the prostate age-related changes emerge as a result of altered hormonal balance caused by approaching climacteric period. However, until now has not been discovered why in some cases the prostate gland enlarges, and in other atrophies, and how the prostate function alters with years. Also there are some questions: what exhibits altered hormonal balance in the ageing body causing the prostate changes; whether it is the organ that passively transforms under the influence of the said hormonal abnormalities or it plays a particular role in the neuroendocrine metamorphoses at the climacteric.

3.3. PROSTATE GLAND DISORDERS

The most frequent age-related disorder in the male urogenital system is nodular hyperplasia of the prostate gland. it is a tumour-like formation that is also called adenoma, hypertrophy, adenomatous prostatopathy and dyshormonal hyperplastic prostatopathy. The term <> is most frequently used although, it is well known that newly formed nodules or nodes in the said organ just outwardly look like a benign tumour and, in fact, are hyperplastic accretion of non-tumour origin. Besides, sometimes they consist of not glandular but rather fibrovascular or smooth-muscle tissue. The term <> of the prostate also does not reflect the essence of the process.

The disorder is determined by imbalance in the genital hormones and belongs to the most incident diseases in elderly and senile men. The clinical signs are well known to appear mostly after 60 and their incidence and severity increase in older age groups. However, preclinical, asymptomatic forms of the disease often occur in young and middle-aged men, as it is demonstrated by autopsy [51, 52].

The nodular hyperplastic process is generally assumed to develop in the periurethral area though it can appear not only in the region of interim zone glands but also in the proper prostatic ones [31].

Some researchers believe that proliferation of stromal elements is of importance in morphogenesis of the prostatic nodular hyperplasia [45]. The early process stages were found at morphologic studies made on consecutive sections to be characterised by formation of nodules of, mainly, stromal structure localised predominantly around the urethra. Usually they are distinctly separated from the surrounding tissue, comprised of spindle cells, collagen fibers and blood vessels and have no elastic fibers at all. In some nodules there is an epithelial component as compressed ducts situated in the peripheral regions of the nodules. The epithelium of the latter often has proliferation signs. Some researchers believe that the glandular tissue accretion is induced with proliferation of the stromal elements emerged under influence of hormonal balance disorders [46]. In case of prostate nodular hyperplasia there is a four-fold absolute increase in the stromal constituent, whereas the glandular one is enlarged only about twofold. Number of the secretory granules in the glandule epithelial cells is diminished. Also smooth muscle tissue is activated.

Growth of the nodular proliferates in the prostate gland is of expansive character. It is also suggested by the fact that around them and, especially, around the nodule (node) conglomerates the fake capsule appear due to condensation of the compressed prostate stroma comprising considerable number of elastic fibers with thickening and hypertrophy in some of them. The nodes of significant size compress and dislocate the prostate gland that became the so-called <> even more. In this <>, among collagen and elastic fibers with separate atrophic smooth muscle cells, one can note atrophic glandular elements of the prostate gland. The prostate shape is often nodular. It even can bulge into the urinary bladder cavity. The organ weight increases sometimes up to 200g and more.

There are four main types of the nodular prostate hyperplasia: 1) adenomatous; 2) fibrous or muscularfibrous; 3) muscular; 4) mixed. The most wide-spread one is the adenomatous form diagnosed in 47 — 70% of cases. Muscular nodes by themselves are found rather seldomly. Besides, it is difficult to differ them from leiomyoma. Incidence of mixed nodular hyperplasia form occupies the 2nd place after the adenomatous one [19, 56].

Along with the adenoma, prostate cancer often develops in elderly and senile men and its etiology is also determined by alteration in the hormonal status. Unfortunately, up to now the prostate cancer in stage of distant metastases is found rather frequently — in about 50%. Asymptomatic nature of the prostate cancer for a long time may explain this fact, since the main condition for successful treatment of the said pathology is early diagnosis. Besides late symptom set the early prostate cancer diagnosis is hindered by peculiarities of its anatomic-topographic location, therefore, in majority of the patients the disease is diagnosed only when such signs as urinary tract obstruction or sharp pains due to bone metastases emerge [54].

Acute and chronic prostatites are also quite frequent in men of any age. Non-specific acute prostatitis can appear through hematogenous or ascending route from the urogenital organs, after instrumental interventions. Specific infection is usually sexually transmitted. The chronic prostatitis etiopathogenesis is still unclear. Three major mechanisms of this disease development in men are postulated: bacterial, autoimmune and hemodynamic ones.

The acute prostatitis is histologically characterised by intraductile leukocyte infiltration and interstitial tissue edema. Sometimes an abscess forms with subsequent breaking into the rectum, urinary tract and perineum. Lymphocyte interstitial infiltration and fibrosis are typical for the chronic prostatitis [39].

3.4. CURRENT METHODS OF THE PROSTATIC GLAND DISORDERS DIAGNOSIS

Up to now rectal palpation of the gland posterior surface has been considered by many urologists as one of the main methods for assessment of the prostate state. It allows to obtain subjective impression of the organ size and consistence.

Modern methods for objective prostate examination are CT, MRT and ultrasound diagnosis. The first two methods allowed to determine the form, size and volume of the prostate with rather high accuracy but are very expensive and rather effort-consuming. USD is not worse with respect to sensitivity and even better in imaging the organ intrinsic structure. If intrarectal probes are used, the visual sonographic picture of the gland provides more information than the computer one. The imaging technique, rapidity and economic value of the method condition its choice as the method for prostate disorder determination [10].

3.5. PROSTATIC GLAND ULTRASOUND DIAGNOSIS

Cross section sonogram of the normal prostate gland

Fig. 10. Cross section sonogram of the normal prostate gland, examination through an abdominal wall. 1 — inferior gland surface, 2 — medium lobe, 3 — side (right) surface, 4 — upper surface, 5 — isthmus, 6 — gland lobe (left)

Longitudinal section of the normal prostate sonogram

Fig. 11. Longitudinal section of the normal prostate sonogram,rectal examination. 1 — anterior surface, 2 — gland lobe (right/left), 3 — apex, 4 — posterior surface, 5 — gland medium lobe, 6 — urethra, 7 — gland base, 8 — urinary bladder

The study is carried out not only through anterior abdominal wall (with 3.5 MHz probe) but also through the rectum (highly-resolving 5 — 7.5 MHz probe). It is advisable to use both ways to obtain more complete and comprehensive information on the prostate status. The examination through the abdominal wall allows to see the gland in general and mainly in cross-section. The rectal study (mostly in longitudinal section) gives possibility to visualise details of the prostate parenchyma.

