Tom 8 • Numer 1 (Suplement 1) • Czerwiec 2021
STEROIDOGENIC ACTIVITY OF LEYDIG CELLS AND ULTRASTRUCTURE OF THEIR MITOCHONDRIA
Małgorzata Brzoskwinia1, Laura Pardyak2,
Alicja Kamińska1, Wacław Tworzydło3, Anna Hejmej1,
Sylwia Marek1, Barbara Bilińska1
1Department of Endocrinology, Institute of Zoology and Biomedical
Research, Faculty of Biology, Jagiellonian University in Krakow,
Poland; 2Center of Experimental and Innovative Medicine, University
of Agriculture in Krakow, Poland; 3Developmental Biology and
Invertebrate Morphology, Institute of Zoology and Biomedical
Research, Faculty of Biology, Jagiellonian University in Krakow, Poland
e-mail: m.brzoskwinia@doctoral.uj.edu.pl
Androgens, including testosterone, play a vital role in
the regulation of male reproduction mediating their biological effects through binding to the androgen receptors (ARs). Leydig cells are the main source of intratesticular testosterone, which is synthesized, like in other steroid-producing cells, from a common substrate cholesterol. Transport of cholesterol into the mitochondria
and its conversion to testosterone require the presence
of carrier proteins and steroidogenic enzymes (Haider:
Int Rev Cytol. 2004, 233, 181–241). It should be emphasized that correct synthesis of androgens depends on the
structural condition of Leydig cells, and any disturbance
in the biosynthesis and availability of steroids may affect
the secretory activity of these cells.
In our studies we used flutamide – a pure non-steroidal anti-androgen that blocks receptor binding of
androgen, disturbing the action of endogenous testosterone (Labrie: Cancer. 1993, 72, 3816–3827). Although
the long-term effects of this anti-androgen on male reproduction are well characterized, its short-term effects
on the male gonad are still elusive. Recent findings by
Bilinska demonstrated that short-term exposure to flutamide applied to adult rats, alters the blood-testis barrier
integrity (Zarzycka et al.: Andrology. 2015, 3, 569-581;
Chojnacka et al.: Reprod Biol Endocrinol. 2016, 14, 14).
Experiments by Sarabay and coworkers (Sarrabay et al.:
Toxicol Appl Pharmacol. 2015, 289, 515–524) showed
that blockage of AR leads to inhibition of the negative
feedback in the hypothalamic-pituitary-gonadal axis and
enhancement of Leydig cell steroidogenic activity. In this
context, direct effects of flutamide at the gonadal level,
specifically on the steroidogenic function of Leydig cells
and its potential autoregulation is of interest.
The results of our latest studies (Brzoskwinia et al.:
J Mol Sci. 2020, 21, 4439) showed that disruption of
androgen signaling by flutamide leads to an increase
in plasma luteinizing hormone, cholesterol, and testosterone concentrations. Moreover, we demonstrated
increase in the intratesticular levels of testosterone that
correspond well to increase in the expression level of
several mitochondrial proteins required for the first step
of steroidogenesis. Morphometric analysis of semithin
testis sections revealed Leydig cells’ hypertrophy, while
ultrastructural analysis showed additionally changes
in the distribution and morphology of their mitochondria. Mutual relationships between cell organelles, visualized due to a computer aided 3D reconstruction of
serial ultrathin sections, revealed that mitochondria fuse
forming local mitochondrial networks. Moreover, morphometric analysis confirmed that percentage of the cell
area occupied by mitochondria was substantially higher
after flutamide exposure. In the light of this, we postulate that enhanced steroidogenic activity of Leydig cells
involves multiplication of Leydig cell’ mitochondria and
consequent formation of highly active mitochondrial networks. Upregulation of dynamin-related protein 1 (Drp1)
expression in Leydig cells supports this assumption. Our
results confirm the idea that blockage of AR, initiates
a compensatory mechanism that causes enhancement
of the steroidogenic activity of Leydig cells.
Supported by a grant OPUS12 2016/23/B/NZ4/01788 from
National Science Centre.
GENETIC CONTROL OF TESTICULAR CELL FUNCTION IN HEALTH AND DESEASE
Michał Duliban1, Piotr Pawlicki2, Agnieszka Miloń1,
Ewelina Górowska-Wójtowicz1, Barbara Bilińska1,
Małgorzata Kotula-Balak2
1Department of Endocrinology, Institute of Zoology and Biomedical
Research, Jagiellonian University in Krakow, Poland, 2University
Centre of Veterinary Medicine UJ-UR, University of Agriculture in
Krakow, Krakow, Poland
e-mail: michal.duliban@doctoral.uj.edu.pl
In the male gonad, estrogens act in paracrine and autocrine way to regulate spermatogenesis and steroidogenesis. Nowadays it is known that in Leydig cells estrogen
signaling is mediated by various types of estrogen receptors (Pardyak et al.: Tissue Cell. 2016, 48, 432-41; Chimento
et al.: Cells. 2020, 9, 2115.). Pathological Leydig cells may
produce an abnormal amount of estrogens, e.g. human
tumor Leydig cells are characterized by an overproduction of estrogens and their metabolites (Van Der Gucht
et al.: Clin. Nuclear Med. 2018, 43, 41–43.).
Our research has demonstrated differences in gene
expression in healthy and tumor human Leydig cells
(Kotula-Balak et al.: unpublished). Detailed analysis
revealed disrupted expression of genes associated with
such processes as: apoptosis, blood vessel development
or cell stress in tumor Leydig cells. A mutation in the
TP53 gene, leading to impaired apoptosis, has also been
described in patients with testicular tumors (Stecher et
al.: Pediatr Blood Cancer. 2008, 50, 701–703). In addition, downregulated expression of genes encoding heat
shock proteins was noted. On the basis of next generation sequencing (NGS) analysis (novel research technique that allows for quick and accurate analysis of the
entire cell, tissue or organ genome) carried out in mouse
testes with disturbed non-classical estrogen signaling (via
estrogen-related receptors and membrane estrogen receptors) changes in the expression of genes involved in processes important for individual testicular cell type function e.g. immune response or post-translational protein
modifications were revealed (Duliban et al.: Reprod Fertil
Dev 2020, 32, 903-913). The breakdown of testis immune
balance may contribute to fertility disorders, and disruption of post-translational protein modification that
may lead to tumorigenesis (Han et al.: Int. J Oncol. 2018,
52, 1081–1094). It is confirmed by significant changes
in the expression of several genes e.g. Bmi1 (polycomb
ring finger oncogene) and Npm1 (nucleophosmin 1), which
actively participate in acceleration of tumor growth.
The application of NGS technique allows to obtain
comprehensive data that provide cross-sectional information on the activity of testicular transcriptome and
can be used to initiate further studies at the proteome or
epigenome levels, including the designing of new diagnostic tests.
Supported by grants SONATA BIS5 2015/18/E/NZ4/ 00519
and OPUS12 2016/23/B/NZ4/01788 from National Science
Centre, Poland.
27
SYMPOSIUM OF SCIENTIFIC TRANINING OF THE POLISH SOCIETY OF ANDROLOGY – 22 n d DAY OF ANDROLOGY
THE SIGNIFICANCE OF HUMAN SPERM CHROMATIN DAMAGE IN IN VITRO PROCEDURES
Kamil Gill1, Aleksandra Rosiak-Gill1,2,
Małgorzata Piasecka1
Department of Histology and Developmental Biology, Pomeranian
Medical Uniwersity, Szczecinie, Poland; 2VitroLive Fertility Clinic
in Szczecin, Poland
e-mail: kamil.gill@pum.edu.pl
Over the last decades, couple infertility has become one
of the emerging global public health issue and classified
by the World Health Organization as a one of the civilization disease (Agarwal et al.: World J Mens Health. 2019,
37 (3), 296–312). In response to this problem development of the assisted reproductive techniques, especially
in vitro fertilization is observed and for many couples this
treatment is the only chance to have biological offspring.
Although the clinical relevance of basic semen analysis
during the in vitro procedure is limited, the influence
of the male factor on reproductive success is not completely eliminated. This thesis is confirmed by outcomes
of in vitro fertilization procedures in which pregnancy
was not achieved despite the lack known female factor.
Therefore, many authors underline the need to develop
and introduce molecular biomarkers of male infertility
assessment Agawrwal i et al.: Int J Mol Sci. 2020, 21(11),
3882; Jerre et al.: Fertil Steril. 2019, 112(1), 46–53; Tang
et al.: J Gynecol Obstet Hum Reprod. 2020, 10, 101868).
The goal of these methods is to enable the prognosis of the
chances of getting pregnant in vitro procedures. In this
aspect, the quality of sperm chromatin is of particular
importance. Its structural abnormalities can affects fertilization process, creation and development of the pronuclei as well as early embryo development observed
before activation of paternal genome (4-cell embryo) –
early paternal effect. Moreover, the late paternal effect
at the 4–8-cell stage of the embryo (when the paternal
genome is fully activated) up to blastocyst stage is found.
For that, many researchers indicate that low quality of
sperm chromatin may result in: 1) a decrease in the percentage of normal fertilized oocytes and percentage of
morphologically normal embryos, 2) a decrease in the
percentage of achieved pregnancies, and 3) an increase in
proportion of miscarriages or even birth defects and epigenetic disorders in the offspring (Okada and Yamaguchi:
Cell. Mol. Life Sci. 2017, 74, 1957–1967; Tesarik: Reprod
Biomed Online. 2005, 10(3), 370–375). However, not
all researchers confirmed a negative impact of sperm
chromatin damages on the reproductive success after
in vitro fertilization (Green et al.: J Assist Reprod Genet.
2020, 37(1), 71–76; Yang et al.: Transl Androl Urol. 2019,
8(4), 356–365). This inconsistency may results from different methods of male gametes selection, application
of diverse sperm chromatin tests and the use of various
statistical tools. Moreover, a large heterogeneity of the
groups enrolled to the studies is observed. Also, it cannot
be ignored fact that the oocyte is equipped with DNA
repair mechanism. First of all, DNA single strand breaks
are repaired. This process may begin at the pronuclei
stage of zygote and be continued until the blastocyst
stage. If the sperm DNA damage does not exceed the
repair capacity of the oocyte, the impact of this damage
may be limited (Ribas-Maynou and Benet: Genes (Basel).
2019, 10(2), 105). Therefore, the ambiguity of the influence of sperm chromatin abnormalities on reproductive success initiates a discussion about clinical value
of sperm nuclear DNA tests.
Study supported by the Pomeranian Medical University (no.
