Testicular dysgenesis syndrome

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Testicular dysgenesis syndrome
Specialty Urology

Testicular dysgenesis syndrome is a male reproduction-related condition characterized by the presence of symptoms and disorders such as hypospadias, cryptorchidism, poor semen quality, and testicular cancer. The concept was first introduced by N.E. Skakkaebaek in a research paper along with the department of Growth and Reproduction in Copenhagen University. [1] The paper suggests the origin and underlying cause of TDS can be detected as early as in fetal life, where environmental and genomic factors could affect the development of the male reproductive system. [2]

Contents

Causes

Central to the cause of irreversible TDS are disruptions to early fetal testes development. This has genetic, environmental, and lifestyle components, however the rapid increase in the incidence of the disorders associated with TDS in the last decades [3] indicates that it is under a powerful environmental influence. The fetal origins of TDS are reinforced by the high incidence of TDS disorders found occurring together in one individual.[ citation needed ] Associated with mutation of Insulin like Factor 3 (INSL3) [4]

Genetic

Many genes have been implicated in the disorders of TDS, with genome wide association studies (GWAS) regularly identifying new gene variants that play a role in abnormal testes development. Some of these are specific to certain disorders, and some are part of a 'risk factor network' that connect TGCC, hypospadias, cryptorchidism, poor semen quality. The majority of these genes are involved in fetal gonad development. Mutations in androgen receptor genes are highly implicated, as these are involved in penile development, testes descent, and testes development. [5] Testicular germ cell cancer (TGCC) shows a strong genetic disposition, with the most significant gene variants being those linked to gonad formation and germ cell function. [6]

Environmental

Exposure of a male fetus to substances that disrupt hormone systems, particularly chemicals that inhibit the action of androgens (male sex hormones) during the development of the reproductive system, has been shown to cause many of the characteristic TDS disorders. These include environmental estrogens and anti-androgens found in food and water sources that have been contaminated with synthetic hormones and pesticides used in agriculture. [7] In historical cases, medicines given to pregnant women, like diethylstilbestrol (DES), have caused many of the features of TDS in fetuses exposed to this chemical during gestation. [8] The impact of environmental chemicals is well documented in animal models. [9] If a substance affects Sertoli and Leydig cell differentiation (a common feature of TDS disorders) at an early developmental stage, germ cell growth and testosterone production will be impaired. [10] These processes are essential for testes descent and genitalia development, meaning that genital abnormalities like cryptorchidism or hypospadias may be present from birth, and fertility problems and TGCC become apparent during adult life. Severity or number of disorders may therefore be dependent on the timing of the environmental exposure. [11] Environmental factors can act directly, or via epigenetic mechanisms, and it is likely that a genetic susceptibility augmented by environmental factors is the primary cause of TDS.

Lifestyle

Links between maternal smoking and TDS are tenuous, but there are stronger associations between maternal alcohol consumption and incidences of cryptorchidism in sons. Smoking does however affect the growth of a fetus, and low birth weight is shown to increase the likelihood of all the disorders encompassed by TDS. Maternal obesity, resulting in gestational diabetes, has also been shown to be a risk factor for impaired testes development and TDS symptoms in sons.

Pathogenesis

Schematic diagram illustrating the pathogenic links that lead to TDS. CIS = carcinoma in situ; GC = Germ Cell TDS schemetic diagram.png
Schematic diagram illustrating the pathogenic links that lead to TDS. CIS = carcinoma in situ; GC = Germ Cell

The TDS hypothesis proposes that testicular dysgenesis, which has various primary causes, can lead to abnormalities in Sertoli and/or Leydig cell function. This leads to both impaired germ cell development and hormonal changes during male sexual differentiation. For instance, insufficient production of testosterone can result in incomplete masculinisation, whilst reduced expression of insulin-like factor 3 can lead to incomplete testes descent. [12] The downstream disorders of such abnormalities can include both genital malformations (e.g. hypospadias and cryptorchidism) and delayed reproductive disorders (e.g. testicular cancer and poor semen quality) which comprise TDS. [13]