An image of the prostate gland with no sonographic alterations, being examined through the anterior abdominal wall, presents an oval formation of rather distinct and smooth shape. The prostate tissue has medium echogeneity and is relatively homogenous (Fig. 10).

At rectal echoscopy the normal prostate gland also looks like an elongated or smoothed oval with its base turned to the urinary bladder (Fig. 11).

The prostate gland disorders are sonographically manifested in form, size, shape and parenchymal structure changes. At first, as a rule, there are found alterations in the gland tissue sonographic structure. Then, as the disease develops, the prostate form and size start to transform. It relates to focal processes (different prostate tumours), as well as to diffuse, mostly, inflammatory changes.

The prostate gland adenoma at the initial stages is manifested in local reconstitution of the tissue structure that becomes heterogeneous in the impaired zone, with various degrees of density (the rarefaction sites alternate with sonographic dense ones). Moreover, the prostate gland still has normal dimensions. As the pathologic process develop the glandular capsule appears as an echopositive line bordering the reconstitution zone. At last, at the late stages, when large nodes are formed, the gland size increases acquiring uneven shape.

The prostate cancer has characteristic sonographic peculiarities. Even at early stages there is gland asymmetry and its shape deformation. In these cases the capsule continuity is still preserved. However, in the separate regions it might be thinned. As the tumour grows, the gland enlarges, mainly, in frontal-backward direction. The inner glandular structure becomes heterogeneous. In the glandular parenchyma there are zones with lowered echogeneity and more homogenous structure (tumour). If the tumour spreads into the surrounding tissues the capsule integrity is violated. One should note that even now sonographic cancer diagnostics is a complicated task because there are benign adenomas and malignant carcinomas that often look alike [9]. If the prostate malignancy is suspected it is necessary to perform gland needle biopsy.

The USD of the acute prostatitis is complicated. Nevertheless, in majority of the cases it is possible to find some enlargement of the prostate size on sonograms. Along with that, its transparency and significant reduction in number of the inner echostructures or their almost full disappearance are rather frequently noted. At monitoring of the prostate gland during the treatment one can note the following changes of the sonographic picture: decrease in the gland hydrophilic and appearing of the inner structures. In case of abscesses development they are visualised as echonegative cyst-like formations with uneven inward surface of the cavity.

Chronic prostatitis most often goes along with presence in the parenchyma of <>, cloud-like sonographic condensations without changes in the gland shape or form. Often the gland chronic inflammation is accompanied by very firm focal inclusions that reflect fibrosis and calcifications. The fibrous-clacified zones look like distinct, intensive, hyoperechogenic foci with acoustic shadow.

Vesiculitis (inflammation of seminal vesicles) is quite often a consequence of inflammatory disease of the prostate or urethra. In case of vesiculitis at the sonograms the seminal vesicles are expanded and their lumens are filled with fluid. In case of the vesicular empyema there is an enlarged filled pus-cavity. The primary tumour of the seminal vesicles is quite a rare case. Most often they are involved in the tumour process if the primary site is localised in surrounding organs, usually in the prostate.

Thus, echography is a valuable method allowing to diagnose a range of disorders in the prostate and seminal vesicles that can not always be found through other diagnostic methods.

3.6. STRUCTURAL CHANGES IN THE PROSTATIC GLAND AT PEPTIDE BIOREGULATORS APPLICATION

We have observed 47 subjects aged from 28 to 74 years with various abnormal alterations in the prostate. The disorder structure and patients' characteristics are given in Table 4.

In 32 patients there were simultaneously defined several types of the prostate pathology. Therefore, the number of cases (79) was higher than the absolute number of the patients (47).

Table 4

Characteristics of the examined patients with various pathologic prostate alterations

Disorder type (nosologic form)

Number of cases

Age (years)

Mean age (X±m)

Benign prostate hyperpIasia

27

47-74

60.5±0.2

Congestive—

inflammatory processes

24

28-61

44.5±0.1

Fibrous—calcified sites

22

29-64

46.5±0.1

Cysts

6

48-52

50.0±0.2

Total:

79

28-74

The most frequent pathologic manifestations in the examined patients were different forms of the prostate adenoma, congestive-inflammatory processes and fibrous-calcified sites. Minimal age of the patient with the prostate adenoma was 47, and inflammation in the gland parenchyma was already found in a 28-year-old patient. Fibrosis and calcified sites were found, actually, in every age group. The cysts (of post-inflammatory origin) were noted mainly in the middle-aged subjects.

In none of the patients the prostate cancer was found, and concentration of the prostate-specific antigen (PSA) in blood did not exceed the normal values.

The clinical signs were noted in 30 patients (64%): there were diagnosed the prostate adenoma in 13 subjects, the prostatitis — in 9 subjects, fibrous-calcified sites in the prostate tissue — in 8 subjects. Considering complaints in a more detailed way one can note that the patients with adenoma mainly suffered from frequent urination (up to 3-10 times per night), weakened urine flow, difficult urination onset, terminal urine dribbling, unpleasant sensations and sometimes pains in the inguinal area. The patients with the prostate inflammation diseases and sites of fibrosis and calcification in the gland parenchyma had similar complaints about nagging, unpleasant sensations and pains in the inguinal area, testicles, frequent daily urination and urge to void urine.

19 patients out of 47 were treated with conventional therapy, which at the end provided short-time positive effect. Other 28 patients were for the first time examined in our hospital. The examination comprised patients' clinical examination, case taking, finding out of complaints, prostate rectal palpation, blood (if necessary — PSA) and urine tests, ultrasound examination with transabdominal and transrectal probes.