WNoZ-322-01/S/19/2021).
DIRECT INTERCELLULAR COMMUNICATION IN SEMINIFEROUS EPITHELIUM AND ITS FUNCTION AFTER ANDROGEN WITHDRAWAL
Anna Hejmej, Alicja Kamińska, Sylwia Marek,
Barbara Bilińska
Department of Endocrinology, Institute of Zoology and Biomedical
Research, Jagiellonian University
Intercellular communication in the male gonads is of
particular interest due to its key role in maintaining
the proper course of spermatogenesis. Initially, research
focused on paracrine communication (Bilińska et al.: Biol
Cell. 1997, 89, 435–442), but further studies revealed
that direct cell-cell interactions are equally important.
Direct communication is based on the transport of
small molecules through gap junctions or on interactions between molecules located in the membranes of
neighboring cells (juxtacrine signaling).
Gap junctions consist of proteins connexins, that form
channels connecting the cytoplasm of adjacent cells. In
the mammalian testis, connexin 43 (Cx43) is the main
component of gap junctions. Studies using Sertoli cellspecific Cx43 knockout mice revealed the critical role of
this protein in Sertoli cell differentiation and initiation
of spermatogenesis (Brehm et al.: Am J Pathol. 2007, 171,
19–31; Chojnacka et al.: Reprod Biol. 2012, 12, 341–346).
In human and rodent testes with impaired spermatogenesis, disturbances in Cx43 expression were demonstrated
(Kotula-Balak et al.: Eur J Histochem. 2007, 51, 261–268).
In rats, androgen signaling inhibition with antiandrogen flutamide resulted in decreased expression and
delocalization of Cx43 at the blood-testis barrier. It was
accompanied by altered distribution of zonula occludens-1
(ZO-1) and structural abnormalities of basal ectoplasmic
specialization. This indicates that Cx43-based communication between Sertoli cells depends on the availability
of androgens (Chojnacka et al.: Reprod Biol Endocrinol.
2016, 31, 14, 14).
Juxtacrine communication, another mechanism of
direct intercellular communication in the testis, involves the Notch signaling pathway. Activation of this pathway
is triggered by binding of the membrane receptor Notch
to specific ligands located in the membranes of the neighboring cell. This leads to receptor proteolysis and translocation of its intracellular domain into the nucleus where
it regulates the transcription of Hes (hairy/enhancer of
split) and Hey (Hes-related with YRPW motif) genes. The
optimal activity of Notch pathway determines spermatogonial stem cell differentiation, influences further steps
of spermatogenesis, and impacts fertility (Garcia et al.:
Development. 2014, 141, 4468–4478; Murta et al.: PLoS
One. 2014, 9, e113365). Disturbed expression of Notch
pathway factors was found in testicular cancer and in
men with non-obstructive azoospermia (Hayashi et al.:
J Androl. 2001, 22, 999–1011; Hayashi et al.: Tumour
Biol. 2004, 25: 99–105).
Our recent studies indicate that androgen withdrawal,
induced by androgen receptor blockade or selective elimination of Leydig cells, altered the expression of Notch1
and Notch2 receptors, as well as their activated forms in
rat testes. Moreover, the expression of the effector genes
Hey1, Hes1, and Hes5 was changed following androgen
withdrawal, which indicates disturbed activity of Notch
pathway. Androgens can therefore be considered as regulators of Notch signaling (Kamińska et al.: Reprod Biol
Endocrinol. 2020, 18, 30). Taken together, the control of
direct intercellular communication in the seminiferous
epithelium is an important aspect of androgen activity
during spermatogenesis. Thus, abnormalities in both
gap junction communication and juxtacrine signaling
may underlie the disturbance of spermatogenic function
under conditions of limited availability of androgens.
Supported by grants HARMONIA3 2012/06/M/NZ4/00146
and OPUS13 2017/25/B/NZ4/01037 (National Science Centre,
Poland).
IMMUNOLOGICAL ASPECTS OF MALE INFERTILITY
Katarzyna Jankowska
The Department of Endocrinology, Center of Postgraduate Medical
Education, Bielanski Hospital, Warsaw, Poland
e-mail: katarzynakamilajankowska@gmail.com
Male infertility can be caused by an immune disorder.
Immune infertility in men is defined as the presence of one or both partners of an immune response
against semen (Dondero et al.: In: Oxford Textbook of
Endocrinology and Diabetes, Oxford University Press,
2011, DOI: 10.1093/med/9780199235292.003.9100).
WHO guidelines list immunological factors as one of
the causes of male infertility (WHO: Manual for the
Standardized Investigation and Diagnosis of the Infertile
Couple. Cambridge University Press, 2000). It is estimated that about 15% of male infertility is immunerelated, either due to recurring infections or an abnormal
autoimmune response involving the epididymis, prostate,
or testes. This ratio is likely to be underestimated as 30%
of male infertility cases are reported to be idiopathic.
Unlike orchitis, epididymitis is a common condition.
The cause of epididymitis is often bacterial infections,
of particular importance are the sexually transmitted
Chlamydia trachomatis and Neisseria gonorrhoeae in young
men and the intestinal Escherichia coli and Enterococcus
faecalis in older men. It has been shown that these infections, even if successfully treated, can cause narrowing
of the epididymal duct, decreased sperm count and azoospermia in up to 40% of patients. Clinical data demonstrate the need for an effective and precisely controlled
immune response to pathogens in the epididymis.
Antisperm antibodies (ASA) may interfere with the
fertilizing ability of the sperm: reduce sperm motility,
reduce the ability to pass through the secretion of the
genital tract in a woman, reduce the ability to penetrate the oocyte, cause sperm agglutination. ASA lead to
reduced sperm motility, i.e. asthenozoospermia. However,
immunological infertility should also be taken into
account in normozoospermia, especially when sperm
functional tests are not normal. The guideline of the
European Association of Urology (EAU) recommend that
diagnostics for immunological disorders should be considered when the semen test result is twice outside the
reference range. This examination is performed when
other causes of the abnormal seminogram have been
excluded (e.g. urogenital infection).
It is currently recommended to perform a mixed
antiglobulin reaction (MAR test) or an immunobead
semen test (Jungwirth et al.: Male Infertility In: EAU
Guidelines, http://uroweb.org/guideline/male-infertility).
The MAR test is used to detect sperm antibodies in semen.
The test should be considered when the examination
of semen shows poor sperm motility or agglutination
of sperm. Genitourinary tract infection must be ruled
out before hand, as it may induce the presence of antibodies. If asthenozoospermia or sperm agglutination
are still present, despite the lack of infection or after
the infection has healed, immune-mediated infertility
should be excluded. The MAR test involves adding latex
beads coated with IgA or IgG antibodies and a mixture
of anti-IgA or anti-IgG antibodies to the semen sample.
If there are IgA or IgG antibodies on the sperm cells,
the spermatozoa are joined with the beads, which can
be seen in the microscope. A result of more than 50% of
sperm associated with the beads is considered positive
and indicates the presence of ASA in an amount that
interferes with the function of the sperm (possibility
of penetration through the cervical mucus and also the
ability to fertilize). This test can only be performed when
there are sperm cells in the semen that show movement.
The immunobead test has a similar meaning. It is more
accurate than the MAR test, but the execution is more
laborious. The immunobead test is not performed with
a fresh sample of semen, but with semen from which elements that may mask the presence of antibodies have
been removed. The principle of the test is similar to the
MAR test (the connection of sperm with latex beads is
observed in a microscope). The evaluation of the immunobead test result is also similar: ≥50% of sperm associated
with the beads are positive, indicating the presence of
ASA in an amount that interferes with sperm function.
This test can only be performed when there are sperm
cells in the semen that show movement.
The role of epididymides is emphasized in the regulation of the immune response (Voisin et al.: Asian J
Androl. 2019, 21(6), 531–539). Epididymal epithelial
cells have developed mechanisms that combat pathogens, including the expression of various TLRs (toll-like
receptors), antimicrobial molecules (nitric oxide, IDO,
β-defensin, etc.), and pro-inflammatory cytokines (IL-1,
IL-6, etc.). Interstitial lymphocytes B in the epididymides
may be responsible for the secretion of local IgA or they
may phagocytose bacteria coated with antibodies and
limit their spread in the tissue and induce specific effector
lymphocytes T. Activated B cells activate helper T cells.
Some an antigen presenting cells (APCs) may migrate
to the draining lymph node to trigger the recruitment
of effector cells to infected epididymides. When the epithelium is damaged by infection, some CX3CR1+ CD11c+
monocytes may be involved in the elimination of disrupted cells or pathogens. Newly identified lymphocytes
T in the epididymis can be activated by APCs or directly
by infected cells. Once activated, they can become cytotoxic, contributing to the clearance of bacteria. Probably
the epididymis is a potential immune reservoir of cytotoxic cells during infection.
Immune infertility is found in 8–20% of infertile
men. Sperm antibodies appear as a result of trauma,
infection of the testicle or the epididymis that breaks the
blood-testicle barrier (e.g. surgery, infections, varicocele).
Not all sperm antibodies cause infertility. It is important whether these antibodies bind to antigen epitopes
necessary for the fertilization of the egg. Currently, it
is recommended to perform tests detecting anti-sperm
antibodies: MAR test or immunobead test. Depending on
the history (psoriasis, vitiligo, thyroid diseases, inflammatory bowel diseases, rheumatic diseases), screening
for other autoimmune diseases (ANA, anti-TPO, antiTg, anti-CCP, celiac disease) may be considered. In many
autoimmune diseases, causal treatment (e.g. biological
treatment) is possible.
Recently, more attention has been paid to the relationship between the state of the immune system and
fertility. In 2018 Brubaker et al. (Brubaker et al.: Andrology.
2018, 6(1), 94–98), showed that men with infertility had
a significantly higher incidence of autoimmune diseases:
rheumatoid arthritis, multiple sclerosis, psoriasis, thyroiditis and Graves’ disease. Hypogonadism may be one
of the components of the autoimmune polyendocrine
syndrome. On the other hand, other publications (Mouvis
et al.: Semin Arthritis Rheum. 2019, 48(5), 911–920)
show that in men with rheumatological diseases who are
treated with, for example, anti-TNF (anti-tumor necrosis
factor) drugs, an improvement in sperm parameters and
an increase in the pregnancy rate in partners are observed.
This would confirm the importance of autoimmune processes in male infertility. This very interesting information requires further research and clinical observations.