Diagnosis

Hypospadias Hypospadias-lg.jpg
Hypospadias
Cryptorchidism - Can see one missing testicle Kriptorkhizm2.jpg
Cryptorchidism - Can see one missing testicle

Hypospadias

Hypospadias presents as an abnormal location for the end of the urethra which is typically found on the distal end of the penis. [14] It is generally diagnosed at birth from visual confirmation of the hallmark features. As well as an unusual location of the urethra, the prepuce (foreskin) is typically incomplete as well. The abnormal 'hooded' prepuce is what often draws attention to the condition but can occur separately to hypospadias.

Cryptorchidism

In cryptorchidism a diagnosis is made from a physical examination which is performed when the baby is lacking one or both testes in the dependant portion of the scrotal sac. [15] 70% of cryptorchid testes can be felt and are unable to be pulled into the scrotum or retreats quickly after being pulled into a higher position. In 30% of cases the testes cannot be felt indicating an intra-abdominal location. The risk factors for cryptorchidism are:

Poor semen quality

Human sperm stained for semen analysis Sperm stained.JPG
Human sperm stained for semen analysis

Poor semen quality is measured not only by the number of sperm a man produces but also by how effective the sperm is at fertilising an egg. The motility and shape of the sperm are important for this role. A man with poor semen quality will often present with fertility problems which is defined as a couple trying to conceive for over 1 year with no success. [16] Diagnosis can be made from semen analysis, taking a sample of the man's semen and running tests to count numbers and quality of the individual sperm.

Testicular cancer

The most common presentation of testicular cancer is a hard, painless lump which can be felt on one of the testis. It is either noticed by a clinician during a routine examination, or the patient themselves. [17] Risk factors for TC include:

The diagnosis is confirmed in different ways. An ultrasound scan can be used to diagnose to a 90-95% accuracy. Bloods can also be taken to look for elevated tumour markers which is also used to analyse the patient's response to treatment. 80% of testicular cancer cases are from the 20-34 year old age range [18]

Related Research Articles

Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species. It is the normal state of a human child or other young offspring, because they have not undergone puberty, which is the body's start of reproductive capacity.

Andrology is a name for the medical specialty that deals with male health, particularly relating to the problems of the male reproductive system and urological problems that are unique to men. It is the counterpart to gynaecology, which deals with medical issues which are specific to female health, especially reproductive and urologic health.

<span class="mw-page-title-main">Testicular cancer</span> Medical condition

Testicular cancer is cancer that develops in the testicles, a part of the male reproductive system. Symptoms may include a lump in the testicle or swelling or pain in the scrotum. Treatment may result in infertility.

<span class="mw-page-title-main">Cryptorchidism</span> Medical condition

Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is from Greek κρυπτός 'hidden' and ὄρχις 'testicle'. It is the most common birth defect of the male genital tract. About 3% of full-term and 30% of premature infant boys are born with at least one undescended testis. However, about 80% of cryptorchid testes descend by the first year of life, making the true incidence of cryptorchidism around 1% overall. Cryptorchidism may develop after infancy, sometimes as late as young adulthood, but that is exceptional.

<span class="mw-page-title-main">Spermatogenesis</span> Production of sperm

Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubules. These cells are called spermatogonial stem cells. The mitotic division of these produces two types of cells. Type A cells replenish the stem cells, and type B cells differentiate into primary spermatocytes. The primary spermatocyte divides meiotically into two secondary spermatocytes; each secondary spermatocyte divides into two equal haploid spermatids by Meiosis II. The spermatids are transformed into spermatozoa (sperm) by the process of spermiogenesis. These develop into mature spermatozoa, also known as sperm cells. Thus, the primary spermatocyte gives rise to two cells, the secondary spermatocytes, and the two secondary spermatocytes by their subdivision produce four spermatozoa and four haploid cells.