The study objective was to investigate effect of organotropic prostate bioregulators, i. e. Prostatilen and Prostalamin, on the structure of the gland with present organic alterations. The regulatory peptides were introduced both intramuscularly (Prostatilen) and orally (Prostalamin) as per the schemes developed at the Institute for application of the peptide bioregulators. Prostalamin is related to the class of cytamines and is applied as a biologically active nutrient. During the treatment course the patients did not use other pharmacological agents. Repeated examination was made in 4.5—6 months after the bioregulation therapy onset.

The control group consisted of 17 patients wherein 7 subjects had different forms of the prostate adenoma, 5 subjects — inflammatory prostate parenchymatous alterations and 5 — fibrosis and calcification sites in the gland. All these subjects were also repeatedly examined but the peptide bioregulators were not administered.

To illustrate the treatment results of the prostate organic pathology using the peptide regulators we would like to present the following clinical examples.

Patient S., 64 years old

Fig. 12. Patient S., 64 years old. The prostate sonograms at transabdominal

(a) and transrectal (b) examination.

At the central part of the gland parenchyma there is a hypoechogenic zone of irregular-triangle form, about: 20x16 mm (marked by arrows) with rather distinct but uneven profile and homogenous inward structure

Patient S., 64 years old

Fig. 13. Patient S., 64 years old. The prostate's sonograms in 6.5 months after the first USD (transabdominal (a) and transrectal (b) examination).

At the pictures one can note considerable diminution of the previously noted

(cf. Fig. 12) formation in the central part of the prostate and normalization of its inner structure (arrow)

Patient S., 57 years old

Fig. 14. Patient S., 57 years old. The prostate sonograms, transrectal examination.

In the gland parenchyma closer to its anterior surface there is an oval hypoechogenic formation with indistinct and uneven shape, 23x36 mm (marked by arrows).

Taking into account specific sonographic picture and at the same time, absence of pronounced capsule one can suggest nodular hyperplasia (forming of adenoma)

Patient S., 64 years old. At the visit (22.09.98) there were complaints of frequent (up to 4—5 times) nocturia, sensation of difficult evacuation of the bladder, diuresis discomfort. At the USD the prostate was slightly enlarged: length — ≈ 4 cm, width — ≈ 5 cm and thickness — ≈ 3.5 cm. At the center there was abnormal formation of the parenchymatous structure as a site with lowered echogeneity (Fig. 12). PSA of 25.09.98: total — 1.101 ng/ml (norm — less than 4 ng/ml), free — 0.067 ng/ml (norm — less than 1 ng/ml). Conclusion: benign prostate hyperplasia. The patient was administered with the peptide bioregulators. In 6.5 months (12.04.99) the patient was examined again: on the sonograms the previously noted prostate formation considerably diminished, its structure became actually normal. The prostate's dimensions became less (Fig. 13). Subjectively the patient stated considerable improvement of general condition, decreased nocturia to 1 — 2 times.

Patient S., 57 years old. The reason for visit to our hospital (08.06.99) was complaints of nocturia (up to 5 times), frequent day urge to void urine, unpleasant sensations in the groin. At the prostate USD it was found that the gland was moderately enlarged (length — ≈ 4 cm, width — ≈ 4.3 cm and thickness — ≈ 4 cm), had trapezoidal form and signs of the adenomatous node forming (Fig. 14). In 4 months after the treatment course at the repeated examination (19.10.99) it was found that the gland size slightly diminished (in particular, thickness was 3.3 cm) and the nodular gland parenchyma reconstitution zone found at the primary examination disappeared (Fig. 15). The patient noted improvement of the general state, decreased nocturia to 2 times.

Patient K., 50 years old

Fig. 15. Patient S., 57 years old, in 4 months after the primary USD.

The prostate sonograms, transrectal examination.

Present at the primary examination the nodular reconstitution of the gland structure is not found now

Patient K., 50 years old. The reason for visit to our hospital (17.05.99) was complaints of nagging perineum pain, slight numbness sensation in the testicles. The USD exhibited that the prostate size and form were normal, and in the apex part. on the anterior surface there was a nodular structural reconstitution, i. e. forming of the adenoma (Fig. 16). The total PSA level in blood test of 19.05.99 — 1.975 ng/ml (norm — less than 4 ng/ml). The patient was administered with the bioregulation therapy course. In 4.5 months (01.10.99) at the ultrasound examination there were not noted any signs of the nodular hyperplasia (Fig. 17).

Patient K., 50 years old

Fig. 16. Patient K., 50 years old. The prostate sonograms, transrectal examination.

At the anterior gland surface closer to the apex there is a round local zone

(14x10 mm) of the nodular hyperplasia (marked by arrows). Due to the given abnormal alterations the anterior gland surface is uneven and bulging

Patient K., 50 years old

Fig. 17. Patient K., 50 years old, in 4.5 months after the primary USD. The prostate sonograms, transrectal examination.

<>In the pictures previously found signs of the nodular hyperplasia of the prostate parenchyma are not noted. The anterior prostate surface profile is smooth

 

Patient C., 58 years old

Fig. 18. Patient C., 58 years old. The prostate sonograms, transrectal examination.

In the central part of the gland there is a horseshoe-like zone of congestion (arrows), fibrosis (bold arrow) and calcification site (white arrow)

Here is a clinical case indicated that under action of the cytomedins in the patients besides normalisation of the prostate parenchymatous structure in the adenomatous nodes the fibrous-calcified zones that frequently accompany the chrome prostate inflammation also diminished.

Patient C., 58 years old. At visit to the hospital (09.04.99) the patient complained of nocturia (4 — 6 times), sensation of difficult evacuation of the bladder, weak urine flow. At the USD there was found moderate enlargement of the prostate: length ≈ 4.5 cm, width — ≈ 5 cm, thickness — ≈ 3.8 cm; in the parenchyma — zones of congestion, fibrosis and solitary calcification sites (Fig. 18). The PSA level in blood was normal. The treatment course with the peptide bioregulators was administered. At the control examination in 7 months (10.11.99) there was found significant abatement in signs of congestion, fibrosis and calcification zone size (Fig. 19).

Here is a clinical case (the control group patient) demonstrating progression of the pathologic process if the bioregulation therapy is not applied.