Piotr Jędrzejczak
AZOOSPERMIA DIAGNOSTICS
AND THERAPEUTIC PLANNING
Division of Infertility and Reproductive Endocrinology, Poznan
University of Medical Sciences, Poland
e-mail: piotrjedrzejczak@gmail.com
Azoospermia affects about 1% of men. It is a serious
challenge for doctors involved in reproductive medicine. During the presentation, the causes of the azoospermia will be presented, as well as diagnostic methods
important in detecting the various forms of this disease.
Particular attention will be paid to the current therapeutic
options in men with a complete absence of sperm in the
ejaculate. Finally, an algorithm for the management of
patients with azoospermia according to modern recommendations will be presented.
ROLE AND HORMONAL REGULATION OF JAGGED AND DELTA-LIKE PROTEINS IN RODENT SERTOLI CELLS
Alicja Kamińska1, Sylwia Marek1,
Małgorzata Brzoskwinia1, Laura Pardyak2,
Anna Hejmej1, Barbara Bilińska1
1Department of Endocrinology, Institute of Zoology and Biomedical
Research, Faculty of Biology, Jagiellonian University, Krakow, Poland,
2Center of Experimental and Innovative Medicine, University of
Agriculture in Krakow, Poland
e-mail: ala.kaminska@uj.edu.pl
Mammalian spermatogenesis is a process controlled by
Sertoli cells, considered the key mediators of androgen
action in the seminiferous epithelium. Androgens act
predominantly by activating the classical intracellular
androgen receptor (AR). It is now well established that
the proper AR signaling in Sertoli cells is required for
maintenance of the blood-testis barrier, completion of
meiosis and spermiation (O’Hara and Smith: Best Pract.
Res. Clin. Endocrinol. Metab. 2015, 29, 595–605). In
addition, androgens regulate the process of spermatogenesis through non-classical signaling pathways
related to the induction of membrane receptors. In 2014,
a member of the zinc transporter family, Zrt- and Irtlike protein 9 (ZIP9), was identified as a novel membrane
androgen receptor (Berg et al.: Endocrinology. 2014, 155,
4237–4249). It has been shown that testosterone, acting through ZIP9, is involved in the regulation of the bloodtestis barrier proteins in Sertoli cells (Bulldan et al.: Cell
Signal. 2016, 28, 1075–1085). Recent studies have confirmed that ZIP9 is localized in Sertoli cells of mouse
and bank vole seminiferous epithelium (Kamińska et al.:
Andrology. 2020, 8, 457–472; Profaska-Szymik et al.: Int.
J. Mol. Sci. 2020, 21, 6888).
Delta-like (DLL) and Jagged (JAG) proteins are membrane ligands activating the Notch signaling pathway
involved in juxtacrine communication in the seminiferous epithelium. In mouse and rat testes, the presence of DLL1, DLL4, and JAG1 ligands has been demonstrated in both Sertoli cells and germ cells (Kaminska
et al.: Reprod Biol Endocrinol. 2020, 18, 30; Murta et al.:
PLoS One. 2013, 8, e72767). Activation of the Notch
pathway by these ligands specifically modulates the
response of Sertoli cells to androgens, influencing AR
and ZIP9 expression. Moreover, it has been found that
disturbances in the activity of the Notch pathway led
to deregulation of the expression of blood-testis barrier
proteins – claudins (Kamińska et al.: Andrology. 2020, 8,
457–472). Therefore, the Notch pathway can be considered as an important factor influencing androgen signaling in Sertoli cells. Further analysis showed that the
expression of Notch pathway ligands (DLL1, DLL4, and
JAG1) in the male gonad is regulated by androgens. In
vitro studies have clarified the mechanism of this regulation, providing evidence for the involvement of both
AR and ZIP9 in this process. These results indicate a role
of classical and non-classical androgen signaling in the
control of the Notch pathway.
Summing up, our results demonstrated a bidirectional
interaction between Delta-like and Jagged proteins and
androgen signaling in rodent seminiferous tubules. The
crosstalk between these mechanisms regulates the physiology of Sertoli cells, and its disruption may affect key
processes in the seminiferous epithelium, such as the
function of blood-testis barrier.
Supported by grants MINIATURA1 2017/01/X/NZ4/00285
and OPUS13 2017/25/B/NZ4/01037 (National Science Centre,
Poland).
NON-CLASSIC ESTROGEN SIGNALING IN THE TESTICULAR INTERSTITIUM
Małgorzata Kotula-Balak1, Agnieszka Miłoń1,
Piotr Pawlicki1, Ewelina Górowska-Wójtowicz2,
Michał Duliban2, Barbara Bilińska2
Sposób przygotowania manuskryptu
1University Centre of Veterinary Medicine JU-UA, University of
Agriculture in Kraków, Poland, 2Department of Endocrinology,
Institute of Zoology and Biomedical Research, Jag
Based on numerous epidemiological and experimental
studies, it is known that estrogen signaling through classical and non-classical estrogen receptors is necessary for
the proper function of the male reproductive system. At
the end of the 20th century, canonical estrogen receptors α and β (ERα and ERβ; estrogen receptor α and β)
have been identified and their role in various types of
testicular cells was determined using animal experimental models and in vitro studies (Bilińska et al.: Mol
Cell Endocrinol. 2001, 10, 189–198; Hess.: Reprod Biol
Endocrinol. 2003, 9, 52). The expression of ERα and
ERβ genes has been demonstrated in human testis,
including pathological conditions, but research aimed
at determining the pattern of protein localization of
these receptors is still ongoing.
Currently, research work is focused on explaining the
role of non-classical estrogen receptors, e.g. estrogenrelated receptors (ERRα, ERRβ and ERRγ – estrogenrelated receptor α, β and γ) and membrane estrogen
receptor (GPER; G-protein coupled estrogen receptor).
In recent years, for the first time, the expression of
ERR in mouse Leydig cells in vitro and in vivo conditions
has been confirmed. Changes in proliferation, apoptosis
and migration were observed in tumor Leydig cells with
modulated ERRα, ERRβ or ERRγ activity (Kotula-Balak
et al.: Tissue Cell. 2018, 52, 78–91). Species-specific
expression of GPER has been demonstrated in all types
of mammalian testicular cells, including human ones
(Fietz et al.: Methods Mol Biol. 2016, 1366, 189–205;
Kotula-Balak et al.: Cell Tissue Res. 2018, 374, 389–412).
An increase in GPER expression and changes in estrogen
levels were noted in rodent and human tumor Leydig
cells (Górowska-Wójtowicz et al.: Tissue Cell. 2019, 61,
51–60). Inactivation of both ERR and GPER in mouse
testes resulted in increased volume of interstitial tissue
and enhanced expression of ERRα, ERRβ or ERRγ genes.
Concomitantly, there was an increase in the number of
telocytes – newly discovered regulatory cells of interstitial
tissue (Pawlicki et al.: Protoplasma. 2019, 256, 393–408).
Due to the unique structure and distribution of telocytes in the interstitial tissue, these cells create structure-communication networks, regulating the steroidogenic function of Leydig cells under the control of ERR
and GPER. Thus, overgrowth of the interstitial tissue in
pathological testis may result from disturbances in the
number and/or function of telocytes and their regulation via ERR and GPER.
In the light of presented data, it seems that apart
from the ERs, non-classical estrogen receptors are an
important components of estrogen signaling in the male
gonad. By controlling Leydig cells and telocytes, ERR and
GPER regulate the production of sex hormones, which
influences spermatogenesis. These receptors can also
serve as additional markers of pathological states of the
testicular interstitial tissue, especially those associated
with changes in the production and concentration of
estrogens.
Supported by grants 2015/18/E/NZ4/00519 (SONATA BIS5)
and 2016/23/B/NZ4/01788 (OPUS12) from the National
Science Centre.
NON-CODING RNA OF SEMINAL PLASMA AS A DIAGNOSTIC AND PROGNOSTIC BIOMARKER OF MALE INFERTILITY
Małgorzata Kotwicka, Weronika Tomaszewska
Department of Cell Biology, Poznan University of Medical Sciences,
Poland
e-mail: mkotwic@ump.edu.pl
In about 60–75% of men diagnosed for infertility, it is
impossible to establish a clear causal factor, which means
that subjects are diagnosed with idiopathic infertility. The
exploration for new biomarkers shows high specificity
and sensitivity towards male infertility and provides
additional information on the molecular mechanisms
underlying this condition, and is therefore necessary.
Since semen is a biological material relatively easy to
obtain in a non-invasive way, it naturally becomes the
object of this research.
Numerous body fluids, such as plasma, serum, saliva,
tears, cerebrospinal fluid, bronchoalveolar lavage fluid,
milk, and urine contain cell-free, non-coding RNA
(ncRNA) molecules. Due to the size of the molecule,
three main classes of ncRNAs have been distinguished:
short non-coding RNA (sncRNA), long non-coding RNA
(lncRNA) and very long non-coding RNA (vlncRNA).
NcRNAs are not translated into proteins but can modulate cellular messenger RNAs (mRNAs) and protein levels
causing mRNA degradation or translation inhibition. Due
to the biogenesis and type of proteins interacting with
them, sncRNA have been divided into three main classes:
microRNA (miRNA), small interference RNA (siRNA) and
PIWI-interacting RNA (piRNA). Extracellular sncRNAs
may reflect the molecular changes taking place in the
cells. This means that profiling their expression can be a
good diagnostic and prognostic tool. However, the great
number of ncRNA molecules involved in cellular processes make this analysis difficult and time-consuming.
Cell-free miRNA and piRNA were found in the
seminal plasma. It should be noted that miRNAs can
be secreted by many cells and tissues, and the seminal
plasma contains fluids secreted by testis, epididymides,
seminal vesicles, bulbourethral glands, or the prostate.
Thus, seminal plasma miRNAs may not provide unambiguous information about the type and location of the
pathological condition. Nevertheless, a change in miRNA
expression patterns (e.g., miR-34b/c, miR 334a/b/c, miR449a, miR-19a, miR-31-5p, miR-539-5p, and miR-941)
has been linked to various histopathological images of the
testes (e.g. Sertoli cell-only syndrome, arrest of maturation of spermatogenesis cells) or semen with the signs of
asthenozoospermia, oligozoospermia, oligoasthenozoospermia and azoospermia (Abu-Halima et al.: Fertil Steril.
2013, 99, 1249–1255; Barcelo et al.: Hum Reprod. 2018,
33, 1087–1098; Hu et al.: Clin Biochem. 2014, 47, 967–72;
Tian et al.: Forensic Sci Int Genet. 2018, 33, 161–167).