<span class="mw-page-title-main">Persistent Müllerian duct syndrome</span> Medical condition

Persistent Müllerian duct syndrome (PMDS) is the presence of Müllerian duct derivatives in what would be considered a genetically and otherwise physically normal male animal by typical human based standards. In humans, PMDS typically is due to an autosomal recessive congenital disorder and is considered by some to be a form of pseudohermaphroditism due to the presence of Müllerian derivatives.

<span class="mw-page-title-main">Anogenital distance</span> Distance from midpoint of the anus to the genitalia

Anogenital distance (AGD) is the distance from the midpoint of the anus to the genitalia, the underside of the vagina, the clitoris or the scrotum. It is considered medically significant for a number of reasons, in both humans and other animals, including sex determination and as a marker of endocrine disruptor exposure. It is regulated by dihydrotestosterone, which can be disrupted by phthalates common in plastics.

<span class="mw-page-title-main">Azoospermia</span> Medical condition of a man whose semen contains no sperm

Azoospermia is the medical condition of a man whose semen contains no sperm. It is associated with male infertility, but many forms are amenable to medical treatment. In humans, azoospermia affects about 1% of the male population and may be seen in up to 20% of male infertility situations in Canada.

Terms oligospermia, oligozoospermia, and low sperm count refer to semen with a low concentration of sperm and is a common finding in male infertility. Often semen with a decreased sperm concentration may also show significant abnormalities in sperm morphology and motility. There has been interest in replacing the descriptive terms used in semen analysis with more quantitative information.

Male infertility refers to a sexually mature male's inability to impregnate a fertile female. In humans it accounts for 40–50% of infertility. It affects approximately 7% of all men. Male infertility is commonly due to deficiencies in the semen, and semen quality is used as a surrogate measure of male fecundity. More recently, advance sperm analyses that examine intracellular sperm components are being developed.

<span class="mw-page-title-main">Female infertility</span> Diminished or absent ability of a female to achieve conception

Female infertility refers to infertility in women. It affects an estimated 48 million women, with the highest prevalence of infertility affecting women in South Asia, Sub-Saharan Africa, North Africa/Middle East, and Central/Eastern Europe and Central Asia. Infertility is caused by many sources, including nutrition, diseases, and other malformations of the uterus. Infertility affects women from around the world, and the cultural and social stigma surrounding it varies.

<span class="mw-page-title-main">XX male syndrome</span> Congenital condition where an individual with a 46,XX karyotype has male characteristics

XX male syndrome, also known as de la Chapelle syndrome, is a rare congenital intersex condition in which an individual with a 46,XX karyotype has phenotypically male characteristics that can vary among cases. Synonyms include 46,XX testicular difference of sex development, 46,XX sex reversal, nonsyndromic 46,XX testicular DSD, and XX sex reversal.

<span class="mw-page-title-main">Gonadal dysgenesis</span> Congenital disorder of the reproductive system

Gonadal dysgenesis is classified as any congenital developmental disorder of the reproductive system in humans. It is atypical development of gonads in an embryo,. One type of gonadal dysgenesis is the development of functionless, fibrous tissue, termed streak gonads, instead of reproductive tissue. Streak gonads are a form of aplasia, resulting in hormonal failure that manifests as sexual infantism and infertility, with no initiation of puberty and secondary sex characteristics.

<span class="mw-page-title-main">Reproductive medicine</span> Branch of medicine

Reproductive medicine is a branch of medicine concerning the male and female reproductive systems. It encompasses a variety of reproductive conditions, their prevention and assessment, as well as their subsequent treatment and prognosis.

Semen quality is a measure of male fertility, a measure of the ability of sperm in semen to accomplish fertilization. Semen quality involves both sperm quantity and quality. Semen quality is a major factor for fertility.

Hypergonadotropic hypogonadism (HH), also known as primary or peripheral/gonadal hypogonadism or primary gonadal failure, is a condition which is characterized by hypogonadism which is due to an impaired response of the gonads to the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and in turn a lack of sex steroid production. As compensation and the lack of negative feedback, gonadotropin levels are elevated. Individuals with HH have an intact and functioning hypothalamus and pituitary glands so they are still able to produce FSH and LH. HH may present as either congenital or acquired, but the majority of cases are of the former nature. HH can be treated with hormone replacement therapy.