Patient K., 62 years old. First time the patient visited the hospital on 20.04.99. After the examination the following diagnosis was set: primary stage of the prostate adenoma. The total PSA level in blood 2.673 ng/ml (norm — less than 4 ng/ml). The ultrasound examination found even gland enlargement and local (nodular) parenchymatous hyperplasia on the prostate anterior surface (Fig. 20). The patient refused to be treated with the bioregulation therapy. In 6 months, 20.10.99, the repeated examination was made. The blood PSA content was normal. At the USD there was found the nodular gland hyperplasia tending to progress (Fig. 21).

Patient C., 58 years old

Fig. 19. Patient C., 58 years old, in 7 months after the primary USD.

The prostate sonograms, transrectal examination.

At the sonograms one can note decrease of the venous-secretory congestion, actually entire elimination of fibrous alterations and considerable abatement of the calcification zone size (white arrow)

Patient K., 62 years old

<>Fig. 20. Patient K., 62 years old. The prostate sonograms, transrectal examination.

The parenchyma of the entire anterior prostate part has lowered echogeneity and altered due to the presence of a large site (≈ 38x30 mm) with structural reconstitution, i. e. a forming adenomatous node (arrows).

The completely formed node should have a distinct capsule

Patient K., 62 years old

Fig. 21. Patient K., 62 years old, in 6 months after the primary USD.

The prostate sonograms, transrectal examination.

At the pictures as well as at the primary examination one can note signs of the node forming. Manifestation of the process slightly increased: the structural reconstitution border became more emphasised, the capsule is shaping (arrows)

In the issue of application of the prostate organotropic agents for correction of the gland organic alterations the positive USD and clinical results were obtained in 33 cases of 79 (42%). In other 46 cases (58%) significant morphologic changes were not found. However, none of the patients exhibited the disorder progression and, moreover, in 25 subjects (54.4%) the general state improved considerably; in 10 subjects (40%) nocturia and inguinal pains disappeared, urine flow enhanced; in 15 subjects (60%) the nocturia became less frequent and inguinal pains alleviated. in the patients with normalized structure of the prostate parenchyma the complaints changes directly correlated with the said morphologic improvements.

In the control group in 4 out of 7 subjects with the prostate adenoma the disorder's progression was noted, and in 3 patients nothing changed considerably. In 5 patients with the chronic gland inflammation there were no evident improving or declining shifts, and in 5 patients with the fibrous-calcified sites the stable sonographic picture was stated.

Distribution of number of the prostate disease cases depending on initially diagnosed disorder and gained positive results during the treatment are given in Table 5.

As one can see from the data presented in the Table, the benign prostate hyperplasia was corrected in the best way: 21 cases of 27 amounting 77.8%. Significantly less positive effect was obtained regarding the congestive-inflammatory gland alterations: 10 cases out of 24 (41.7%). In the patients with fibrosis foci and calcified zone in the gland parenchyma in 6 cases of 22 they slightly decreased, and in 3 cases fully disappeared. In our study there were not found any positive effects of the regulating peptides on restoration of the gland structure in the subjects with cyst formations: in all 6 cases form, size and inner texture of the cyst-like formations found at the initial examination did not change.

As the nodular prostate hyperplasia is a frequently noted disorder in the men of particular age only, namely, 50 years old and older, then we could not statistically justify relationship between the bioregulation therapy manifestation and the patients' age in such narrow age limits (p>0.05). However, in all the patients with the benign prostate hyperplasia the gland morphologic structure more or less restored to normal due to impact of the bioregulation therapy.

Table 5

Distribution of number of cases with noted prostate disorders depending on disease type and obtained positive results

Distribution of number of cases with noted prostate disorders depending on disease type and obtained positive results

The obtained results indicate that application of the complex of the organotropic prostate peptides (Prostatilen and Prostalamin) brings forth restoration of the gland tissue altered owing to the organic disorder development suggesting these agents to be used in the patients with the benign prostate hyperplasia of various severity.

Chapter 4 - EFFECT OF PEPTIDE BIOREGULATORS ON MORPHOLOGY OF OTHER GLANDULAR ORGANS

This chapter presents clinical cases illustrating the positive peptide bioregulating therapy effects as inhibition of tumour-like pineal gland formation growth, pancreatic parenchymatous structure normalisation, restoration of the breast fibroglandular tissue structure.

4.1. PINEAL GLAND (EPIPHYSIS)

4.1.1. Summary on the pineal gland structure and functions

Pineal gland or pineal body /glandula pinealis, epiphysis (PNA) [38]/ is an endocrine gland of neuroglial origin related to diencephalon epithalamus and participating in homeostasis maintenance.

The pineal gland in adults is a non-pair round or spheric formation, length about 5 —15 mm, width — about 3 —10 mm and thickness about 2 — 6 mm. The gland weight is about 170 mg. The gland is located above a lamina of optical bodies and is held by leads with which the gland has no functional relations.

The pineal gland is supplied through branches of anterior, medium and posterior cerebral arteries. At the optical bodies surface there is a rich arterial network around the gland. The venous blood flows into versa cerebri magna or its branches and into dura mater sinuses. There were not found lymphatic capillaries in the pineal gland. Innervation is made by sympathetic nerves of upper cervical nodes of the sympathetic trunk coming to the gland from a pineal nerve (n. pinealis).

From fine connective tissue capsule surrounding the pineal gland and making the continuation of pia mater encephali into the gland, there penetrate the intersections, which divide the parenchyma into lobules and form the gland stroma. The gland parenchyma comprises pineal and glial cells.

There are several following types of the pineal gland structure: cellular, trabecular and alveolar. The cellular type is found in newborns and infants and characterised with entire absence or insignificant number of stromal elements in the gland. The trabecular type is distinguished by the stromal growth that, however, does not fully isolate the parenchymal parts from each other. The alveolar type is mostly found in elderly and senile subjects and characterised with the gland lobular structure. In the connective tissue intersections along with inherent gland elements there is a great number of glial elements.