On the other hand, piRNA are upregulated especially
in pachytene spermatocytes and round spermatids.
They seem to play a preliminary role in spermatogenesis, studies showed that silencing of PIWI protein
expression inhibited sperm formation and maturation. piRNAs, includes piR-31068, piR-31925, piR43771, piR-43773 and piR-30198, were present in the
seminal plasma and their expression is associated with
the reduced biological value of the semen (Hong et al.:
Scientific Reports. 2016, 6: 224–229). Recent studies
also pointed out that to long non-coding RNA and circulating DNA (cfs-DNA) as a potential markers in the
diagnosis of infertility.
An analysis of the available literature shows that
ncRNAs represent a promising complement to traditional male infertility biomarkers.
THE INFLUENCE OF SRAS-COV2- (COVID-19) VIRUS INFECTION ON MALE REPRODUCTIVE HEALTH
Maciej Kurpisz, Monika Frączek
Institute of Human Genetics, Polish Academy of Sciences, Poznan,
Poland
e-mail: maciej.kurpisz@igcz.poznan.pl
Severe acute respiratory syndrome coronavirus 2
(SARS-Cov-2) can be now presented as a common
pandemic microbial agent with adverse multi-organ
effects directed, among the others, to male reproductive
system. Its promiscuity within organism can be linked
to numerous receptors mediating its harmful actions to
the host. One of them and seemingly a prominent player
appears to be, ACE-2, (angiotensin-converting enzyme
2) which is expressed almost on the all morphotic elements of the male gonad. Another enzyme, expressed
on adult testis spermatogonia is TMPRSS2 (transmembrane serine protease 2 enzyme) which cleaves capsid
S of the virus. The other assisting receptors for Cov-2
are BSG (basigin) inducing metalloproteases of extracellular matrix, expressed on oolemma and trophectoderm membranes which presents opportunity for early
embryonal damage, ANPEP (alanyl aminopeptidase N)
is overexpressed in Parkinson disease as well through
epigenetic mechanisms may induce cancerogenesis in
a prostate gland (it is also expressed in endometrium).
In turn, receptor DPP4/CD26 (dipeptidyl peptidase-4)
has been expressed on epithelial and endothelial cells
of vasculature belonging to circulatory system of lung,
kidneys, intestine and heart – thus could potentially
induce cytokine storm or thrombotic process. Interaction
of SARS-Cov-2 with ACE-2 receptor may lead to dysfunction in hypothalamus-pituitary-testis axis. Principally
it is due to primary dysfunction of Sertoli cells – secondarily it involves germ cells. SARS-Cov-2 does not
primarily trigger autoimmune orchitis but it acts
altering endocrine, inflammatory and innate immunity within male gonad – often exaggerated through release of reactive oxygen species (ROS) associated
with pro-inflammatory stage. Other, visible disturbing
syndromes in male reproductive ability are associated
rather with therapeutic process than virus presence per
se. Adverse effects may be caused by anti-viral drugs
and glucocorticosteroids. They both may exert cytotoxic
actions towards actively dividing cells thus impairing
spermatogenesis. Also polyclonal antibodies occasionally
applied may be harmful due to possible cross reactivity.
Additionally, glucocorticosteroids destroy cell junctions
in spermatogenetic epithelium affecting blood-testis
barrier. Infiltrating leucocytes (due to inflammatory state
invoked by SARS-Cov-2) may produce reactive oxygen
species and cytokines as well as may augment cytokine
secretion and synthesis in male gonad itself giving a
ground for initiation of local cytokine storm. Due to
all these circumstances the classical sperm parameters
(sperm quality) may deteriorate which makes necessity
of careful semen oxidative stress monitoring as well as
application of antioxidants. Testosterone supplementation should be also considered. Particularly when
applying anti-viral drugs a grace period in trying for
offspring should be considered for at least few month
(epigenetic phenomena or sperm DNA damage should
be considered which strictly speaking is a prerequisite to abandon procreative activities during that time.
Infertility may be induced primarily due to Sertoli cells
dysfunction. Another problem could be asymptomatic
infections in children of pre-pubertal or early reproductive age. Long-term carriership of the SARS-Cov-2
in semi-privileged site should be taken into attention.
SPERM DNA FRAGMENTATION – DIAGNOSTICS AND TREATMENT
Sposób przygotowania manuskryptu
Krzysztof Łukaszuk1,2
INVICTA Fertility and Reproductive Center, Gdansk, Warsaw,
Wroclaw, Bydgoszcz, Poland; 2Medical University of Gdansk, Faculty
of Health Sciences Department of Obstetrics and Gynecological
Nursing, Gdansk, Poland
e-mail: krzysztof.lukaszuk@invicta.pl
Globally, about 140 million people (13–15% of couples)
remain childless after a year of trying. Only a small
minority seeks any treatment. The male factor is the least
known aspect of the diagnosis of the causes of infertility. So far, there are no clearly defined cut off values
for identifying sperm reproductive potential based on
standard semen analysis. The value of the World Health
Organization (WHO) standards for semen analysis is still
being questioned. The most common deviations from
the test standard – in terms of sperm count, motility
and morphology do not withstand a detailed analysis
of their causal relationship with pregnancy. Based on
current research, it is even difficult to determine whether
standard semen analysis parameters are clearly related to
the cause of infertility. Thus the search continues for tests
that would facilitate diagnostics and treatment management of an infertile couple. The most convincing is the
analysis of sperm DNA fragmentation and other abnormalities related to the genetic material contained in the
sperm. Properly chromatin remodeling, from histones
to protamines, in the nucleus of mature spermatozoa
has a protective function for DNA. Sperm chromatin
integrity is essential for normal reproductive function.
Its disorders cause: infertility, poorer embryo quality,
lower implantation rate and an increased risk of miscarriage or having a sick child. The oocyte can effectively
repair sperm chromatin damage to some extent, but the
effectiveness of the repair mechanisms in the oocytes
declines with age.
The mechanisms of sperm DNA damage known so
far include: apoptosis or anomalies arising during the
spermatogenesis process, DNA strand breaks during
chromatin remodeling in the process of spermiogenesis, non-nuclear DNA damage mainly by oxygen free
radicals during transport through the seminal tubules
and in the epididymis, DNA fragmentation induced
by endogenous caspases and endonuclease, damaging
effects of radio- and chemotherapy and environmental
toxins. The main one appears to be the oxidative stress.
It can be related to internal factors (such as protamine
deficiency and DNA packaging defects) affecting up to
15% of infertile men. We should also take into account
external factors – inflammation of the genital organs,
heat, radiation, chemotherapy, smoking. Smoking generates high levels of oxidative stress and reduces the
concentration of antioxidants in semen plasma.
Unfortunately, sperm DNA fragmentation does not
correlate with the basic sperm parameters. Increased
sperm DNA damage was observed in approximately 5%
of infertile men with normal sperm parameters compared with 25% in the group of patients with abnormal
sperm parameters. Increased sperm DNA fragmentation index indicates reduced male fertility regardless of
sperm count, motility and morphology. The results of
the assessment of the sperm chromatin structure assay
(SCSA) allowed for the best assessment of the chances
of a successful pregnancy in the case of planning the
first pregnancy, also in couples undergoing intrauterine
insemination (IUI).
That shows why it is so important to use sperm DNA
fragmentation analysis in the evaluation of an infertile couple. In order to be able to effectively diagnose
the cause of infertility, one must have an appropriate
diagnostic tool. We currently have several methods
for determining sperm DNA damage. Unfortunately,
the increased popularity of such test and their commercialization lead to introduction of unreliable tests
to the market, that easy to perform and inexpensive
to buy. As a result, a group of clinics charges unaware
patients for the unreliable tests the fees comparable to
reliable tests for, obtaining a 1000% margin. The tests
that have proven reliability and quality include SCSA, TUNEL (TdT-mediated dUTP nick-end labeling) and
comet assay. Among the tests not confirmed by independent studies, one should mention the commercial
hit – sperm chromatin dispersion (SCD) test– falsely
called the sperm DNA fragmentation test.
So far, it has not been clearly established where to
place the sperm DNA fragmentation in the treatment
algorithm – does it belong in the initial diagnosis,
extended diagnosis, before in vitro fertilization or after
its failure. We currently have a tool for at least partial
separation of sperm with high fragmentation of sperm
DNA, so the question arises whether we should use it
also after sperm separation for in vitro fertilization.
ANDROGENETIC ALOPECIA AND MEN’S HEALTH
Mariola Marchlewicz1, Ewa Duchnik2
Department of Dermatology and Venereology, Pomeranian
Medical University in Szczecin, Poland, 2Department of Aesthetic
Dermatology, Pomeranian Medical University in Szczecin, Poland
e-mail: mariola.marchlewicz@pum.edu.pl
The presence of healthy, properly growing hair is very
important for the well-being of men. The processes of
hair growth and replacement are regulated, among other
factors by androgens, in some places androgens have no
effect, in other stimulate or inhibit hair growth. In men,
high levels of androgens stimulate the growth of facial,
suprapubic and chest hair. However, in the scalp androgens can cause baldness. Hair follicles are androgensensitive due to the expression of Androgen Receptor
(AR) in dermal papilla cells (DPCs). The AR expression
is significantly higher in DPCs of the chin and areas
subject to androgenetic alopecia than in non-balding
skin of the occipital region.
Androgenetic Alopecia (AGA) affects approximately
50% of adult men under the age of 50 and over 70%
over the age of 70. The clinical presentation of AGA is
that hair lost is initially in the frontal area and then
in the top of the head. The severity of the disease is
assessed on the Hamilton – Norwood scale. The primary
pathogenetic process in AGA, is mediated by dihydrotestosterone (DHT), hair follicle miniaturization in
androgen-dependent areas. Genetic (single nucleotide
polymorphism in exon 1 of the AR gene within the long
arm of X chromosome), hormonal (testosterone, DHT)
and environmental factors are important in the pathogenesis of AGA.
It is thought that in AGA there is, within the hair follicle, an altered interaction between DPCs and keratinocytes. In the DPCs the androgen/AR complex influences
the synthesis of factors that regulate both the function
of these cells autocrinally and the function of follicular
epithelial cells paracrinally, e.g. through IGF-1 (insulinlike growth factor 1), within DPCs, in areas of baldness
skin, the level of secretion of this cytokine is as much
as 6 times lower than in non-baldness skin, what confirms the important role of IGF-1 in inhibiting baldness.