XXXYsyndrome is a genetic condition characterized by a sex chromosome aneuploidy, where individuals have two extra X chromosomes. People in most cases have two sex chromosomes: an X and a Y or two X chromosomes. The presence of one Y chromosome with a functioning SRY gene causes the expression of genes that determine maleness. Because of this, XXXY syndrome only affects males. The additional two X chromosomes in males with XXXY syndrome causes them to have 48 chromosomes, instead of the typical 46. XXXY syndrome is therefore often referred to as 48,XXXY. There is a wide variety of symptoms associated with this syndrome, including cognitive and behavioral problems, taurodontism, and infertility. This syndrome is usually inherited via a new mutation in one of the parents' gametes, as those affected by it are usually infertile. It is estimated that XXXY affects one in every 50,000 male births.

Diethylstilbestrol (DES), a synthetic nonsteroidal estrogen which was previously used clinically to support pregnancy, has been linked to a variety of long-term adverse effects in women who were treated with it during pregnancy and in their offspring.

<span class="mw-page-title-main">Male infertility crisis</span> Observed decline in male fertility and sperm quality

The male infertility crisis is an increase in male infertility since the mid-1970s. The issue attracted media attention after a 2017 meta-analysis found that sperm counts had declined by 52.4 percent between 1973 and 2011. The decline is particularly prevalent in Western countries such as New Zealand and Australia, Europe and North America. A 2022 meta-analysis reported that this decline extends to non-Western countries, namely those in Asia, Africa, Central America, and South America. This meta-analysis also suggests that the decline in sperm counts may be accelerating.

Sexual anomalies, also known as sexual abnormalities, are a set of clinical conditions due to chromosomal, gonadal and/or genitalia variation. Individuals with congenital (inborn) discrepancy between sex chromosome, gonadal, and their internal and external genitalia are categorised as individuals with a disorder of sex development (DSD). Afterwards, if the family or individual wishes, they can partake in different management and treatment options for their conditions.