The pineal gland participates in such vital processes as growth, pubescence, homeostasis maintenance as well as in relationship of the intrinsic body medium and environment. Its main function is regulation of circadian (daily) rhythm and the organism adaptation to changing illumination conditions. During evolution the pineal gland being sensoric organ transforms into a secretory one.

There are the following biologically active substances in the gland: serotonin, melatonin, noradrenaline, histamine, etc. Presence of the biogenic amines in pinealocytes as well as capacity for uptake and decarboxylation of their precursors allows to refer the pineal gland cells to neuroendocrine or APUD system ones.

The pineal gland is a peculiar neuroendocrine transmitter acting as per principle <>. A specific stimulus for the gland is a light signal. Illumination (considering the light spectrum) inhibits transformation of serotonin into melatonin and other methoxyindols and facilitates accumulation in the pineal gland of serotonin and its metabolites produced during oxidative deamination. In darkness serotonin is intensively transformed into N-acetylserotonin, and the latter — into melatonin. Presence of daily and season rhythms in physiologic activity of the pineal gland coinciding with secretory peripheral endocrine glands suggests that it is a biologic clock regulator in the organism. The melatonin's content in the human blood plasma is about 50 ng/ml at daytime, and about 60 —140 ng/ml at night with maximal concentration around 3 a.m. The melatonin excretion with urine (mainly as 6-oxyrnelatonin) varies from 0 to 26.4 ng for 8-hour period. About 60 — 70% of melatonin is excreted in urine between 11 p.m. and 7 a.m.

The pineal gland, that is highly sensitive to changes of the Earth magnetic field, is believed to be a peculiar <> participating in animal spatialisation. It is capable of differentiation and following data integration with various environmental impacts on an organism and adaptation of the hormonal homeostasis system to them. It comprises complicated adaptive function of the pineal gland.

The pineal gland hormones inhibit bioelectric brainwork and neuropsychic activity rendering hypnotic, analgesic and sedative effects. In the patients with depression and obstinate insomnia melatonin excretion in urine is decreased. Altered secretion and rhythm of melatonin release so often coincide with psychic disorders that some researchers consider as a genetic marker. The pineal body has some influence on tumour processes. If the pineal gland is removed tumour growth acceleration and melanoma development are observed in laboratory animals. Water-alkalic extracts obtained from the pineal gland tissue possess antitumour activity associated with stimulation of immunocompetent cells, macrophages, etc.

4.1.2. Pineal gland disorders

Organic impairment of the pineal gland is observed, in particular, in case of cysts and tumours therein.

True cysts can be inlayed with ependymal, pineal and, more often, glial cells. Large, multiple cysts frequently simulate a tumour especially if they have hemorrhages in their walls. Such cysts compress the Sylvius aqueduct and cause secondary hydrocephaly or local brain compression.

The pineal gland tumours constitute about 1 —1.5% of all cerebral tumours and are mostly observed at the age of 14 to 18 years. Germinogenic tumours (germinomas, teratomas, embryonal carcinomas, choriocarcinomas, etc.) prevail being about 50 —70% of the pineal gland area tumours. The tumours developing from the pineal cells are divided into pineocytomas and pineoblastomas. Pineocytomas are referred to benign tumours. They are encapsulated and sometimes contain cysts. Pineoblastomas are malignant and frequently metastasise in the brain ventricles, subarachnoid cerebral and spinal spaces.

Treatment of cysts and pineal gland tumours is mainly surgical. However, the intervention is associated with a range of dangerous complications that can emerge during the operation and the postoperative period. Most often palliative surgery is employed to treat for hydrocephalic occlusion.

A prognosis is usually unfavourable. However, in case of timely treatment it is possible to prolong the patient's life for months and even years.

4.1.3. Current diagnostic methods of pineal gland disorders

To examine the pineal gland a functioning biologic testing based on the rnelatonin capacity is applied to lighten amphibian melanophores. The urine concentration of the main melatonin metabolite, 6-oxymelatonin, is determined by fluometry, and the melatonin concentration in the blood plasma and cerebro-spinal fluid is manifested in radioimmunologic assay as well as with gas-liquid chromatography. To determine some pineal methoxyindols, immunohistologic and radionuclide assays are used. The pineal gland functional activity can also be estimated with activity at main enzymes participating in production of methylated pineal indoles.

The pineal gland examination also includes head CT and MRT. In 50-75% of cases in adults there are calcified inclusions in the gland. The CT and MRT are the main methods for diagnostics of the pineal gland tumours.

4.1.4. Structural changes in the pineal gland at peptide bioregulators application

We have monitored 36-year-old patient P. with a volume pineal gland formation

She thinks the disease started in 1991 when first headache, rickety walk and staggering appeared. The woman associated the disease with the past stress. With time, the state aggravated: there appeared hand tremor, fear and from 1994 short-time insensibility. By examination the diagnosis was not put. She was treated as an out-patient with, mainly, symptomatic agents.

In 1994 due to the condition declination she was admitted to the hospital. At examination (that included the brain CT) the thyroid gland disorder and maxillary sinusitis were suspected. The patient was administered with the treatment to restore the thyroid gland function that caused further deterioration: headaches severity increased sharply, nausea and insomnia emerged. In 1997 the brain MRT was made. Here we provide the entire conclusion after MRT on 10.07.97: <>. The next examination was made on 15.07.97: <>.

The patient was referred to a profile medical institution where the surgical intervention was proposed which the patient rejected.

In August, 1997, the patient came to our hospital. She was administered with a bioregulation therapy course comprising a complex of regulatory peptides including Thymalin, Epithalamin, Cortexin, Cerebramin and Hepatamin.

After the applied treatment the patient felt better promptly as she said <>). The headache diminished (the interval between them increased to 2 — 3 months), there was no hand tremor or fear. She caught cold less frequently though before it happened quite often. In total, for 2 years the patient was treated with 4 cycles of the bioregulation therapy with 6-month intervals.

The repeated head MRT examination was made on 16.01.1998 (with contrasting and angiography): <>.

Patient P., 36 years old

Fig. 22. Patient P., 36 years old. Head MR tomograms in frontal (a)

section. MR angiogram of cerebral vessels (b). In the picture there is (a) an enlarged pineal gland (arrow). In the angiogram (b) there are no abnormalities

In 1999 the patient underwent the head MRT twice — in

March and December. There is an opinion of 20.03.99: <>.