Androgens also alter the transcription of genes, in
DPCs, regulating the hair growth cycle. They are responsible for reducing the number of cells in the hair follicle,
as high levels of DHT induce apoptosis of DPCs and loss
of their proliferative properties.
As a consequence, there is a shortening of the anagen
phase and a reduction in the size of the follicles. The
activity of DPCs, keratinocytes and melanocytes changes,
which leads to the transformation of the final hair follicles into the follicle in which shorter, thinner and discolored hair are formed (Marchlewicz et al.: Post Androl
Online. 2014, 1(2), 14–24).
In addition to the negative impact of AGA on quality
of life, a growing number of studies have shown its association with increased cardiovascular risk. Men with AGA
are more common to have metabolic syndrome, obesity,
hypertension, dyslipidemia, insulin resistance and accelerated atherosclerosis. The criteria for diagnosing the
metabolic syndrome are met by 20-57% of patients
with AGA. The patomechanism of the coexistence of
AGA and cardiovascular diseases is complex and includes
genetic factors (increased sensitivity to androgens and
increased 5α - reductase activity), hormonal (increased
insulin, aldosterone, leptin) and inflammatory factors
(cytokines, reactive oxygen species). Patients with AGA
have an inflammatory reaction around the hair follicles,
and serum levels of oxidative stress markers have been
found to be increased in patients with early onset AGA.
Studies show an association of AGA with increased levels
of cholesterol and triglycerides in the blood serum and
higher values of systolic and diastolic blood pressure in
these men (Wernicka et al.: Przegl Dermatol. 2018, 105,
716–725).
PROGNOSTIC SIGNIFICANCE OF FUNCTIONAL TESTS IN REPRODUCTION
Katarzyna Marchlewska
Department of Andrology and Reproductive Endocrinology, Medical
University of Lodz, Poland
e-mail: katarzyna.marchlewska@umed.lodz.pl
In recent years, a lot of attention has been paid to study
the sperm quality. A significant progress has been made
in understanding the importance of sperm chromatin
integrity as well as the impact of oxidative stress on
male fertility. However, the assessment of sperm function seems to be no less important.
One of parameters describing sperm function in the
basic semen analysis is motility. Often, for prognostic
purposes, an index called total motile sperm count
(TMSC) is also calculated. The reference values for this
parameter are still under discussion. Some authorssuggest the cut-off value above 10, others above 5 or even
above 1 million. This index is usually used when qualifying a couple for intrauterine insemination (IUI), but
also to predict the chances of natural fertilization. Many
studies has shown that the motility does not ensure that
the sperm is involved in the reproductive process. Under
natural conditions, about 1% of spermatozoa deposited
during sexual intercourse enter the uterus. This number
is constantly reduced as sperm migrate through subsequent sections of the female reproductive system. That
is why the assessment of their migration ability is such
an important parameter related to male gametes hyperactivation, chemo- and thermotaxis.
The capability of sperm to migration is assessed
using a functional test such as the migration test,
often called the “swim up” test. The result of the
test indicates the number of sperm that migrate in
1 hour from 1 mL of native semen sample to 1.2 mL
of human tubal fluid-like medium and is expressed
as the motile sperm concentration (million/mL) after
the preparation. The test is used to predict the chances
of natural fertilization, IUI and classic in vitro fertilization (IVF). It has no cut-off value because during
interpretation it should be remembered that result does
not take into account the total ejaculate volume so it
should be considered individually. In the literature the
limit values for number of motile sperms that will be
transfer into the uterus during evaluation of fertilization effectiveness using IUI method ranges from 0.8 to
20 million sperm. However, the American Society for
Reproductive Medicine (ASRM) published data showing
that the effectiveness of insemination increases with
the number of sperm transferred to the uterus, but
only to 9 million and then remains constant. On the
other hand, if qualification for the IVF procedure is
considered, the sperm number of 70–100 thousand
per each oocyte ensure the optimal conditions.
Fertilization is a multistep and complex process and
there is a paucity of diagnostic methods that are dedicated to evaluate the function of male gametes at each
stage. One of these tests indicates sperm maturity and
assesses their ability to bind to hyaluronic acid (hyaluronan binding assay – HBA). Physiologically, hyaluronic
acid is found in the corona radiata of the oocyte and is
degraded by an enzyme hyaluronidase located on the
sperm heads. As recommended by the test manufacturer, a value of ≥80% of the motile sperm responding to
the test was considered normal. However, other studies
suggest that HBA value of <
60% significantly indicates
decreased sperm maturity (Huszar et al., Reprod Biomed,
2007, 14, 650–663), while patients with a binding score
≤65% have a reduced chance of having mature sperm
randomly selected for ICSI (Worrilow et al., Hum Reprod,
2013, 28, 306–314). The data of our own studies concerning the frequency of impairment of sperm function
in the population of men referred for semen analysis in
the Lodz agglomeration will be presented.
FOLLICLE-STIMULATING HORMONE (FSH) REGULATES NOTCH SIGNALING IN RAT TESTIS DURING PUBERTY
Sylwia Marek1, Alicja Kamińska1,
Małgorzata Brzoskwinia1, Laura Pardyak2,
Anna Hejmej1, Barbara Bilińska1
Department of Endocrinology, Institute of Zoology and Biomedical
Research, Faculty of Biology, Jagiellonian University in Krakow,
Poland; 2Center of Experimental and Innovative Medicine, University
of Agriculture in Krakow, Poland
e-mail: s.marek@doctoral.uj.edu.pl
The function of the mammalian male gonad is maintained by the hypothalamic-pituitary axis, whose activation during puberty is associated with pulsatile secretion
of gonadotropin-releasing hormone (GnRH) from hypothalamus. Follicle-stimulating hormone (FSH) released
in response to this signal, is involved (along with androgens) in the control of spermatogenesis. Studies on rodent
models have shown that FSH, by regulating Sertoli cell
function, reduces apoptosis of germ cells during the first
wave of spermatogenesis, and influences the proliferation
and differentiation of spermatogonia (O’Shaughnessy:
Semin Cell Dev Biol. 2014, 29, 55–65).
Sertoli cells support spermatogenesis through mutual
interactions and communication with germ cells. One
type of direct intercellular interactions in the seminiferous epithelium is communication via the Notch signaling pathway (Murta et al.: PLoS One. 2013, 8, e72767).
Although in recent years the role of Notch signaling
in spermatogenesis has been the subject of in-depth
research, the regulation of this pathway in the seminiferous epithelium is still poorly understood.
Our recent studies using pubertal rats exposed to
GnRH antagonist followed by FSH supplementation,
have shown that the function of Notch pathway in the
testes is modulated by FSH. The expression of Notch1,
Notch2, and Notch3 receptors, as well as the levels of
their active forms, were altered in the seminiferous epithelium, both in Sertoli cells and in germ cells, of FSHtreated rats. The expression of Notch pathway effector
genes Hes1 and Hey1 was also investigated, and the localization of HES1 and HEY1 proteins in the seminiferous
tubule was confirmed by immunohistochemical analysis.
Decreased Hes1 expression was found after FSH signaling activation, which may indicate a reduction in the
Notch pathway activity in the seminiferous epithelium.
The results presented herein demonstrate that in
seminiferous epithelium FSH regulates direct intercellular communication based on the Notch pathway. The
interplay between FSH and Notch pathways may be a
molecular mechanism responsible for the effect of FSH
on the ability of Sertoli cells to support germ cells. These
observations may therefore contribute to elucidating the
basis of impaired germ cell development associated with
disturbed FSH action.
Supported by a grant OPUS13 2017/25/B/NZ4/01037
(National Science Centre, Poland).
THERE WAS SEX AND TESTOSTERONE REMAINED
Marek Mędraś
Department of Sports Medicine and Dietetics, University School of Physical
Education, Wrocław, Poland, Polish Anti-Doping Laboratory, POLADA
e-mail: m.medras@gmail.com
During the lecture, the information on sex differentiation
and then into the problem of gender verification in competitive sport from a historical perspective will be presented.
Moreover, the issue of testosterone levels in healthy women
and with hyperandrogenism will be analyzes. These data
will be confronted with recommendations of sports organizations regarding acceptable testosterone levels in female
athletes. Finally, the cases of sex development disorders
(46,XY DSD) encountered in competitive sports (androgen
insensitivity syndrome, 5α-reductase deficiency, 17-β hydroxysteroid dehydrogenase deficiency, congenital adrenal hyperplasia, Leydig cell hypoplasia) will be presented.
THE IMPORTANCE OF HORMONAL BALANCE IN THE REPRODUCTIVE TISSUES OF THE TURKEY WITH YELLOW SEMEN SYNDROME
Laura Pardyak1, Alicja Kaminska2,
Malgorzata Brzoskwinia2, Anna Hejmej2,
Malgorzata Kotula-Balak3, Jan Jankowski4,
Mariola Slowinska5, Andrzej Ciereszko4, Barbara Bilinska2
1Center of Experimental and Innovative Medicine, University of
Agriculture in Krakow, Poland, 2Department of Endocrinology,
Institute of Zoology and Biomedical Research, Jagiellonian
University in Krakow, Poland, 3University Centre of Veterinary
Medicine JU-UA, University of Agriculture in Krakow, Poland,
4Department of Poultry Science, Faculty of Animal Bioengineering,
University of Warmia and Mazury in Olsztyn, Poland, 5Department
of Gamete and Embryo Biology, Institute of Animal Reproduction
and Food Research, Polish Academy of Sciences, Olsztyn, Poland
e-mail: laura.pardyak@urk.edu.pl
It is well established that some male turkeys produce
yellow semen instead of the normal white semen (WNS).
Yellow semen syndrome (YSS) in domestic turkey
(Meleagris gallopavo) was detected over thirty years ago
by identifying seminal plasma having both a yellow color
and a high protein concentration (Thurston et al.: Poult
Sci. 1982, 61, 1905–1911). Moreover, the YSS has been
characterized as containing abnormal sperm, spermatids
and causes reduced fertilizing capacity and hatchability
compared to the WNS produced by most turkeys. More
recently, spermatozoa motility characteristics has been
disturbed in YSS turkeys as demonstrated by a computerassisted sperm analysis (Slowinska et al.: Poult Sci, 2011,
90, 181–190). Although semen quality parameters have
been presented in detail, the cause of YSS still remains
unclear. It is noteworthy that male turkeys producing
yellow semen are of special interest as an animal model
for the investigation of reproductive changes associated
with unexplained low sperm quality. In many mammalian species the balance between testosterone and estradiol is crucial for spermatogenesis, normal sperm maturation within the epididymis, and proper functioning of
the ductus deferens. Compared with extensive studies
on mammals, very little is known about the importance
of testosterone metabolism and the androgen:estrogen
ratio within the reproductive tissues of domestic birds.