References

  1. ↑ Skakkebæk, N. E.; Meyts, E. Rajpert-De; Main, K. M. (2001-05-01). "Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects: Opinion". Human Reproduction. 16 (5): 972–978. doi: 10.1093/humrep/16.5.972 . ISSN   0268-1161. PMID   11331648.
  2. ↑ VIRTANEN, H; RAJPERTDEMEYTS, E; MAIN, K; SKAKKEBAEK, N; TOPPARI, J (1 September 2005). "Testicular dysgenesis syndrome and the development and occurrence of male reproductive disorders". Toxicology and Applied Pharmacology. 207 (2): 501–505. doi:10.1016/j.taap.2005.01.058. PMID   16005920.
  3. ↑ Toppari, J; Larsen, J C; Christiansen, P; Giwercman, A; Grandjean, P; Guillette, L J; Jégou, B; Jensen, T K; Jouannet, P (1996-08-01). "Male reproductive health and environmental xenoestrogens". Environmental Health Perspectives. 104 (Suppl 4): 741–803. doi:10.1289/ehp.96104s4741. ISSN   0091-6765. PMC   1469672 . PMID   8880001.
  4. ↑ Ferlin, A.; Bogatcheva, N. V.; Gianesello, L.; Pepe, A.; Vinanzi, C.; Agoulnik, A. I.; Foresta, C. (June 2006). "Insulin-like factor 3 gene mutations in testicular dysgenesis syndrome: clinical and functional characterization". Molecular Human Reproduction. 12 (6): 401–406. doi: 10.1093/molehr/gal043 . ISSN   1360-9947. PMID   16687567.
  5. ↑ Skakkebæk, N. E.; Meyts, E. Rajpert-De; Main, K. M. (2001-05-01). "Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects: Opinion". Human Reproduction. 16 (5): 972–978. doi: 10.1093/humrep/16.5.972 . ISSN   0268-1161. PMID   11331648.
  6. ↑ Skakkebaek, Niels E.; Meyts, Ewa Rajpert-De; Louis, Germaine M. Buck; Toppari, Jorma; Andersson, Anna-Maria; Eisenberg, Michael L.; Jensen, Tina Kold; Jørgensen, Niels; Swan, Shanna H. (2016-01-01). "Male Reproductive Disorders and Fertility Trends: Influences of Environment and Genetic Susceptibility". Physiological Reviews. 96 (1): 55–97. doi:10.1152/physrev.00017.2015. ISSN   0031-9333. PMC   4698396 . PMID   26582516.
  7. ↑ Meyts, Ewa Rajpert-De (2006-05-01). "Developmental model for the pathogenesis of testicular carcinoma in situ: genetic and environmental aspects". Human Reproduction Update. 12 (3): 303–323. doi: 10.1093/humupd/dmk006 . ISSN   1355-4786. PMID   16540528.
  8. ↑ Gill, W. B.; Schumacher, G. F.; Bibbo, M.; Straus, F. H.; Schoenberg, H. W. (1979-07-01). "Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities". The Journal of Urology. 122 (1): 36–39. doi:10.1016/s0022-5347(17)56240-0. ISSN   0022-5347. PMID   37351.
  9. ↑ Skakkebæk, N. E.; Meyts, E. Rajpert-De; Main, K. M. (2001-05-01). "Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects: Opinion". Human Reproduction. 16 (5): 972–978. doi: 10.1093/humrep/16.5.972 . ISSN   0268-1161. PMID   11331648.
  10. ↑ Skakkebaek, Niels E.; Meyts, Ewa Rajpert-De; Louis, Germaine M. Buck; Toppari, Jorma; Andersson, Anna-Maria; Eisenberg, Michael L.; Jensen, Tina Kold; Jørgensen, Niels; Swan, Shanna H. (2016-01-01). "Male Reproductive Disorders and Fertility Trends: Influences of Environment and Genetic Susceptibility". Physiological Reviews. 96 (1): 55–97. doi:10.1152/physrev.00017.2015. ISSN   0031-9333. PMC   4698396 . PMID   26582516.
  11. ↑ Skakkebæk, N. E.; Meyts, E. Rajpert-De; Main, K. M. (2001-05-01). "Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects: Opinion". Human Reproduction. 16 (5): 972–978. doi: 10.1093/humrep/16.5.972 . ISSN   0268-1161. PMID   11331648.
  12. ↑ Sharpe, Richard M.; Skakkebaek, Niels E. (2008). "Testicular dysgenesis syndrome: mechanistic insights and potential new downstream effects". Fertility and Sterility. 89 (2): e33–e38. doi: 10.1016/j.fertnstert.2007.12.026 . PMID   18308057.
  13. ↑ Bay, Katrine; Asklund, Camilla; Skakkebaek, Niels E.; Andersson, Anna-Maria (2006-03-01). "Testicular dysgenesis syndrome: possible role of endocrine disrupters". Best Practice & Research Clinical Endocrinology & Metabolism. Endocrine Disrupters. 20 (1): 77–90. doi:10.1016/j.beem.2005.09.004. PMID   16522521.
  14. ↑ "BMJ Best Practice: Anatomical Penile Abnormalities".
  15. ↑ "BMJ Best Practice: Cryptorchidism".
  16. ↑ "NHS Choices: Infertility - Diagnosis". 2017-10-23.
  17. ↑ "BMJ Best Practice: Testicular Cancer".
  18. ↑ Jemal, A; Siegel, R; Ward, E; Murray, T; Xu, J; Thun, MJ (2007). "Cancer Statistics, 2007". CA: A Cancer Journal for Clinicians. 57 (1): 43–66. doi: 10.3322/canjclin.57.1.43 . PMID   17237035.
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