Opinion of 11.12.99: <

15x16x16 mm. The contrast enhancement is of annular type (cyst capsule zone). The brain side ventricles are moderately enlarged; S>D. The III and IV ventricles, basal cisterns. The chiasma region — with no peculiarities. The subarachnoid convex spaces are moderately enlarged. The median structures are not dislocated. Conclusion: MRT picture of the volume cyst-like formation of the pineal gland. No negative changes comparing to the data of 20.03.99>> (Fig. 23).

As it was noted above, the organic pineal gland disorder, in particular, the cysts, tumours do not regress spontaneously. The treatment can be only surgical (as a palliative surgery) and the prognosis is mostly unfavourable. We hope that in the case with patient P. application of the bioregulation therapy based on the specific complex of the regulatory peptides facilitated suspension of the volume pathologic process growth in the pineal region. There are no doubts that clinical signs were partially eliminated — the patient, actually, got rid of subjective manifestation of the tormenting disease and disability.

Patient P., 36 years old

Fig. 23. Patient P., 36 years old. Head MR tomograms of 20.03.99 (a) and 11.12.99 (b).

By the given tomograms one can note stabilisation of the pathologic process in the pineal gland. During 9 months the tumour-like formation did not grow (marked by arrows)

4.2. PANCREAS

The peptide bioregulation therapy can be applied in the patients with signs of chronic pancreatic inflammation. Below are the clinical cases (5 observations) of visual improvement of the pancreatic parenchyma in the patients with chronic pancreatitis.

4.2.1. Summary on the pancreas structure and functions

Pancreas /pancreas (PNA) [38] / is a non-pair organ located deeply retroperitoneally, transversally regarding the spinal column, approximately at the level of the 2nd lumbar vertebra. The gland length — about 12.5—17 cm, width — about 4—7cm, thickness — 1.5—3.5 cm. The weight — about 70 g. At the elderly subjects the gland is partially atrophied and its weight and volume diminish. The following parts are distinguished in the gland: head, body and tail. There is a range of peculiarities in the morphologic structure. Firstly, it is structural duality: glandular tissue and Langerhans islands. Their tissue volume ratio is 99 : 1. Secondly, the gland does not have a well-formed capsule, determining particularities of its disorders.

The morphologic duality conditions the functions. The pancreas resembles two organs in one — intrasecretory (Langerhans islands) and extrasecretory (glandular tissue). The intrasecretory activity is associated with release of a range of substances with hormonal properties such as insulin, glucagon, lipocain. callicreine, paduitine, etc. The external secretion product is the so-called pancreatic juice. An important component of the pancreatic juice is its enzyme system. The juice contains enzymes for digestion of almost all nutrients — amylase, lipase, trypsin, chymotrypsin, pepsidase, collagenase, ribo- and desoxyribonuclease, etc. The external pancreatic secretion has a double regulating mechanism, i. e. nervous and humoral.

4.2.2. Pancreas disorders

Chronic pancreatitis is a progressive pancreatic disease that is manifested with repeated relapses, irreversible morphologic alterations in the gland parenchyma causing constant or progressive functional disturbance. The etiologic factors for the chronic pancreatitis are the following: disorders of the biliary ducts, influence of alcohol, therapeutics, viruses, autoimmune and genetic disorders. Considering the pathogenic mechanisms of the chronic pancreatitis one should take into account that the pancreas is a potent endocrine organ and hormones released in blood by the pancreatic endocrine cells affect other organs and systems.

The macroscopic autopsy picture of the chronic pancreatitis is characterised by uneven gland surface. At histologic examination there is heterogeneous rough destruction of the parenchyma, its lobules are of different size due to diffuse connective tissue overgrowth among them; in them there are zones of fat necrosis, atrophy and destruction of duct epithelium forming cicatricial stenosis. There are also found intraductile calcified protein precipitates. The ducts are occluded with protein masses or stones and enlarged, their epithelium is flattened and ulcered.

The main clinical manifestations of the chronic pancreatitis are pains, dyspeptic syndrome, weight loss, functional insufficiency symptoms of the insular system.

4.2.3. Current diagnostic methods of pancreas disorders

For the chronic pancreatitis diagnostics a complex of clinical, instrumental and laboratory tests is applied. One can effectively utilise the USD, CT. For assessment of the pancreatic functional activity in case of the pancreatitis determination of amilase content in the urine and in the blood serum, lipase and trypsin content in the blood serum, trypsin content in feces and coprogram are considered to be the most reliable. To assess extrasecretory pancreatic function the highest value is attributed to secretine-pancreosimine assay with determination of trypsin in duodenal contents.

4.2.4. Pancreas ultrasound diagnosis

The pancreatic USD is preferably performed after fasting. Usually it is started with a patient in horizontal position on his/her back for longitudinal and transverse scanning. Generally, the gland head and body can be visualised in 90% and a tail — in 50%. The main criteria for the pancreas sonographic assessment are its form, size, profile character, elasticity, sonographic structure and Wirsung's duct diameter. The gland forms can be different. At the longitudinal scanning it is defined as an oval formation. The gland's size is assessed as per frontal-backward size that in norm should not excess for a head 35 mm, for a body —25 ram and for a tail —30 mm. The pancreas profile is smooth, distinctly bordered from the surrounding structures. Preserved elasticity is indicated by deflection of the gland when pressing with the probe at this area. The organ sonographic structure is homogenous, sometimes small-grain, and regarding intensity it is equal or slightly higher than the liver sonographic structure. The Wirsung's duct can be visualised only in 1/3 of cases and not at full length but as fragments. Its normal diameter does not exceed 2 mm.