Thus, the aim of the present study was placed on understanding a connection between the hormone levels and
the lower quality of sperm occurring in YSS male.
The study was performed on testicular, epididymal,
ductal and semen samples collected from adult YSS and
WNS turkeys using several techniques such as immunohistochemistry, Western blotting, qRT-PCR (quantitative real-time polymerase chain reaction), and electron microscopy (Pardyak et al.: Br Poult Sci, 2018, 59,
591–603; Pardyak et al.: Poult Sci, 2020, 99, 555–566).
The results revealed a non-homogeneous distribution
of aromatase and its markedly enhanced expression levels
in all reproductive tissues and sperm of YSS males compared to WNS ones, what may reflect a higher endogenous
synthesis of estrogens in the males with abnormal yellow
semen. This suggestion was confirmed by increased estradiol concentration measured in YSS testes compared to
the value of WNS testis samples. Additionally, a positive
correlation between increased estradiol concentration and
elevated expression of estrogen receptor alpha (ERα) and
estrogen receptor beta (ERβ) in YSS testes and epididymis
was observed. The in vivo results were in line with ex vivo
experiments where YSS and WNS testis explants were
incubated with estradiol. Moreover, transmission electron
microscopy observations revealed that YSS spermatozoa
have a reduced fibrous sheath thickness compared with
WNS spermatozoa, which may suggest impaired sperm
motility in turkeys with the yellow semen syndrome.
Taken together, our data suggest that the androgen:estrogen ratio provides a mechanistic basis for amplification of differences between turkeys with white and
yellow semen. It may indicate a potential relationship
between hormonal imbalance and lower semen quality
in turkeys with YSS as indicated by structural disorders
of the proximal part of the YSS spermatozoa tail.
Supported by a grant 2017/25/N/NZ9/00585 (PRELUDIUM
13) from the National Science Centre to L.P.
LATE ONSET HYPOGONADISM – CURRENT OPINIONS ON DIAGNOSIS AND TREATMENT
Michał Rabijewski
Department of Reproductive Health, Centre for Postgraduate Medical
Education, Warsaw, Poland
e-mail: mirab@cmkp.edu.pl
Late-onset hypogonadism (LOH) is a syndrome characterized by clinical and biochemical evidence of low testosterone (T) levels with advancing age, and is promoted by senescence. LOH affects the hypothalamicpituitary-testis axis. Additionally, metabolic disorders
can have a greater impact on causing hypogonadism
than tissue senescence, which is reflected in decreased
male quality of life, mood, sexual performance as well
as increased morbidity and mortality. On the other
hand, T deficiency is a risk factor for the metabolic
disorders, diabetes, and atherosclerosis (vicious cycle).
Testosterone replacement therapy (TRT) is widely used
to restore T levels and can improve symptoms and signs
of T deficiency including decreased libido, erectile dysfunction, depressed mood, loss of muscle and bone
mass, by increasing serum T levels to physiologic range.
In recent years, several guidelines for TRT have been
develop, but despite similar principles, there are still
important differences both for the diagnostic workup
and follow-up. Discrepancies were reported both for
total and free T levels for diagnosis and for total testosterone for monitoring. Numerous preparations of T
have been developed to improve pharmacokinetics and
patient compliance. It is important to use the appropriate and safe preparation for each patient. Longterm TRT in patients with LOH is safe in terms of
its impact on heart disease and the risk of prostate
diseases. Although, the effects of TRT on the cardiovascular system are complex and rather positive, but
several clinical observations reveal neutral or occasionally detrimental effects, mostly due to confounding
factors. It appears, that TRT is safe once other comorbidities are addressed.
ANDROGEN RECEPTOR AND ANDROGENS INSENSITIVITY SYNDROMES
Michał Rabijewski
Department of Reproductive Health, Centre for Postgraduate Medical
Education, Warsaw, Poland
e-mail: mirab@cmkp.edu.pl
The androgen receptor (AR) play a significant role in
male sexual differentiation and the development and
function of male reproductive and organs. Because of
AR’s widely varied and important roles, its abnormalities have been identified in various diseases. Androgen
insensitivity syndrome (AIS) is a genetic condition
where affected people have male chromosomes and
male gonads with complete or partial feminization of
the external genitals. AIS results from mutations in
the androgen receptor gene, located on the long arm
of the X chromosome (Xq11-q12) which iss associated
with functioning Y sex chromosome and abnormality
on X sex chromosome. AIS is devided into CAIS (complete androgen insensitivity syndrome) with external
female genitalia and lacking female internal organs,
PAIS (partial androgen insensitivity syndrome) with
external genitalia appearance on a spectrum (male
to female), and MAIS (mild androgen insensitivity
syndrome) with impaired sperm development and/or
impaired masculinization. MAIS is the most common
cause of mild hypogonadism at elevated testosterone
(T) levels. in some men we observe the AR gene polymorphism leading to a slight but clinically significant
decrease in T action, which causes clinical symptoms
of hypogonadism at normal T levels. The negative influence of AR gene polymorphism on bone mineral density,
lipids and mood was demonstrated but positive influence on prostate volume. AR gene polymorphism should
be taken into account in patients with symptoms of
hypogonadism and the normal T levels, and may also
modulate the risk of side effects during testosterone
replacement therapy.
INTESTIN MICROFLORA, DISEASES OF THE INTESTINES AND CANCER AND BENIGN HYPERPLASIA OF THE PROSTATE GLAND
Weronika Ratajczak1,2, Olimpia Sipak3,
Maria Laszczyńska2
1Department of General Pharmacology and Pharmacoeconomics,
2Department of Histology and Development Biology, 3Department
of Obstetrics and Pathology of Pregnancy, Pomeranian Medical
University in Szczecin, Poland
e-mail: veronica.ratajczak@gmail.com
Benign prostatic hyperplasia (BPH) is one of the most
commonly diagnosed urological diseases in men over 50
years of age. BPH is characterized by prostatic stromal
cell proliferation, leading to prostatic bladder obstruction (BOO) and lower urinary tract symptoms (LUTS),
which together reduce quality of life (QoL). The development of BPH is very often associated with the existence of comorbidities, such as diabetes, cardiovascular
diseases, and even neurological diseases (Cho et al.: Curr
Bladder Dysfunct Rep. 2020, 15, 60–65). Many studies
also indicate a relationship between the metabolic syndrome (MetS) and the risk of LUTS and BPH (Zhao et
al.: Urol J. 2016, 13, 2717–2726). The factor that contributes to the initiation of pathological changes in the
prostate, and consequently its benign hyperplasia, is
chronic inflammation resulting, among others, from
metabolic disorders (Gacci et al.: BMC Urol. 2017, 17:22).
Moreover, an additional factor that influences the occurrence of inflammation in the body is disturbances in the
intestinal microflora.
The intestinal microflora is one of the elements of
the bacterial ecosystem in mammals. The microorganisms that inhabit the gut are one of the key elements
involved in modulating the immune response from the
moment of birth. More and more research is currently
37
SYMPOSIUM OF SCIENTIFIC TRANINING OF THE POLISH SOCIETY OF ANDROLOGY – 2 being carried out on the effect of bacterial metabolites,
including short-chain fatty acids (SCFA), on homeostasis,
not only in the intestinal microenvironment, but also
in cells and tissues of other organs. SCFAs are a group
of compounds made up of six carbon atoms (C1 - C6),
with the majority of acids being: butyric acid (C4), propionic acid (C3), and acetic acid (C2) (Tramontano et al.:
Nat Microbiol. 2018, 3, 514–522).
So far, disturbances in the intestinal microflora
and its impact on inflammation and prostate diseases
have not yet been thoroughly analyzed. The influence
of SCFAs on the development of BPH has also not been
studied. Only a few publications on the impact of the
intestinal microflora on the prostate are available in
scientific data bases. They mainly concern the influence of intestinal bacteria on the synthesis of metabolites and androgens, which may be associated with
the development of prostate cancer in humans (Liss et
al.: Eur Urol. 2018, 74, 575–582). A study conducted
in mice, on the other hand, revealed that pathogenic
intestinal bacteria can promote the development of
prostate cancer by activating systemic immune cells
(Poutahidis et al.: PLoS One. 2013; 8:e73933). There
are also reports of the impact of inflammatory bowel
disease (IBD) on the risk of prostate cancer (Burns et
al.: Eur Urol. 2019, 75, 846–852). So far, differences
in the composition of the intestinal microflora have
only been confirmed in a pilot study, in which the composition of the intestinal microflora was analyzed in
patients with prostate cancer, and with BPH (Golombos
et al.: Urology. 2018, 111, 122–128). The results of the
research by Liss et al. indicate that bacteria predominating in men diagnosed with prostate cancer (PCa)
were Bacteroides and Streptococcus spp. The exact mechanism by which the intestinal microflora affects the
prostate gland has not so far been fully elucidated. It
seems very likely, however, that disturbed intestinal
microflora does not directly affect the prostate gland,
but contributes to the development of chronic systemic
inflammation. Inflammatory Cells and inflammatory
factors (including cytokines) from the intestinal environment, along with the circulation, can get into the
gland and there cause ‘local’ inflammation and stimulate the growth factors of the prostate stroma, which
in turn may lead to prostatic diseases.
The own study compared the SCFAs profile between
healthy patients and patients diagnosed with BPH, with
regard to MetS as a factor predisposing to the development of prostate hyperplasia. The conducted study
is the first to show changes in the tested SCFA levels
between these two groups. Nevertheless, further research
is needed (including testing in animal models) to determine whether there is a ‘microbiota-gut-prostate axis’
and whether the intestinal microflora and its metabolites contribute to the development of BPH.
Study supported by the Pomeranian Medical University (no.
WNoZ-322-03/S/16/2020).
NGS (NEXT GENERATION SEQUENCING) ANALYSIS IN FERTILITY DIAGNOSTICS
Marzena Skrzypczak-Zielinska, Monika Frączek
Institute of Human Genetics, Polish Academy of Sciences, Poznan,
Poland
e-mail: mskrzypczakzielinska@gmail.com; framon@man.poznan.pl
Genetic analyzes play an important role in determining
the causes of reproductive failure in couples. Genetic
factors are considered responsible in at least 10–15% of
cases of male infertility (Ambulkar et al. J. Clin. Diagn.
Res. 2014, 8, 88–91). Karyotype analysis has become a
standard. Chromosome aberrations occur in 7% of infertile men, which is 30 times more frequent than in the
general population. Another cause of male infertility are
microdeletions of the Y chromosome or aberrations and
mutations of genes responsible for male sexual development, e.g. located in the Yp11.2 region. On the other
hand, patients with bilateral or unilateral absence or
obstruction of the vas deferens should be ordered to
check for the presence of mutations in the CFTR (cystic
fibrosis transmembrane conductance regulator) gene
(Łukaszuk et al. Gin Perinat Prakt. 2018, 3, 112–140;
Kaminski et al. Int J Mol Sci. 2020, 21, 5274). However,
the possibilities of genetics do not end there.
Modern technologies open up new areas of research in
the diagnosis of infertility. Next generation sequencing
(NGS) is such a technology, which is used, e.g., in genetic
preimplantation diagnostics (PDG) as part of the in vitro
procedure in order to reduce the risk of serious chromosomal defects in the embryo (before a woman becomes
pregnant), and in the detection of monogenic diseases
and disorders related to the occurrence of translocation
in the offspring. Performing the NGS analysis is especially recommended for individuals with a positive genetic
history, couples who have experienced recurrent spontaneous abortions or whose offspring have been diagnosed
with genetic disorders, as well as women deciding to
become pregnant after 35 years of age (Łukaszuk et al.:
Gin Perinat Prakt. 2018, 3, 112–140). With PGD diagnosis significantly increases the percentage of embryo
implantation and birth of healthy children.
Another crucial aspect of the use of NGS in the diagnosis of infertility is the characteristics of the microbiome
of the reproductive system. Because the human body contains more microbes than human cells, the microbiome
(being termed the ‘second human genome’) has a huge
potential to influence human physiology (Tsonis et al.: Ann
Transl Med. 2020, 8, 1707). To date, the use of NGS supports the explanation of the functional, quantitative and
mechanistic aspects of the complex microorganism-host
interactions, particularly in relation to the gut microbiome. Meanwhile, the sperm microbiome is an area of
growing scientific interest due to important implications
for male reproductive health, the health of couples, and
even the health of the offspring by transmitting microorganisms to the partner and offspring (Baud et al. Front Microbiol. 2019, 10, 234; Chen et al. Exp Ther Med. 2018,
15, 2884–2890). An indication of a particular species of
bacteria having an impact on sperm function may facilitate the development of new therapies (eg. probiotics).
Currently, however, the data are inconclusive and more
research is needed (Farahanii et al.: Andrology. 2021, 9,
115–144). Nevertheless, it should be expected that NGS
analyzes are the future of broadly understood molecular and genetic diagnostics also in infertility research.
EAA GUIDELINES ON KLINEFELTER SYNDROME
Jolanta Słowikowska-Hilczer
Department of Andrology and Reproductive Endocrinology, Medical
University of Lodz, Poland
e-mail: jolanta.slowikowska-hilczer@umed.lodz.pl
Klinefelter’s syndrome is the most common (0.1–0.2% of
male newborns) genetically determined cause of infertility and hypergonadotrophic hypogonadism in men. It
develops as a result of numerical aberration of X chromosomes (most often 47,XXY). During childhood and early
puberty, the hypothalamic-pituitary-testis axis is usually
normal. The clinical picture of hypergonadotropic hypogonadism develops from mid-puberty (stage G III according
to Tanner’s classification) due to progressive degeneration
of the structure and impairment of testicular function
(Wikström and Dunkel: Horm Res. 2008, 69, 317–326).
The phenotype is varied, ranging from nearly normal to
significantly abnormal. The phenotype in newborns with
Klinefelter syndrome is usually normal male. Often the
only clinical feature is small testes, which are most often
not identified until puberty. Patients with this syndrome
are most often infertile, but in about half of the cases it
is possible to find spermatozoa in the testicles (Rohayem
et al.: Andrology. 2015, 3, 868–875), and they also have
a higher risk of developing, e.g. for breast cancer, metabolic syndrome, cardiovascular diseases, osteopenia /
osteoporosis, autoimmune diseases. Additionally, there
are various levels of cognitive, social and behavioral disorders as well as learning difficulties. Early diagnosis for
this syndrome is recommended in order to implement
early therapeutic and preventive treatment against comorbidities (Zitzmann et al.: Andrology. 2021, 9, 145–167).
ANTI-MÜLERIAN HORMON AND INHIBIN B – THEIR ROLE IN ANDROLOGICAL DIAGNOSTIC
Renata Walczak-Jędrzejowska
Department in Andrology and Reproductive Endocrinology, Medical
University of Lodz
e-mail: renata.walczak-jedrzejowska@umed.lodz.pl
Anti-Müllerian hormone (AMH), also called Müllerian
inhibiting factor (MIF), and Inhibin B (INHB) are
glycoproteins belonging to the transforming growth
factor β (TGFβ, transforming growth factor β). The
main physiological role of AMH is the regression of the
Müllerian ducts in the fetal period, while INHB regulates
FSH secretion from the pituitary by negative feedback.
In the male, they are produced by Sertoli cells in seminiferous tubules starting from the fetal period and are
considered to be markers of their function (Iliadou et al.:
Hormones. 2015, 14(4), 504–514). The dynamics of secretion of both hormones changes throughout the life span
of men, which determines the possibility of using their
concentrations measurement in andrological diagnostic.
Measurements of AMH and INHB concentrations
in blood serum is used in pediatric patients. In the
pre-pubertal period, the concentrations of both hormones remain at relatively constant level. During socalled “minipuberty”, i.e. the temporary activation of
the hypothalamic-pituitary-gonadal axis, the assessment of their concentration is an additional marker of
the proper development of the testicles and function
of Sertoli cells. In turn, after its completion, i.e. during
so-called “hormonal silence” period, AMH and INHB
become the only hormonal markers of testicular activity.
Currently, both hormones are used, for example, in the
differential diagnosis of testicular failure, congenital
hypogonadotropic hypogonadism or sexual differentiation disorders (Rey: Adv Lab Med. 2020, doi.org/10.1515/
almed-2020-0024). Recently, the possibility of using the
assessment of AMH and INHB levels in boys in the prepuberty and pubertal period in order to early diagnose
isolated Sertoli cell dysfunction is suggested (LaVignera
et al.: J Clin Med. 2019, 8(5), 636–342)..
With the beginning of puberty and the activation the
hypothalamic-pituitary-testicular axis, changes in the
secretion of AMH and INHB occur. The AMH concentration decreases to the values corresponding to the concentration values in pre-pubertal girls, while INHB concentration increases to the values observed in adult men.
Measurement of the concentration of INHB along
with the measurement of the concentration of follicle
stimulating hormone (FSH) in adult men has been used
for years as a marker of the proper function of Sertoli
cells, and thus testicular spermatogenic activity. However,
despite many attempts, so far it has not been possible
to established the cut-off value clearly indicating an
impartment in spermatogenesis or reduced sperm quality.
Recent studies also question previous reports showing
a higher predictive value of INHB concentration compared to other sex hormones in predicting the chance
of obtaining sperm from testicular biopsy in men with
obstructive azoospermia (NOA) (Arshad et al.: Int Urol
Nephrol. 2020, 52(11), 2015–2038). Although attempts
to use serum AMH measurements in adult men as an
additional marker of Sertoli cell function and spermatogenesis did not bring expected results, it was possibly
to demonstrate a relationship between semen quality
and AMH concentrations in seminal plasma (Vitku et al.: Basic Clinl Androl, 2017, 27, 19). When it comes to
the use of AMH concentration as a predictor of sperm
biopsy in men with NOA, the results are inconclusive
(Alfano i et al.: Sci Rep. 2017, 7(1), 17638; La Marca et al.:
Hum Reprod Update. 2010, 16(2), 113–130).
OAT – NEW RECOMMENDATIONS BY THE EUROPEAN ACADEMY OF ANDROLOGY
Artur Wdowiak
Diagnostic Techniques Unit, Medical University of Lublin, Lublin,
Polnad
e-mail: wdowiakartur@gmail.com
Oligoasthenoteratozoospermia (OAT) is a decrease in the
amount, progressive motility, and percentage of morphologically normal spermatozoa, diagnosed based on two
semen analyses. The etiology of OAT varies and is most
often multifactorial. Abnormalities of semen parameters
in OAT are most frequently explained by the concept
of oxidative stress. Recommendations of the European
Academy of Andrology suggest, after making the diagnosis of OAT, conducting a thorough medical history,
physical examination, as well as USG and hormonal
diagnostics (Colpi et al.: Andrology. 2018, 6, 513–524).
Appropriately performed diagnostics allows the selection of a proper treatment method. Gonadotropins, antiestrogens, aromatase inhibitors, and antioxidants are
used in the therapy of OAT (Majzoub et al.: Arab Jour
Urol. 2018, 2; 16(1), 113–124). The treatment undertaken
should be accompanied by the potential change of life
style. Management of a patient with OAT should also
include the reproductive capacity of the female partner,
which is determined primarily by women age. The lack of
improvement of semen parameters, or no pregnancy after
treatment and low reproductive potential of the partner
are an indication for applying the assisted reproductive
technology as soon as possible. At present, the most effective treatment method is intracytoplasmic sperm injection (ICSI) (Janicka et al.: Gin Pol. 2021, 92(1), 7–15).
MICROSCOPIC TESTICULAR SPERM EXTRACTION
Jan Karol Wolski1,2
1Fertility Clinic “nOvum”, Warsaw, Poland, 2Department of Urological
Cancer, The Maria Sklodowska-Curie National Research Institute
of Oncology, Warsaw, Poland
e-mail: jkwolski@op.p
In 1998 Peter Schlegel described for the first time the use
of an operating microscope testicular biopsy in a man
with azoospermia (Schlegel: Hum Reprod. 1999;14(1),
131–135). The microscopic testicular sperm extraction
(m-TESE), microsurgical method allows to find groups of
promising tubules within damaged gonads where spermatogenesis may occur, giving an advantage over classical
surgical (open) and percutaneous needle biopsy. According
to guidelines from the European Association of Urology
Guidelines on Sexual and Reproductive Health (EAU)
2020, m-TESE is particularly useful for non-obstructive
azoospermia. An magnification of 20–25× results in at
least 1.5-fold greater effectiveness in sperm obtains compared to a classic biopsy. The Sperm Retrieval Rate (SSR)
is 52% (Bernie et al.: Fertil Steril, , 2015, 104, 1099–1103).