Chronic pancreatitis is characterised by a combination of three different types of morphologic processes: inflammation, fibrosis and atrophy, and at that severity and spread for each of them can differ. Therefore, the sonographic picture of the chronic pancreatitis is defined with extreme variability. In the period between exacerbation, the gland size diminution, considerable changes of its form and shape are noted, Moreover, the organ sonographic structure is heterogeneous with prevalence of enhanced. It has peculiar diverse character as combination of zones of lowered, medium and enhanced reflection. Especially bright sonographic signals are gained from calcifications in the gland parenchyma and stones in the ducts that can provide an acoustic shadow as well. Besides, the anechogenic zones can be often detected corresponding to pseudocysts or cyst-like enlargements of the Wirsung's duct. The latter is usually enlarged at full length.

4.2.5. Structural changes in the pancreas at peptide bioregulators application

Correction for the altered pancreatic parenchyma was made by combined application of Epithalamin, Thymalin and pancreatic and liver bioregulators — Pancramin. and Hepatamin.

Below are cases of our clinical practice.

Patient M., 52 years old. First time the patient appeared at our hospital on 24.06.99 complaining of digestive disorder as frequent defecation (up to 3 —4 times per day) that he had suffered from for several years, constant pains in the epigastric area increasing after meal. The examination showed that the patient had chronic pancreatitis. At the USD the pancreas was distinctly visualized (thickened capsule), it was of grips-like form due to enlarged head and tail and uneven shape. In the gland structure (mainly of the head and tail) there were calcified sites. The parenchyma in general was heterogeneous (Fig. 24). The patient was administered with a course of peptide bioregulators and in five month after the first visit, on 16.11.99, he was examined again. At the control USD the head and tail size diminished considerably, calcifications disappeared; intensity of the parenchymatous sonographic compacting did not change but became evenly homogenous (Fig. 25). The patient subjectively noted significant improvement of the general state, abdominal pains terminated and the defecation frequency was not higher than once a day.

Patient M., 52 years old

Fig. 24. Patient M., 52 years old. Pancreatic sonogram, longitudinal section.

One can see unusual form of the gland, heterogeneity of the parenchymatous structure, calcified sites (marked by arrows)

Patient M., 52 years old

Fig. 25, Patient M., 52 years old, in 5 months after the primary USD.

Pancreatic sonogram, longitudinal section.

The presented picture reflects sonographic image of positive changes of the disease development: gland form and structure normalized, calcifications disappeared

Patient C., 59 years old

Fig. 26. Patient C., 59 years old. Pancreatic sonogram, longitudinal section.

The gland's surface is uneven, the parenchyma is heterogeneous due to fibrous alterations

Patient C., 59 years old

Fig. 27. Patient C., 59 years old. Pancreatic sonogram, longitudinal section in 7 months after the primary USD.

Visually one can note positive changes of the disorder's development the fibrous sites almost disappeared

Patient C., 59 years old. At the first visit (09.04.99) the main complaint was frequent (2 —3 times a day) defecation, flatulence, tympanites and arching abdominal pains. The examination exhibited the chronic pancreatitis. The USD showed deformation of the gland form, shape haziness and roughness, enhanced parenchymatous echogeneity, its heterogeneity due to multiple fibrosis sites (Fig. 26). In 7 months (10.11.99) after the treatment with administration of the complex of the peptide bioregulators the general pancreatic echogeneity decreased and the fibrous sites almost disappeared (Fig. 27). The disease clinical signs in the patients diminished significantly.

The conducted clinical observations indicate positive effect of the peptide bioregulation therapy for restoration of the normal pancreatic tissue in the patients with the chronic pancreatitis signs.

4.3. MAMMARY GLANDS (BREASTS)

4.3.1. Summary on the breast structure and functions

Breast /mamma (PNA) [38]/. The breasts are located at the frontal chest surface at the level between III to VI or VII ribs. Form, size, position of the breasts depend on the woman's age, degree of her genital development, pregnancy period, menstrual cycle and individual peculiarities. The breast is surrounded with fibred capsule. From the anterior surface of the gland body penetrating through fat cellular tissue and superficial fascia to deep skin layers and a clavicle, a great amount of firm connective tissue bands being continuation of the interlobular septa. These ligaments (Kuppfer's ligaments) support the breast. Similar ligaments connect posterior surface of the gland body to the major pectoralis muscle fascia.

The following structures are distinguished in the breast: proper glandular structures, parenchyma and connective tissue stroma. The breast of a pubescent woman consists of 15—25 lobes and each of them is a complicated alveolar glandule with lobar lacteal duct opening at the nipple top. Before reaching the nipple the ducts enlarge and form lacteal sinuses, which accumulate milk produced in the alveoli. Among the lobes there are intercalations of fibred connective and fatty tissue penetrated with vessels and nerves. The lobes comprise lobules formed with multiple branching lacteal ducts.

The main breast function is synthesis and secretion of milk designated for an infant's feeding. During the woman's lifetime the breasts undergo certain changes caused by the menstrual cycle, pregnancy, labor, lactation, age involutory processes. At the climax, as the ovary function diminishes, the estrogen level decreases and, to compensate this, hypophysial follicle-stimulating hormone production enhances. According to the age endocrine reconstitution in the woman's organism involution of the glandular structures in the breasts is gradual. The glandular lobules and ducts become empty, atrophic and then are substituted with fibrous and fatty tissue.

4.3.2. Breast disorders

The mostly frequent breast tumour, fibroadenoma, is related to benign tumours of non-epithelial origin and is mainly revealed at the age of 15—35 years. Fibroadenoma is a nodular formation consisting of proliferating epithelial elements, ducts and connective tissue stroma. As per the growth character, the following types are distinguished: pericanalicular and intracanalicular fibroadenomas. Some oncologists refer fibroadenomas to a variation of dyshormonal hyperplasia.

Fibroadenomas can be found in any breast zone, but more often in the upper-external quadrants; sometimes they are multiple. Usually the tumour looks like a round node, well-bordered from surrounding tissues and easily movable, up to 1—3 cm in diameter. Against the background of fibroadenoma, cancer develops rarer than against the background of dyshormonal hyperplasia.

The prognosis of the breast benign tumours in case of surgical treatment is favourable.