Between 06.10.2012 and 05.03.2021, 396 m-TESE
biopsies were performed in the non-homogeneous group
of men with azoospermia: an average age of 34 years
(range: 17–44 years). M-TESE was the first procedure performed in 55/396 (14%) patients. The Klinefelter Group
consisted of 47/396 (12%). Most patients recived stimulation of spermatogenesis before surgery: androgen
+ antiestrogen (Adamopoulos et al.: Fertil Steril. 1997.
67(4), 756–762), or gonadotropin (LH, FSH) or clomiphene. In addition, antioxidants were included. The procedures were carried out under general anesthesia, as the
one–day-surgery. Type of microscope: Seiler Evolution
XR6 (94), Carl Zeiss S7 (6), Leica M860 2 × 2 (296) and
the magnification 25× were used. Access to the testes –
cutting in the middle line through the scrotum seam (lac.
raphe scrotum). After the procedure, prophylactic antibiotic therapy (cephalosporin) was administered for 5 days.
SSR achieved in the years 2012–2018 – 30.5%; 2019 –
36,7% and in the year 2020 – 42%. In the Klinefleter
syndrome group sperm was found in 8/47 subjects
(17%). Complications: 3/396 (0.76%) scrotum hematomas requiring surgical intervention, 5/396 (1,26%)
massive scrotum and penile ecchymosis, 3/396 (0.76%)
secondary wound healing. Until January 1, 2021, m-TESE
sperm were used in 132 IVF/ICSI procedures, 19 pregnancies were obtained after fresh mTESE and 23 from
frozen sperm (42/132 – 31.8%). 27 children were born
(including one twin pregnancy). Embryo transfer (ET)
miscarriages: 5 after fresh ET and 6 after frozen ET. Four
pregnancies still developing.
M-TESE, testicular biopsy using the operating microscope, increases the chance to find sperm in men with
nonobstructive azoospermia, finally allows incorporated
them into the reproduction protocol IVF/ICSI.
SEX LIFE OF HYPOGONADAL MEN
Kornelia Zaręba
Department of Obstetrics and Gynecology, Center of Postgraduate
Medical Education, Warsaw, Poland
e-mail: konelia3@poczta.onet.pl
The appropriate level of testosterone in adulthood
influences the majority of the sex life aspects in men:
dreaming and fantasizing about sex, sex drive, arousal,
spontaneous erections, erections in the mechanism of sensory stimulation and the appropriate response to
drugs used in sexology. Psychogenic erections are also
partially due to the level of testosterone.
Hypogonadism occurs considerably more commonly
due to the mechanism of body aging (LOH, late-onset
hypogonadism) apart from the classic forms which result
from the abnormal function of the testes, hypothalamus
and the pituitary gland. It requires treatment not only
because of the deteriorating quality of life, but also
due to high mortality (almost 5.5-fold increase). In the
long-term perspective it leads to osteoporosis, metabolic
syndrome, insulin resistance, cognitive disorders, infertility and anemia. Sexologists also meet patients with
hypogonadism resulting from body weight increase and
prolonged exposure to stress. The most common symptoms reported by men with hypoandrogenism include:
decreased libido (91%), energy loss (89%), erectile dysfunction (79%), somnolence in the afternoon (77%), and
reduced physical endurance (66%).
The treatment of sexual disorders in hypogonadal
men is a complex and individually-tailored task. It
involves the introduction of lifestyle changes (reduction in alcohol consumption, smoking cessation, diet
and physical activity influencing the vascular status),
psychotherapy and pharmacological treatment. The
first-line intervention should involve the correction of
potentially-reversible causes. Pharmacological treatment
consists both in the substitution of testosterone and stimulating the male gonad to produce testosterone, which
is preferred by men trying to get offspring. Normal testosterone concentrations are achieved after 2–3 weeks
of therapy. Its effect on the sexual function depends on
the dose and differs in various individuals from 2 to 4.5
ng/mL. Inhibitors of phosphodiesterase type-5 (iPDE5)
remain first-line treatment in patients reporting erectile
dysfunction. Second-line treatment involves the local
administration of prostaglandin E1 (PGE1) (alprostadil).
Numerous studies confirmed the effectiveness of iPDE5
combined with testosterone in patients in whom monotherapy was unsuccessful (with the minimal treatment
duration of 3 months). Concomitant diseases are another
important aspect, especially in men with the diagnosis
of LOH, as they may be a contraindication for the use
of testosterone and require alternative therapeutic solutions. Sexual disorders may frequently result from depressive disorders and depression which may also be due to
hypogonadism. The treatment should then include antidepressive drugs with a negligible effect on libido, e.g.
bupropion which influences the dopaminergic receptor
and is used at a dose of 150 mg/day. In case of a marked
anxiety component it is recommended to use medications such as agomelatine, bupropion and moclobemide.
In many cases it is necessary to include psychotherapy,
predominantly cognitive behavioral therapy.
REKLAMA
Oddajemy do rąk czytelników starannie przygotowany
podręcznik „Andrologii” przygotowany przez najlepszych specjalistów w kraju. To pierwsze tak obszerne
opracowanie na temat zdrowia mężczyzn na rynku wydawniczym. Obszerne, całościowe ujęcie zagadnień andrologicznych przygotowane przez andrologów, endokrynologów,
urologów, seksuologów, chirurgów, pediatrów, genetyków,
biologów, diagnostów, a także psychologów i prawników.
Andrologia jest dziedziną medycyny, która zajmuje
się męskim układem płciowym i zdrowiem mężczyzn
w zakresie prawidłowego rozwoju płciowego, płodności,
sprawności seksualnej i starzenia się, z zachowaniem
dobrej jakości życia.
Jako dziedzina medycyny andrologia wyodrębniła
się na pograniczu endokrynologii, urologii, seksuologii,
medycyny rozrodu i pediatrii. Obejmuje takie problemy
zdrowotne mężczyzn jak: niepłodność, niedobór androgenów, zaburzenia seksualne i zaburzenia rozwoju płciowego.
W ostatnich latach obserwuje się niezwykle dynamiczny rozwój andrologii spowodowany zastosowaniem
nowych metod badawczych z dziedziny biochemii, biologii molekularnej i genetyki oraz powrót do bardziej
intensywnych badań nad zaburzeniami męskiego układu
płciowego. Powstają coraz doskonalsze metody diagnostyki laboratoryjnej i obrazowej. Pojawiają się nowe preparaty stosowane w terapii zaburzeń hormonalnych, seksualnych i niepłodności. Opracowywane są rekomendacje
dotyczące postępowania w zaburzeniach andrologicznych oparte na coraz silniejszych dowodach naukowych.
Praktyczna księga postępowania diagnostycznego
i terapeutycznego w zaburzeniach andrologicznych.
Ewa Rajpert-De Meyts, MD, PhD, DMSc
Konsultant naukowy, Department of Growth and Reproduction, Copenhagen University Hospital
(Rigshospitalet), Sekretarz Europejskiej Akademii Andrologii (EAA)
Znakomity podręcznik andrologii obejmujący wszystkie
aspekty tej multidyscyplinarnej dziedziny, która zajmuje
się problemami zdrowia specyficznymi dla mężczyzn,
więc wymaga znajomości wielu aspektów endokrynologii,
urologii, medycyny rozrodu, seksuologii, diagnostyki
laboratoryjnej, genetyki, onkologii i chorób wewnętrznych, szczególnie kardiologii. Gorąco polecam książkę
specjalistom różnych dyscyplin. Uważam również, że
powinna być obowiązkową lekturą dla każdego praktykującego androloga, a także dla specjalistów w leczeniu
niepłodności, włączając ginekologów.
Książka będzie niezwykle pomocna dla młodych lekarzy,
którzy planują specjalistyczne egzaminy z andrologii.
Wielką zaletą książki jest kompleksowe podejście
do tematu, ze szczegółowym omówieniem najnowszej
wiedzy dotyczącej męskiej fizjologii i patologii od wczesnego okresu rozwojowego aż do wieku starczego, co
uczyni ją bardzo przydatną również dla pediatrów, urologów dziecięcych i lekarzy ogólnych. Nie pominięto
również ważnych aspektów psychologicznych, etycznych i prawnych. Redaktor naukowy i autorzy są ekspertami na najwyższym poziomie w skali międzynarodowej
i ich zalecenia są oparte na najnowszych doniesieniach
ze światowego piśmiennictwa i przyjętych dowodach
naukowych, z komentarzami i doświadczeniami dostosowanymi do specyfiki sytuacji w kraju. Książka jest
dowodem postępów polskiej andrologii i na pewno przyczyni się do dalszego rozwoju tej dynamicznej dyscypliny.
Książka, którą przeczytałam z wielkim zainteresowaniem, jest jednym z najlepszych podręczników andrologii, jakie kiedykolwiek widziałam – i to w skali międzynarodowej. Gratulacje za wybór tematów i autorów
należą się redaktorowi naukowemu, prof. Jolancie
Słowikowskiej-Hilczer, długoletniej przewodniczącej
Polskiego Towarzystwa Andrologicznego. Imponująca
jest wszechstronność tematyki pasująca do nowoczesnego holistycznego podejścia do pacjenta.
prof. Aleksander Giwercman
Uniwersytet w Lund, Malmö, Szwecja
Trzymanie w ręku nowego podręcznika z andrologii klinicznej zdecydowanie nie jest codziennym wydarzeniem!
Jest to doskonała publikacja nie tylko pod względem treści,
lecz także pedagogicznego sposobu przedstawienia informacji, zarówno w odniesieniu do zestawu tematów, struktury poszczególnych rozdziałów, jak i szerokiego wyboru
wysokiej jakości ilustracji i tabel. Wszystkie rozdziały są
napisane przez ekspertów w swojej dziedzinie. Książka
jest nie tylko doskonałym narzędziem dla tych lekarzy,
którzy chcą zostać andrologami klinicznymi, lecz także klinicystów reprezentujących inne specjalności oraz badaczy
zainteresowanych zagadnieniami związanymi z chorobami męskiego układu płciowego. Jestem przekonany,
że niezależnie od tego, do której z tych kategorii należysz, ta książka udzieli odpowiedzi na wiele pytań z dziedziny andrologii. Gratuluję moim polskim Koleżankom
i Kolegom opracowania, które z pewnością będzie dobrym
dodatkiem do ich innych działań mających na celu rozwój
polskiej andrologii. Miejmy nadzieję, że w przyszłości
pojawią się kolejne wydania książki, która może stać się
inspiracją dla andrologów z innych krajów do stworzenia
podobnych publikacji w różnych językach.