4.3.3. Current diagnostic methods of breast disorders

Women with the breast disorders are examined in a complex way, with the use of general clinical (case taking, examination, palpation) and additional methods. X-rays investigation and mammography are of particular value for complex diagnostics of the breast disorders. The cytologic examination is a part of morphologic diagnostics. Its object can be imprints, smears and scrapings, nipple discharge, puncture material from a pathologic site by a fine needle (aspiration biopsy). The histologic investigation of the biopsy tissue material is the most reliable diagnostic method of the breast tumours. The ultrasound sonography is now one of the leading methods for the breast disorder diagnostics.

4.3.4. Breast ultrasound diagnostics

The breast USD is usually conducted with high-frequency (5 — 7.5 MHz) probes with a patient in horizontal position on the back (for better breast flattening on the anterior chest wall). Each breast is examined by quadrants that obligatory are marked at tomograms. Changing the compression degree one can also conduct differential diagnosis between cysts and solid masses because the cysts are able at that to change their configuration. The optimal ductile visualisation is possible at radial scanning (from a nipple to periphery). The sonographic image of the breast varies depending on age, constitutional particularities and the functional breast state. At the sonograms skin, nipples, Kuppfer's ligaments, pre- and retromammal spaces, glandular lobules, pectoralis muscle, rib profiles and enlarged lymph nodes are distinguished.

Fibroadenomas at the USD resemble formations with regular round form and distinct smooth shape, homogenous acoustic structure with diminished echogeneity without enhancement but, sometimes, with enhanced sonographic signal behind the dorsal wall and lateral shadow.

Simplicity of the investigation, high informative value and relative USD safety allow to use this method extensively to verify different condensations in the female breasts as well as during the patient's monitoring.

4.3.5. Structural changes in the breasts at peptide bioregulators application

Patient L., 50 years old

Fig. 28, Patient L., 50 years old. Sonograms of the right (a) and left (b, c) breasts.

In the lower sector of the right breast there is (a) an abnormal formation ≈ 13x10 mm without signs of a capsule (bold arrow). In the upper sector of the left breast (b, c) there are also small inclusions (arrows)

Nine patients at the age of 43 to 58 years with diagnosed fibroadenomatosis were observed in our hospital. The patients were administered with treatment comprising a complex of the peptide bioregulators consisting of Epithalamin, Prostalamin and Ovariamin (ovarian bioregulator).

After the conducted treatment course of the bioregulation therapy, a number of nodular formations in the breasts of 4 patients considerably decreased, and in 2 patients the fibroadenomatosis signs fully disappeared.

The control group included 5 patients with similar diagnosis treated with conventional therapy. In the control group no significant changes were observed in 6 months after the trial onset.

Patient L., 50 years old

Fig. 29. Patient L., 50 years old, in one month after the primary USD.

Sonograms of the right (a) and left (b) breasts.

At the control images there is visually notable (a) almost two-fold diminution of the right breast formation (size at the examination of about 6x5 mm).

In the left breast one of the formations (c — at Fig. 28) fully disappeared, and another (b — at Fig. 28) — without considerable changes (b)

Patient L., 50 years old

Fig. 30. Patient L., 50 years old, in 6.5 months after the primary examination. Sonograms of the right (a) and left (b) breasts.

In the right breast (a) pathologic alterations are not visible.

In the left breast (b) — the small formation is still (arrow)

Below some clinical cases are presented.

Patient L., 50 years old. From the case history: in March, 1999, the patient found out a hard consistence formation in the right breast. At oncologic examination a neoplasm was suspected and a surgical intervention was recommended. But the patient rejected the surgery and came to our hospital on 23.04.99. USD was made that showed a hypoechogenic abnormal formation of about 1.3x1 cm with an irregular form and uneven shape in the lower sector of the right breast (Fig. 28a). It was impossible to identify the formation by the sonographic image, however, the pathologic formation character mostly suggested fibroadenoma. In the left breast there were revealed small hypoechogenic sites (Fig. 28b, c). The patient was treated with a bioregulation therapy course. In a month after the treatment onset (25.05.99), at the repeated USD, there was found that the abnormal formation in the right breast decreased two-fold (Fig. 29a), and in the left breast one of the sites fully disappeared (Fig. 29b). The control breast USD on 04.11.99 in 6.5 months after the primary examination exhibited absence of pathologic alterations in the right breast (Fig. 30).

CONCLUSION

Long-term research showed that one of the elements of the human adaptation to the environmental factors impacts consists in the system of bioregulation. The therapy based on peptide bioregulators was found to be able to restore altered functions and diminished compensation adaption capacities of the human organism. Our research allowed to reveal another unique property of peptide bioregulators — ability to restore an altered organ and tissue morphology. The best results regarding restoration of the normal tissue structure under the influence of the bioregulation therapy were obtained mainly in the glandular organs such as the thyroid gland, pancreas, prostate and mammary glands. It is worth emphasising the high efficacy of peptide bioregulators application in treatment for thyroid gland adenomas and benign prostate hyperplasia: the node formations found at USD not only diminished considerably in size but even fully disappeared.

There was discovered a new phenomenon of peptide bioregulators capacity to significantly effect the organ morphologic structure. It is to be underscored the theoretic suggestion hereof was made by V. Kh. Khavinson and V. G. Morozov already in 1992 [42]: <<... cytomedins participate in regulation of both cellular differentiation and proliferation altering the functional genome activity and biosynthesis processes depending on the state of a pluricellular system. Furthermore, it is necessary to stress possibility for self-regulation with help of the cytomedins on number and functional activity of cell elements in population>>. And now this scientific hypothesis was proved in clinical practice.

To substantiate the principles and methods of the bioregulation therapy it is necessary to further study and analyse the mechanisms of action of peptide bioregulators, their pharmacodynamics in various pathologic processes.

This publication presents the results of clinical study of peptide bioregulators tissue-specific properties. If profound theoretical analysis of the discovered phenomenon yet to be done, practical implementation of the found new features of peptide bioregulators is evident even now — there is a possibility to talk about a novel approach in the treatment for some diseases. For instance, many organic impairments of the glandular and other organs are well known to be hardly curable with conservative methods. These disorders, as a rule, require surgical intervention. Application of this class of medicines as peptide bioregulators allow to hope for deliverance from some disease through non-surgical way due to capacity of these drugs to restore the structure of an impaired organ tissue.

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